study table online

• Track Order
• Become a Franchisee New
• Find a Store
• Bulk Orders
• UL Services

Study Tables

If there is anything that has the potential to bring out the best in your work, it is the right study table that fits snugly with your needs and enhances the corners of your room. Study tables are an essential addition for working professionals as it allows for more organization without taking away from the style of your space. While a study table design can vary, it is important to keep in mind the requirements of your storage, the material used in its construction, the functionality of the desk, and also the ease of its maintenance, long-term. A wooden study table offers this and so much more. From options that range from light to heavy storage, and classic to modern styles, Urban Ladder’s wooden study tables have one common factor of being strong, super durable, and among the easiest to maintain, especially for those who are working from home. Browse through our collection of study tables and pick the one closest to your needs.

• Price Clear 1889 327000
• ₹1,889-₹6,999 ₹7,000-₹8,999 ₹9,000-₹12,999 ₹13,000-₹327,000
• By Urban Ladder
• By The Home Dekor
• By Wood You
• By Direct Factory to Home Private Limited (DF2H)
• By Gudsmith
• By Vishwakarma Antique
• By Woodenmood
• By A Globia Creations
• By Decorative
• By Orange Tree
• SimplyWud By Urban Ladder
• By Saffron Art
• Aara Craft By Urban Ladder
• By Boingg! - A Happy Start
• By Saffron Art & Crafts
• By Ujjwal Wood
• By Vintej Home
• Open And Closed
• Non Storage
• Engineered Wood
• Recommended
• Price: Low to High
• Price: High to Low
• New Arrivals

Interested In Our Study Tables?

By continuing, you agree to our Terms of Service and Privacy & Legal Policy

Study Tables Price List

Buy a study table online at an affordable price.

Wondering how to keep your child focused during study time and not have them wander about the house? You need a study table! No matter how many times you try to ward off the idea, this piece of furniture is essential to help children learn. A study table for students comes in various designs and patterns. Some have multiple functional features, while others are portable and handy. If you have trouble picking out the right one for your home, Urban Ladder has got you covered.

We at Urban Ladder have the best study table collection online to save you from the hassle of traveling around town. With the latest designs, a modern approach and affordable prices, we bring you the best study tables in India.

Explore The Types Of Study Table At Best Price On Urban Ladder

Study tables are essential furniture pieces that provide a dedicated space for focused work, learning, and studying. Budget-friendly options are widely available, ensuring that you can find a suitable study table price without breaking the bank. These cost-effective study tables are designed to offer functionality and quality at reasonable prices, making them an excellent choice for students, young professionals, or anyone looking for a practical yet affordable workspace solution. Whether you require a space-saving solution or extra storage, an adjustable desk for ergonomic support, or a portable option for flexibility, Urban Ladder's selection meets the full range of requirements. You can get your study table best price with us too!

Wall mounted Study Table

Study table with storage, adjustable height desk, ergonomic study tables, foldable study table, portable study table, different materials of study table as per your budget.

When selecting a material for your tableaux of focus, consider factors such as your personal style preferences, study table price, and the overall aesthetic of your workspace. Whether you choose the warmth of wood, the sleekness of metal, or the elegance of marble, a well-chosen study table material can enhance the ambiance and functionality of your study space. Our stunning range will gift you the perfect low cost study table, at great functional value and aesthetic. Let us have a look:

Engineered Wood Study Table

Solid wood study table, metal study table, marble study table, choose from the stunning range of finish available for study table and chair set, teak finish:, mahogany finish, walnut finish :, melamine finish, matte finish, wenge finish.

Each finish has its unique charm and complements different decor styles. The choice of finish for your study table for students with chair, ultimately depends on your personal preferences and the overall aesthetic you wish to achieve in your study space.

What Are The Benefits Of Buying Study Table Online

• Wide Selection : Online platforms provide a vast array of study table options, catering to different budgets and styles. You can explore a variety of designs, materials, and sizes, ensuring you find the perfect study table low price for your convenience.
• Convenience : Shopping for a study table online eliminates the need to visit multiple physical stores, saving you time and effort. You can browse through various options from the comfort of your home and make a purchase at any time that suits you.
• Customer Reviews: Online platforms provide customer reviews and ratings for study tables, giving you valuable insights into the product's quality, durability, and customer satisfaction. This information can help you make an informed decision and choose a study table that offers the best value for your budget.
• Easy Comparison : Online shopping allows you to compare prices, features, and specifications of different study tables with just a few clicks. This enables you to make a well-informed decision and select a study table that meets your requirements without burning any wallet holes.
• Discounts and Deals: Online retailers often offer special discounts, promotions, and exclusive deals, allowing you to save money on your study table purchase. By keeping an eye out for sales events or subscribing to newsletters, you can take advantage of these cost-saving opportunities and find a budget-friendly study table that suits your needs.

Things To Consider Before Selecting A Study Table

Key features of a study table, pick the right study table size, invest in comfortable study tables, importance of the study table material, pick a suitable design for your study table, top features in a study table that are essential.

A study table is a crucial piece of furniture for many reasons, which is why it's essential to consider certain features that can enhance its functionality and meet your specific requirements. Let's explore some of the top features to look for in a study table:

Surface Area

Storage options, portability, adjustable height, drawers and compartments, why buy a study table for your home & office from urban ladder.

Now that we have established the importance of a study table, we can almost hear your thoughts on traveling all the way in traffic to buy this furniture. With Urban Ladder, your favorite table is just a click away. Buy study table online on Urban Ladder and get products that match your home decor right from the comfort of your couch.

The Urban ladder website not only offers you multiple options under each category of the table but also ensures the study table price will suit your budget.

Other Study Table-Related Furniture Available On Urban Ladder

Q. is a study table important for students.

A study table helps students focus their energy on just their books and props them up in the right position keeping them alert. Another aspect of studying involves writing, and tables help students develop healthy writing habits. Sitting up keeps the body alert and the muscles are engaged during this activity.

Q. How Do I Decorate My Study Table?

Whether you are a student or an officer-goer, a study table is a personal piece of furniture that helps you keep your belongings organized. Decorate your table with things that keep you motivated to study or work. If that means putting up motivational quotes or a flower vase, so be it.

Q. What Are The Advantages Of A Study Table?

Besides being a personal piece of furniture, children and students always attach many memories to their study table. It also helps channel their energies towards studying in an organized manner. Many students and college-goers also use their tables to learn new hobbies such as arts and crafts which they develop into a lucrative career later in life.

• Open access
• Published: 11 January 2024

Associations between genetically predicted plasma protein levels and Alzheimer’s disease risk: a study using genetic prediction models

• Jingjing Zhu 1   na1 ,
• Shuai Liu 1   na1 ,
• Keenan A. Walker 2 ,
• Hua Zhong 1 ,
• Dalia H. Ghoneim 1 ,
• Zichen Zhang 3 ,
• Praveen Surendran 4 ,
• Sarah Fahle 4 ,
• Adam Butterworth 4 , 5 ,
• Md Ashad Alam 6 , 7 ,
• Hong-Wen Deng 6 ,
• Chong Wu 3 &
• Lang Wu 1  

Alzheimer's Research & Therapy volume  16 , Article number:  8 ( 2024 ) Cite this article

1411 Accesses

1 Citations

10 Altmetric

Metrics details

Specific peripheral proteins have been implicated to play an important role in the development of Alzheimer’s disease (AD). However, the roles of additional novel protein biomarkers in AD etiology remains elusive. The availability of large-scale AD GWAS and plasma proteomic data provide the resources needed for the identification of causally relevant circulating proteins that may serve as risk factors for AD and potential therapeutic targets.

We established and validated genetic prediction models for protein levels in plasma as instruments to investigate the associations between genetically predicted protein levels and AD risk. We studied 71,880 (proxy) cases and 383,378 (proxy) controls of European descent.

We identified 69 proteins with genetically predicted concentrations showing associations with AD risk. The drugs almitrine and ciclopirox targeting ATP1A1 were suggested to have a potential for being repositioned for AD treatment.

Conclusions

Our study provides additional insights into the underlying mechanisms of AD and potential therapeutic strategies.

Summary box

What is already know on this topic.

There is one study evaluating associations between genetically predicted protein levels in dorsolateral prefrontal cortex and risk of Alzheimer’s disease (AD); another study focuses on 38 dementia-associated proteins to determine associations of their genetically predicted levels in plasma with AD risk; a third study assesses 184 cerebrospinal fluid proteins, 100 plasma proteins, and 27 brain proteins using protein quantitative trait loci as instruments for their associations with AD risk. Existing studies did not systematically evaluate associations of predicted levels proteins across the proteome in plasma using genetic prediction models, findings of which may identify novel proteins to confer translational perspective for risk assessment and therapeutic strategies of AD.

What this study adds

Our study identifies 69 potential AD-associated proteins in plasma using comprehensive genetic prediction models as instruments. We also prioritize drugs almitrine and ciclopirox targeting ATP1A1 to have a potential for being repositioned for AD treatment.

How this study might affect research, practice, or policy

The promising proteins identified in our study could be further investigated for their roles in AD risk assessment and therapeutic strategies.

Introduction

Alzheimer’s disease (AD), the most common cause of dementia, has become a growing public health concern due to an unprecedented increase in life expectancy globally. In the USA, reported deaths from AD have increased 146.2% between 2000 and 2018, making it the sixth leading cause of death [ 1 ]. It is predicted that the annual cost of caring for AD patients will reach to a trillion dollars by 2050. AD is an irreversible and progressive disorder with neuropathological changes often occurring long before any symptom becomes apparent. The abnormal accumulation of amyloid-beta (Aβ) plaques, a hallmark of AD, is known to occur as early as two decades before the onset of clinical symptoms [ 2 ]. Abnormal phosphorylation of tau, the second canonical AD protein aggregate, is believed to occur shortly thereafter (15–20 years before symptom onset) [ 3 ]. While a great deal of research effort has focused on targeting pathological Aβ aggregates and tau neurofibrillary tangles, several drugs were approved by U.S. Food and Drug Administration (FDA), including Aduhelm® [ 4 ] and Leqembi® [ 5 ]. These approved drugs could relieve symptoms while whether they can cure AD relies on further analyses. As a result, it is critical to identify novel biomarkers and biological pathways that may contribute to AD risk.

Physiological changes that take place outside the brain (e.g., immune, vascular, and metabolic changes) have been shown to directly influence the function of neural cells and relate strongly to risk of developing AD [ 6 , 7 ]. The identification of circulating peripheral proteins that drive the associations between peripheral biological changes and increased risk for AD may enhance our understanding of AD pathogenesis and thereby inform future therapeutic strategies. In addition to Aβ and tau, a number of proteins have also been recognized to be related to AD [ 8 ]. Translational and epidemiological research indicates that biological processes which operate outside of the central nervous system can contribute considerably to one’s risk of developing AD [ 6 , 9 ]. These peripheral biological processes can be reflected in plasma and serum protein composition, i.e., secreted proteins. Identifying proteins that are causally associated with AD-relevant outcomes will deepen our understanding regarding how peripheral molecular changes, biological pathways, and regulatory mechanisms influence AD risk.

AD is highly heritable. Twin and family studies support that genetic factors could play a role in at least 80% of AD cases [ 10 ]. A recent genome-wide association study (GWAS) has identified 29 independent disease-associated risk loci by studying 71,880 (proxy) cases and 383,378 (proxy) controls of European ancestry [ 11 ]. The present study aimed at identifying novel protein biomarkers for AD through evaluating the associations between genetically predicted protein concentrations and AD risk, a design of proteome-wide association study (PWAS). Similar to the design of Mendelian randomization (MR) and transcriptome-wide association study (TWAS) [ 12 , 13 , 14 , 15 ], such a design can potentially reduce common biases imbedded in conventional epidemiological studies, such as selection biases, residual confounding, or reverse causality. We established and validated comprehensive protein genetic prediction models to fully capture the genetically regulated components of protein levels by using both cis - and trans -acting elements, thus providing higher statistical power than only using cis -acting elements alone (a common practice for related studies). We then related genetically predicted plasma concentrations to AD risk and, in doing so, causally implicated 69 circulating proteins in the AD pathogenesis, shedding light on the peripheral biology of AD.

The genome and plasma proteome data of European descendants included in the INTERVAL study (subcohort 1 and subcohort 2) was used to establish and validate protein genetic prediction models. Detailed information about the INTERVAL study dataset has been described elsewhere [ 16 ]. In brief, participants were aged 18–80 and were generally in good health. The SOMAscan assay was used to measure the relative concentrations of 3620 plasma proteins or protein complexes. Quality control (QC) was performed at the sample and SOMAmer level. After excluding eight non-human protein targets, a total of 3283 SOMAmers remained for further study. DNA was used to assay ~ 830,000 variants on the Affymetrix Axiom UK Biobank genotyping array. Standard sample and variant QC was conducted, as described in the original publication [ 16 ]. SNPs were further phased using SHAPEIT3 and imputed using a combined 1000 Genomes Phase 3-UK10K reference panel via the Sanger Imputation Server, resulting in over 87 million imputed variants. Such SNPs were filtered using criteria of (1) imputation quality of at least 0.7, (2) minor allele frequency (MAF) of at least 5%, (3) Hardy–Weinberg equilibrium (HWE) p  ≥ 5 × 10 −6 , (4) missing rates < 5%, and (5) presenting in the 1000 Genome Project data for European populations. In total, there were 4,662,360 variants passing these criteria.

In subcohort 1 ( N  = 2481), protein levels were log transformed and adjusted for age, sex, duration between blood draw and processing, and the first three principal components of ancestry. For the rank-inverse normalized residuals of each protein of interest, we followed the TWAS/FUSION framework [ 17 ] to develop genetic prediction models, using nearby SNPs (within 100 kb) of potentially associated SNPs as potential predictors. A false discovery rate (FDR) < 0.05 and P -value ≤ 5 × 10 −8 were used to determine potentially associated SNPs in cis- and trans- regions, respectively. We defined cis- region as a region within 1 Mb of the transcriptional start site (TSS) of the gene encoding the target protein of interest. Subsequently, we extracted all SNPs located within 100 kb of the aforementioned potentially associated SNPs to serve as potential predictors for establishing protein prediction models, excluding any ambiguous SNPs. In order to include potential predictors from both cis and trans regions, we converted all the chromosome numbers to Z and combined them as a single pseudo chromosome. Four methods, namely, best linear unbiased predictor, elastic net, LASSO, and top1, were used for establishing the models. For developed protein prediction models with prediction performance ( R 2 ) of at least 0.01 [ 15 , 18 , 19 , 20 , 21 , 22 , 23 ], which is a common threshold used in relevant studies, we further conducted external validation using subcohort 2 ( N  = 820) data. In brief, we generated predicted expression levels by applying the established protein prediction models to the genetic data, and then compared the predicted v.s. measured levels of each protein of interest. We selected proteins with a model prediction R 2 of ≥ 0.01 in subcohort 1 and a correlation coefficient of ≥ 0.1 in subcohort 2 for the downstream association analysis.

To assess the associations between genetically predicted circulating protein levels and AD risk, we applied the validated protein prediction models to the summary statistics from a large GWAS meta-analysis of AD risk [ 24 ]. Instead of using the conventional approach of including clinically diagnosed AD alone, this GWAS combined clinically confirmed and parental diagnoses based by-proxy phenotypes, which has been demonstrated to confer great value in substantially increasing statistical power [ 25 ]. In brief, this study included a total of 85,934 cases (39,106 clinically diagnosed AD and 46,828 proxy AD) and 401,577 controls of European ancestry, which were obtained from various sources including The European Alzheimer & Dementia Biobank dataset (EADB), GR@ACE/DEGESCO study, The Rotterdam Study (RS1 and RS2), European Alzheimer’s Disease Initiative (EADI) Consortium, Genetic and Environmental Risk in AD (GERAD) Consortium/Defining Genetic, Polygenic, and Environmental Risk for Alzheimer’s Disease (PERADES) Consortium, The Norwegian DemGene Network, The Neocodex–Murcia study (NxC), The Copenhagen City Heart Study (CCHS), Bonn studies, and UK Biobank. Detailed information on study participants as well as genotyping and imputation methods for the samples from each of the included study can be found in the supplementary files of the original GWAS paper [ 24 ]. Risk estimates for the single marker association analyses were adjusted for sex, batch (if applicable), age (if applicable), and top principal components (PCs).

The TWAS/FUSION framework was used to determine the protein-AD associations, by leveraging correlation information between SNPs included in the prediction models from the phase 3, 1000 Genomes Project data of European ancestry [ 17 ]. We calculated the PWAS test statistic Z -score =  w'Z /( w' Σ s,s w ) 1/2 , where the Z is a vector of standardized effect sizes of SNPs for a given protein (Wald z -scores), w is a vector of prediction weights for the abundance feature of the protein being tested, and the Σ s,s is the LD matrix of the SNPs estimated from the 1000 Genomes Project as the LD reference panel. The Bonferroni correction P -value < 0.05 was used to determine significant associations between genetically predicted protein concentrations and AD risk.

Ingenuity Pathway Analysis (IPA, Ingenuity System Inc, USA)) and Protein–Protein Interaction analysis via STRING database (version 12.0) with 0.400 confidence level [ 26 ] was implemented to cluster and classify enriched pathways for the identified proteins using default interaction resources, including Textmining, Experiments, Databases, Co-expression, Neighborhood, Gene Fusion, and Co-occurrence. We also investigated potentially repositionable drugs targeting the genes encoding associated proteins, by using the GREP (Genome for REPositioning drugs) tool [ 27 ]. We further conducted molecular docking analysis considering ATP1A1 protein as the drug target protein and almitrine and ciclopirox as the drug agents [ 28 ].

In this study, potential predictors were identified for 1870 proteins, and protein prediction models were successfully established for 1864 proteins. For the 1413 of the remaining proteins, there was no SNP showing an association at FDR < 0.05 for cis SNPs and P -value ≤ 5 × 10 −8 for trans SNPs. After internal and external validation, there were 1389 proteins showing internal and external validation performance of R 2  ≥ 0.01. The median external validation R 2 was 0.06. There were 459, 189, and 38 proteins that showed external validation R 2  ≥ 0.1, 0.2, and 0.5, respectively. Overall, proteins that could be predicted well in INTERVAL subcohort 1 also tended to be predicted well in subcohort 2 in external validation analyses (a correlation coefficient of 0.96 for R 2 in two data sets; Fig.  1 ). Using the TWAS/FUSION framework, we examined the association for a total of 1340 proteins. For the remaining 49 proteins, more than half of the SNPs included in the models were not present in the AD GWAS summary; therefore, their associations with AD risk were not considered. We identified 69 proteins with genetically predicted concentrations showing associations with AD risk after Bonferroni correction ( P -value < 3.01 × 10 −5 ) (Table  1 ; Fig.  2 ). Of those 69 proteins, positive associations were observed for 45 of them, and inverse associations were observed for 24 (Table  1 ; Fig.  2 ).

Performance of protein expression prediction models in INTERVAL subcohort1 and subcohort2 datasets for proteins showing internal and external validation performance of R 2  ≥ 0.01

Associations Z scores for proteins showing an association at Bonferroni corrected P -value ≤ 0.05 with AD risk

For those proteins associated with AD risk, the Core Analysis was performed in Ingenuity Pathway Analysis. Assembly of RNA Polymerase I Complex and DNA Double-Strand Break Repair by Non-Homologous End Joining were two canonical pathways showing significant enrichments at P  < 0.05 (Table S 2 ; Figure S 1 ). In the Network Analysis, Cell-To-Cell Signaling and Interaction, Hematological System Development and Function, Immune Cell Trafficking was identified which involved 19 associated proteins (Table S 3 ; Figure S 2 ). Based on the Disease and Biological Functions analysis, the top disease functional categories identified were shown in Table S 4 .

Protein interactions of 69 associated proteins were investigated using the STRING database (Figure S 3 ). In the network, five proteins (ILT-4, PRPC, SHPS1, Siglec-3, and Siglec-9) had three or more interactions with other proteins. Among them, Siglec-3 (known as CD33) was reported as a risk factor for AD and both the mRNA level and protein abundance were found to be increased in AD patients compared to the age-matched controls [ 29 ]. This finding is consistent with our current study ( Z -score = 4.47, P -value = 7.78 × 10 −6 ).

Based on The Anatomical Therapeutic Chemical (ATC) test using GREP, the drugs almitrine and ciclopirox targeting ATP1A1 were suggested to have a potential for being repositioned for AD treatment (odds ratio (OR) = 63.0; P  = 0.022 for almitrine; OR = 35.9, P  = 0.035 for ciclopirox).

For molecular docking analysis, we downloaded the 3D structure of ATP1A1 protein from Protein Data Bank (PDB) with source code 3KDP and almitrine and ciclopirox drug from the PubChem database [ 30 , 31 ]. AutoDock-Vina produced − 7.6 kcal/mol binding energy for ATP1A1 protein with almitrine drug agent and − 6.2 kcal/mol binding energy for ATP1A1 protein with ciclopirox drug agent. Figure  3 showed the 3D structure (left) and 2D schematic diagram (right) of the ATP1A1 potential target and almitrine drug with interacting amino acids: Leu80, Thr81, Met164, Arg198, Phe245, Ala271, Thr272, Ala274, Ser275, Asp740, Val741, Gln744, and Ala745. Figure  4 showed the 3D structure (left) and 2D schematic diagram (right) of the ATP1A1 potential target and ciclopirox drug.

The 3D structure (left) and 2D schematic diagram (right) of the ATP1A1 potential target and almitrine drug

The 3D structure (left) and 2D schematic diagram (right) of the ATP1A1 potential target and ciclopirox

To our knowledge, the present study is the first large population-based study to systematically investigate the associations between genetically predicted circulating protein concentrations in plasma and AD risk using genetic instruments of comprehensive protein prediction models. Overall, we identified 69 proteins that were significantly associated with AD risk after Bonferroni correction. If validated in future studies, our findings could add substantial new knowledge to the etiology of AD and provide a list of protein markers to facilitate precision preventive or therapeutic trials of AD.

Recently, plasma proteins including Aß 42 and phosphorylated tau (p-tau217, p-tau181, and others) have been identified as promising plasma biomarkers for clinically and pathologically defined AD [ 32 , 33 , 34 ]. While these biomarkers will be incredibly useful for participant risk stratification, it remains vitally important to identify additional AD biomarkers to further understand the pathophysiological processes leading to AD. By examining associations of genetically predicted protein levels in plasma with AD risk, we are able to go beyond a traditional examination of protein-AD association and begin to understand whether proteins may be causally relevant. For example, although plasma levels of YKL-40 [ 35 ] have been associated with AD, we did not observe evidence of an association for genetically predicted levels of YKL-40 ( Z  = 1.50; P  = 0.13). This finding seems to support that although specific proteins such as YKL-40 could be strong biomarkers, they may not be causally relevant.

We identified multiple AD-associated proteins using proteomic and genetic methods that were reported for the first time (Table  1 ). For some of them, there is already existing evidence from functional work supporting their potential links with AD. For example, cofilin-1, as a major actin depolymerizer in the central nervous system, plays a crucial role in maintaining the structure and proper function of neurons [ 36 ]. Cofilin rods, which are primarily composed of actin and cofilin-1 and form in response to stressing conditions, have been suggested to be associated with neurodegenerative diseases such as AD by disrupting dendritic transportation and inducing synaptic dysfunction [ 36 , 37 ]. Additional research is warranted to understand the identified associations for the other proteins.

By using GREP, the drugs almitrine and ciclopirox were suggested to be potentially repositionable for AD treatment. A double-blind controlled study involving patients with memory loss, lack of concentration, impaired mental alertness, and emotional instability supported that almitrine-raubasine could improve cognitive impairments [ 35 ]. Another controlled multicenter study investigating patients with cognitive decline (assessed by MMSE, SCAG) again suggested almitrine-raubasine significantly improved symptomatology compared with placebo [ 38 ]. Three other trails conducted in China involving 206 patients with vascular dementia also supported significant beneficial effect of almitrine-raubasine combination on the improvement of cognitive function measured by MMSE [ 39 ], although high risk of bias was observed. Other research supported that ciclopirox could protect neuronal cells from cell death and astrocytes from peroxynitrate toxicity [ 40 , 41 ]. Future work may be warranted to further investigate whether almitrine and ciclopirox can indeed treat AD.

The strengths of our study include a high statistical power to identify AD-associated proteins given the large sample size in the main association analysis. Instead of merely using individual protein quantitative trait loci (pQTL) as instruments, we developed comprehensive protein genetic prediction models using a state-of-the-art method and externally validated their performance before applying them to downstream association tests. Our previous work has supported that compared with individual QTLs, comprehensive prediction models can better capture genetically regulated components of molecular levels and thus further increase statistical power [ 42 ]. In two recently published studies, pQTLs in plasma were used to assess proteins potentially associated with AD risk [ 43 , 44 ]. It is expected that the current work should have improved power as well as scope compared with these two existing studies. Particularly, in Walker et al. [ 44 ], only proteins showing an association for the directly measured levels were tested. In Yang et al. [ 43 ], a relatively smaller dataset ( n  = 636) was used to determine plasma pQTLs. Correspondingly, a smaller number of pQTLs for 127 proteins were identified for association analyses. In Wingo et al. [ 45 ], prediction models for 376 proteins in brain tissue were established, and 13 proteins were identified to be associated with AD risk. It is also worth noting that in the previous studies, AD GWAS summaries involving a less number of cases and controls were employed. Walker and Yang utilized the GWAS summary data from the Kunkle study [ 46 ], comprising 21,982 clinically diagnosed AD cases and 41,944 cognitively normal controls, while Wingo employed the AD GWAS summary data from the Jansen study [ 11 ], encompassing 71,880 cases (clinically diagnosed AD and AD-by-proxy) and 383,378 controls. In the present study, we utilized a more comprehensive GWAS summary data from a more recent study, including 85,934 cases (comprising 39,106 clinically diagnosed AD and 46,828 proxy AD) and 401,577 controls. We checked the associations of the proteins reported in these previous studies in the current work. Interestingly, only three of the reported proteins showed consistent associations (same effect direction and nominal P -value < 0.05) in the current work (Table S 5 ). To further examine the robustness of these results, we extended our examination by using two independent protein genetic prediction models established by others using independent methods, namely Atherosclerosis Risk in Communities (ARIC) European ancestry models [ 47 ] and INTERVAL cis- models [ 48 ]. Notably, when we focused only on plasma, a majority of the examined proteins did not exhibit significant associations with the risk of AD when using either ARIC European ancestry or INTERVAL cis -models. This observation that aligns well with results based on our developed models suggests that these prior findings could potentially be false positives. Again, such a discrepancy could be potentially attributed to the relatively limited utility of individual pQTL SNPs in fully elucidating the genetically regulated components of protein levels. Further studies are warranted to better characterize the other previously reported proteins.

Several limitations of the current work also need to be acknowledged. First, our findings may be subject to potential pleiotropic effects, limiting the ability to draw causal insights. Second, given the nature of our study of using genetic instruments to predict plasma protein levels, we are only able to capture the genetically regulated components of the protein concentrations, without incorporating the components influenced by exogenous exposures. Like the concept of transcriptome-wide association studies (TWAS), our proteome-wide association study (PWAS) aims to investigate the relationship between the genetically determined components of protein levels and disease risk. Further prospective studies with measured protein levels in pre-disease plasma samples are needed to better evaluate the relationship. Finally, when we establish genetic models to estimate such genetically determined components of protein levels, we carefully controlled for age, sex, duration between blood draw and processing, and top genetic principal components. However, we acknowledge that specific factors such as smoking and body mass index (BMI) were not controlled for during model construction using the INTERVAL dataset due to a lack of relevant data available to us [ 49 ]. Future studies are in need to validate our findings.

In conclusion, in this large association study using genetic instruments, we identified multiple novel AD risk-associated proteins. If validated with further investigations, our study may add additional knowledge to the underlying mechanisms of AD.

Availability of data and materials

Summary statistics of the GWAS meta-analysis of AD risk by Bellenguez et al. are available at GWAS Catalog ( https://www.ebi.ac.uk/gwas/ ) under accession no. GCST90027158. For the INTERVAL SomaLogic study, the individual-level genotype and protein data, and full summary association results from the genetic analysis, are available through the European Genotype Archive (accession number EGAS00001002555). Summary association results are also publicly available at http://www.phpc.cam.ac.uk/ceu/proteins/ , through PhenoScanner ( http://www.phenoscanner.medschl.cam.ac.uk ) and from the NHGRI-EBI GWAS Catalog ( https://www.ebi.ac.uk/gwas/downloads/summary-statistics ). The scripts and protein genetic prediction models are available at https://github.com/Arthur1021/Protein-prediction-models .

2020 Alzheimer’s disease facts and figures. Alzheimers Dement. 2020;16(3):391–460.

Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA, Salvado O, et al. Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol. 2013;12(4):357–67.

Article   CAS   PubMed   Google Scholar  

Barthélemy NR, Li Y, Joseph-Mathurin N, Gordon BA, Hassenstab J, Benzinger TLS, et al. A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease. Nat Med. 2020;26(3):398–407.

Article   PubMed   PubMed Central   Google Scholar  

Haddad HW, Malone GW, Comardelle NJ, Degueure AE, Poliwoda S, Kaye RJ, et al. Aduhelm, a novel anti-amyloid monoclonal antibody, for the treatment of Alzheimer’s Disease: a comprehensive review. Health Psychol Res. 2022;10(3):37023.

PubMed   PubMed Central   Google Scholar  

van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388(1):9–21.

Article   PubMed   Google Scholar  

Yousef H, Czupalla CJ, Lee D, Chen MB, Burke AN, Zera KA, et al. Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1. Nat Med. 2019;25(6):988–1000.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Shen X-N, Niu L-D, Wang Y-J, Cao X-P, Liu Q, Tan L, et al. Inflammatory markers in Alzheimer’s disease and mild cognitive impairment: a meta-analysis and systematic review of 170 studies. J Neurol Neurosurg Psychiatry. 2019;90(5):590–8.

Mantzavinos V, Alexiou A. Biomarkers for Alzheimer’s disease diagnosis. Curr Alzheimer Res. 2017;14(11):1149–54.

James ED, Niblett PG. Provisional study to quantify and compare parameters of urine leakage in stress and instability incontinence. Br J Urol. 1988;62(3):223–7.

Tanzi RE. The genetics of Alzheimer disease. Cold Spring Harb Perspect Med. 2012;2(10):a006296.

Jansen IE, Savage JE, Watanabe K, Bryois J, Williams DM, Steinberg S, et al. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nat Genet. 2019;51(3):404–13.

Birney E. Mendelian randomization. Cold Spring Harb Perspect Med. 2022;12(4):a041302.

PubMed   Google Scholar  

Gamazon ER, Wheeler HE, Shah KP, Mozaffari SV, Aquino-Michaels K, Carroll RJ, et al. A gene-based association method for mapping traits using reference transcriptome data. Nat Genet. 2015;47(9):1091–8.

Liu D, Zhu J, Zhou D, Nikas EG, Mitanis NT, Sun Y, et al. A transcriptome-wide association study identifies novel candidate susceptibility genes for prostate cancer risk. Int J Cancer. 2022;150(1):80–90.

Zhong H, Liu S, Zhu J, Wu L. Associations between genetically predicted levels of blood metabolites and pancreatic cancer risk. Int J Cancer. 2023;153(1):103–10.

Sun BB, Maranville JC, Peters JE, Stacey D, Staley JR, Blackshaw J, et al. Genomic atlas of the human plasma proteome. Nature. 2018;558(7708):73–9.

Gusev A, Ko A, Shi H, Bhatia G, Chung W, Penninx BWJH, et al. Integrative approaches for large-scale transcriptome-wide association studies. Nat Genet. 2016;48(3):245–52.

Liu D, Zhou D, Sun Y, Zhu J, Ghoneim D, Wu C, et al. A transcriptome-wide association study identifies candidate susceptibility genes for pancreatic cancer risk. Cancer Res. 2020;80(20):4346–54.

Zhu J, O’Mara TA, Liu D, Setiawan VW, Glubb D, Spurdle AB, et al. Associations between genetically predicted circulating protein concentrations and endometrial cancer risk. Cancers. 2021;13(9):2088.

Zhu J, Yang Y, Kisiel JB, Mahoney DW, Michaud DS, Guo X, et al. Integrating genome and methylome data to identify candidate DNA methylation biomarkers for pancreatic cancer risk. Cancer Epidemiol Biomark Prev Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol. 2021;30(11):2079–87.

Article   CAS   Google Scholar  

Liu D, Zhu J, Zhao T, Sharapov S, Tiys E, Wu L. Associations between genetically predicted plasma N-glycans and prostate cancer risk: analysis of over 140,000 European descendants. Pharmacogenomics Pers Med. 2021;14:1211–20.

CAS   Google Scholar  

Sun Y, Zhu J, Zhou D, Canchi S, Wu C, Cox NJ, et al. A transcriptome-wide association study of Alzheimer’s disease using prediction models of relevant tissues identifies novel candidate susceptibility genes. Genome Med. 2021;13(1):141.

Zhong H, Zhu J, Liu S, Ghoneim DH, Surendran P, Liu T, et al. Identification of blood protein biomarkers associated with prostate cancer risk using genetic prediction models: analysis of over 140, 000 subjects. Hum Mol Genet. 2023;32:ddad139.

Article   Google Scholar  

Bellenguez C, Küçükali F, Jansen IE, Kleineidam L, Moreno-Grau S, Amin N, et al. New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nat Genet. 2022;54(4):412–36.

Liu JZ, Erlich Y, Pickrell JK. Case-control association mapping by proxy using family history of disease. Nat Genet. 2017;49(3):325–31.

Szklarczyk D, Gable AL, Nastou KC, Lyon D, Kirsch R, Pyysalo S, et al. The STRING database in 2021: customizable protein–protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res. 2021;49(D1):D605–12.

Sakaue S, Okada Y. GREP: genome for REPositioning drugs. Bioinforma Oxf Engl. 2019;35(19):3821–3.

Alam MA, Shen H, Deng H-W. A robust kernel machine regression towards biomarker selection in multi-omics datasets of osteoporosis for drug discovery. 2022. https://doi.org/10.48550/ARXIV.2201.05060 .

Griciuc A, Serrano-Pozo A, Parrado AR, Lesinski AN, Asselin CN, Mullin K, et al. Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron. 2013;78(4):631–43.

Kim S, Chen J, Cheng T, Gindulyte A, He J, He S, et al. PubChem 2019 update: improved access to chemical data. Nucleic Acids Res. 2019;47(D1):D1102–9.

Kim SY, Jeong H-H, Kim J, Moon J-H, Sohn K-A. Robust pathway-based multi-omics data integration using directed random walks for survival prediction in multiple cancer studies. Biol Direct. 2019;14(1):8.

Palmqvist S, Janelidze S, Quiroz YT, Zetterberg H, Lopera F, Stomrud E, et al. Discriminative accuracy of plasma phospho-tau217 for Alzheimer disease vs other neurodegenerative disorders. JAMA. 2020;324(8):772–81.

Palmqvist S, Janelidze S, Stomrud E, Zetterberg H, Karl J, Zink K, et al. Performance of fully automated plasma assays as screening tests for Alzheimer disease-related β-amyloid status. JAMA Neurol. 2019;76(9):1060–9.

Janelidze S, Berron D, Smith R, Strandberg O, Proctor NK, Dage JL, et al. Associations of plasma phospho-tau217 levels with tau positron emission tomography in early Alzheimer disease. JAMA Neurol. 2021;78(2):149–56.

Craig-Schapiro R, Perrin RJ, Roe CM, Xiong C, Carter D, Cairns NJ, et al. YKL-40: a novel prognostic fluid biomarker for preclinical Alzheimer’s disease. Biol Psychiatry. 2010;68(10):903–12.

Chen B, Wang Y. Cofilin rod formation in neurons impairs neuronal structure and function. CNS Neurol Disord Drug Targets. 2015;14(4):554–60.

Schönhofen P, de Medeiros LM, Chatain CP, Bristot IJ, Klamt F. Cofilin/actin rod formation by dysregulation of cofilin-1 activity as a central initial step in neurodegeneration. Mini Rev Med Chem. 2014;14(5):393–400.

Allain H, Bentué-Ferrer D. Clinical efficacy of almitrine-raubasine. An overview Eur Neurol. 1998;39(Suppl 1):39–44.

Alzheimer’s Association. 2016 Alzheimer’s disease facts and figures. Alzheimers Dement J Alzheimers Assoc. 2016;12(4):459–509.

Farinelli SE, Greene LA. Cell cycle blockers mimosine, ciclopirox, and deferoxamine prevent the death of PC12 cells and postmitotic sympathetic neurons after removal of trophic support. J Neurosci Off J Soc Neurosci. 1996;16(3):1150–62.

Lublin A, Isoda F, Patel H, Yen K, Nguyen L, Hajje D, et al. FDA-approved drugs that protect mammalian neurons from glucose toxicity slow aging dependent on cbp and protect against proteotoxicity. PLoS ONE. 2011;6(11):e27762.

Yang Y, Wu L, Shu X-O, Cai Q, Shu X, Li B, et al. Genetically predicted levels of DNA methylation biomarkers and breast cancer risk: data from 228 951 women of European descent. J Natl Cancer Inst. 2020;112(3):295–304.

Yang C, Farias FHG, Ibanez L, Suhy A, Sadler B, Fernandez MV, et al. Genomic atlas of the proteome from brain, CSF and plasma prioritizes proteins implicated in neurological disorders. Nat Neurosci. 2021;24(9):1302–12.

Walker KA, Chen J, Zhang J, Fornage M, Yang Y, Zhou L, et al. Large-scale plasma proteomic analysis identifies proteins and pathways associated with dementia risk. Nat Aging. 2021;1(5):473–89.

Wingo AP, Liu Y, Gerasimov ES, Gockley J, Logsdon BA, Duong DM, et al. Integrating human brain proteomes with genome-wide association data implicates new proteins in Alzheimer’s disease pathogenesis. Nat Genet. 2021;53(2):143–6.

Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, et al. Author Correction: Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat Genet. 2019;51(9):1423–4.

Zhang J, Dutta D, Köttgen A, Tin A, Schlosser P, Grams ME, et al. Plasma proteome analyses in individuals of European and African ancestry identify cis-pQTLs and models for proteome-wide association studies. Nat Genet. 2022;54(5):593–602.

Pathak GA, Singh K, Miller-Fleming TW, Wendt FR, Ehsan N, Hou K, et al. Integrative genomic analyses identify susceptibility genes underlying COVID-19 hospitalization. Nat Commun. 2021;12(1):4569.

Wingerd J, Sponzilli EE. Concentrations of serum protein fractions in white women: effects of age, weight, smoking, tonsillectomy, and other factors. Clin Chem. 1977;23(7):1310–7.

Download references

Acknowledgements

We would like to acknowledge authors of the GWAS meta-analysis of AD risk by Jansen et al. to make their GWAS summary statistics to be available. Participants in the INTERVAL randomized controlled trial were recruited with the active collaboration of NHS Blood and Transplant England ( www.nhsbt.nhs.uk ), which has supported field work and other elements of the trial. DNA extraction and genotyping were co-funded by the National Institute for Health Research (NIHR), the NIHR BioResource ( http://bioresource.nihr.ac.uk ), and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014) [*]. The academic coordinating center for INTERVAL was supported by core funding from the: NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024), UK Medical Research Council (MR/L003120/1), British Heart Foundation (SP/09/002; RG/13/13/30194; RG/18/13/33946), and NIHR Cambridge BRC (BRC-1215-20014) [*]. A complete list of the investigators and contributors to the INTERVAL trial is provided in reference [**]. The academic coordinating center would like to thank blood donor center staff and blood donors for participating in the INTERVAL trial.

*The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

**Di Angelantonio E, Thompson SG, Kaptoge SK, Moore C, Walker M, Armitage J, Ouwehand WH, Roberts DJ, Danesh J, INTERVAL Trial Group. Efficiency and safety of varying the frequency of whole blood donation (INTERVAL): a randomized trial of 45 000 donors. Lancet. 2017 Nov 25;390(10110):2360-2371.

This research is supported by University of Hawaii Cancer Center and Florida State University. L.W. is also supported by U54 HG013243. Keenan Walker was supported by the Intramural Research Program of the National Institutes of Health (National Institute on Aging).

Author information

Jingjing Zhu and Shuai Liu contributed equally to this work and are co-first authors.

Authors and Affiliations

Cancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, 96813, USA

Jingjing Zhu, Shuai Liu, Hua Zhong, Dalia H. Ghoneim & Lang Wu

Laboratory of Behavioral Neuroscience, National Institute On Aging, Intramural Research Program, Baltimore, MD, USA

Keenan A. Walker

Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Zichen Zhang & Chong Wu

MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK

Praveen Surendran, Sarah Fahle & Adam Butterworth

NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK

Adam Butterworth

Tulane Center for Biomedical Informatics and Genomics., Division of Biomedical Informatics and Genomics, Deming Department of Medicine, Tulane University, 1440 Canal Street, New Orleans, LA, 70112, USA

Md Ashad Alam & Hong-Wen Deng

Center for Outcomes Research, Ochsner Clinic Foundation, New Orleans, LA, 70121, USA

Md Ashad Alam

You can also search for this author in PubMed   Google Scholar

Contributions

L.W., C.W. and J. Z. conceived and designed the study. S.L. and D.G. developed the protein genetic prediction models. S.L. and J.Z. performed statistical analyses. H.Z. performed IPA and PPI analyses. M.A.A. performed molecular docking analysis. J.Z. wrote the first version of manuscript. L.W. and K.W. helped with drafting the manuscript. C.W. contributed to statistical analyses. Z.Z., P.S., S.F., A.S.B., M.A.A., and H-W. D. contributed to interpretation of results and/or manuscript revision. All authors have reviewed and approved the final manuscript.

Corresponding authors

Correspondence to Chong Wu or Lang Wu .

Ethics declarations

Ethics approval and consent to participate.

This study was approved by the University of Hawaii Institutional Review Board (2019–00402).

Consent for publication

Not applicable.

Competing interests

L.W. provided consulting service to Pupil Bio Inc. and received honorarium. No potential conflicts of interest were disclosed by other authors.

Additional information

Publisher’s note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Additional file 1: figure s1..

Enriched canonical pathways for the identified associated proteins. The and p-value below each term indicates the significance level of each pathway. Figure S2. The network was identified by Ingenuity Pathway Analysis (IPA). A solid line represents a direct interaction between two nodes and a dotted line indicates an indirect interaction. Figure S3. Network nodes represent proteins and edges represent protein-protein associations.

Additional file 2: Table S1.

Risk SNPs identified to be associated with AD risk in previous GWAS or fine-mapping studies. Table S2. Ingenuity Canonical Pathways. Table S3. Network analysis. Table S4. Disease and Biological Functions analysis. Table S5. Association results of the proteins reported in previous studies.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ . The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Cite this article.

Zhu, J., Liu, S., Walker, K.A. et al. Associations between genetically predicted plasma protein levels and Alzheimer’s disease risk: a study using genetic prediction models. Alz Res Therapy 16 , 8 (2024). https://doi.org/10.1186/s13195-023-01378-4

Download citation

Received : 18 February 2023

Accepted : 30 December 2023

Published : 11 January 2024

DOI : https://doi.org/10.1186/s13195-023-01378-4

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Genetic instrument
• Protein biomarker
• Alzheimer’s disease

Alzheimer's Research & Therapy

ISSN: 1758-9193

• General enquiries: [email protected]

• Open access
• Published: 01 March 2024

The clinical efficacy and safety of berberine in the treatment of non-alcoholic fatty liver disease: a meta-analysis and systematic review

• Qilong Nie 1   na1 ,
• Mingyang Li 1   na1 ,
• Caiyang Huang 2 ,
• Yongwei Yuan 1 ,
• Qiuyan Liang 1 ,
• Xiaojun Ma 2 ,
• Tengyu Qiu 1 , 2 &
• Jianhong Li   ORCID: orcid.org/0000-0002-8272-9246 2  

Journal of Translational Medicine volume  22 , Article number:  225 ( 2024 ) Cite this article

2580 Accesses

1 Citations

1 Altmetric

Metrics details

Non-alcoholic fatty liver disease (NAFLD) is becoming increasingly prevalent worldwide, emerging as a significant health issue on a global scale. Berberine exhibits potential for treating NAFLD, but clinical evidence remains inconclusive. This meta-analysis was conducted to assess the efficacy and safety of berberine for treating NAFLD.

This study was registered with PROSPERO (No. CRD42023462338). Identification of randomized controlled trials (RCTs) involved searching 6 databases covering the period from their initiation to 9 September 2023. The primary outcomes comprised liver function markers such as glutamyl transpeptidase (GGT), alanine transaminase (ALT), aspartate transaminase (AST), lipid indices including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), homeostasis model assessment for insulin resistance (HOMA-IR) and body mass index (BMI). Review Manager 5.4 and STATA 17.0 were applied for analysis.

Among 10 RCTs involving 811 patients, berberine demonstrated significant reductions in various parameters: ALT (standardized mean difference (SMD) = − 0.72), 95% confidence interval (Cl) [− 1.01, − 0.44], P  < 0.00001), AST (SMD = − 0.79, 95% CI [− 1.17, − 0.40], P  < 0.0001), GGT (SMD = − 0.62, 95% CI [− 0.95, − 0.29], P  = 0.0002), TG (SMD = − 0.59, 95% CI [− 0.86, − 0.31], P < 0.0001), TC(SMD = − 0.74, 95% CI [− 1.00, − 0.49], P  < 0.00001), LDL-C (SMD = − 0.53, 95% CI [− 0.88, − 0.18], P  = 0.003), HDL-C (SMD = − 0.51, 95% CI [− 0.12, 1.15], P  = 0.11), HOMA-IR (SMD = − 1.56, 95% CI [− 2.54, − 0.58], P  = 0.002), and BMI (SMD = − 0.58, 95% CI [− 0.77, − 0.38], P  < 0.00001). Importantly, Berberine exhibited a favorable safety profile, with only mild gastrointestinal adverse events reported.

This meta-analysis demonstrates berberine's efficacy in improving liver enzymes, lipid profile, and insulin sensitivity in NAFLD patients. These results indicate that berberine shows promise as an adjunct therapy for NAFLD.

Trial registration The protocol was registered with PROSPERO (No. CRD42023462338). Registered on September 27, 2023

Graphical Abstract

Non-alcoholic fatty liver disease (NAFLD) is a clinicopathologic syndrome characterized by hepatic steatosis. This condition is often associated with metabolic comorbidities such as obesity, diabetes mellitus, and dyslipidemia [ 1 ]. The overall global prevalence of NAFLD was 38.2% from 2016 to 2019, and it has persistently increased over the past three decades [ 2 ]. Contrary to the initial perception of NAFLD as primarily affecting Western populations, it's worth emphasizing its elevated prevalence in North America, the Middle East, Asia, and numerous developing nations [ 3 ]. NAFLD typically exhibits no symptoms in its early stages, yet it carries the potential risk of progressing to cirrhosis and subsequently hepatocellular carcinoma, significantly impacting life expectancy [ 4 ].

The treatments of NAFLD can be divided into two categories: non-drug treatment strategies and medication-based treatments. Among non-drug treatments, lifestyle interventions stand out as a pivotal cornerstone therapy, with the regulation of glycolipid metabolism continuing to be the primary target in treating NAFLD [ 5 ]. Moreover, many drugs currently employed in clinical settings exhibit limited efficacy. Therefore, various novel drugs are still under development, represented by PPAR agonists, farnesoid X receptor agonists, and ethnopharmacological therapies [ 5 ].

Berberine is an odorless yellow powder, with a typical alkaloid bitter taste [ 6 ]. In China, the State Drug Administration has approved berberine for over-the-counter sale. Previous research has indicated that berberine enhances insulin sensitivity in patients, aiding in the regulation of blood sugar and lipid levels. Consequently, it finds application in clinical therapies for NAFLD [ 7 , 8 , 9 , 10 ].

The therapeutic efficacy of berberine in the treatment of NAFLD has been extensively validated through animal experimentation. In animal studies, the administration of berberine has the potential to enhance Sirtuin 1 expression, facilitate the deacetylation and stability of carnitine palmitoyl transferase 1A protein, and enhance liver fatty acid oxidation, thereby ameliorating NAFLD [ 11 ]. Additionally, Berberine alleviates NAFLD through intestinal microbiota—intestinal barrier—liver inflammation, and oxidative stress axis [ 12 ]. However, clinical studies have presented contradictory results regarding its efficacy. For example, in Nejati’s study [ 13 ], berberine failed to significantly lower the levels of lipids, fasting blood glucose, or liver enzymes in NAFLD patients. Another study [ 14 ] also reported no significant effect of berberine on HDL-C levels. Collectively, these findings indicate that berberine may have a limited influence on lipid metabolism in NAFLD patients. The meta-analysis, by pooling numerous studies, enlarges sample sizes, improves accuracy, and enhances statistical potency, thereby rendering the findings more compelling. Simultaneously, it can quantify and scrutinize the discrepant results across various studies, helping to discern whether the inconsistency is attributable to methodological heterogeneity or imperfections in the research data, such as small sample sizes, narrow age brackets, unequal gender representation, or technological limitations.

Therefore, the objective of this study was to assess the clinical efficacy and safety of berberine in the treatment of NAFLD through meta-analysis, aiming to provide more precise evidence for clinical decision-making.

This meta-analysis was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (The PRISMA Statement [ 15 ]), and the protocol was registered with PROSPERO (No. CRD42023462338).

Datasets and research technique

The following databases were included in this study: Wanfang Data; the Chinese National Knowledge Infrastructure; the Cochrane Central Register of Controlled Trials; Web of Science; Embase; and PubMed. Searches in these databases encompassed the entire period from their creation to September 9, 2023, with no language restrictions. The following search terms were used: ((((((((((nonalcoholic fatty liver) OR (nonalcoholic steatohepatitis)) OR (Non alcoholic Fatty Liver Disease)) OR (NAFLD)) OR (Nonalcoholic Fatty Liver Disease)) OR (Fatty Liver*, Nonalcoholic)) OR (Liver*, Nonalcoholic Fatty)) OR (Nonalcoholic Fatty Liver*)) OR (Nonalcoholic Steatohepatitis)) OR (Steatohepatitides, Nonalcoholic)) AND ("Berberine"[Mesh]) (Additional file 1 : Table S1),

Independent searches were performed by two researchers in various databases employing specific keywords. Following this, a comparative analysis of the results was executed to ascertain completeness and accuracy. To encompass a wide range of relevant articles, citations from reviews on similar topics were also manually searched.

Inclusion and exclusion criteria

The study’s eligibility criteria adhere to the PICOS framework (participants, interventions, comparisons, outcomes, and study design). The inclusion criteria are as follows: participants diagnosed with NAFLD (P). The experimental group received either berberine or a combination of berberine with other drugs (I). The control group received the same treatment as the experimental group excluding the berberine intake. (C). The article reports one or more of the following results: body mass index (BMI), total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), glutamyl transpeptidase (GGT), alanine transaminase (ALT), aspartate transaminase (AST), homeostasis model assessment for insulin resistance (HOMA-IR) (O). The study was conducted using a randomized controlled trial (RCT) methodology (S).

The exclusion criteria are as follows: (1) animal experiments, (2) reviews and case reports, (3) duplicate publications, (4) articles with incomplete data or that do not meet our specified requirements, and (5) individuals with alcoholic fatty liver disease or viral hepatitis.

Data extraction

The data extraction and analysis were conducted independently by two evaluators. The extracted data comprised details such as the first author, publication year, total number of trial participants, respective numbers of experimental and control groups, intervention measures employed, and duration of the intervention.

Included outcomes are all expressed as mean ± SD: changes in BMI (kg/m 2 ), TC (mmol/L), TG (mmol/L), LDL-C (mmol/L), HDL-C (mmol/L), GGT (U/L), ALT (U/L), AST (U/L), HOMA-IR.

Quality assessment and risk of bias

The assessment of bias risk was independently conducted by two investigators using the Cochrane Collaboration’s Tool for Assessing Risk of Bias [ 16 ], classifying risk of bias as “high risk”, “low risk”, or “unclear risk”. The following terms were included in the Cochrane Collaboration’s Tool for Assessing Risk of Bias: selection bias, performance bias, detection bias, attrition bias, reporting bias, and other bias. These terms evaluated the methods employed for generating the randomization schedule and concealing treatment allocation, along with how blinding was implemented for participants, personnel, and outcomes. Additionally, we rigorously evaluated any indications of incomplete outcome data and selective reporting of outcomes; any disagreements were settled through discussions.

Data synthesis and statistical analysis

Assessment and identification of heterogeneity.

All analyses, completed by Review Manager (version 5.4) and STATA (version 17.0), presented results for continuous data as standardized mean difference (SMD) with a 95% CI. Heterogeneity between studies was estimated using the Higgins’ I 2 test and stratified as follows: 0 ≤ I 2  < 25%, “No heterogeneity”; 25% ≤ I 2  < 50%, “Low heterogeneity”; 50% ≤ I 2  < 75%, “High heterogeneity”; 75% ≤ I 2 , “Severe heterogeneity””. When I 2  < 50%, a fixed-effect model was used for analysis, whereas I 2  > 50%, a random-effect model was used for analysis.

Subgroup analysis and sensitivity tests were conducted to identify the sources of the heterogeneity. When I 2  > 50%, subgroup analyses were conducted based on the total intake of berberine (< 100 g, 100–200 g, > 200 g), daily intake of berberine (< 1.5 g/d, = 1.5 g/d, > 1.5 g/d), duration of berberine intervention (< 4 months, = 4 months, > 4 months) and whether or not diabetes was combined (only NAFLD, NAFLD with Diabetes). In addition, sensitivity tests were performed by systematically removing one study at a time, aiming to reveal highly biased reports.

Assessment of publication bias

Given the tendency for papers with positive results to receive easier publication, our meta-analysis considered the impact of publication bias through the utilization of the funnel plot, the Egger linear regression test [ 17 ], and Begg’s test [ 18 ].

Literature selection

After implementing our research strategy, a total of 505 articles were obtained. Subsequently, following the removal of duplicates, 317 articles underwent screening based on their titles and abstracts. Among these, 279 articles were excluded due to failure to meet the inclusion criteria, which included not being randomized controlled trials (RCTs), not encompassing patients with NAFLD, lacking the utilization of berberine, or insufficient data for comprehensive reporting. Upon careful examination of the full texts of the remaining 38 articles, 28 articles were excluded due to reasons such as lack of full text (n = 8), double or serial publication (n = 7), and incomplete data availability (n = 13). Ultimately, a total of 10 articles [ 13 , 14 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ] were included in this meta-analysis (Fig.  1 ).

Flow diagram of the studies selection process

Study characteristics

A total of 10 RCTs involving 811 patients, conducted between 2010 and 2022, were included in this study. Among these studies, 8 RCTs [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ] were carried out in China, while 2 RCTs [ 13 , 14 ] in Iran and England. In 7 RCTs [ 14 , 20 , 21 , 22 , 23 , 24 , 25 ], patients with NAFLD had comorbid diabetes, and metformin was administered to both the control and treatment group; while in the remaining 3 RCTs [ 13 , 19 , 26 ], the control group received lifestyle interventions. In 9 RCTs, the daily intake of berberine fluctuated between [ 14 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ] 0.6 g and 2 g, except for one study [ 13 ] where it was administered at 6.35 g/day. Berberine interventions ranged from a minimum of 7 weeks to a maximum of 24 weeks. Among these, 7 RCTs [ 19 , 20 , 21 , 22 , 24 , 25 , 26 ] reported the diagnostic criteria for guidelines for the management of non-alcoholic fatty liver disease: an updated and revised edition (revised in 2010 [ 27 ]) and guidelines for diagnosis and treatment of nonalcoholic fatty liver diseases (revised in 2006 [ 28 ]). The remaining 3 RCTs [ 13 , 14 , 23 ] did not provide diagnostic criteria for NAFLD (Table  1 ).

Risk of bias assessment

The results of the risk of bias assessment of involved 10 studies are presented in Fig.  2 . Among them, 3 studies [ 13 , 19 , 20 ] were categorized as low risk of bias due to their utilization of either the random numbers table or computer-generated random-allocation sequence for randomization. In contrast, the remaining 7 studies [ 14 , 21 , 22 , 23 , 24 , 25 , 26 ] did not provide detailed methodology for randomization, resulting in an assessment of unclear risk. Notably, the allocation concealment was an unclear risk for all studies. Out of the reviewed studies, only two [ 13 , 24 ] were deemed to exhibit a low risk of bias in terms of blinding, primarily because they adhered to the double-blinding principle. The rest of the studies [ 14 , 19 , 20 , 21 , 22 , 23 , 25 , 26 ] were categorized as “high risk”. All the test results included in RCT were objective indicators, such as TC, TG, LDL-C, and HDL-C, etc. Therefore, detection bias was labeled as “low risk”. Regarding other biases, none of the studies provided adequate information for assessing whether there was a significant risk of bias and thus assessed as “unclear risk”.

Assessment of risk of bias

Effects of berberine on liver functions

Alanine transaminase

A total of 8 RCTs [ 14 , 19 , 20 , 21 , 22 , 23 , 25 , 26 ], involving 720 patients with NAFLD, were conducted to evaluate the levels of ALT biomarker. The meta-analysis results demonstrated that berberine exhibited significant efficacy in reducing ALT levels (SMD = − 0.72, 95% CI [− 1.01, − 0.44], P  < 0.00001, I 2  = 72%; Fig.  3 ). Subgroup analysis based on the duration of berberine intervention showed that heterogeneity was significantly diminished in the 4-month group (I 2  = 0%). Moreover, a significant reduction in heterogeneity was also observed in the NAFLD with diabetes subgroup analysis (I 2  = 3%) (Table  2 , Additional file 2 : Fig. S1).

Forest plot for meta-analysis of ALT

Aspartate transaminase

In 7 RCTs comprising 632 individuals with NAFLD, [ 19 , 20 , 21 , 22 , 23 , 25 , 26 ], berberine demonstrated efficacy in reducing AST levels, showing a remarkable reduction in the enzyme (SMD = − 0.79, 95% CI [− 1.17, − 0.40], P  < 0.0001, I 2  = 82%; Fig.  4 ). The subgroup analysis, specifically examining the duration of berberine intervention, revealed a significant reduction in heterogeneity within a specific group (= 4 months, I 2  = 4%). Moreover, within the subgroup analysis of NAFLD patients with diabetes, heterogeneity was notably reduced to 17% (Table  2 , Additional file 2 : Fig. S2).

Forest plot for meta-analysis of AST

Glutamyl transpeptidase

A total of 659 patients with NAFLD were included in 7 RCTs [ 14 , 19 , 20 , 21 , 23 , 25 , 26 ], and the levels of GGT were assessed. The results showed that a significant decrease in GGT levels was noted when comparing the two groups (SMD = − 0.62, 95% CI [− 0.95, − 0.29], P  = 0.0002, I 2  = 77%; Fig.  5 ). Furthermore, analysis of the subgroup based on the duration of berberine intervention revealed a notable decrease in heterogeneity (= 4 months, I 2  = 17%) (Table  2 , Additional file 2 : Fig. S3).

Forest plot for meta-analysis of GGT

Effects of berberine on lipid indices

Triglycerides.

There were 10 studies [ 13 , 14 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ] involving 811 patients that compared TG levels, and among these participants, 422 were in the experimental group and 265 were in the control group. The comprehensive analysis revealed that berberine exhibited potential in reducing TG levels in NAFLD patients (SMD = − 0.59, 95% CI [− 0.86, − 0.31], P  < 0.0001, I 2  = 73%; Fig.  6 ). Heterogeneity was effectively eliminated in all four subgroup analyses: total intake of berberine (100–200 g, I 2  = 0%), daily intake of berberine (= 1.5 g/day, I 2  = 0%), duration of berberine intervention (= 4 months, > 4 months, I 2  = 0%), and whether or not diabetes was combined (NAFLD with diabetes, I 2  = 0%)]. Notably, these subgroups excluded the two studies with polar extreme data [ 14 , 18 ] (Table  2 , Additional file 2 : Fig. S4).

Forest plot for meta-analysis of TG

Total cholesterol

The TC levels were compared among 724 participants across 9 RCTs [ 13 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Among them, 367 were in the experimental group and 357 were in the control group. The two groups exhibited a statistically significant disparity (SMD = − 0.74, 95% CI [− 1.00, − 0.49], P  < 0.00001, I 2  = 63%; Fig.  7 ). This indicated that TC levels in the experimental group were significantly lower than those in the control group. Additionally, no significant reduction in heterogeneity was observed in the subgroup analysis (Table  2 , Additional file 2 : Fig. S5).

Forest plot for meta-analysis of TC

Low-density lipoprotein cholesterol

Among the 6 RCTs [ 13 , 14 , 20 , 23 , 25 , 26 ], a significant therapeutic effect on LDL-C was observed in 301 patients with NAFLD. The results demonstrated a significant reduction in LDL-C levels following berberine intervention (SMD = − 0.53, 95% CI [− 0.88, − 0.18], P  = 0.003, I 2  = 74%; Fig.  8 ). Of all the subgroup analyses, only the one focusing on daily berberine intake showed a significant decrease in heterogeneity (> 1.5 g/day, I 2  = 29%) (Table  2 , Additional file 2 : Fig. S6).

Forest plot for meta-analysis of LDL-C

High-density lipoprotein cholesterol

The HDL-C levels were evaluated in 4 RCTs [ 13 , 20 , 23 , 25 ] involving a total of 352 patients with NAFLD. Among these, two groups exhibited a significant statistical difference, indicating that berberine demonstrated superior therapeutic efficacy in increasing HDL-C levels (SMD = 0.51, 95% CI [− 0.12, 1.15], P  = 0.11, I 2  = 88%; Fig.  9 ). Besides, no substantial decrease in heterogeneity was observed across all four subgroup analyses conducted (Table  2 , Additional file 2 : Fig. S7).

Forest plot for meta-analysis of HDL-C

Effects of berberine on homeostasis model assessment for insulin resistance

The levels of HOMA-IR were meticulously monitored in a total of 472 patients diagnosed with NAFLD across 5 rigorously conducted RCTs [ 20 , 21 , 23 , 25 , 26 ]. The meta-analysis findings support the conclusion that berberine exhibited a potential for reducing HOMA-IR levels (SMD = − 1.56. 95% CI [− 2.54, − 0.58], P  = 0.002, I 2  = 96%; Fig.  10 ). In the subgroup analysis of NAFLD with diabetes, heterogeneity was effectively reduced to 67%, with no significant reduction observed in the other three subgroup analyses (Table  2 , Additional file 2 : Fig. S8).

Forest plot for meta-analysis of HOMA-IR

Effects of berberine on body mass index

A total of 5 RCTs [ 13 , 20 , 23 , 25 , 26 ] comprising 420 patients with NAFLD were included, and their BMI levels were reported. The meta-analysis demonstrated a significant improvement in BMI levels with the treatment of berberine (SMD = − 0.58, 95% CI [− 0.77, − 0.38], P  < 0.0001, I 2  = 45%; Fig.  11 ). Given the level of heterogeneity at 45%, subgroup analysis was omitted (Table  2 ).

Forest plot for meta-analysis of BMI

Adverse effects of berberine

A total of 5 RCTs [ 14 , 19 , 22 , 24 , 25 ] reported adverse effects including nausea, gastroesophageal reflux disease, constipation, etc. The statistics in Table  3 revealed that gastrointestinal reactions were the predominant adverse effects, with diarrhea and nausea being particularly prevalent. Besides, none of these symptoms were considered to be severe or irreversible. Indeed, all the adverse effects were resolved following appropriate symptomatic treatment.

Publication bias

The funnel plot revealed asymmetry, but Begg and Egger’s tests did not reveal any significant bias ( P  > 0.05) in these results. Although Begg and Egger’s tests are more reliable for detecting potential bias in a larger pool of studies (usually more than 25), they were still important reference tools for this study (Fig.  12 , Additional file 2 : Fig. S9).

Funnel plots for assessing publication bias. a GGT; b TG; c AST; d ALT; e LDL-C; f HDL-C; g BMI; h TC; and i HOMA-IR

Sensitivity analysis

To assess the robustness and reliability of the comprehensive findings in the meta-analysis, sensitivity analysis was employed. This method involved systematically removing individual studies and conducting a new meta-analysis with the remaining ones. We then examined whether the results exhibited significant discrepancies compared to those before exclusion, thereby ensuring the robustness of our findings. For all assessments, the results remained consistent following sensitivity analysis with the exclusion of included data. Specifically, data from eight studies were available for analysis of ALT levels. Upon exclusion of Zhao’s study, a notable decrease in heterogeneity was observed (I 2  = 0%) (Additional file 2 : Fig. S10). During our sensitivity analysis, despite the absence of a statistically significant change in HDL-C levels among NAFLD patients treated with berberine in the initial findings, a more detailed examination through sensitivity analysis highlighted the subtleties inherent in these results. This was particularly evident due to the discernible impact on the overall outcomes resulting from the exclusion of specific studies from the analysis. These observations underscore the paramount importance of meticulously considering variables such as study duration, quality, and participant characteristics when elucidating the implications of berberine on NAFLD patients.

Summary of the main results

This meta-analysis of 10 RCTs with 811 patients provides evidence that berberine when employed as an adjunct therapy, can improve liver enzymes, dyslipidemia, insulin resistance, and body weight in patients with NAFLD while exhibiting minimal adverse effects. It is noteworthy that several outcomes demonstrated heterogeneity. The heterogeneity observed in certain indicators might be attributed to significant bias in individual studies, particularly in cases involving ALT, AST, and HOMA-IR. This can be explained through sensitivity analysis (Additional file 2 : Fig. S10). Conversely, for the heterogeneity observed in lipid profiles, subgroup analysis, and sensitivity analysis failed to identify the sources, potentially stemming from initial variations in the measurement methods of each indicator.

In our subgroup analysis, we found that elevating the dosage of berberine did not yield a statistically significant improvement in its efficacy concerning lipid profiles. However, extending the duration of administration, particularly beyond 4 months, might be more beneficial for regulating lipid profiles. Conversely, regarding liver and kidney function indicators, a lower daily intake proved to be more effective in improving liver function indicators. Therefore, based on these results, it is suggested that a lower dose with long-term intake of berberine may confer more substantial benefits for patients with NAFLD in a clinical setting.

Potential mechanisms of berberine in the treatment of NAFLD

NAFLD is characterized by hepatic lipid accumulation in individuals who do not consume significant amounts of alcohol. The pathogenesis of NAFLD is intricate and multifactorial. Key mechanisms include: (1) Insulin resistance, which leads to enhanced lipolysis in adipose tissue and increased influx of free fatty acids into the liver, contributing to hepatic steatosis; (2) Adipokine imbalance, with altered levels of adipokines such as elevated leptin and resistin, as well as decreased adiponectin, promoting inflammation, insulin resistance, and hepatic steatosis; (3) Oxidative stress causing increased reactive oxygen species and lipid peroxidation damage hepatocytes, and activating inflammatory pathways and stellate cells leading to fibrosis; (4) Dysbiosis in gut microbiota resulting in changes that increase intestinal permeability, facilitating the translocation of bacteria and bacterial products, thereby promoting hepatic inflammation; (5) Hepatic inflammation involving activation of Kupffer cells and recruitment of inflammatory cells releasing cytokines and chemokines that aggravates insulin resistance while causing hepatocyte injury [ 29 , 30 ]. In summary, the development of NAFLD involves multiple parallel hits derived from adipose tissue, gut microbiota dysbiosis, and the liver itself. The interplay among these factors generates a hepatic environment characterized by pro-inflammatory and pro-fibrogenic processes, consequently precipitating steatosis, inflammation, and fibrosis.

Berberine improves insulin sensitivity by increasing the expression and enhancing the activation of insulin receptor (InsR) [ 31 ]. As shown by previous studies, berberine upregulates InsR expression via a protein kinase C-dependent mechanism. Moreover, berberine also improves insulin sensitivity by inhibiting protein tyrosine phosphatase 1B activity, thereby affecting the phosphorylation of InsR and insulin receptor substrate 1 (IRS-1) [ 32 , 33 ]. Berberine alleviates insulin resistance by activating the Adenosine Monophosphate-activated protein kinase (AMPK) pathway in muscle and liver tissue, thereby enhancing glucose uptake and glycogen synthesis [ 31 , 34 , 35 ]. The HOMA-IR index serves as a pivotal parameter for assessing insulin sensitivity. Besides, HOMA-IR enables the quantification of insulin resistance and β cell function based on basal glucose and insulin concentrations, making it a widely utilized surrogate marker for assessing insulin resistance in research studies. In this meta-analysis, the administration of berberine resulted in a significant reduction in HOMA-IR among patients with NAFLD, as well as those presenting with concomitant diabetes.

Patients with NAFLD commonly exhibit significant dysregulation of serum lipid profile. The findings of this meta-analysis indicate that berberine can effectively regulate the levels of these biomarkers. Besides, intrahepatic TG accumulation indicates imbalanced hepatic energy metabolism and serves as a biomarker of NAFLD [ 36 , 37 ]. The levels of intrahepatic TG are regulated by the equilibrium among hepatic lipid synthesis, decomposition, and excretion. Lipid synthesis involves a cascade of enzymatic reactions that convert acetyl-CoA into fatty acids, ultimately leading to TG production. Meanwhile, TG decomposition primarily occurs through mitochondrial β-oxidation of fatty acids, resulting in the generation of both heat and ATP. Additionally, the process of hepatic lipid synthesis commences with the generation of acetyl-CoA, serving as the fundamental precursor for fatty acid biosynthesis [ 38 ].

Berberine improves lipid metabolism in the liver through several mechanisms. One such mechanism involves the upregulation of microsomal triglyceride transfer protein [ 39 ], promoting the release of TG from liver cells into the bloodstream. This reduces TG accumulation in hepatocytes and alleviates hepatic steatosis. Berberine also increases the expression and enhances the activity of Adenosine Triphosphate-binding cassette transporter A1, which mediates the efflux of cholesterol and phospholipids from hepatocytes onto apolipoproteins to form HDL particles [ 40 ]. This facilitates cholesterol release from liver cells.

In addition, berberine enhances mitochondrial function through coordinated effects on energy metabolism, oxidative stress, and mitochondrial biogenesis. Moreover, the activation of transcription factors, such as peroxisome proliferator-activated receptor gamma coactivator 1-α, induced by berberine, promotes mitochondrial biogenesis through the up-regulation of gene expression associated with this process. Furthermore, Berberine also reduces mitochondrial reactive oxygen species (ROS) generation by activating sirtuin 3 [ 41 ]. In skeletal muscle, berberine promotes mitochondrial biogenesis, and the modulation of sirtuin 1 activity may also contribute to berberine’s mitochondrial effects [ 35 , 42 ]. These mechanisms suggest that berberine exhibits efficacy in ameliorating lipid metabolism disorders associated with NAFLD.

In addition to lipid metabolism disorders, inflammation is also an important factor in the decline of liver function in NAFLD patients. Elevated levels of inflammatory cytokines such as tumor necrosis factor-α and interleukin-1β can induce liver cell damage through mechanisms involving oxidative stress, mitochondrial dysfunction, and apoptosis [ 43 ]. Damaged liver cells further exacerbate inflammation and impair liver function, initiating a vicious cycle that worsens hepatitis and leads to liver dysfunction [ 44 ]. Berberine suppresses inflammation by inhibiting phosphoinositide 3-kinase/protein kinase B and nuclear factor κ-light-chain-enhancer of activated B cells pathways involved in inflammatory responses while activating AMPK and nuclear factor erythroid 2-related factor (Nrf2) pathways known for the anti-inflammatory effects [ 45 , 46 ]. Our study demonstrates that berberine exerts a dual effect on insulin sensitivity and liver function, effectively mitigating insulin resistance while significantly enhancing hepatic function by alleviating inflammation.

Other than regulating glucolipid metabolism and reducing inflammation, berberine also ameliorates NAFLD by modulating gut microbiota and alleviating oxidative stress. Berberine modulates the gut microbiota by enhancing the abundance of beneficial bacteria like Bifidobacterium and Lactobacillus while reducing opportunistic pathogens [ 47 , 48 ]. Berberine can modulate the physiological axis connecting the gut and the liver, leading to a balanced composition of intestinal microbes, maintenance of intestinal integrity, and reduction in enterogenic endotoxins entering the liver. As a result, this multifaceted influence contributes to effectively reducing liver inflammation and steatosis.

Berberine reduces oxidative stress in the liver by activating Nrf2 and antioxidant response element antioxidant pathway and increasing the expression of antioxidant factors like superoxide dismutase, inducible nitric oxide synthase, and heme oxygenase-1 [ 49 , 50 ]. In previous studies, Berberine has demonstrated efficacy in clearing reactive oxygen species (ROS) and malondialdehyde. Through enhancing antioxidant defenses and reducing ROS accumulation, berberine protects against oxidative injury in the liver[ 51 ] (Fig.  13 ).

Molecular pathway mechanisms of berberine therapy for NAFLD

Berberine also exhibits excellent safety in both animal toxicology studies and demonstrates favorable safety profiles in clinical observations [ 52 ]. In our meta-analysis, the included study reported dosages ranging from 0.6 to 6.35 g. All observed adverse reactions were mild, and recovery from these reactions could be achieved through symptomatic treatment. Furthermore, the pharmacokinetic studies reveals a significantly higher concentration of berberine metabolites in the liver (50–70 times greater than plasma levels) following oral administration [ 53 ]. The distribution of berberine extends beyond the blood–brain barrier, with its metabolites exhibiting widespread presence in various organs including the liver, muscle, kidney, lung, heart, brain, pancreas, and adipose tissue [ 54 ]. Considering the extensive tissue absorption and broad pharmacological effects, berberine may hold significant therapeutic potential for the treatment of NAFLD, a multi-system metabolic disorder. This underscores its significance in addressing the condition.

Quality of evidence

In our systematic review, we utilized the GRADEpro guideline development tool to rigorously evaluate the efficacy of berberine in the management of NAFLD. This evaluation integrated findings from 10 RCTs for each outcome, spanning a broad patient cohort. Our findings demonstrated a consistent benefit of berberine across several critical endpoints, including improvements in liver enzymes (GGT, AST, ALT), lipid profiles (LDL-C, HDL-C, TC, TG), BMI, and HOMA-IR, as evidenced by SMD ranging from moderate to substantial effect sizes (0.51 to 1.56). The quality of evidence for each outcome was diligently assessed based on GRADE criteria, addressing concerns related to the risk of bias, inconsistency, indirectness, and imprecision. The high quality of evidence ( ⊕ ⊕ ⊕ ⊕ ) across all outcomes suggests a robust confidence level in the effect estimates, reinforcing the potential of berberine as a significant therapeutic intervention in NAFLD (Table 4 ).

Strengths of this study

This meta-analysis pools data from several RCTs, resulting in a larger sample size. This larger pooled dataset enhances the statistical power of the analysis, allowing for a more precise estimation of the effects of berberine treatment on NAFLD. This is particularly advantageous for identifying small yet clinically significant differences that individual studies may be insufficiently powered to detect. By integrating findings from multiple studies, meta-analysis assists in addressing discrepancies and apparent contradictions observed in individual RCTs. This comprehensive approach helps elucidate whether observed variations are random, stem from methodological differences, or represent genuine heterogeneity in treatment effects. Additionally, through an in-depth observation of all included RCTs, four subgroup analyses were conducted to explore the sources of heterogeneity observed. Moreover, an analysis and summary of the safety of berberine were also performed.

Previous meta-analyses, such as the study by Ren [ 55 ], have focused on animal research. Basic research lays the groundwork for clinical studies, and when combining the findings from meta-analyses, a consistent pattern emerges in the effects of berberine on lipid profiles and other indicators in both animals and humans. However, built upon clinical trials, this study holds increased relevance for its potential clinical application. Importantly, this analysis underscores the multi-factorial benefits of berberine, not only in enhancing liver function but also in addressing metabolic dysfunctions associated with NAFLD. Our findings advocate for the inclusion of berberine in the therapeutic regimen for NAFLD, pending further research on its long-term benefits and safety profile.

Limitations of this study

However, the potential of berberine as a treatment for NAFLD needs to be approached cautiously due to several notable limitations inherent in this meta-analysis. The study involved a relatively small cohort of 811 patients, mainly from trials conducted in China, hampering generalizability to other ethnic populations. Additionally, there was heterogeneity amongst the trials in optimal berberine dosage and duration of treatment. Several trials exhibited unclear or high risk of bias, undermining the reliability of the results. The brief treatment durations, ranging from 7 to 24 weeks, constrain the ability to draw conclusive insights regarding long-term efficacy and safety. Larger-scale RCTs, spanning more diverse populations and longer treatment periods, alongside metabolomic profiling, are essential for providing higher-quality evidence regarding the therapeutic value of berberine in NAFLD.

Conclusions

This meta-analysis provides preliminary evidence that berberine may be an effective adjunct therapy for improving several metabolic parameters in patients with NAFLD. The mechanism behind the efficacy of berberine in treating NAFLD remains unclear. Yet, existing evidence indicates its potential as a therapeutic option for NAFLD.

Availability of data and materials

The Supplementary Material includes the original contributions presented in the study; for further inquiries, please direct them to the corresponding author.

Abbreviations

Adenosine monophosphate-activated protein kinase

Body mass index

Farnesoid X receptor

Homeostasis model assessment for insulin resistance

Insulin receptor

Insulin receptor substrate 1

Lifestyle intervention;

Non-alcoholic fatty liver disease

Nuclear factor erythroid 2-related factor

Peroxisome proliferation-activated receptor

Randomized controlled trial

Reactive oxygen species

Standardized mean difference

Tricarboxylic acid

Triglyceride

95% Confidence interval

Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, Harrison SA, Brunt EM, Sanyal AJ. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American association for the study of liver diseases. Hepatology. 2018;67(1):328–57.

Article   PubMed   Google Scholar  

Younossi ZM, Golabi P, Paik JM, Henry A, Van Dongen C, Henry L. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology. 2023;77(4):1335–47.

Golabi P, Paik JM, AlQahtani S, Younossi Y, Tuncer G, Younossi ZM. Burden of non-alcoholic fatty liver disease in Asia, the Middle East and North Africa: data from global burden of disease 2009–2019. J Hepatol. 2021;75(4):795–809.

Article   CAS   PubMed   Google Scholar  

Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, George J, Bugianesi E. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15(1):11–20.

Rong L, Zou J, Ran W, Qi X, Chen Y, Cui H, Guo J. Advancements in the treatment of non-alcoholic fatty liver disease (NAFLD). Front Endocrinol. 2022;13:1087260.

Article   Google Scholar  

Battu SK, Repka MA, Maddineni S, Chittiboyina AG, Avery MA, Majumdar S. Physicochemical characterization of berberine chloride: a perspective in the development of a solution dosage form for oral delivery. AAPS PharmSciTech. 2010;11(3):1466–75.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Pérez-Rubio KG, González-Ortiz M, Martínez-Abundis E, Robles-Cervantes JA, Espinel-Bermúdez MC. Effect of berberine administration on metabolic syndrome, insulin sensitivity, and insulin secretion. Metab Syndr Relat Disord. 2013;11(5):366–9.

Bagade A, Tumbigeremutt V, Pallavi G. Cardiovascular effects of berberine: a review of the literature. J Restor Med. 2017;6:37–35.

Chang XX, Wang Z, Zhang JL, Yan HM, Bian H, Xia MF, Lin HD, Jiang JD, Gao X. Lipid profiling of the therapeutic effects of berberine in patients with nonalcoholic fatty liver disease. J Transl Med. 2016;14:1–11.

Cicero AF, Baggioni A. Berberine and its role in chronic disease. Adv Exp Med Biol. 2016;928:27–45.

Wang P, Li R, Li Y, Tan S, Jiang J, Liu H, Wei X. Berberine alleviates non-alcoholic hepatic steatosis partially by promoting SIRT1 deacetylation of CPT1A in mice. Gastroenterol Rep. 2023;1:1. https://doi.org/10.1093/gastro/goad032 .

Dai YF, Zhu WY, Zhou JX, Shen T. The combination of berberine and evodiamine ameliorates high-fat diet-induced non-alcoholic fatty liver disease associated with modulation of gut microbiota in rats. Braz J Med Biol Res. 2022;55(1): e12096.

Nejati L, Movahedi A, Salari G, Moeineddin R, Nejati P. The effect of berberine on lipid profile, liver enzymes, and fasting blood glucose in patients with non-alcoholic fatty liver disease (NAFLD): a randomized controlled trial. Med J Islam Repub Iran. 2022;36:39.

PubMed   PubMed Central   Google Scholar  

Harrison SA, Gunn N, Neff GW, Kohli A, Liu LP, Flyer A, Goldkind L, Di Bisceglie AM. A phase 2, proof of concept, randomised controlled trial of berberine ursodeoxycholate in patients with presumed non-alcoholic steatohepatitis and type 2 diabetes. Nat Commun. 2021;12(1):5503.

Article   ADS   CAS   PubMed   PubMed Central   Google Scholar  

Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7): e1000097.

Article   PubMed   PubMed Central   Google Scholar  

Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343: d5928.

Sterne JA, Egger M, Smith GD. Systematic reviews in health care: investigating and dealing with publication and other biases in meta-analysis. BMJ. 2001;323(7304):101–5.

Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50(4):1088–101.

Yanan Z, Cai L, Long L, Jing C, Fengjuan W, Na L. Effect of berberine hydrochloride combined with metformin on patients with nonalcoholic fatty liver disease. Chin Minkang Med. 2022;34(14):51–3+57.

Google Scholar  

Jinhua H, Tingting H, Jinghua W, Jingwen Y, Jing W, Qiuling Z. Effects of berberine hydrochloride combined with metformin on body fat composition and liver fat content in patients with type 2 diabetes mellitus complicated with NAFLD. Zhejiang Med Sci. 2021;43(21):2327–31.

Benli H. Effect of metformin combined with berberine hydrochloride on the level of interleukin-17 and transforming growth factor-β in the treatment of nonalcoholic fatty liver disease. J Mod Chin West Integr Med. 2017;26(05):496–9.

Junfeng C. Efficacy and safety of berberine combined with metformin in the treatment of non-alcoholic fatty liver with type 2 diabetes mellitus. Inner Mongolia Tradit Chin Med. 2016;35(05):67–8.

Yan HM, Xia MF, Wang Y, Chang XX, Yao XZ, Rao SX, Zeng MS, Tu YF, Feng R, Jia WP, et al. Efficacy of berberine in patients with non-alcoholic fatty liver disease. PLoS ONE. 2015;10(8): e0134172.

Jie N, Haitao Z, Dingding L, Xiaoqian W. Efficacy of berberine combined with metformin in the treatment of type 2 diabetes mellitus with nonalcoholic fatty liver. Mod Drug Appl China. 2013;7(23):155–6.

Yanfang C, Weiwei C, Lili Z, Yan F. Clinical observation of berberine combined with metformin in the treatment of type 2 diabetes mellitus with nonalcoholic fatty liver. Mod Prev Med. 2012;39(18):4885–6, 4889.

Ruimiao B, Beibei Z, Ridong Z, Jing W. Effect of berberine on insulin resistance and serum adiponectin in nonalcoholic fatty liver. Pract Gerontol. 2011;25(05):423–6.

The Chinese National Work-shop on Fatty Liver and Alcoholic Liver Disease for the Chinese, Liver Disease Association. Guidelines for management of nonalcoholic fatty liver disease: an updated and revised edition (revised in 2010). Chin J Hepatol 2010;18(3):163.

The Chinese National Work-shop on Fatty Liver and Alcoholic Liver Disease for the Chinese, Liver Disease Association. Guidelines for diagnosis and treatment of nonalcoholic fatty liver diseases. Chin J Hepatol 2006;14(3):161.

Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism. 2016;65(8):1038–48.

Arab JP, Arrese M, Trauner M. Recent insights into the pathogenesis of nonalcoholic fatty liver disease. Annu Rev Pathol. 2018;13:321–50.

Kong WJ, Zhang H, Song DQ, Xue R, Zhao W, Wei J, Wang YM, Shan N, Zhou ZX, Yang P, et al. Berberine reduces insulin resistance through protein kinase C-dependent up-regulation of insulin receptor expression. Metabolism. 2009;58(1):109–19.

Zhang L, Wu X, Yang R, Chen F, Liao Y, Zhu Z, Wu Z, Sun X, Wang L. Effects of berberine on the gastrointestinal microbiota. Front Cell Infect Microbiol. 2020;10: 588517.

Yu M, Alimujiang M, Hu L, Liu F, Bao Y, Yin J. Berberine alleviates lipid metabolism disorders via inhibition of mitochondrial complex I in gut and liver. Int J Biol Sci. 2021;17(7):1693–707.

Zhao L, Cang Z, Sun H, Nie X, Wang N, Lu Y. Berberine improves glucogenesis and lipid metabolism in nonalcoholic fatty liver disease. BMC Endocr Disord. 2017;17(1):13.

Gomes AP, Duarte FV, Nunes P, Hubbard BP, Teodoro JS, Varela AT, Jones JG, Sinclair DA, Palmeira CM, Rolo AP. Berberine protects against high fat diet-induced dysfunction in muscle mitochondria by inducing SIRT1-dependent mitochondrial biogenesis. Biochim Biophys Acta. 2012;1822(2):185–95.

Fabbrini E, Sullivan S, Klein S. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology. 2010;51(2):679–89.

Korenblat KM, Fabbrini E, Mohammed BS, Klein S. Liver, muscle, and adipose tissue insulin action is directly related to intrahepatic triglyceride content in obese subjects. Gastroenterology. 2008;134(5):1369–75.

He A, Chen X, Tan M, Chen Y, Lu D, Zhang X, Dean JM, Razani B, Lodhi IJ. Acetyl-CoA derived from hepatic peroxisomal β-oxidation inhibits autophagy and promotes steatosis via mTORC1 activation. Mol Cell. 2020;79(1):30-42.e34.

Chen P, Li Y, Xiao L. Berberine ameliorates nonalcoholic fatty liver disease by decreasing the liver lipid content via reversing the abnormal expression of MTTP and LDLR. Exp Ther Med. 2021;22(4):1109.

Yang XJ, Liu F, Feng N, Ding XS, Chen Y, Zhu SX, Yang LC, Feng XF. Berberine attenuates cholesterol accumulation in macrophage foam cells by suppressing AP-1 activity and activation of the Nrf2/HO-1 pathway. J Cardiovasc Pharmacol. 2020;75(1):45–53.

Liu H, You L, Wu J, Zhao M, Guo R, Zhang H, Su R, Mao Q, Deng D, Hao Y. Berberine suppresses influenza virus-triggered NLRP3 inflammasome activation in macrophages by inducing mitophagy and decreasing mitochondrial ROS. J Leukoc Biol. 2020;108(1):253–66.

Xu Y, Yu T, Ma G, Zheng L, Jiang X, Yang F, Wang Z, Li N, He Z, Song X, et al. Berberine modulates deacetylation of PPARγ to promote adipose tissue remodeling and thermogenesis via AMPK/SIRT1 pathway. Int J Biol Sci. 2021;17(12):3173–87.

Schwabe RF, Brenner DA. Mechanisms of liver injury. I. TNF-alpha-induced liver injury: role of IKK, JNK, and ROS pathways. Am J Physiol Gastrointest Liver Physiol. 2006;290(4):G583–9.

Shen Y, Malik SA, Amir M, Kumar P, Cingolani F, Wen J, Liu Y, Zhao E, Farris AB, Raeman R, et al. decreased hepatocyte autophagy leads to synergistic IL-1β and TNF mouse liver injury and inflammation. Hepatology. 2020;72(2):595–608.

Khezri MR, Mohammadipanah S, Ghasemnejad-Berenji M. The pharmacological effects of berberine and its therapeutic potential in different diseases: role of the phosphatidylinositol 3-kinase/AKT signaling pathway. Phytother Res. 2023;38(1):349–67.

Cao J, Chen M, Xu R, Guo M. Therapeutic mechanisms of berberine to improve the intestinal barrier function via modulating gut microbiota, TLR4/NF-κ B/MTORC pathway and autophagy in cats. Front Microbiol. 2022;13: 961885.

Wu L, Xi Y, Yan M, Sun C, Tan J, He J, Li H, Wang D. Berberine-based carbon quantum dots improve intestinal barrier injury and alleviate oxidative stress in C57BL/6 mice with 5-fluorouracil-induced intestinal mucositis by enhancing gut-derived short-chain fatty acids contents. Molecules. 2023;28(5):2148.

Dong Y, Fan H, Zhang Z, Jiang F, Li M, Zhou H, Guo W, Zhang Z, Kang Z, Gui Y, et al. Berberine ameliorates DSS-induced intestinal mucosal barrier dysfunction through microbiota-dependence and Wnt/β-catenin pathway. Int J Biol Sci. 2022;18(4):1381–97.

Deng Y, Tang K, Chen R, Nie H, Liang S, Zhang J, Zhang Y, Yang Q. Berberine attenuates hepatic oxidative stress in rats with non-alcoholic fatty liver disease via the Nrf2/ARE signalling pathway. Exp Ther Med. 2019;17(3):2091–8.

CAS   PubMed   PubMed Central   Google Scholar  

Shin JS, Choi HE, Seo S, Choi JH, Baek NI, Lee KT. Berberine decreased inducible nitric oxide synthase mRNA stability through negative regulation of human antigen r in lipopolysaccharide-induced macrophages. J Pharmacol Exp Ther. 2016;358(1):3–13.

Yang S, Zhu H, Li Y, Lin H, Gabrielson K, Trush MA, Diehl AM. Mitochondrial adaptations to obesity-related oxidant stress. Arch Biochem Biophys. 2000;378(2):259–68.

Rad SZK, Rameshrad M, Hosseinzadeh H. Toxicology effects of Berberis vulgaris (barberry) and its active constituent, berberine: a review. Iran J Basic Med Sci. 2017;20(5):516–29.

Zhu X, Bian H, Gao X. The potential mechanisms of berberine in the treatment of nonalcoholic fatty liver disease. Molecules. 2016;21(10):1336.

Kumar A, Ekavali, Chopra K, Mukherjee M, Pottabathini R, Dhull DK. Current knowledge and pharmacological profile of berberine: an update. Eur J Pharmacol. 2015;761:288–97.

Article   ADS   CAS   PubMed   Google Scholar  

Ren S, Ma X, Wang R, Liu H, Wei Y, Wei S, Jing M, Zhao Y. Preclinical evidence of berberine on non-alcoholic fatty liver disease: a systematic review and meta-analysis of animal studies. Front Pharmacol. 2021;12: 742465.

Download references

Acknowledgements

Not applicable.

This work was supported by the Foshan Fourteenth Five-Year Plan, with an emphasis on the implementation of key specialty construction projects.

Author information

Qilong Nie and Mingyang Li contributed equally to this paper.

Authors and Affiliations

The Eighth Clinical Medical College, Guangzhou University of Chinese Medicine, Foshan, 528051, Guangdong, China

Qilong Nie, Mingyang Li, Yongwei Yuan, Qiuyan Liang & Tengyu Qiu

Foshan Hospital of Traditional Chinese Medicine, Guangzhou University of Chinese Medicine, No. 6, Qinren Road, Chancheng District, Foshan, 528051, Guangdong, China

Caiyang Huang, Xiaojun Ma, Tengyu Qiu & Jianhong Li

You can also search for this author in PubMed   Google Scholar

Contributions

QN, ML: formal analysis; writing—original draft; and writing—review and editing, XM and CH: conceptualization; data curation, TQ and YY: validation; visualization, QL: investigation; methodology, JL: funding acquisition and supervision.

Corresponding author

Correspondence to Jianhong Li .

Ethics declarations

Ethics approval and consent to participate, consent for publication, competing interests.

The authors declare that they have no competing interests.

Additional information

Publisher's note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Additional file 1: table s1..

Literature search strategy.

Additional file 2: Figure S1.

Subgroup analysis of ALT. Figure S2. Subgroup analysis of AST. Figure S3. Subgroup analysis of GGT. Figure S4. Subgroup analysis of TG. Figure S5. Subgroup analysis of TC. Figure S6. Subgroup analysis of LDL-C. Figure S7. Subgroup analysis of HDL-C. Figure S8. Subgroup analysis of HOMA-IR. Figure S9. Egger’s test and Begg’s test. Figure S10. Sensitivity analysis.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ . The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Cite this article.

Nie, Q., Li, M., Huang, C. et al. The clinical efficacy and safety of berberine in the treatment of non-alcoholic fatty liver disease: a meta-analysis and systematic review. J Transl Med 22 , 225 (2024). https://doi.org/10.1186/s12967-024-05011-2

Download citation

Received : 12 December 2023

Accepted : 20 February 2024

Published : 01 March 2024

DOI : https://doi.org/10.1186/s12967-024-05011-2

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

Journal of Translational Medicine

ISSN: 1479-5876

• Submission enquiries: Access here and click Contact Us
• General enquiries: [email protected]

• Open access
• Published: 14 May 2024

Evaluation of the feasibility of a midwifery educator continuous professional development (CPD) programme in Kenya and Nigeria: a mixed methods study

• Duncan N. Shikuku 1 , 2 ,
• Hauwa Mohammed 3 ,
• Lydia Mwanzia 4 ,
• Alice Norah Ladur 2 ,
• Peter Nandikove 5 ,
• Alphonce Uyara 6 ,
• Catherine Waigwe 7 ,
• Lucy Nyaga 1 ,
• Issak Bashir 8 ,
• Eunice Ndirangu 9 ,
• Carol Bedwell 2 ,
• Sarah Bar-Zeev 10 &
• Charles Ameh 2 , 11 , 12  

BMC Medical Education volume  24 , Article number:  534 ( 2024 ) Cite this article

212 Accesses

10 Altmetric

Metrics details

Midwifery education is under-invested in developing countries with limited opportunities for midwifery educators to improve/maintain their core professional competencies. To improve the quality of midwifery education and capacity for educators to update their competencies, a blended midwifery educator-specific continuous professional development (CPD) programme was designed with key stakeholders. This study evaluated the feasibility of this programme in Kenya and Nigeria.

This was a mixed methods intervention study using a concurrent nested design. 120 randomly selected midwifery educators from 81 pre-service training institutions were recruited. Educators completed four self-directed online learning (SDL) modules and three-day practical training of the blended CPD programme on teaching methods (theory and clinical skills), assessments, effective feedback and digital innovations in teaching and learning. Pre- and post-training knowledge using multiple choice questions in SDL; confidence (on a 0–4 Likert scale) and practical skills in preparing a teaching a plan and microteaching (against a checklist) were measured. Differences in knowledge, confidence and skills were analysed. Participants’ reaction to the programme (relevance and satisfaction assessed on a 0–4 Likert scale, what they liked and challenges) were collected. Key informant interviews with nursing and midwifery councils and institutions’ managers were conducted. Thematic framework analysis was conducted for qualitative data.

116 (96.7%) and 108 (90%) educators completed the SDL and practical components respectively. Mean knowledge scores in SDL modules improved from 52.4% (± 10.4) to 80.4% (± 8.1), preparing teaching plan median scores improved from 63.6% (IQR 45.5) to 81.8% (IQR 27.3), and confidence in applying selected pedagogy skills improved from 2.7 to 3.7, p  < 0.001. Participants rated the SDL and practical components of the programme high for relevance and satisfaction (median, 4 out of 4 for both). After training, 51.4% and 57.9% of the participants scored 75% or higher in preparing teaching plans and microteaching assessments. Country, training institution type or educator characteristics had no significant associations with overall competence in preparing teaching plans and microteaching ( p  > 0.05). Qualitatively, educators found the programme educative, flexible, convenient, motivating, and interactive for learning. Internet connectivity, computer technology, costs and time constraints were potential challenges to completing the programme.

The programme was feasible and effective in improving the knowledge and skills of educators for effective teaching/learning. For successful roll-out, policy framework for mandatory midwifery educator specific CPD programme is needed.

Peer Review reports

Introduction

Quality midwifery education underpins the provision of quality midwifery care and is vital for the health and well-being of women, infants, and families [ 1 ]. The recent State of the World’s Midwifery report (SoWMy) (2021) indicates that urgent investments are needed in midwifery, especially quality midwifery education, to improve health outcomes for women and neonates. Despite evidence to support midwifery, midwifery education and training is grossly underfunded in low- and middle-income countries (LMICs) with variation in the quality, content and duration of content between and within countries [ 2 ]. Barriers to achieving quality education are: inadequate content, lack of learning and teaching materials, insufficient and poorly trained educators and weak regulation, midwifery educators having no connection with clinical practice or opportunities for updating their knowledge or skills competencies [ 3 , 4 ].

The WHO, UNFPA, UNICEF and the International Confederation of Midwives’ (ICM) seven-step action plan to strengthen quality midwifery education, and ICM’s four pillars for midwives to achieve their potential emphasize strengthening midwifery faculty to teach students as a key priority [ 4 , 5 ]. Consequently, ICM recommends that (i) at least 50% of midwifery education curriculum should be practise-based with opportunities for clinical experience, (ii) midwifery faculty should use fair, valid and reliable formative and summative assessment methods to measure student performance and progress in learning and (iii) midwifery programmes have sufficient and up-to-date teaching and learning resources and technical support for virtual/distance learning to meet programme needs [ 6 ]. To achieve this, WHO’s Midwifery Educator Core Competencies and ICM’s Global Standards for Midwifery Education provide core competencies that midwifery educators must possess for effective practice [ 6 , 7 ]. The WHO’s global midwifery educator survey in 2018–2019 reported that fewer than half of the educators (46%) were trained or accredited as educators [ 5 ]. Educators are important determinants of quality graduates from midwifery programmes [ 7 ]. However, the survey identified that none of the educators felt confident in all of WHO’s midwifery educator core competencies [ 5 ]. Further evidence shows that many midwifery educators are more confident with theoretical classroom teaching than clinical teaching despite advances in teaching methods and have low confidence in facilitating online/virtual teaching and learning [ 4 , 8 , 9 ]. To remain competent, design and deliver competency-based curriculum and strengthen midwifery practice, ICM and WHO emphasize that midwifery faculty should engage in ongoing professional development as a midwifery practitioner, teacher/lecturer and leader [ 6 , 10 , 11 ]. However in many settings there is inadequate provision or access to faculty development opportunities [ 12 ].

Continuous professional development (CPD)

Continuous professional development has been defined as the means by which members of the profession maintain, improve and broaden their knowledge, expertise, and competence, and develop the personal and professional qualities required throughout their professional lives [ 13 ]. This can be achieved through multiple formal educational pathways based on the ICM Global Standards for Midwifery Education whilst incorporating the ICM Essential Competencies for Basic Midwifery Practice [ 6 , 14 ]. There are formal CPD activities where there is structured learning that often follows set curricula, usually approved by independent accreditation services or informal CPD that is usually self-directed learning. Participating in accredited CPD programmes is beneficial to the profession. A requirement of regular CPD renewal by a country to maintain licensure ensures an up-to-date, relevant nursing and midwifery workforce [ 15 ] and increases the legitimacy of CPD [ 16 ]. Structured learning (direct or distant), mandatory training, attending workshops and conferences, accredited college/university courses and trainings, research and peer review activities are opportunities for CPD [ 17 ]. Importantly, these CPD programmes are essential for safe, competent and effective practice that is essential to the universal health coverage (UHC) & maternal and newborn health SDGs agenda particularly in developing countries [ 18 , 19 ].

Whilst regulatory bodies and employers in many countries have requirements for midwives to complete CPD programmes and activities, these programmes and supporting activities are found to be ineffective if CPD is irrelevant to the practitioners’ practice setting, attended only because of monetary or non-monetary benefits, geared towards improving a skill for which there is no demonstrated need, and taken only to meet regulatory requirements rather than to close a competency gap [ 20 ]. In most LMICs, midwifery licensure is permanent, without obligation to demonstrate ongoing education or competence [ 15 ]. Consequently, CPD processes are not in place, and if in place, not fully utilised. A systematic review on CPD status in WHO regional office for Africa member states reported that nurses and midwives are required to attend formalised programmes delivered face-to-face or online, but only16 out of 46 (34.7%) member states had mandatory CPD programmes [ 15 ]. This underscores the need for designing regulator approved midwifery educator CPD programmes to improve the quality of midwifery education in LMICs.

Modes and approaches for delivery of CPD

Face-to-face contact is a common mode of delivery of CPD although mHealth is an emerging platform that increases access, particularly to nurses and midwives in rural areas [ 12 , 21 ]. Emerging platforms and organisations such as World Continuing Education Alliance (WCEA) offer mHealth learning opportunities in LMICs for skilled health personnel to access CPD resources that can improve health care provider knowledge and skills and potentially positively impact healthcare outcomes [ 22 ]. Although there is evidence of capacity building initiatives and CPD for midwifery educators in LMICs [ 23 ], these have been largely delivered as part of long duration (2-year) fellowship programmes and led by international organisations. In addition, these programmes have largely focused on curriculum design, leadership, management, research, project management and programme evaluation skills in health professions education with little on teaching and learning approaches and assessment for educators [ 24 , 25 , 26 ]. Successful CPD initiatives should be (i) accredited by the national regulatory bodies (Nursing and Midwifery Councils); (ii) multifaceted and provide different types of formal and informal learning opportunities and support; (iii) combine theory and clinical practice to develop the knowledge, skills and attitudes and (iv) must be adapted to fit the local context in which participants work and teach to ensure local ownership and sustainability of the initiatives [ 16 ].

Short competency-based blended trainings for educators improve their competence and confidence in delivering the quality midwifery teaching. However, systems for regular updates to sustain the competencies are lacking [ 27 , 28 ]. Evidence on effectiveness of the available CPD initiatives is limited. Even where these initiatives have been evaluated, this has largely focused on the outcomes of the programmes and little attention on the feasibility and sustainability of such programmes in low-resourced settings [ 24 , 25 , 29 ]. As part of global investments to improve the quality of midwifery education and training, Liverpool School of Tropical Medicine (LSTM) in collaboration with the UNFPA Headquarters Global Midwifery Programme and Kenya midwifery educators developed a blended midwifery educator CPD programme (described in detail in the methods section). The CPD programme modules in this programme are aligned to the WHO’s midwifery educators’ core competencies [ 7 ] and ICM essential competencies for midwifery practice [ 14 ]. The programme is also aligned to the nursing and midwifery practice national regulatory requirements of Nursing and Midwifery Councils in LMICs such as Kenya and Nigeria, and relevant national policy [ 30 , 31 , 32 ].This programme aimed at sustaining and improving the educators’ competencies in delivery of their teaching, assessments, mentoring and feedback to students. To promote uptake, there is need to test the relevance and practicability of the CPD programme. Feasibility studies are used to determine whether an intervention is appropriate for further testing, relevant and sustainable in answering the question – Can it work [ 33 ]? The key focus of these studies are acceptability of the intervention, resources and ability to manage and implement intervention (availability, requirements, sustainability), practicality, adaptation, integration into the system, limited efficacy testing of the intervention in controlled settings and preliminary evaluation of participant responses to the intervention [ 33 , 34 , 35 ].

This study evaluated the feasibility of the LSTM/UNFPA midwifery educator CPD programme using the Kirkpatrick’s model for evaluating training programmes [ 36 ]. This model is an effective tool with four levels for evaluating training programmes. Level 1 (Participants’ reaction to the programme experience) helps to understand how satisfying, engaging and relevant participants find the experience. Level 2 (Learning) measures the changes in knowledge, skills and confidence after training. Level 3 (Behaviour) measures the degree to which participants apply what they learned during training when they are back on job and this can be immediately and several months after the training. This level is critical as it can also reveal where participants might need help to transfer learning during the training to practice afterwards. Level 4 (Results) measures the degree to which targeted outcomes occur because of training. In this study, participants’ reaction to the programme – satisfaction and relevance of the programme to meeting their needs (level 1) and change in knowledge, confidence and skills after the CPD programme (level 2) were assessed. Also, user perspectives and barriers to implementing the CPD programme were explored.

Study design

This was a mixed methods intervention study using a concurrent nested/embedded/convergent design conducted in Kenya and Nigeria in May and June 2023. This was designed to evaluate the feasibility of the midwifery educator CPD programme. The goal was to obtain different but complementary data to better understand the CPD programme with the data collected from the same participants or similar target populations [ 37 ].

The quantitative component of the evaluation used a quasi-experimental pre-post and post-test only designs to evaluate the effectiveness of the blended CPD programme intervention among midwifery educators from mid-level training colleges and universities from the two countries. Pre and post evaluation of knowledge (online self-directed component) and skills (developing a teaching plan during the face-to-face component) was performed. Post intervention evaluation on programme satisfaction, relevance of CPD programme and microteaching sessions for educators was conducted.

The qualitative component of the evaluation included open-ended written responses from the midwifery educators and master trainers to describe what worked well (enablers), challenges/barriers experienced in the blended programme and key recommendations for improvement were collected. In addition, key informant interviews with the key stakeholders (nursing and midwifery councils and the national heads of training institutions) were conducted. Data on challenges anticipated in the scale up of the programme and measures to promote sustainability, access and uptake of the programme were collected from both educators and key stakeholders.

A mixed methods design was used for its strengths in (i) collecting the two types of data (quantitative and qualitative) simultaneously, during a single data collection phase, (ii) provided the study with the advantages of both quantitative and qualitative data and (iii) helped gain perspectives and contextual experiences from the different types of data or from different levels (educators, master trainers, heads of training institutions and nursing and midwifery councils) within the study [ 38 , 39 ].

The study was conducted in Kenya and Nigeria. Kenya has over 121 mid-level training colleges and universities offering nursing and midwifery training while Nigeria has about 300. Due to the vastness in Nigeria, representative government-owned nursing and midwifery training institutions were randomly selected from each of the six geo-political zones in the country and the Federal Capital Territory. Mid-level training colleges offer the integrated nursing and midwifery training at diploma level while universities offer integrated nursing and midwifery training at bachelor/master degree level in the two countries (three universities in Kenya offer midwifery training at bachelor level). All nurse-midwives and midwives trained at both levels are expected to possess ICM competencies to care for the woman and newborn. Midwifery educators in Kenya and Nigeria are required to have at least advanced diploma qualifications although years of clinical experience are not specified.

It is a mandatory requirement of the Nursing and Midwifery Councils for nurse/midwives and midwifery educators in both countries to demonstrate evidence of CPD for renewal of practising license in both countries [ 40 , 41 ]. A minimum of 20 CPD points (equivalent to 20 credit hours) is recommended annually for Kenya and 60 credit hours for Nigeria every three years. However, there are no specific midwifery educator CPD that incorporated both face-to-face and online modes of delivery, available for Kenya and Nigeria and indeed for many countries in the region. Nursing and midwifery educators are registered and licensed to practice nursing and midwifery while those from other disciplines who teach in the midwifery programme are qualified in the content they teach.

Study sites

In Kenya, a set of two mid-level colleges (Nairobi and Kakamega Kenya Medical Training Colleges (KMTCs) and two universities (Nairobi and Moi Universities), based on the geographical distribution of the training institutions were identified as CPD Centres of Excellence (COEs)/hubs. In Nigeria, two midwifery schools (Centre of Excellence for Midwifery and Medical Education, College of Nursing and Midwifery, Illorin, Kwara State and Centre of Excellence for Midwifery and Medical Education, School of Nursing Gwagwalada, Abuja, FCT) were identified. These centres were equipped with teaching and EmONC training equipment for the practical components of the CPD programme. The centres were selected based on the availability of spacious training labs/classes specific for skills training and storage of equipment and an emergency obstetrics and newborn care (EmONC) master trainer among the educators in the institution. They were designated as host centres for the capacity strengthening of educators in EmONC and teaching skills.

Intervention

Nursing and midwifery educators accessed and completed 20 h of free, self-directed online modules on the WCEA portal and face-to-face practical sessions in the CPD centres of excellence.

The design of the midwifery educator CPD programme

The design of the CPD modules was informed by the existing gap for professional development for midwifery educators in Kenya and other LMICs and the need for regular updates in knowledge and skills competencies in delivery of teaching [ 9 , 15 , 23 , 28 ]. Liverpool School of Tropical Medicine led the overall design of the nursing and midwifery educator CPD programme (see Fig.  1 for summarised steps taken in the design of the blended programme).

This was a two-part blended programme with a 20-hour self-directed online learning component (accessible through the WCEA platform at no cost) and a 3-day face-to-face component designed to cover theoretical and practical skills components respectively. The 20-hour self-directed online component had four 5-hour modules on reflection practice, teaching/learning theories and methods, student assessments and effective feedback and mentoring. These modules had pretest and post-test questions and were interactive with short videos, short quizzes within modules, links for further directed reading and resources to promote active learning. This online component is also available on the WCEA platform as a resource for other nurses and midwifery educators across the globe ( https://wcea.education/2022/05/05/midwifery-educator-cpd-programme/ ).

Practical aspects of competency-based teaching pedagogy, clinical teaching skills including selected EmONC skills, giving effective feedback, applying digital innovations in teaching and learning for educators and critical thinking and appraisal were delivered through a 3-day residential face-to-face component in designated CPD centres of excellence. Specific skills included: planning and preparing teaching sessions (lesson plans), teaching practical skills methodologies (lecture, simulation, scenario and role plays), selected EmONC skills, managing teaching and learning sessions, assessing students, providing effective feedback and mentoring and use of online applications such as Mentimeter and Kahoot in formative classroom assessment of learning. Selected EmONC skills delivered were shoulder dystocia, breech delivery, assisted vaginal delivery (vacuum assisted birth), managing hypovolemic shock and pre-eclampsia/eclampsia and newborn resuscitation. These were designed to reinforce the competencies of educators in using contemporary teaching pedagogies. The goal was to combine theory and practical aspects of effective teaching as well as provide high quality, evidence-based learning environment and support for students in midwifery education [ 4 ]. These modules integrated the ICM essential competencies for midwifery practice to provide a high quality, evidence-based learning environment for midwifery students. The pre and post tests form part of the CPD programme as a standard assessment of the educators.

As part of the design, this programme was piloted among 60 midwifery educators and regulators from 16 countries across Africa at the UNFPA funded Alliance to Improve Midwifery Education (AIME) Africa regional workshop in Nairobi in November 2022. They accessed and completed the self-directed online modules on the WCEA platform, participated in selected practical sessions, self-evaluated the programme and provided useful feedback for strengthening the modules.

The Nursing and Midwifery Councils of Kenya and Nigeria host the online CPD courses from individual or organisation entities on the WCEA portal. In addition, the Nursing Council of Kenya provides opportunities for self-reporting for various CPD events including accredited online CPD activities/programmes, skill development workshops, attending conferences and seminars, in-service short courses, practice-based research projects (as learner, principal investigator, principal author, or co-author) among others. In Nigeria, a certificate of attendance for Mandatory Continuing Professional Development Programme (MCPDP) is required as evidence for CPD during license renewal. However, the accredited CPD programmes specific for midwifery educators are not available in both countries and Africa region [ 15 , 42 ].

Midwifery educator CPD programme design stages

Participants and sample size

Bowen and colleagues suggest that many feasibility studies are designed to test an intervention in a limited way and such tests may be conducted in a convenience sample, with intermediate rather than final outcomes, with shorter follow-up periods, or with limited statistical power [ 34 ].

A convenience random sample across the two countries was used. Sample size calculations were performed using the formula for estimation of a proportion: a 95% confidence interval for estimation of a proportion can be estimated using the formula: \(p\pm 1.96\sqrt{\frac{\text{p}(1-\text{p})}{n}}\) The margin of error (d) is the second term in the equation. For calculation of the percentage change in competence detectable Stata’s power paired proportion function was used.

To achieve the desired level of low margin of error of 5% and a 90% power (value of proportion) to detect competence change after the training, a sample of 120 participants was required. Using the same sample to assess competence before and after training, so that the improvement in percentage competent can be derived and 2.5% are assessed as competent prior to training but not after training (regress), a 90% power would give a 12% improvement change in competence after the training.

A random sample of 120 educators (60 each from Kenya & Nigeria; 30 each from mid-level training colleges and universities) were invited to participate via an email invitation in the two components of the CPD programme (Fig.  2 ). Importantly, only participants who completed the self-directed online modules were eligible to progress to the face-to-face practical component.

Flow of participants in the CPD programme (SDL = self-directed online learning; F2F = face-to-face practical)

For qualitative interviews, eight key informant interviews were planned with a representative each from the Nursing and Midwifery Councils, mid-level training institutions’ management, university and midwifery associations in both countries. Interviews obtained data related to challenges anticipated in the scale up of the programme and measures to promote sustainability, access and uptake of the programme.

Participant recruitment

Only nursing and midwifery educators registered and licensed by the Nursing and Midwifery Councils were eligible and participated. This was because they can access the WCEA website with the self-directed online programme via the Nursing and Midwifery Councils’ websites, only accessible to registered and licensed nurses and midwives.

The recruitment process was facilitated through the central college management headquarters (for mid-level training colleges’ educators) and Nursing and Midwifery Councils (for university participants). Training institutions’ heads of nursing and midwifery departments were requested to share the contact details of all educators teaching midwifery modules, particularly the antepartum, intrapartum, postpartum and newborn care modules in the two countries. A list of 166 midwifery educators from 81 universities and mid-level training colleges was obtained through the Heads of the Department in the institutions.

The research lead, with the assistance by the co-investigator from Nigeria then randomly sampled 120 educators based on institution type and region for representativeness across the countries. Following the selection of participants, the two investigators shared the electronic detailed participant study information sheet and consent form to the potential participants one week before the start of the self-directed online modules. Clear guidance and emphasis on the conduct of the two-part program including completing the mandatory four self-directed online modules was provided. Due to the large number of eligible participants, the recruitment and consenting process was closed after reaching the first 30 participants consenting per institution type and region, with 1–2 educators per institution randomly recruited. This allowed as many institutions to be represented across the country as possible. Participants received a study information sheet and an auto-generated copy of the electronic consent form completed in their emails. Other opportunities for participating in the two-part programme were provided as appropriate for those who missed out. Only those who completed the four online modules were invited for the practical component. A WhatsApp community group for the recruited participants was formed for clarifications about the study, troubleshooting on challenges with online access and completion of the modules before and during the programme.

Self-directed online component

Upon consenting, the contact details of the educators from each level were shared with WCEA program director for generation of a unique identification code to access the self-directed online modules on the WCEA portal. Educators completed their baseline characteristics (demographic and academic) in the online platform just before the modules. Each self-directed online module was estimated to be completed in five hours. Only after completing a module was the participant allowed to progress to the next module. The modules were available for participants to complete at their own time/schedule. An autogenerated certificate of completion with the participant’s post-completion score was awarded as evidence of completing a module. Participants completed a set of 20 similar pretest and posttest multiple choice questions in each module for knowledge check. A dedicated staff from WCEA actively provided technical support for educators to register, access and complete the online modules. At the end of each module, participants completed a self-evaluation on a 5-point Likert scale for satisfaction (0 = very unsatisfied, 1 = unsatisfied, 2 = neutral, 3 = satisfied and 4 = very satisfied) and relevance of the modules (0 = very irrelevant, 1 = irrelevant, 2 = neutral, 3 = relevant and 4 = very relevant). This provided participants’ reactions to the different components of the modules on whether they met the individual educator’s development needs. In addition, participants responded to the open-ended questions at the end of the modules. These were on what they liked about the modules, challenges encountered in completing the modules and suggestions for improvement of the modules. A maximum period of two weeks was given for educators to complete the modules before progressing to the practical component.

Practical component

The practical component was delivered by a pool of 18 master trainers who received a 1-day orientation from the research lead before the training. The master trainers were a blend of experienced midwifery and obstetrics faculty in teaching and clinical practice actively engaged in facilitating EmONC trainings selected from Kenya and Nigeria. Four of these master trainers from Kenya participated in the delivery of both sets of trainings in Kenya and Nigeria.

Only educator participants who completed the self-directed online modules and certified were invited to participate in a 3-day residential practical component. Two separate classes were trained (mid-level and university level educators) per country by the same group of eight master trainers. The sessions were delivered through short interactive lectures; small group and plenary discussions; skills demonstrations/simulations and scenario teaching in small breakout groups; role plays and debrief sessions. Sessions on digital innovations in teaching and learning were live practical sessions with every participant using own laptop. Nursing and Midwifery Councils representatives and training institutions’ managers were invited to participate in both components of the programme.

Participant costs for participating in the two-part CPD programme were fully sponsored by the study. These were internet data for completing the self-directed online component and residential costs – transport, accommodation, and meals during the practical component.

Data collection

Self-directed online knowledge pretests and post-tests results, self-rated measures of satisfaction and relevance of the modules including what they liked about the modules, challenges encountered in accessing and completing the modules and suggestions for improvement data was extracted from the WCEA platform in Microsoft Excel.

On day 1 of the practical component, participants using their personal computers developed a teaching plan. On the last day (day 3), participants prepared a teaching plan and powerpoint presentation for the microteaching sessions. No teaching plan template from the trainers was provided to the participants before the training. However, they used formats from their institutions if available. A standard teaching plan template was provided at the end of the training.

The group of master trainers and participants were divided into groups for the microteaching sessions which formed part of the formative assessment. Each participant delivered a powerpoint presentation on a topic of interest (covered in the teaching plan) to the small group of 13–15 participants. This was followed by a structured session of constructive feedback that started with a self-reflection and assessment. This was followed by peer supportive and constructive feedback from the audience participants and faculty/master trainers identifying areas of effective practice and opportunities for further development. Each microteaching session lasted 10–15 min. Each of the microteaching session presentation and teaching plan were evaluated against a pre-determined electronic checklist by two designated faculty members independently during/immediately after the microteaching session. The checklist was adapted from LSTM’s microteaching assessment of the United Kingdom’s Higher Education Academy (HEA)’s Leading in Global Health Teaching (LIGHT) programme. The evaluation included preparing a teaching plan, managing a teaching and learning session using multiple interactive activities, designing and conducting formative assessments for learning using digital/online platforms, and giving effective feedback and critical appraisal. The master trainers received an orientation training on the scoring checklist by the lead researcher/corresponding author.

Self-rated confidence in different teaching pedagogy skills were evaluated before (on day 1) and after (day 3) the training on a 5-point Likert scale (0 = not at all confident, 1 = slightly confident, 2 = somewhat confident, 3 = quite confident and 4 = very confident). A satisfaction and relevance of practical component evaluation on a 5-point Likert scale was completed by the participants on an online designed form on day 3 after the microteaching sessions of the practical component. This form also had a similar qualitative survey with open-ended questions on what they liked about the practical component, challenges encountered in completing the practical component and suggestions for improvement of the component.

Using a semi-structured interview guide, six qualitative key informant interviews, each lasting about 30–45 min, were conducted by the lead researcher with the Nursing and Midwifery Councils focal persons and training institutions’ managers. These were audio recorded in English, anonymized, and deleted after transcription. These interviews were aimed at getting their perspectives on the programme design, anticipated barriers/enablers with the CPD programme and strategies for promoting uptake of the CPD programme. These interviews were considered adequate due to their information power (indicating that the more information the sample holds, relevant for the actual study, the lower amount of participants is needed) [ 43 ] and upon obtaining data saturation, considered the cornerstone of rigor in qualitative research [ 44 , 45 ].

Assessment of outcomes

Participants’ reaction to the programme (satisfaction and relevance) (Kirkpatrick level 1) was tested using the self-rated 5-point Likert scales. Change in knowledge, confidence and skills (Kirkpatrick level 2) was tested as follows: knowledge through 20 pretest and post-test multiple choice questions per module in the self-directed online modules; confidence in applying different pedagogy skills through the self-rated 5-point Likert scale; and teaching skills through the observed microteaching sessions using a checklist.

Reliability and validity of the data collection tools

The internal consistency (a measure of the reliability, generalizability or reproducibility of a test) of the Likert scales/tools assessing the relevance of the online and practical modules and satisfaction of educators with the two blended modules were tested using the Cronbach’s alpha statistic. The Cronbach’s alpha statistics for the four Likert scales/tools ranged from 0.835 to 0.928, all indicating acceptably good to excellent level of reliability [ 46 ]. Validity (which refers to the accuracy of a measure) of the Likert scales were tested using the Pearson correlation coefficient statistic. Obtained correlation values were compared to the critical values and p-values reported at 95% confidence intervals. All the scales were valid with obtained Pearson correlation coefficients reported − 0.1946, which were all greater than the critical values ( p  < 0.001) [ 46 ]. The semi-structured interview guides for the qualitative interviews with the training institutions’ managers and midwifery councils (regulators) were developed and reviewed by expert study team members with experience in qualitative research.

Data management and analysis

Data from the online/electronic tools was extracted in Microsoft Excel and exported to SPSS version 28 for cleaning and analysis. Normality of data was tested using the Kolmogorov-Smirnov test suitable for samples above 50. Proportions of educator characteristics in the two countries were calculated. Differences between the educator characteristics in the two countries were tested using chi-square tests (and Fishers-exact test for cells with counts of less than 5).

For self-rated relevance of CPD programme components and satisfaction with the programme on the 0–4 Likert scales, descriptive statistics were calculated (median scores and proportions). Results are presented as bar graphs and tables. Cronbach alpha and Pearson correlation coefficients were used to test the reliability and validity of the test items respectively.

Change in knowledge in online modules, confidence in pedagogy skills and preparing teaching plans among educators was assessed by comparing pre-training scores and post-training scores. Descriptive statistics are reported based on normality of data. Differences in the scores were analysed using the Wilcoxon signed ranks tests, a non-parametric equivalent of the paired t-test. Differences between educators scores in microteaching by country and institution type were performed by Mann-Whitney U test. Level of competence demonstrated in the teaching plan and microteaching skill was defined as the percentage of the desired characteristics present in the teaching plan and microteaching session, set at 75% and above. The proportion of participants that achieved the desired level of competence in their teaching plan and microteaching skill was calculated. Binary logistic regression models were used to assess for the strengths of associations between individual educator and institutional characteristics (age, gender, qualifications, length of time as educator, training institution and country) and the overall dichotomised competent score (proportion achieved competence in teaching plan and microteaching skills). P-values less than 0.05 at 95% confidence interval were considered statistically significant.

Preparation for qualitative data analysis involved a rigorous process of transcription of recorded interviews with key informants. In addition, online free text responses by midwifery educators on what worked well, challenges encountered, and recommendations were extracted in Microsoft Excel format and exported to Microsoft Word for data reduction (coding) and theme development. Qualitative data was analysed using thematic framework analysis by Braun and Clarke (2006) as it provides clear steps to follow, is flexible and uses a very structured process and enables transparency and team working [ 47 ]. Due to the small number of transcripts, computer assisted coding in Microsoft Word using the margin and comments tool were used. The six steps by Braun and Clarke in thematic analysis were conducted: (i) familiarising oneself with the data through transcription and reading transcripts, looking for recurring issues/inconsistencies and, identifying possible categories and sub-categories of data; (ii) generating initial codes – both deductive (using topic guides/research questions) and inductive coding (recurrent views, phrases, patterns from the data) was conducted for transparency; (iii) searching for themes by collating initial codes into potential sub-themes/themes; (iv) reviewing themes by generating a thematic map (code book) of the analysis; (v) defining and naming themes (ongoing analysis to refine the specifics of each sub-theme/theme, and the overall story the analysis tells); and (vi) writing findings/producing a report. Confidentiality was maintained by using pseudonyms for participant identification in the study. Trustworthiness was achieved by (i) respondent validation/check during the interviews for accurate data interpretation; (ii) using a criterion for thematic analysis; (iii) returning to the data repeatedly to check for accuracy in interpretation; (iv) quality checks and discussions with the study team with expertise in mixed methods research [ 39 , 47 ].

Integration of findings used the parallel-databases variant and are synthesised in the discussion section. In this common approach, two parallel strands of data are collected and analysed independently and are only brought together during interpretation. The two sets of independent results are then synthesized or compared during the discussion [ 39 ].

Quantitative findings

Midwifery educators’ characteristics.

A total of 116 (96.7%) and 108 (90.0%) educators from 81 institutions completed the self-directed online learning and practical component respectively from the two countries. There were no significant differences between countries in educators’ qualifications, when last taught a midwifery class and whether attended any CPD training in the preceding year before the study ( p  > 0.05). Overall, only 28.7% of the educators had a midwifery related CPD training in the preceding year before the study. Midwifery educator characteristics are outlined below (Table  1 ).

Change in knowledge

This was assessed in each of the four self-directed online modules. The results from ranked scores based on Wilcoxon signed ranks test showed significant improvements in educators’ knowledge in all the four online modules completed ( p  < 0.001). The highest mean score improvement was observed in students’ assessment module, 48.1% (SD ± 15.1) to 85.2% (SD ± 15.7), a 37.1% improvement. Improvements in knowledge in the other modules were as follows: reflective practice (27.6%), mentoring and giving effective feedback (27.4%) and teaching methods (19.2%). Overall knowledge score for all modules improved from 52.4% (SD ± 10.4) to 80.4 (SD ± 8.1), p  < 0.001 (Table  2 ).

Relevance of self-directed online modules

The internal consistency of each of the four modules was tested with Cronbach’s alpha. The overall Cronbach’s alpha for the four items was 0.837, a good and acceptable level of reliability. All the four modules assessed were valid with calculated Pearson correlation coefficient values greater than the critical value of 0.1946 ( p  < 0.001) at 95% confidence interval.

Educators from the two countries, on a scale of 0–4 rated the online modules as very relevant with a median score of 4 out of 4 (IQR 0) for each of the four modules: reflective practice, teaching methods, students’ assessments and mentoring and giving effective feedback. There were no ratings of 0, 1 and 2 for all the modules (Fig.  3 ).

Educators’ ratings of the relevance of self-directed online modules

Satisfaction with the self-directed online modules

The internal consistency of each of the eight items was tested with Cronbach’s alpha. The overall Cronbach’s alpha for the eight items was 0.928, an excellent level of reliability. All the eight items assessed were valid with their obtained Pearson correlation coefficient values greater than the critical value of 0.1946 ( p  < 0.001) at 95% confidence interval.

Each of the eight items rated on satisfaction had a median score of 4 out of 4 (IQR 0). Over 80% of the educators were very satisfied with the online modules’ content as presented in a logical format and informative. Also, the modules helped them to learn something new, updated their knowledge and the materials were useful and valuable for their practice. Over 70% were very satisfied with the modules as they helped them refresh their knowledge and skills with the links and activities embedded in the modules useful in adding to their learning. None of the educators were dissatisfied (rated 0 or 1) with the online modules (Table  3 ).

Change in confidence in different pedagogy skills

The internal consistency of each of the eight items assessed was tested with Cronbach’s alpha using the baseline data. The overall Cronbach’s alpha for the eight items was 0.893, a good level of reliability. All the eight items assessed were valid with their obtained Pearson correlation coefficient values greater than the critical value of 0.1946 ( p  < 0.001) at 95% confidence interval.

Changes in confidence before and after the training were compared using the Wilcoxon signed rank test, a parametric equivalent of the paired t-test when data is not normally distributed. The mean score of self-rated confidence of educators on a scale of 0–4 for all the eight skills significantly improved after the training from 2.73 (SD ± 0.68) to 3.74 (SD ± 0.34) ( p  < 0.001). Mean confidence was highest in facilitating a lecture (3.23, SD ± 0.8) and lowest on using digital innovations (Mentimeter) in formative assessment of teaching/learning (1.75, SD ± 1.15) before the training. These improved significantly after the training to 3.84 (SD ± 0.41) for facilitating a lecture and 3.50 (SD ± 0.63) for using digital innovations (Mentimeter) in formative assessment of teaching/learning, p  < 0.001. The mean confidence of educators was largely average before the training and significantly improved after the training in six skills ( p  < 0.001). These were designing learning outcomes using measurable Bloom’s taxonomy verbs, preparing a teaching plan, identifying relevant resources to enhance learning, facilitating a scenario teaching, facilitating a practical simulation/demonstration and giving effective feedback for learning (Table  4 ).

Preparing a teaching plan and microteaching skills

The overall median score in preparing a teaching plan was 63.6% (IQR 45.5) before the training and improved significantly to 81.8% (IQR 27.3) after the training, p  < 0.001. The median scores differed significantly by country before and after the training. Before the training, Kenyan educators had higher median scores (72.7%, IQR 27.3) compared to Nigeria counterparts (54.5%, IQR 36.4), p  < 0.001. After the training, Kenyan educators had significantly higher median scores (81.2%, IQR 18.2) than Nigerian counterparts (72.7%, IQR 18.2), p  = 0.024. However, there were no significant differences in the median scores between the training institutions before and after the training, p  > 0.05. For microteaching, the overall median score was 76.5% (IQR 29.4). There were no significant differences between countries and training institutions in the microteaching scores, p  > 0.05. Kenya educators (82.4%, IQR 29.4) had slightly higher scores than Nigeria (76.5%, IQR 29.4), p  = 0.78. Mid-level educators (79.4%, IQR 29.4) had slightly higher scores than university educators (76.5%, IQR 28.7), p  = 0.515 (Table  5 ).

The inter-rater reliability/agreement of the eight pairs of assessors in both countries were assessed by Cohen Kappa statistic. The Kappa statistics for the eight pairs ranged between 0.806 and 0.917, p  < 0.001, showing near perfect agreement between the pairs of assessors.

Association between independent educator and institutional characteristics and the microteaching skill scores

Categorised skills scores (≥ 75% mean score as competent) showed that 55 (51.4%) and 62 (57.9%) of the educators scored 75% or higher in the teaching plan preparation and microteaching skill assessments respectively. Logistic regression analysis showed that educator’s country, age, gender, qualifications, training institution type and length as educator were not significantly associated with the overall categorised teaching plan or microteaching scores ( p  > 0.05).

Relevance of the practical component

The internal consistency of each of the six skills items was tested with Cronbach’s alpha. The overall Cronbach’s alpha for the six items was 0.866, a good level of reliability. All the six skills items assessed were valid with their obtained Pearson correlation coefficient values greater than the critical value of 0.1946 ( p  < 0.001) at 95% confidence interval.

On a self-rating Likert scale of 0–4, the median score for each of the six skills assessed and trained was 4 out of a maximum of 4, indicating that the educators found the different pedagogy skills very relevant after the training. Over 80% of the educators rated the sessions on teaching plan (85.2%), scenario teaching (87.0%), simulation/demonstration teaching (82.4%) and giving effective feedback (85.2%) as very relevant. Over three-quarters (77.8%) of the educators rated the sessions on lecture teaching and use of digital innovations (Mentimeter) in assessment as very relevant (Fig.  4 ).

Relevance of the practical components

Satisfaction with the practical component

The internal consistency of each of the six skills items was tested with Cronbach’s alpha. The overall Cronbach’s alpha for the six items was 0.835, a good level of reliability. All the six skills items assessed were valid with their obtained Pearson correlation coefficient values greater than the critical value of 0.1946 ( p  < 0.001) at 95% confidence interval.

On a self-rating Likert scale of 0–4, the median score for each of the six skills assessed was 4 out of a maximum of 4, indicating that educators were very satisfied with the practical skills sessions. Over 70% of the educators were very satisfied with the sessions on giving effective feedback (79.6%), lecture teaching (75.9%), scenario and simulation teaching (73.1% each). Two-thirds of the educators (67.6%) were very satisfied with the digital innovations in teaching (use of Mentimeter) for formative assessment in teaching and learning. All educators were satisfied with the preparing of teaching plan in teaching and learning with the majority (63.0%) as very satisfied while the remaining 37.0% satisfied. None of the educators were dissatisfied with the practical component of the training (Fig.  5 ).

Satisfaction with practical skills

Qualitative findings

What educators liked about the self-directed online modules.

Educators from both levels and countries had similar views on the online component. These are broadly summarised under the sub-themes: (i) educative and relevant for practice, (ii) flexible and convenient learning and (iii) motivating, interesting and interactive.

Educative and relevant for practice

Educators reported the online modules as educative and informative and, improved their knowledge in teaching, assessments, reflective practice and providing effective feedback to students to promote learning as well as increasing their self-confidence and critical thinking skills. Besides, educators found the modules valuable and relevant for their professional growth and practice.

“The modules were well organized, they were relevant to my practice and met my expectations” university midwifery educator, Kenya. “The materials are very rich with current information to guide. Very informative & valuable to my professional growth” university midwifery educator, Nigeria.

Flexible and convenient learning

Educators reported that they could access and complete the online modules at their flexible and convenient time. This flexibility enhanced and stimulated them to complete the informative modules at their comfort times either at home or office without disruption to their schedules.

“(The modules) gave me ample time to read at my own pace and time without any hurry to understand the content well. They were well organised. Also, flexibility of learning and the access to materials was excellent” university midwifery educator, Kenya. “It is flexible and convenient. It empowers the learner to take ownership of the learning process. Learning is personalized” mid-level training college midwifery educator, Nigeria.

Motivating, interesting and interactive

Educators reported that the online modules were well structured, motivating, interesting and had components that promoted interaction for learning. For example, pretests, various quizzes within the modules and posttest questions and the added specific short extra reading segments promoted interaction and learning.

“The intermittent assessment questions. It helped maintain my focus” university midwifery educator, Nigeria . “Very interactive. They were very informative and extra reading assignments complemented the content” university midwifery educator, Kenya .

Challenges encountered with the self-directed online learning modules

Four sub-themes emerged that summarised the challenges experienced by midwifery educators in the two countries to access and complete the self-directed online modules. These are (i) network/internet connectivity, (ii) technology challenges, (iii) electricity power supply and power outages and, (iv) time constraints.

Network/internet connectivity

Network and internet connectivity difficulties and fluctuations was the commonest reported challenge in completing the self-directed online modules by educators from both countries. This affected the access, progress, downloading extra resources embedded within the modules and completing the integrated evaluations within the modules.

“Accessing the modules, problem with submitting forms and exams, had network problem” mid-level training college midwifery educator, Nigeria . “I kept going offline and I would have to restart every time. They were too internet dependent” university midwifery educator, Kenya.

Technology challenges

Technological challenges were observed as well as reported among educators from both countries. These ranged from poor access to emails due to forgotten email addresses, usernames or passwords, difficult access and navigation through the online modules, completing the matching questions that required dragging items, completing the evaluations and downloading certificates after completion of the modules.

“I am not very good with ICT, so I had issues using my laptop” mid-level training college midwifery educator, Nigeria. “Accessibility was difficult. I had to restart the process a number of times. The modules would sometimes take you back more than 20 slides which delayed the completion rate” university midwifery educator, Kenya.

Electricity power supply interruptions and fluctuations

Power interruptions, fluctuations and outages especially in Nigeria were cited as a challenge to complete the online modules. This delayed the completion of the modules as electric power was critical to access and complete the modules on either WCEA app on mobile phones or computers.

“The modules should not start from beginning whenever there is interrupted power supply” MLC midwifery educator, Nigeria. “Network failure due to interrupted power supply” university midwifery educator, Nigeria.

Time constraints

Although educators commented the flexibility with which to complete the online modules, time to complete the online modules was also cited as a challenge in both countries.

“It requires a lot of time, this is a challenge because I am also involved with other activities at the place of work which require my attention” university midwifery educator, Kenya.

What educators liked about the practical component

Educators written feedback on what they liked about the practical component of the CPD programme was categorised into the four sub-themes: new knowledge and relevant for practice; improved knowledge, skills and confidence to teach; enhanced participatory and active learning; individualised support in learning.

New knowledge and relevant for practice

The practical component provided new learning particularly on the use of digital platforms (Mentimeter and Kahoot) for formative assessment to evaluate learning during classroom teaching. In their integrated teaching using both online and face-to-face delivery, use of technology (Mentimeter and Kahoot) in classroom assessment was not a common practice as most of them had not heard about the available online platforms. They found Mentimeter (and Kahoot) to be interesting resources for formative assessments in class to facilitate teaching and learning. The techniques of giving effective feedback using the sandwich and ‘stop, start, continue’ methods were viewed to promote interaction between the educator and the learner for effective learning. Educators also acknowledged new knowledge and skills updates on EmONC relevant for their practice.

“Giving feedback, innovation of the online formative assessment, the teaching plan. I wish we would adapt them for daily application rather than the traditional teacher centered one.” Mid-level training college educator, Kenya . “(I liked) Everything, especially the technological innovations for assessment” Mid-level training college educator, Nigeria .

Improved knowledge, skills and confidence to teach

Educators reported that the practical sessions were interactive and engaging with good combination of theory and practice which facilitated learning. They reported that participating in the practical component enabled them to update and improve their knowledge, skills and confidence in planning and delivering theoretical and practical teaching using multiple methods. Similar improvements were reported on preparing and conducting students’ assessments and giving effective feedback to promote learning. On use of technology in formative assessments, the interactive practical sessions boosted the confidence of educators in using Mentimeter (and Kahoot) online platforms during classroom teaching.

“It helped build my confidence, had hands on practice on clinical skills and teaching skills, learnt about outdated practices and current evidence based clinical and teaching skills.” Mid-level training college educator, Nigeria . “They were very interesting especially the scenarios and skills. I was able to enhance my practical skills and technology in evaluating learning.” University midwifery educator, Kenya .

Enhanced participatory and active learning

The practical component complemented the self-directed online learning for educators. They highly commented and benefitted from the hands-on opportunities to actively engage through return demonstrations during the practical programme. This component also enabled them to brainstorm and contribute actively during the sessions. They highlighted that the practical component enhanced and reinforced learning through active participation in demonstrations, questions, group discussions and plenary sessions.

“This face-to-face module provided me with the opportunity to brainstorm with other educators, facilitators and resource persons. This will enhance my teaching skills.” Mid-level training college midwifery educator, Nigeria . “Interaction with facilitators who could clarify points that I had earlier not understood, interaction with other participants and was also able to learn from them.” University midwifery educator, Kenya .

Individualised support in learning

Educators received individualised peer support and learning during the practical component. They had opportunities within the small breakout groups for peer learning and one-to-one support from the facilitators to update and learn new knowledge and skills.

“A chance to get immediate feedback was availed by the presenters.” University midwifery educator, Kenya . “Facilitators were well informed and gave learners opportunity for return demonstration and support.” Mid-level training college midwifery educator, Kenya .

Challenges encountered with the practical component

Key challenges reported by the mixed group of educators and master trainers across the two countries include: inadequate time, computer technology challenges and poor internet connectivity for practical components.

Inadequate time

Although small breakout sessions were utilised to provide each educator with an opportunity to practice the skills, it was commonly reported that time was inadequate for skills demonstrations and return demonstrations by all educators. This was especially for areas educators had inadequate knowledge and new skills that were observed thus adequate time for teaching and repeat demonstrations for mastery was required. Similar observations were made by the master trainers who felt that some educators had never encountered some of the basic EmONC skills demonstrated or never practised and thus required a longer duration for familiarisation and practice.

“Time was short hence not enough to return demo” Mid-level training college midwifery educator, Kenya . “Some of the things were new and required more time for demonstration and practice.” Mid-level training college midwifery educator, Nigeria .

Computer technology challenges and poor internet connectivity for practical components

Some educators encountered technical difficulties in using computers during the practical component. In some cases, this was compounded by poor network/internet connectivity. This delayed completion of practical components requiring the use of computers including pretests, preparing teaching plans and presentations, post-tests and classroom demonstrations using digital innovations in teaching and learning. However, assistance was provided by the trainers as appropriate to those who needed technical support.

“(There were) technical challenges with use of computers for few participants.” Master trainer, Nigeria . “Slow internet can hinder smooth flow of sessions.” Master trainer, Kenya .

Key areas for additional support

For quality education and training, master trainers generally recommended that all educators should be trained and regularly supported in the basic EmONC course to strengthen their competencies for effective teaching of EmONC skills. Further support in computer technology use including basics in navigation around windows/programmes, formatting in Microsoft Office Word and Powerpoint, literature searching, and referencing were other critical components to be strengthened.

Perspectives from training institutions managers and midwifery regulators

Measures to ensure midwifery educators take specific cpds that have been designed to improve their teaching competencies.

Key informant interviews with the pre-service training institutions’ managers and nursing and midwifery councils from the two countries were conducted and revealed key strategies outlined below that should ensure access and completion of the blended CPD programme specific for educators’ teaching competencies.

Awareness creation, integrating programme into policy and performance appraisal

The aspect of online CPD was highlighted as a new concept in Nigeria. Due to this novelty, the country was reluctant to accredit many online CPD programmes for in-service and pre-service nursing and midwifery personnel. However, the regulatory Nursing and Midwifery Council of Nigeria had established monitoring mechanisms to evaluate its uptake to meet the definition of CPD and is still work in progress.

“For the online, it’s actually a relatively new concept, in fact because of monitoring and evaluation, we have struggled with accepting online CPDs… So, we’re struggling on how to develop a guideline for online CPDs. So, we’re now starting with the WCEA. So far, only the WCEA has that approval to provide CPD…We said let’s look at how this works out before we can extend it to other providers.” Nursing and Midwifery Council, Nigeria .

Both countries emphasized the need to create awareness of the CPD programme for midwifery educators and a policy framework for CPD. Regulators emphasized the need to have the CPD programme as mandatory for all midwifery educators through a policy directive. They suggested that the blended CPD programme should form a mandatory specified proportion of the content addressing their specific competencies. Besides, the training institution recommended that the programme should form part of the educator’s performance appraisal on a regular basis. Active monitoring systems were suggested to be in place to ensure compliance of participation and completion to acquire specific relevant competencies in pedagogy.

“…Ensure that educators take the particular modules before license renewal. Tie modules that are related to midwifery education to the educators and make them mandatory. Yes, we make it as a matter of policy that you should be taking these courses over and over again.” Nursing and Midwifery Council, Nigeria .

It was strongly suggested that attaching incentives as motivators to completing the programme would attract educators to complete the CPD programme. These incentives include certification, recognition for participation in curriculum reviews, national examination setting, facilitating national examinations, promotion and service and eligibility as trainers of trainers to colleagues.

“You attach a course, one training, you cannot guarantee that these courses will be taken. So we find a way to attach something to it. You must have evidence that you attended these programs. So once you attach something like that, they will all flock because there is an incentive to it. Because we say, as an educator, before you go after every examination to examine students, you must have taken these courses.” Nursing and Midwifery Council, Nigeria .

Internet connectivity

Training institutions’ managers suggested investments in internet connectivity for training institutions to support educators access and complete the self-directed online programme. This was also highlighted as a critical challenge for the online component by the educators in both countries.

“The issues of internet connectivity and I think we need to be proactive about it so that we have a way to constantly bring it to the forefront especially in our policies. But connectivity would be a major area to look at as people are using their money.” Mid-level training college manager, Kenya .

Anticipated challenges in the scale-up of the CPD programme

Key challenges anticipated in the roll-out and scale-up of the blended CPD programme were identified as inadequate skills of the educators in the use of information and communication technology during the practical component (including preparation of powerpoint presentations and completing tasks using a computer), and participant costs to attend the practical component (including participants’ residential costs and investments in proctor technology for ensuring academic integrity and monitoring and evaluation tool for educators’ compliance.) It was also emphasized that due to low remuneration of the educators, additional costs from their pocket to undertake the CPD could be a limiting factor for the intended faculty development initiatives. Other challenges included maintaining quality and academic integrity of the programme, potential bias in the selection of educators to attend future CPD programmes that is based on pre-existing relationships and ensuring an adequate pool of in-country trainers of trainers with midwifery competencies to deliver the practical component of the CPD programme.

There were strong suggestions that personal commitment by educators was required for personal and professional development. There were observations that educators sometimes completed the professional development programmes purely for relicensing and not necessarily for professional development. Regulators and institutional managers emphasized that educators need to understand the value of continuous professional development and create time to participate in the targeted CPD programmes to improve their competencies.

“We do advise our nurses, or we continue to inform them that taking these courses shouldn’t be tied to license renewal. It shouldn’t be tied to licence expiration or renewal of licences. You should continue to take these courses to develop yourself and not waiting until your licence expired before you take the courses. Yes, we actually try as much as possible to dissociate the renewal of licences with these courses.” Nursing and Midwifery Council, Nigeria .

Key results

Our study evaluated the feasibility of what the authors believe to be the first blended programme with online and face-to-face learning available in Africa, as a tool to reach midwifery educators in both urban and rural low-resource areas. In addition, our study is in line to an important call by WHO, UNFPA, UNICEF and ICM for an effective midwifery educator with formal preparation for teaching and engages in ongoing development as a midwifery practitioner, teacher/lecturer and leader [ 6 , 7 ]. Consequently, our intervention is part of investments for improving and strengthening the capacity of midwifery educators for quality and competent midwifery workforce as recommended by multiple global reports [ 4 , 5 , 11 ] and other publications [ 12 , 15 , 23 , 42 ]. Our study findings showed that the midwifery educators were very satisfied with the blended CPD programme. Educators rated the programme as highly relevant, educative, flexible, interesting and interactive, improved their knowledge, confidence and practical skills in their professional competencies for practice. Use of digital technology in teaching and students’ assessment was found to be an effective and innovative approach in facilitating teaching and learning. Key challenges experienced by educators included deficiencies in computer technology use, internet/network connectivity for online components, time constraints to complete the blended programme and isolated electric power outages and fluctuations which affected completion of the self-directed online components. Costs for participating and completing the programme, motivation, investments in information and communication technology, quality assurance and academic integrity were highlighted as critical components for the scale-up of the programme by institutional managers and training regulators. Establishment of a policy framework for educators to complete mandatory specific and relevant CPD was recommended for a successful roll-out in the countries.

Interpretation of our findings

Our study findings demonstrated that educators found the theoretical and practical content educative, informative and relevant to their practice. Recent evidence showed that midwifery educators had no/limited connection with clinical practice or opportunities for updating their knowledge or skills [ 15 , 42 ]. This underscores the value and importance of regular opportunities of CPD specific for educators to improve their professional competencies. It has provided these educators with a flexible educational model that allows them to continue working while developing their professional practice.

The use of a blended programme was beneficial as educators’ needs were met. It provided opportunities for educators to reflect, critically think, internalise and complement what was learned in the self-directed online component during the practical phase. This approach has been considered a means to adequately prepare midwifery faculty and improving national midwifery programmes in low-resource and remote settings [ 48 , 49 ]. Use of self-directed online platforms has emerged as a key strategy to improve access to CPD with flexibility and convenience as educators take responsibility for their own learning. Evidence suggests that the flexibility of net-based learning offers the midwifery educators a new and effective educational opportunity that they previously did not have [ 50 , 51 ]. A practical – based learning is important in pre-service education settings where the capacity of midwifery educators needs to be strengthened [ 52 , 53 ]. However, without continuous regular training, the midwives’ competence deteriorate and this in turn threaten the quality of pre-service midwifery education [ 52 , 54 ]. Implementation of this flexible blended educational model allows educators to continue working while developing their professional practice.

The quality of educators is an important factor affecting the quality of graduates from midwifery programmes to provide quality maternal and newborn health services [ 7 ]. Evidence suggests that many midwifery educators are more confident with theoretical classroom teaching than clinical practice teaching and that they also struggle to maintain their own midwifery clinical skills [ 4 , 5 ]. Our findings showed that the programme was effective, and educators improved their knowledge, confidence and skills in teaching, students’ assessment, effective feedback, reflective practice, mentoring and use of digital innovations in teaching and assessments. Our findings are similar to other related models of capacity building midwifery educators in other developing countries [ 24 , 50 , 53 , 55 , 56 , 57 ]. It is expected that educators will apply the learning in their planning for teaching, delivery of interactive and stimulatory teaching, monitoring learning through formative and summative assessments and mentoring their students into competent midwives. This is a pathway for accelerating the achievement of maternal and newborn health SDGs, universal health coverage, ending preventable maternal mortalities and every newborn action plan targets.

The value for CPD on educators’ knowledge, confidence and skills has been demonstrated with opportunities for improvement. Specific CPD targeted to relevant professional competencies is beneficial to the profession, quality of graduates for maternal and newborn health care and global targets. However, further investments in strengthening capacity of educators in EmONC skills and information and communication technology for effective teaching and learning is mandatory. Related challenges with individual technical capacity, technological deficiencies and infrastructure to support the technological advancement have been reported in other studies that have used a blended learning approach [ 58 ]. Resource constraints – financial and infrastructural (e.g. computers) as well as internet access are key challenges to participation in CPD activities especially the self-directed learning [ 16 ]. Designing self-directed modules that can be accessed and completed offline will increase access especially in poorly connected settings with electric power and network coverage.

Strengths and limitations

This study assessed the feasibility a blended midwifery educator CPD programme in low resource settings. This was conducted in a multi-country and multi-site context which provided opportunities for learning across the two countries, two levels of training institutions and specific in-country experiences [ 20 ]. The study served to improve awareness of the availability of the CPD programme so that (1) regulators can ensure that midwifery educators take this as part of mandatory CPD required for relicensing and (2) training institutions can plan to support their educators access/participate in the practical components of the programme after the study. It is a mandatory requirement of the Nursing and Midwifery Councils of Kenya and Nigeria for nurse/midwives and midwifery educators to demonstrate evidence of CPD for renewal of practising license [ 40 , 41 ]. The use of mixed methods research design with multiple evaluations was relevant to address the aims and objectives of the study and ensure methodological rigour, depth and scientific validity as recommended for good practice in designing pilot studies [ 37 , 38 ]. This also enhanced triangulation of findings and enabled the capturing of broad perspectives important in strengthening sustainable implementation of the blended CPD programme [ 39 ]. Preliminary findings were disseminated to participant stakeholders from Kenya and Nigeria at the knowledge management and learning event in Nairobi. This approach enhanced the credibility and trustworthiness of the final findings reported. We believe our study findings from different participants using multiple data collection methods are robust, transparent and trustworthy for generalization to other contexts [ 38 ].The self-directed learning component of the blended CPD programme is hosted on the WCEA platform which is accessible to healthcare professionals in over 60 countries in Africa, Asia and Middle East and accredited for continuous professional development (59). Although our sample size was small, it is sufficient, geographically representative for training institutions across the countries and acceptable for feasibility studies [ 34 ].

The additional cost analysis of implementing the blended midwifery educator CPD programme is relevant and key to the uptake, scale-up and sustainability of the programme but this was not conducted due to limited funding. Different CPD programme funding models exist. In Nigeria, educators are required to meet the costs for accessing and completing the CPD programme components, while in Kenya the cost of accessing the online component is minimal (internet access costs only) and the face-to-face component has to be funded. The cost of implementing the programme should be explored in future studies and optional models for sustainable funding explored with stakeholders.

Implications

Our findings show demand for the CPD programme. Regular continuous professional development could help to bridge the gap between theory and practice and improve the quality of teaching by midwifery educators. A blended CPD programme is effective in improving the teaching and clinical skills of midwifery educators and increasing their confidence in effective teaching. However, midwifery educators require motivation and close support (individual capacity, time, technological infrastructure and policy) if the blended CPD approach is to be mandatory and successfully implemented in resource limited settings. Besides, regular quality assurance modalities including review of content, monitoring and evaluation of uptake of the CPD programme should be undertaken to ensure that updated and relevant content is available.

For quality CPD programmes, hands-on teaching is more effective than didactic classroom teaching and should be used when feasible to transfer clinical skills. Distance education models (self-directed learning) in combination with short residential training and mentoring should be embraced to strengthen capacity strengthening of midwifery educators; and CPD programmes must consider the local context in which participants work and teach [ 16 , 23 ]. Evidence has shown that knowledge and clinical skills are retained for up to 12 months after training [ 54 ]. Taking the CPD programme annually will potentially maintain/improve knowledge, skills and practice by midwifery educators for quality teaching and learning leading to a competent midwifery workforce.

For quality midwifery education and practice, educators need contact with clinical practice to strengthen classroom teaching [ 6 , 7 ]. This will promote and enable students to acquire the skills, knowledge, and behaviours essential to become autonomous midwifery practitioners. Therefore, demonstrating relevant practical clinical CPD should be included in midwifery educator CPD policy. In addition, a business case by the CPD hubs on the sustainability of the face-to-face practical components in the centres is necessary. Stakeholder engagement on cost and sustainability are required as key policy components for the scale-up of the blended midwifery educator CPD programme for impact.

The blended CPD programme was relevant, acceptable and feasible to implement. Midwifery educators reacted positively to its content as they were very satisfied with the modules meeting their needs and rated the content as relevant to their practice. The programme also improved their knowledge, confidence and skills in teaching, students’ assessments and providing effective feedback for learning and using digital/technological innovations for effective teaching and learning. Investments in information and communication technology, quality assurance and academic integrity were highlighted as critical components for the scale-up of the programme. For successful and mandatory implementation of the specific midwifery educator CPD programme to enhance practice, a policy framework by midwifery training regulators is required by countries.

Data availability

The datasets generated and/or analysed during the current study are not publicly available due to the confidentiality of the data but are available from the corresponding author on request.

Renfrew MJ, McFadden A, Bastos MH, Campbell J, Channon AA, Cheung NF, et al. Midwifery and quality care: findings from a new evidence-informed framework for maternal and newborn care. Lancet. 2014;384(9948):1129–45.

Article   Google Scholar  

World Health Organization, United Nations Population Fund, International Confederation of Midwives. The State of the World’s Midwifery 2021: Building a health workforce to meet the needs of women, newborns and adolescents everywhere 2021. https://www.unfpa.org/publications/sowmy-2021 .

Filby A, McConville F, Portela A. What prevents quality midwifery care? A systematic mapping of barriers in low and middle income countries from the provider perspective. PLoS ONE. 2016;11(5):e0153391.

WHO. Strengthening quality midwifery education for Universal Health Coverage 2030: Framework for action 2019. https://www.who.int/publications/i/item/9789241515849 .

United Nations Population Fund, International Confederation of Midwives, World Health Organization. The State of the World’s Midwifery 2021: Building a health workforce to meet the needs of women, newborns and adolescents everywhere 2021. https://www.unfpa.org/publications/sowmy-2021 .

International Confederation of Midwives. ICM Global Standards for Midwifery Education. (Revised 2021) 2021. https://www.internationalmidwives.org/assets/files/education-files/2021/10/global-standards-for-midwifery-education_2021_en-1.pdf .

WHO. Midwifery educator core competencies: building capacities of midwifery educators 2014. https://www.who.int/hrh/nursing_midwifery/14116_Midwifery_educator_web.pdf .

Gavine A, MacGillivray S, McConville F, Gandhi M, Renfrew MJ. Pre-service and in-service education and training for maternal and newborn care providers in low-and middle-income countries: an evidence review and gap analysis. Midwifery. 2019;78:104–13.

Shikuku DN, Tallam E, Wako I, Mualuko A, Waweru L, Nyaga L, et al. Evaluation of capacity to deliver Emergency Obstetrics and Newborn Care updated midwifery and reproductive health training curricula in Kenya: before and after study. Int J Afr Nurs Sci. 2022;17:100439.

Google Scholar  

International Confederation of Midwives. Global Standards for Midwifery Regulation. 2011. https://www.internationalmidwives.org/assets/files/regulation-files/2018/04/global-standards-for-midwifery-regulation-eng.pdf .

World Health Organization. Global strategic directions for nursing and midwifery 2021–2025. Geneva: World Health Organization. 2021. https://iris.who.int/bitstream/handle/10665/344562/9789240033863-eng.pdf?sequence=1 .

Smith RM, Gray JE, Homer CSE. Common content, delivery modes and outcome measures for faculty development programs in nursing and midwifery: a scoping review. Nurse Educ Pract. 2023:103648.

Nursing and Midwifery Board of Australia. Registration standard: Continuing professional development 2016 3rd January 2022. https://www.nursingmidwiferyboard.gov.au/Registration-Standards/Continuing-professional-development.aspx .

International Confederation of Midwives. Essential competencies for midwifery practice: 2019 Update. 2019.

Baloyi OB, Jarvis MA. Continuing Professional Development status in the World Health Organisation, Afro-region member states. Int J Afr Nurs Sci. 2020;13:100258.

Mack HG, Golnik KC, Murray N, Filipe HP. Models for implementing continuing professional development programs in low-resource countries. MedEdPublish. 2017;6(1).

Lucas A. Continuous professional development, friend or foe? Br J Midwifery. 2012;20(8):576–81.

Ingwu JA, Efekalam J, Nwaneri A, Ohaeri B, Israel C, Chikeme P, et al. Perception towards mandatory continuing professional development programme among nurses working at University of Nigeria Teaching Hospital, Enugu-Nigeria. Int J Afr Nurs Sci. 2019;11:100169.

Hasumi T, Jacobsen KH. Healthcare service problems reported in a national survey of South africans. Int J Qual Health Care. 2014;26(4):482–9.

Giri K, Frankel N, Tulenko K, Puckett A, Bailey R, Ross H. Keeping up to date: continuing professional development for health workers in developing countries. IntraHealth Int. 2012.

Botha A, Booi V, editors. mHealth implementation in South Africa. 2016 IST-Africa Week Conference; 2016: IEEE.

World Continuing Education Alliance (WCEA). World Continuing Education Alliance: About us2022 3rd January 2022. https://lmic.wcea.education/about-us/ .

West F, Homer C, Dawson A. Building midwifery educator capacity in teaching in low and lower-middle income countries. A review of the literature. Midwifery. 2016;33:12–23.

van Wyk JM, Wolvaardt JE, Nyoni CN. Evaluating the outcomes of a faculty capacity development programme on nurse educators in sub-saharan Africa. Afr J Health Professions Educ. 2020;12(4):201–5.

Frantz JM, Bezuidenhout J, Burch VC, Mthembu S, Rowe M, Tan C, et al. The impact of a faculty development programme for health professions educators in sub-saharan Africa: an archival study. BMC Med Educ. 2015;15(1):1–8.

Fullerton JT, Johnson PG, Thompson JB, Vivio D. Quality considerations in midwifery pre-service education: exemplars from Africa. Midwifery. 2011;27(3):308–15.

Shikuku DN, Tallam, E., Wako, I., Mualuko, A., Waweru, L., Nyaga, L., ... & Ameh, C. Evaluation of capacity to deliver Emergency Obstetrics and Newborn Care updated midwifery and reproductive health training curricula in Kenya: Before and after study. 2022

Shikuku DN, Jebet J, Nandikove P, Tallam E, Ogoti E, Nyaga L, et al. Improving midwifery educators’ capacity to teach emergency obstetrics and newborn care in Kenya universities: a pre-post study. BMC Med Educ. 2022;22(1):1–10.

Akiode A, Fetters T, Daroda R, Okeke B, Oji E. An evaluation of a national intervention to improve the postabortion care content of midwifery education in Nigeria. Int J Gynecol Obstet. 2010;110(2):186–90.

Nursing Council of Kenya. Continuing Professional Development guidelines. Nursing Council of Kenya; 2021.

Nursing and Midwifery Council of Nigeria. Promoting & Maintaining Excellence in Nursing Education and Practice: Functions2022. https://www.nmcn.gov.ng/function.html .

Ministry of Health. Kenya Health Policy 2014–2030: Towards attaining the highest standard of health 2014. http://publications.universalhealth2030.org/uploads/kenya_health_policy_2014_to_2030.pdf .

Orsmond GI, Cohn ES. The distinctive features of a feasibility study: objectives and guiding questions. OTJR: Occupation Participation Health. 2015;35(3):169–77.

Bowen DJ, Kreuter M, Spring B, Cofta-Woerpel L, Linnan L, Weiner D, et al. How we design feasibility studies. Am J Prev Med. 2009;36(5):452–7.

Arain M, Campbell MJ, Cooper CL, Lancaster GA. What is a pilot or feasibility study? A review of current practice and editorial policy. BMC Med Res Methodol. 2010;10(1):1–7.

Kirkpatrick DL. Implementing the four levels: A practical guide for effective evaluation of training programs: Easyread super large 24pt edition: ReadHowYouWant. com; 2009.

Warfa A-RM. Mixed-methods design in biology education research: Approach and uses. CBE—Life Sci Educ. 2016;15(4):rm5.

Creswell JW, Creswell JD. Research design: qualitative, quantitative, and mixed methods approaches. Sage; 2017.

Creswell JW, Clark VLP. Designing and conducting mixed methods research. Third ed: Sage; 2018.

NCK Online CPD Portal: Continuous Professional Development [Internet]. 2021. https://osp.nckenya.com/cpd? .

Nursing and Midwifery Council of Nigeria. Promoting & maintaining Excellence in nursing education and practice: Renewal of License. 2022. Available from. https://www.nmcn.gov.ng/renewal.html .

Warren N, Gresh A, Mkhonta NR, Kazembe A, Engelbrecht S, Feraud J et al. Pre-service midwifery education in sub-saharan Africa: a scoping review. Nurse Educ Pract. 2023:103678.

Malterud K, Siersma VD, Guassora AD. Sample size in qualitative interview studies: guided by information power. Qual Health Res. 2016;26(13):1753–60.

Muellmann S, Brand T, Jürgens D, Gansefort D, Zeeb H. How many key informants are enough? Analysing the validity of the community readiness assessment. BMC Res Notes. 2021;14(1):1–6.

Hennink M, Kaiser BN. Sample sizes for saturation in qualitative research: a systematic review of empirical tests. Soc Sci Med. 2022;292:114523.

Shumway JM, Harden RM. AMEE Guide 25: the assessment of learning outcomes for the competent and reflective physician. Med Teach. 2003;25(6):569–84.

Braun V, Clarke V. Using thematic analysis in psychology. Qualitative Res Psychol. 2006;3(2):77.

Erlandsson K, Doraiswamy S, Wallin L, Bogren M. Capacity building of midwifery faculty to implement a 3-years midwifery diploma curriculum in Bangladesh: A process evaluation of a mentorship programme. Nurse Educ Pract. 2018;29:212–8.

Erlandsson K, Byrskog U, Osman F, Pedersen C, Hatakka M, Klingberg-Allvin M. Evaluating a model for the capacity building of midwifery educators in Bangladesh through a blended, web-based master’s programme. Global Health Action. 2019;12(1):1652022.

Hatakka M, Osman F, Erlandsson K, Byrskog U, Egal J, Klingberg-Allvin M. Change-makers in midwifery care: exploring the differences between expectations and outcomes—A qualitative study of a midwifery net-based education programme in the Somali region. Midwifery. 2019;69:135–42.

Erlandsson K, Osman F, Hatakka M, Egal JA, Byrskog U, Pedersen C, et al. Evaluation of an online master’s programme in Somaliland. A phenomenographic study on the experience of professional and personal development among midwifery faculty. Nurse Educ Pract. 2017;25:96–103.

Bogren M, Rosengren J, Erlandsson K, Berg M. Build professional competence and equip with strategies to empower midwifery students–an interview study evaluating a simulation-based learning course for midwifery educators in Bangladesh. Nurse Educ Pract. 2019;35:27–31.

Msosa A, Msiska M, Mapulanga P, Mtambo J, Mwalabu G. Simulation-based education in classroom and clinical settings in sub-saharan Africa: a systematic review. Higher Education, Skills and Work-Based Learning; 2023.

Ameh CA, White S, Dickinson F, Mdegela M, Madaj B, van den Broek N. Retention of knowledge and skills after emergency Obstetric Care training: a multi-country longitudinal study. PLoS ONE. 2018;13(10):e0203606.

Evans C, Razia R, Cook E. Building nurse education capacity in India: insights from a faculty development programme in Andhra Pradesh. BMC Nurs. 2013;12(1):1–8.

Koto-Shimada K, Yanagisawa S, Boonyanurak P, Fujita N. Building the capacity of nursing professionals in Cambodia: insights from a bridging programme for faculty development. Int J Nurs Pract. 2016;22:22–30.

Kitema GF, Laidlaw A, O’Carroll V, Sagahutu JB, Blaikie A. The status and outcomes of interprofessional health education in sub-saharan Africa: a systematic review. J Interprof Care. 2023:1–23.

Ladur AN, Kumah EA, Egere U, Mgawadere F, Murray C, Ravit M et al. A blended learning approach for capacity strengthening to improve the quality of integrated HIV, TB, and Malaria services during antenatal and postnatal care in LMICs: a feasibility study. medRxiv. 2023:2023.05. 04.23289508.

World Continuing Education Alliance (WCEA). Improving Health Outcomes: WCEA delivering sustainable solutions for CPD & lifelong learning2023 26th December 2023. https://wcea.education/ .

Download references

Acknowledgements

The study was made possible through the financial support of the Johnson and Johnson Foundation for the three-year “Design, implementation and evaluation of Nursing/Midwifery CPD Educator Programme in Kenya” (2021 – 2023) and the Alliance to Improve Midwifery Education through UNFPA Headquarters. Special acknowledgement to nursing and midwifery educators from mid-level training colleges and universities in Kenya and Nigeria, Ministries of Health, Nursing Council of Kenya, Nursing and Midwifery Council of Nigeria, KMTC headquarters management who participated in the study. Also, we specially appreciate the World Continuing Education Alliance for the dedicated support with the online modules and expert trainers who participated in the delivery of the face-to-face training component: Aisha Hassan, Dr. Mojisola Ojibara, Dr. Eniola Risikat Kadir, Aminat Titi Kadir, Benson Milimo, Esther Ounza, Marthar Opisa, Millicent Kabiru, Sylvia Kimutai, Dr. Joyce Jebet, Dr. Steve Karangau, Dr. Moses Lagat and Dr. Evans Ogoti. Gratitude to Boslam Adacha and Roselynne Githinji for their dedicated support with data preparation for analysis and Dr. Sarah White for her statistical analysis expert guidance and support. Thank you also to Geeta Lal at UNFPA Headquarters. Lastly, the authors would like to acknowledge the special technical and logistical support provided by the LSTM – Kenya team (Onesmus Maina, Martin Eyinda, David Ndakalu, Diana Bitta, Esther Wekesa and Evans Koitaba) and LSTM Nigeria team (Dr. Michael Adeyemi and Deborah Charles) during the trainings.

The study was funded by the Johnson and Johnson Foundation as part of the three-year “Design, implementation and evaluation of Nursing/Midwifery CPD Educator Programme in Kenya” and the Alliance to Improve Midwifery Education through UNFPA. The Johnson and Johnson Foundation were not involved in the research – study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

Author information

Authors and affiliations.

Liverpool School of Tropical Medicine (Kenya), P.O. Box 24672-00100, Nairobi, Kenya

Duncan N. Shikuku & Lucy Nyaga

Liverpool School of Tropical Medicine (UK), Liverpool, L3 5QA, UK

Duncan N. Shikuku, Alice Norah Ladur, Carol Bedwell & Charles Ameh

Liverpool School of Tropical Medicine (Nigeria), Utako District, P.O Box 7745, Abuja, Nigeria

Hauwa Mohammed

Moi University, P.O. Box 4606-30100, Eldoret, Kenya

Lydia Mwanzia

Masinde Muliro University of Science and Technology, P.O. Box 190-50100, Kakamega, Kenya

Peter Nandikove

Maseno University, P.O. Box 3275-40100, Kisumu, Kenya

Alphonce Uyara

Kenya Medical Training College, P.O Box 30195-00100, Nairobi, Kenya

Catherine Waigwe

Department of Family Health, Ministry of Health (Kenya), P.O. Box 30016-00100, Nairobi, Kenya

Issak Bashir

Aga Khan University of East Africa, P.O Box 39340-00623, Nairobi, Kenya

Eunice Ndirangu

Burnet Institute, 85 Commercial Road Prahran Victoria, Melbourne, Australia

Sarah Bar-Zeev

University of Nairobi, P. O. Box 19676-00100, Nairobi, Kenya

Charles Ameh

Diponegoro University, JI. Prof Sudarto No 13, Temalang, Kec, Tembalang, Kota, Semarang, Jawa Tengah, 50275, Indonesia

You can also search for this author in PubMed   Google Scholar

Contributions

DNS, SBZ and CA conceived the idea and designed the study protocol; DNS designed the online data collection tools/checklists/assessments, performed data extraction, cleaning, analysis and interpretation of the results, drafted the primary manuscript, reviewed and prepared it for publication; DNS, HM, LM, PN and AU conducted the training intervention, collected data and reviewed the drafts and final manuscript; AL participated in the design of the study, qualitative data analysis, interpretation of findings and reviewed draft manuscripts; CW, LN, IB, EN, CB and SBZ participated in the design of the study procedures and substantively reviewed the drafts and final manuscript. CA reviewed study procedures, data collection tools, provided oversight in investigation, analysis, interpretation and substantively reviewed the manuscript drafts. SBZ and CA obtained funding for the study. All the authors read and approved the final manuscript.

Corresponding author

Correspondence to Duncan N. Shikuku .

Ethics declarations

Ethics approval and consent to participate.

Ethics review and approvals were obtained from Liverpool School of Tropical Medicine’s Research Ethics Committee (LSTM REC No. 23 − 004) and in-country ethical approvals from Kenya (MTRH/MU – IREC FAN 0004383; NACOSTI License No: NACOSTI/P/23/25498) and Nigeria (NHREC Approval Number NHREC/01/01/2007- 31/03/2023). Participation in the study was strictly voluntary and did not form part of the educator’s performance appraisals. Not taking part in the study did not disadvantage some educators who consented but missed out. Informed electronic and written consent was obtained from all participants. Unique participant codes were used for identification and all the data collection tools/forms and datasets were de-identified with no participant identifying information. All interviews were conducted at the offices of the respective stakeholders maintaining privacy during data collection process.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ . The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Cite this article.

Shikuku, D.N., Mohammed, H., Mwanzia, L. et al. Evaluation of the feasibility of a midwifery educator continuous professional development (CPD) programme in Kenya and Nigeria: a mixed methods study. BMC Med Educ 24 , 534 (2024). https://doi.org/10.1186/s12909-024-05524-w

Download citation

Received : 24 January 2024

Accepted : 06 May 2024

Published : 14 May 2024

DOI : https://doi.org/10.1186/s12909-024-05524-w

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Continuous professional development
• Feasibility

BMC Medical Education

ISSN: 1472-6920

• Submission enquiries: [email protected]
• General enquiries: [email protected]

All Results For “foldable-study-table”

• All Carts & Stands
• Craft & Sewing Tables
• Desktop Organizers & Desk Pads
• Folding Tables
• Storage Racks & Shelving Units
• Workbenches
• Computer & Training Tables
• Beauty Organizers
• Bike & Sport Racks
• Home Office Furniture Sets
• End & Side Tables
• All Patio Tables
• Toddler & Kids Table & Chair Sets
• Activity Tables
• Folding Chairs
• Makeup Vanities
• Kitchen & Dining Tables

Special Offers

Shop by color, customer rating, price per item, availability, showing results for "foldable-study-table".

Folding Computer Desk, No Assembly Required

Rated 5 out of 5 stars. 153 total votes

FREE Shipping

Get it Tomorrow

Advantage 1. No assembly is required, can be opened and folded in a few seconds; 2. Feet can be adjusted within 1-2 cm, allowing stability under an uneven floor.

• Top Material: Manufactured Wood
• Base Material: Manufactured Wood

Very sturdy table and no assembly required!! Most tables are flimsy…this one isn’t!! I will use this when entertaining over the holidays to serve appetizers and beverages. It opens and folds up in an instant. I highly recommend this table!!. Joseph. Scranton, PA. 2022-10-28 18:18:29

Kaviyon Extendable Unfinished Dining Table

by Ebern Designs

Rated 4.5 out of 5 stars. 244 total votes

Free shipping

Folding Dining, Versatile Dinner Table with 6 Wheels and 2 Storage Racks, Space Saving Kitchen, Dining Room Table, 31.5 in x 51.2 in x 28.4 in

• Wood Species: Oak
• Seating Capacity When Fully Extended: 4
• Seating Capacity When Fully Collapsed: 1

Foldaway Height Adjustable Sit Stand Desk

by Symple Stuff

Rated 4.5 out of 5 stars. 458 total votes

• Base Material: Metal
• Adjustable Height: Yes
• Assembly Required: Yes

Garaway Writing Desk

by Ivy Bronx

Rated 5 out of 5 stars. 31 total votes

Enhance your living and work space with this beautiful, 33.5-inch wide, all acrylic computer desk in smoke gray with enough table top space to fit your laptop or PC, keyboard, monitor, desk lamp, fan, organizer and other accessories.

• High-quality clear 100% acrylic material
• Modern and sleek design,Match Well with Furniture
• Necessary hardware and instruction provided, Easy to put it together
• Multi-purpose Slim Desk,it is a Laptop Study Table,also console table

4-Foot Plastic Folding Table, Indoor Outdoor Desk with Carrying Handle and Height Adjustable

by Bring Home Furniture

Rated 4.5 out of 5 stars. 26 total votes

This folding plastic table is a clean-looking, versatile piece perfect for use indoors or outdoors. It folds in half with a carry handle, so you can easily take it out and about with you when you're camping or enjoying a day out in the countryside. Benefit from the adjustable height of the table legs, so you don't have to worry about the unevenness of the ground outside causing the table to become unstable. In addition, the steel frame legs provide the support needed to have our plastic folding tables stand up to heavy static loads. It is a great compact table for camping, picnics, caravanning, and for use where space is an issue.

• Heat-Resistant Tabletop - Made of thermotolerant plastic, you can place a cup of tea or hot food on the tabletop directly.

Mccorkle Foldable Kitchen Table Drop Leaf Dining Table

by Wade Logan®

Rated 4 out of 5 stars. 558 total votes

Get it by Tue. May 28

Bring space-conscious dining to your apartment kitchen or small dining room with this storage dining table. Crafted from particle board, the rectangular table top can be extended to 51'' to accommodate up to six guests when needed. The base of the kitchen table features a 2-tier shelf, perfect for keeping table linens and dinnerware within easy reach. With its foldable functionality, this dining table is ideal for those looking to maximize their space.

• Seating Capacity When Fully Extended: 6
• Seating Capacity When Fully Collapsed: 4
• Table Mechanism: Drop Leaf

Sooo. This ended up being a very nice efficient piece for my studio apartment. It took one person to put it together. Can be used as a deskdining table. Very versatile. Took about 40min along to put together. I would have given it 5 stars if the engineered wood wouldn’t chip so easy and if it included wheels on the bottom because it is very heavy to move. Overall I love it and got it at a great price. Would definitely recommend.. Courtney. Sanford, FL. 2021-09-11 22:03:13

8Ft Heavy Duty Folding Table, Indoor Outdoor Portable Plastic Picnic Desk with Steel Legs and Handle

Rated 4.5 out of 5 stars. 21 total votes

• Lightweight And Portable - Lightweight tabletop and frame, comes with a handle that makes it easy to carry by one person after folding.

Ailed 30W Shelving Unit With Fold-Out Desk

by Brayden Studio®

The Orion 30W Tall Storage Cabinet with Doors and a Fold-Out Desk presents a practical solution for keeping your home organized while handling daily tasks. The hidden desk cabinet coordinates with Orion Murphy Beds (sold separately) for convenient bedside storage but can also be used in another area of the home. Take advantage of the hideaway desk to complete projects and assignments or browse the web. The small desk supports 50 pounds and conveniently retracts when not in use. The upper portion of the tall cabinet features open and closed storage to organize materials and display decorations. The middle section has a built-in USB port and power outlet for electronic devices, while the bottom includes a small shelf and closed storage for supplies. This tall accent cabinet with a hideaway desk is North American made with globally sourced materials and is backed by a 5 Year Warranty.

• Built-In Electrical Outlet: Yes

47.24'' Folding Table, Collapsible Transformer Dinner Table with 2 Storage Shelves

Rated 5 out of 5 stars. 3 total votes

Let us embellish your art life! Make your house a home by expressing your style. Adhering to the "quality-oriented, customer first" service concept, We know that home is a warm harbor, and is the home of the soul. Therefore, we are committed to creating a home environment that not only meets your individual needs but is also practical and aesthetically pleasing. From simple modern to retro style, from the living room, and bedroom to the kitchen, and bathroom, We can provide you with professional, thoughtful design advice.

Murphy Folding Table and Wall Shelf

by UPP Ultimate Premium Products

Rated 5 out of 5 stars. 1 total vote

Multi-functional furniture might be the coolest thing ever! They can be used as one thing for one situation, and can become an entirely different piece of furniture to fit your needs in a different circumstance. Best for Caravans & Tiny Houses. This unique table can be used as both a table or a tall shelf depending on your needs. Need an extra table while having a dinner party where you'll need extra seating spots? Just roll your shelf over and turn it into a table that can fit 5 or 6 more people. 📏 SIZE: The height of the table from the ground is 30 inches ( 77 cm ) Table top 27.5 x 38,5 inches ( 70x 98 cm ) Bookcase shelf spacing 10 inches (24 cm) Wood thickness 0.8 inches (20 mm) 📏 Bookshelf Height:44 inches (113 cm) Its width is 29 inches (74 cm) Depth 10.2 inches - 26 cm (top shelf) 9,4 inches - 24 cm other shelves

• Table Top Shape: Rectangular
• Product Type: Other
• Top Material: Solid Wood
• Top Metal Finish Application:
• Base Material: Solid Wood

Arden Height Adjustable Standing Desk

by The Twillery Co.®

Rated 4.5 out of 5 stars. 220 total votes

This standing desk is designed to elevate your workspace and make it more versatile. With its adjustable height feature, you can easily switch between sitting and standing positions throughout the day. This desk is crafted from stainless steel in a rustic, scratch-resistant wood tone, and it has a T-shape base with a black finish for a sleek and modern look. It comes with a built-in hutch for accent pieces, while three drawers are ideal for organizing your office essentials. Plus, this desk includes cable management, locking casters, and a programmable memory controller for easy height adjustments.

• Lockable casters: Swivel casters rotating 360° make your corner standing desk move more flexible and protect your floor from scratches.

Arlynda 36" Wall Mounted Folding Desk Stowable Foldable Table Workspace

Rated 4.5 out of 5 stars. 3 total votes

Are you still struggling with limited floor space? Desperate for a functional yet stylish workspace? Look no further! This wall mounted desk is a masterful blend of innovation and aesthetics, designed to maximize productivity while preserving valuable room space. Add sophistication and function to your life without compromising on space. Crafted from eco-friendly MDF engineered wood and complemented with Sky Oak accents, our wall desk effortlessly harmonizes with any home or office decor. Its elegant, clean-lined design redefines minimalism, offering you a chic and modern workstation. From a laptop desk to a dressing table or kitchen cupboard, the versatility of this wall desk knows no bounds! Equipped with a spacious flip-down door that transforms into a generous work surfaceand multi-tiered shelves for storage, this desk adapts to all your needs, with well organized arrange. The exquisite metal hooks provide convenient hanging space. Say goodbye to complex assembly. The folded surface can also be used as a blackboard to help record daily schedules, important information, daily-to-do. Grab yours today and turn any empty wall into a productivity haven.

• Quality Materials - Built from high-quality MDF, and reinforced metal accessories to ensure long-lasting performance.
• Easy Installation - All desks come with an easy-to-follow installation guide. You will complete the assembly easily.

Althoff 52.76'' Rectangular Folding Table

Rated 4.5 out of 5 stars. 39 total votes

This is a foldable structure dining table, it can accommodate up to four people when extended. Two drop leaf panels lift to create a rectangular tabletop, while two open frame legs fold out to support the drop leaves. Best of all, the table folds down to form a narrow console that can be leaned against a wall or the back of a sofa when not in use.

Gisborne Metal Base Computer Desk

by 17 Stories

Rated 4.5 out of 5 stars. 17 total votes

Fits perfectly into any tight space which allows you to take full advantage of your abode office workspace! Space-saving whilst still providing you with plenty of room for gaming, handcrafting, studying, working and other desktop activities! Large surface to meet your different needs for working and gaming.Built-in hutch can display max two monitors and release your neck.Storage shelves is perfect for storage and displaying documents.Bottom Drawer is designed for letter size file folder.

Rachette 31.5" Wall Folding Desk, Mounted Floating Table

Rated 5 out of 5 stars. 4 total votes

This wall-mounted table can be used as a computer table, desk, writing table, small dining table, kitchen storage table, coffee table, makeup table, work table, etc. It is very suitable for installation in small rooms in narrow kitchens, corridors, study rooms, living rooms, bedrooms, bathrooms or other houses.

Rigueiro Metal Base Computer Desk

Rated 5 out of 5 stars. 295 total votes

Experience a new level of productivity with our industrial two-person desk. This double workstation features a spacious 78.74" long desktop, and comfortably accommodates two persons, making it an ideal solution for collaborative projects or shared spaces.

Keb Adjustable Metal Base Standing Desk

by Inbox Zero

Rated 5 out of 5 stars. 64 total votes

Get it by Wed. May 29

This modern and sleek design fits perfectly in any decor. Work and study with style on the glass table top finished with rounded edges giving you ultra comfort and elegance. Stay connected and never run out of power with our integrated wireless charger. You can charge your phone, watch, and headphone easily without any cable mess.

• Three state memory
• Storage drawer with organizer
• 10 minutes assembly with pre-assembled desktop and legs

Large Folding Desk Workstation

Rated 4.5 out of 5 stars. 23 total votes

Multi-Purpose Foldable Desk: A perfect companion to your office work, gaming equipment, and many more! Not having enough storage at home or office is frustrating. The added pressure of buying products that you aren’t sure about can also be stressful. 17 Stories creates products that require no assembly and thus no added stress. Most of the 17 Stories products are built with powder-coated steel that prevents corrosion when used outside. All items are well-pre-assembled, sturdy, and mobile, allowing you to use them hassle-free right out of the box. 17 Stories Foldable Computer Desk Created to be effortlessly comfortable and functional, the 17 Stories Multi-Purpose Table (or Computer Desk) will allow you to get down to business, be creative, or simply browse the Internet with ease. Made with a steel frame and a wood top, this desk is chip-resistant and long-lasting. The Desk was designed overall to blend well with any decor. The smooth black finish gives it an added style dimension for those who want to place it in their living room or a one-room loft. The options are endless! Opens and folds in less than 60 seconds. Removable tabletop for lightweight moving. No assembly is required. No tools are required for setup. Locking mechanisms to secure the desk surface in place. Storage space Saving. Folds flat for easy storage. Durable enough for everyday use for your office work, gaming equipment, and many more!

• Base Material: Manufactured Wood; Steel

PJ Wood Folding TV Tray Tables with Compact Storage Rack, 5 Piece Set

Rated 4.5 out of 5 stars. 136 total votes

Get ideal convenience and sleek design all-in-1 with the 5-piece PJ Wood Folding TV Tray Table set. These folding TV trays by PJ Wood are the best go-to tray tables. They come in handy for those nights when you’re not in the mood to sit at the table and want to relax and eat in front of the TV. They're also great for bringing the office home, and just want an easy way to sit down and get some work done. These tray tables expand and collapse with ease. Rectangular in shape and made from solid wood, these tables feature a flat and spacious conventional tabletop that makes them perfect for versatile use. The solid wood construction ensures that these tables stand up against time. The trays store easily behind a door, in a closet, or even behind the sofa thanks to the handy storage rack. Collapse each table when finished, and set it into the storage rack in an upright, filed position for easy and compact storage. For those lazy nights on the couch, trust in the convenience of the 5-piece set of PJ Wood Folding TV Tray Tables.

• Watch your favorite show while eating a delicious meal, or enjoy a late-night snack with this 5-piece set of multifunctional folding table trays.
• Simply pull out a table from the rack, expand it, and stand it upright for a fully functioning table.
• This charming 5-piece snack table set is made from solid and sturdy wood that stands the test of time.
• Collapse each table when finished, and set it into the storage rack in an upright, filed position for easy and compact storage.

They are great because I am Handicap a They help me out alot. Anonymous. . 2023-03-11 14:39:25

19.09'' Solid Wood Rectangular Portable Folding Table (Set of 2)

Rated 4.5 out of 5 stars. 110 total votes

Get ideal convenience and sleek design all-in-1 with the 2-piece set of PJ Wood folding TV tray tables. These folding TV trays by PJ Wood are the best go-to tray tables. They come in handy for those nights when you’re not in the mood to sit at the table and just want to relax and eat in front of the TV. They're also great for when you bring the office home, and just want an easy way to sit down and get some work done. These tray tables expand and collapse with ease. Rectangular in shape and made from solid wood, these tables feature a flat and spacious conventional tabletop that makes them perfect for versatile use. The solid wood construction ensures that these tables stand up against time. The trays store easily behind a door, in a closet, or even behind the sofa thanks to the handy storage rack. Collapse each table when finished, and set it into the storage rack in an upright, filed position for easy and compact storage. For those lazy nights on the couch, trust in the convenience of the 5-piece set of PJ Wood folding TV tray tables.

• Watch your favorite show while eating a delicious meal, or enjoy a late-night snack with this 2-piece set of multifunctional folding table trays.
• This charming 2-piece snack table set is made from solid and sturdy wood that stands the test of time.
• Each sofa snack table measures 14.57" wide, 19.09" long, and 26.00" tall, and contains a spacious, flat surface.

Ahraya Floating Fold-Away Writing Desk

by Latitude Run®

Rated 4.5 out of 5 stars. 238 total votes

This floating desk with a built-in bookcase is the ideal WFH solution for spaces lower on square footage. Its wall-mounted design gives you that home office you've always wanted – and it folds away for efficient space usage. It's made from solid and engineered wood, and it rests on a sled leg that folds down. Six, open shelves in the base of this desk provide storage for office supplies, papers, and files, as well as a display showcase for decorative items.

• Top Material: Manufactured Wood + Solid Wood

Great piece!!!! Easy to assemble definitely need 2 people to hang it. The only recommendation ( a must) is to attach the folding part (the metal piece that has 8 little screws) on first before attaching all others together. If you don’t it is super difficult because you don’t have enough room for your hand to turn screwdriver. The desk is super sturdy and it a huge space saver. Looks great in my daughters room. Purchasing another one for my other daughter!!!. Debbie. STAFFORD, VA. 2018-04-08 22:19:19

Floating Desk

Rated 4 out of 5 stars. 14 total votes

A wall-mounted folding table is the ultimate solution for whatsoever your domestic or commercial needs to enhance the limited space. This simple white floating desk is a popular household item that is contemporary and multipurpose, going well with any modern decor. Made from a high-quality solid wood board with a scratch-resistant, sleek finish, the convertible folding computer desk is sturdy and durable with little maintenance. Three strong metal hangers and a standing board ensure the folding desk is stable and safely mounted onto the wall.

This desk is amazing! This desk is such a high functioning space saver! Its a little bigger than a medicine cabinet but folds out to be an actual desk! This desk was so easy to put together yet made very sturdy! Fabulous!!! We love it!. Amanda Heaven Hugs. Suwanee GA. 2021-04-12 17:22:05

58 x 36 Height Adjustable Foldable Craft Table with Wheels

The Leg and Shelf are well made of sturdy material, with no issues with wobble after locking down the wheels. This crafting table is on casters that lock/unlock which makes it easy to move without scratching the new floors but also stationary when needed. The sewing machine, cutting & pinning tools will fit on the shelves which are great for storage purposes and easy accessibility. This sewing table can be easily folded to 12" W and fits into a tight spot for storage. This folding table can not only be used for cutting fabric/designing patterns or as an extra workspace for craft projects but also can be used as a computer desk in the living room or dining room. You can use this collapsible table for various purposes, and it has already made it so much easier to do things.

• Require Assembly

Just what I needed good quality and not hard to put together.. Lorraine. Spanish Fork, UT. 2022-10-01 16:30:10

Trinette 23.6" Wall Mounted Table, Multifunctional Fold Down Wall Mounted Laptop Computer Desk

by Red Barrel Studio®

Rated 4.5 out of 5 stars. 57 total votes

Wall mount foldable desk with shelf is designed to fit in your space, style, and fit on your budget. 2 In 1 new design floating desks with storage create a concentrated workspace without taking up much space. Constructed of high-quality MDF, this desk is durable and sturdy. A simple and stylish look adds an elegant feel to your home, it can be combined with any decoration style. The foldable desk is multi-function, not only can it be a computer desk but also a cabinet.

30.31" x 19.69" Height Adjustable Folding Rectangular Table

Are you looking for an easy-to-carry folding table? This folding table's reinforced legs and solidly constructed triangular structure allow each leg to support up to approximately 110 pounds, providing great stability for your daily use. Adjustable height and foldable design provide you with a more personalized experience and convenience.

• Lightweight & Portable: the lightweight(8.15 lbs) and foldable design allow you to easily carry it to different work sites and store it in the corner.

Perfect for my needs. Sturdy not wobbly. I’m very happy. Dorothy. Okeechobee, FL. 2023-05-09 06:53:51

Dylan-Mackie Floating Desk

Rated 4.5 out of 5 stars. 89 total votes

Simple style & wide application wall-mounted folding table, smooth and clear contour show the essence of simplicity, compatible with different kinds of decoration style, a temporary working desk for holding a laptop, or book at home, or as a storage shelf in the bedroom, living room, kitchen to display daily use gadgets.

Stesha Height Adjustable Mobile Portable Standing Computer Desk

Rated 4.5 out of 5 stars. 60 total votes

Compact, nice looking, bargain for price: A portable but functional desk. Laptop space, pull-out keyboard tray, additional storage shelf, railing for hanging headset, adjustable height, and removable wheels. All these useful functions are perfectly concentrated on a small table.

• From sitting to standing, the height of the desk can be adjusted from 30” to 44”. The height can be adjusted according to your own needs.

Noah 2.6' Round Plastic Bar Height Folding Event Table by Flash Furniture

by Flash Furniture

Rated 5 out of 5 stars. 44 total votes

Whether you're hosting a home, school, or business event, this bar table is great for when you need a mixing bar or a little extra surface space for guests. It's perfect for indoor or outdoor special events and cook-outs at home or when you're serving snacks around the pool and is commercial-rated for use in banquet halls or convention centers. The table comfortably seats up to 3 adults to provide an ideal area for arts and crafts, working on projects, and entertaining. The legs fold for easy transportation and compact storage after use, and the non-marring floor caps protect floors from damage. Constructed from waterproof, impact, and stain-resistant materials, this bar height table withstands years of quality use.

• Overall: 43.75'' H x 31.25'' L x 31.25'' W
• Overall Product Weight: 19lb.

Great all purpose table! Great price as well. nicole. PENN HILLS, PA. 2023-04-10 15:59:47

35.4'' H Laptop Cart with Wheels

Rated 4.5 out of 5 stars. 734 total votes

This laptop table is perfect as a bedside table, writing table, laptop table, sofa side table, end table, and study table.

• Product Type: Laptop/Computer Cart or Stand
• Maximum Overall Height - Top to Bottom: 35.4''
• Wheels / Casters Included: Yes
• : 28''

Lasherrie Height Adjustable Standing Desk With A Layer

Rated 4.5 out of 5 stars. 66 total votes

Elevate your work experience with the electric height adjustable standing desk, designed to promote a healthy and efficient way of working. Say goodbye to back tension and hello to a standing working posture that suits you best.

• Enjoy a layered design that maximizes your high-rise space while keeping your work area organized
• The desk includes a cup holder, drawer, two cable management holes, a basket for power strips and plugs, and a hook for your headset or bag

Annakathryn Solid Wood Base Writing Desk

Rated 4.5 out of 5 stars. 191 total votes

Ideal for any small or temporary workspace, this folding desk creates a quick productivity station. It's crafted from engineered wood with a solid bamboo base, and it features a streamlined design that's just right for contemporary aesthetics. A 31'' long tabletop provides ample space for your laptop, notebook, and, of course, a cup of coffee. We love that its neutral hues make it easy to pair with any décor or color scheme. Plus, when you're finished with work, the desk folds down flat for easy storage in a closet.

I bought this desk to use on the days I work from home and I love it! It is very well made and sturdy but also very easy to set up and stow away when you’re done. Great item!!. Amber. Latham, NY. 2019-10-16 12:57:05

Foldable Tiltable Sturdy Computer Desk Personal Laptop Tray Activity Bedside Table

by MoNiBloom

Rated 4.5 out of 5 stars. 41 total votes

Sometimes after work or study, all you want is to relax with a great meal in front of the TV. Fortunately, there is no longer any need to haul your plate to the couch and eat from your lap. TV trays offer both practicality and style, upgrading your at-home cinema experience. These TV trays allow you to have a real meal, in a civilized way, all while catching up on your favorite shows.

• Adjustable height - Multi-slots are down below the table to apply different heights
• Tiltable tabletop - The tabletop features 3 different angles from -20° to 25°. Good for a snack table or tablet holder.
• Sturdy metal frame - MoNiBloom's folding table can hold up dozens of pounds based on the reinforced metal material.
• Plastic foot caps - This table is equipped with plastic foot caps, which prevent unwanted sliding and floor scratches

Murphy Folding Table Solid Wood

✅ Multi-functional furniture might be the coolest thing ever! They can be used as one thing for one situation and can become an entirely different piece of furniture to fit your needs in a different circumstance. This unique table can be used as both a table or a tall shelf depending on your needs. Need an extra table while having a dinner party where you'll need extra seating spots? Just roll your shelf over and turn it into a table that can fit 5 or 6 more people.

St. Nicholas Foldable Sewing Table with Wheels

Rated 4.5 out of 5 stars. 1212 total votes

Time to get crafty! Create the perfect space to bring your thoughts and ideas to life with this craft and sewing table from the Sauder Select collection. Its melamine top surface is heat, stain, and scratch-resistant so there are no worries when you break out the glue and scissors. It includes a drop leaf for extra work space! It also features storage behind a roll-open door that includes two storage bins and a hidden shelf for a sewing machine. Other features include two adjustable shelves behind the door and easy-roll casters to make it simple to transport your hobby mobile to any room. This versatile sewing machine cart or craft table makes creating and crafting a breeze.

• Top Material: Engineered wood
• Base Material: Engineered wood
• Foldable: Yes
• Weight Capacity: 20lb.

47'' x 16'' Foldable Sewing Table with Sewing Machine Platform and Wheels

by NSdirect

Rated 4 out of 5 stars. 115 total votes

Looking for a sewing table? This is the perfect one for you. The foldable design not only saves space but also has multi-purpose use. It can be a sewing table, a craft table, or a side table, and is perfect for home use. There are 2 hidden bins and 1 shelf attached for storage purposes, you can put your sewing tools. This sewing table is finished white and is made of high-quality MDF board, you don’t need to worry about it being damaged when expanding it due there is a lock that keeps the stability of the extended desktop. You can push the craft table to any position smoothly with universal wheels attached, and fix it at any place you want with the breaker.

• Weight Capacity: 300lb.

While I like the easy and convenience of this table, it’s pretty difficult to open and close on a carpeted floor. It’s not super sturdy so when the sewing machine really gets going I get a little nervous. Everything kind falls out of the storage every time I move it. It works for my purposes for now. If you aren’t someone who uses their machine all the time, this is a good option. Note It is a bit of a chore to assemble. While tools are provided, my hands were much happier when I brought out my own screwdriver with a better grip.. Katie. Omaha, NE. 2022-07-24 18:03:40

Simply Bamboo 20'' Solid Wood Square Portable Folding Table

by Casual Contemporary Living/Eccostyle

Rated 4.5 out of 5 stars. 6 total votes

This solid bamboo folding occasional side table is a wonderful solution for adding display space and function to any room. Large enough to fit your lighting, phone, beverage, and accessories. The sturdy frame and tabletop are expertly crafted from environmentally friendly solid bamboo. This portable surface folds flat and can be stored away when no longer in use, granting a positive impact on the environment and your room. Conveniently locks into position when in use, giving a strong stable display space. Featuring an optional higher table setting and a contemporary urban design, this piece is scaled for today's smaller living spaces.

• Solid bamboo construction
• Dowel to lock into an upright position
• Folds flat for quick and easy storage
• No assembly required

This folding table is good, but It’s too low, even when raised the 2inches, but that’s probably my fault for not reading the specs. Too low to use as a eating tray. The best thing about it is that it’s made from Bamboo and it’s sturdy, uses pegs on one 12 of the table top that insert into the other 12. Pretty neat. It does have a pretty finish. To me, it’s a decent table for use other than eating from, but it is overpriced.. Ellen. Alabama. 2022-02-19 10:33:06

Erommy 58" x 36" Foldable Craft Table with Wheels

Rated 4.5 out of 5 stars. 130 total votes

The hobby table's shelf and leg are well made of sturdy material, with no issues with wobble after locking down the wheels. This crafting table is on casters that lock/unlock which makes it easy to move without scratching the new floors but also stationary when needed. The sewing machine, cutting & pinning tools will fit on the shelves which are great for storage purposes and easy accessibility. This sewing table can be easily folded to 12" W and fits into a tight spot for storage. This folding table can not only be used for cutting fabric/designing patterns or as an extra workspace for craft projects but also can be used as a computer desk in the living room or dining room. You can use this collapsible table for various purposes, and it has already made it so much easier to do things.

• Adjustable Width: Yes
• Product Type: Craft Table
• Top Color: White
• Adjustable Depth: No
• Base Color: White

Love the desk. It is tall great if you want to stand and work or with a high desk chair. It saves space and allows for storage.. Veronica. BALTIMORE, MD. 2023-01-29 14:27:26

Solid Wood Floating Desk

Rated 5 out of 5 stars. 5 total votes

The floating desk is designed to fit mall spaces, style, and fit your budget. Modern style makes furniture a welcome addition to your home and office space. Widely Applicable: The wall-mounted desk is ideal for offices, homes, studies, and bedrooms. You can place pinheads, books, and magazines on the wall-mounted desk shelf. The hanging desk is a great fit small room with a fordable function and will save space. Designed to fit in your space, style, and fit on your budget. Modern style makes furniture a welcome addition to your home and office space. Designed to fit in your space, style, and fit on your budget.

• Ample Storage Space
• wall-mounted design for space-saving
• Easy to clean and assemble
• Plywood materials
• Scratch-resistant and water-resistant.

Sehorn Extendable Metal Base Dining Table

Rated 4.5 out of 5 stars. 442 total votes

Grab a seat and gather around for an evening with friends, dinner with the kids, or a rousing game night with the family. A table from the Sehorn collection is the perfect piece to make it happen. This modern table features a spacious top surface that provides you with room for various items like dinnerware, your laptop, board games, and home decor items too. Need more space? No worries. This drop-leaf dining table features a flip-up table extension with slide-out supports to provide you with that extra table space you need. Table with leaf will have you ready to entertain your family and friends. We hope you like what you see. Ebern designs designers travel the world and bring back the best and latest in style, finish, and color trends. This inspiring world travel is evident in the cutting-edge and innovative furniture solutions we offer to you.

• Base Material: Steel
• Seating Capacity When Fully Collapsed: 2
• Table Mechanism: Self-Storing Leaf

Parker 11-Piece Folding Rectangular Training Table and Chairs Set by Flash Furniture

Rated 4.5 out of 5 stars. 147 total votes

Maximize the space in your training facility, classroom, or office with this 11-piece rectangular training table and chairs set. Host a sip and paint party, set up your products at convention centers, and much more. The set of 10 lightweight folding chairs features drain holes and a textured seat for safe, comfortable seating. Both the chairs and table have a foldable design to allow for easy transportation and compact storage after use, and the non-marring floor caps protect floor surfaces. Constructed with waterproof plastic and durable powder-coated legs, this multipurpose training table and chair set withstands years of quality use in indoor settings.

• Overall: 29'' H x 96'' L x 30'' W
• Overall Product Weight: 109.04lb.

Worked great..it was for a memorial.. Marianne. US. 2023-01-18 16:50:59

Monroe 5-Piece Folding Padded Card Table and Chairs Set by Flash Furniture

Rated 4.5 out of 5 stars. 519 total votes

Whether you're hosting family gatherings, catering events, marathon game nights, barbecues, parties, business events, or a last-minute get-together with friends, this 5-piece card table and chairs set provides a reliable, on-demand seating solution. The folding card table is the perfect size for card and board games or poker nights and features a padded tabletop to help slow down thrown cards from sliding off the table during those competitive card games. Both the table and chairs are lightweight and easy to fold up for portability, and they feature protective plastic floor glides that slide smoothly to protect flooring surfaces from damage. Suitable for indoor or outdoor spaces, this card table set is great for hospitality facilities, community centers, or dining rooms.

• Overall: 27.75'' H x 33.5'' L x 33.5'' W
• Overall Product Weight: 47lb.

It would have been good if there was no tear in one of the chairs and scratch on the same chair, so I didn’t give 5. Bad on quality control. There was a still a plastic cover and I saw it right away! So please be careful in wrapping or covering, maybe it should padded with foam not just very thin cover, really disappointed!!!!. Anonymous. NJ. 2022-07-23 12:50:24

32'' Solid Wood Square Portable Folding Table

by Stakmore Company, Inc.

Rated 5 out of 5 stars. 1017 total votes

Add an elegant touch to your game room with the Stakmore straight-edge wood 32" folding card table. It is available in many finishes that you can choose from. The square folding card table is made from solid wood which makes it sturdy and long-lasting. It is foldable and folds to 3" deep for extra storage. The square table is perfect for playing cards and can also be converted into a dining table. It is portable and ideal for four players. This straight edge wood 32" folding card table from Stakmore is a nice addition to any home.

• Overall: 29.5'' H x 32'' L x 32'' W
• Overall Product Weight: 35lb.

This table is beautifully made, compact for storage & transport. The wood top is beautiful. It has served as a place holder as we are on the hunt to buy a dining table for our unfurnished condo. After which it will find many uses for extra seating, a project table or puzzle. Without a lot of storage space it is easy to store in a closet. This table pairs beautifully with the Wayfair “Simple Mission Padded folding chair. We bought 2. Great purchase!!!. Patricia. RI. 2022-02-18 12:27:45

Annalie Floating Desk

Rated 4.5 out of 5 stars. 37 total votes

This cabinet with a stylish chalkboard front easily folds out (Murphy bed style) and converts into a convenient workspace that is perfect for your computer usage, scrapbooking, crafting, sewing, paying bills, homework and so much more! Also can use it as a bar or serving table when you have company! The front of the cabinet is a chalkboard and when opened, there are multiple storage units to keep your belongings. Also has side shelves for extra storage.

• Built-In Electrical Outlets: Yes

Folding Balcony Table

by Arlmont & Co.

Rated 4.5 out of 5 stars. 43 total votes

Whether working from home on a nice day or enjoying a meal, do it outside in style with this beautiful space saving balcony table. The Arlmont & Co. Balcony Space Saver Folding Table makes for an elegant selection for those looking to incorporate a table in a limited amount of space - perfect for apartment/decks/patios/balconies. Our table is made from weather-resistant acacia wood making it ideal for any climate and durable in any weather. The Arlmont & Co. Balcony Space Saver Table folds up for compact storage to maximize the amount of space in a limited setting and requires minimal assembly - attach to any deck or balcony in minutes!

• Made from weather-resistant acacia wood
• Folds for easy and convenient storage
• Table Measures 26.97"(L) x 15.75"(W) x 31.97"(H)
• Measures 25 inches high to the top of the table
• 50 pound max load capacity

Kreutzer Height Adjustable Standing Gaming Desk

Rated 4.5 out of 5 stars. 109 total votes

Choose this home office desk to create a comfortable working environment. The electric adjustable height, memory system makes it suitable for sitting or standing work, providing solutions for your health. The frame is made of metal to keep it stable, and the wide wooden desktop with a monitor stand provides ample space to hold your office supplies. Attention to healthy and stylish, our ergonomic standing desk is built for you to enjoy every working time.

Varennes Folding Desk

Rated 4 out of 5 stars. 10 total votes

Strength and functionality come together in this writing desk. It's a no-nonsense, classic piece that makes a statement in your home office or living room. When you're not using it, the desktop folds down and the outer frames slide in to save on space. This desk rests on four lockable wheels, so you can move it to just the right spot. It's clean-lined and crafted from steel, while the rectangular top measures a hair under 4' wide and is made from engineered wood in a matching tone.

Brantley Floating Desk

by Hashtag Home

Rated 5 out of 5 stars. 159 total votes

Turn any empty wall into your home office with this space-saving floating desk! Crafted of manufactured wood in a two-tone white and oak finish, this wall-mounted desk strikes a rectangular silhouette. Just pull down its hinged face using its leather handle to create a perfect platform for your laptop. An open ledge upper shelf is great for displaying accessories, while a tack board backing is great for memos and notes.

• : Ball Bearing Glides

Burns Industrial 35.5" Home Office Folding Computer or Laptop Desk

Rated 4 out of 5 stars. 11 total votes

Get into a normal work from home routine by setting up a dedicated office space to perform your work duties instead of the dining room table. When you need something simple and functional this folding computer desk is at your service. Setup your desktop or use as a laptop table. If you're short on space this foldable desk folds to 2.75" depth to store behind your sofa. This attractive industrial style desk is highlighted by light and dark colored variations. Create a school environment at home for your remote learning student. This student desk can be used in the home or dorm room. The industrial style desk can be your all-in-one creative space for work, play and meals.

• Open access
• Published: 11 May 2024

Inotuzumab ozogamicin for the treatment of adult acute lymphoblastic leukemia: past progress, current research and future directions

• Nicholas J. Short 1 ,
• Elias Jabbour 1 ,
• Nitin Jain 1 &
• Hagop Kantarjian 1  

Journal of Hematology & Oncology volume  17 , Article number:  32 ( 2024 ) Cite this article

891 Accesses

25 Altmetric

Metrics details

Inotuzumab ozogamicin (INO) is an anti-CD22 antibody-drug conjugate that was first evaluated in B-cell lymphomas but was subsequently shown to be highly effective in acute lymphoblastic leukemia (ALL). INO improved response rates and survival in a randomized study in adults with relapsed/refractory B-cell ALL, leading to its regulatory approval in the United States in 2017. While the formal approval for INO is as monotherapy in relapsed/refractory ALL, subsequent studies with INO administered in combination with chemotherapy and/or blinatumomab both in the frontline and salvage settings have yielded promising results. In this review, we discuss the clinical development of INO in ALL, highlighting lessons learned from the initial clinical trials of INO, as well as the many ongoing studies that are seeking to expand the role of INO in ALL.

Introduction

The anti-CD22 antibody drug conjugate inotuzumab ozogamicin (INO) was developed in the early 2000s based on initial preclinical data showing promising activity in B-cell lymphoid diseases. These laboratory observations were then followed by several early phase clinical trials that showed significant efficacy of INO in acute lymphoblastic leukemia (ALL), ultimately prompting to its evaluation in a large, randomized trial in adults with relapsed/refractory CD22-positive B-cell ALL. In the pivotal INO-VATE study, INO significantly improved response rates and overall survival (OS) compared with conventional chemotherapy, leading to its approval by the Food and Drug Administration (FDA) in August 2017 [ 1 ]. Figure  1 shows a timeline of its clinical development. In this review, we discuss the lessons learned during its development and how these are being applied to current research efforts. We will also discuss the new research that is attempting to expand the potential applications of INO in B-cell ALL, including using it in combination with chemotherapy and/or other immunotherapies, in the frontline treatment of ALL, and in treatment of measurable residual disease (MRD).

Timeline of the clinical development of inotuzumab ozogamicin in acute lymphoblastic leukemia. For context, approval dates for other novel immunotherapies in adult B-cell acute lymphoblastic leukemia are also shown

Drug mechanism and preclinical development

INO is an IgG anti-CD22 monoclonal antibody drug conjugate that was developed by Celltech (a British biotechnology company) and Wyeth (a pharmaceutical company, later purchased by Pfizer in 2009). It is covalently linked to calicheamicin dimethyl hydrazide with acid-labile 4-(4’-acetylphenoxy) butanoic acid liner [ 2 ]. INO has sub-nanomolar binding affinity to CD22 and is rapidly internalized upon binding, after which it delivers the calicheamicin toxin intracellularly where it binds to the minor DNA groove and leads to double-strand cleavage and subsequent apoptosis. INO was first shown in preclinical studies to be active against B-cell lymphoma cell lines [ 2 ]. Subsequent studies were performed in mouse models of aggressive B-cell lymphomas, showing both monotherapy activity as well as synergy with rituximab or chemotherapy, including CVD and CHOP [ 3 , 4 , 5 ]. Given the clear preclinical activity in B-cell lymphoma models, INO was also tested in CD22-positive ALL models, where it induced complete tumor regression and cures in mice, warranting its clinical development in ALL [ 5 , 6 ].

Phase I and II studies

The first study of INO in humans was a phase I study in adults with relapsed or refractory CD22-positive B-cell non-Hodgkin’s lymphoma [ 7 ]. Seventy-nine patients were treated, and the maximum tolerated dose (MTD) was 1.8 mg/m 2 administered as a single dose every 3–4 weeks. Thrombocytopenia was the dose-limiting toxicity, with 90% of patients experiencing thrombocytopenia of any grade, which was grade ≥ 3 in 63%. Encouraging activity was observed, and the overall response rate was 39% among all patients, with response rates in follicular lymphoma and diffuse large B-cell lymphoma of 69% and 15%, respectively, at the MTD. Investigator-initiated pilot studies at MD Anderson Cancer Center were ongoing simultaneously, though the chosen regulatory approval path by the company was initially in lymphomas. Fortunately, by the time the phase III pivotal trial in lymphoma had failed to meet the primary study endpoint in 2014 [ 8 , 9 ], the pilot studies in ALL had shown encouraging results, thus shifting the regulatory focus to ALL.

The investigator-initiated phase II study at MD Anderson Cancer Center evaluated INO in children and adults with CD22-positive relapsed or refractory ALL (Table  1 ). In the initial publication, 49 patients received INO at a dose of 1.3 mg/m 2 to 1.8 mg/m 2 administered once every 3–4 weeks [ 10 ]. The population was heavily pretreated, with 73% of patients being treated as second or later salvage. The complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate was 57%, and the median OS was 5.1 months. The most common adverse events were fever (59%), transaminase elevation (57%), and hyperbilirubinemia (29%). An important observation was that allogeneic hematopoietic stem cell transplantation (HSCT) increased the risk of toxicity. Among the 26 patients who underwent HSCT following INO, the 1-year OS rate was only 20%, driven by higher rates of non-relapse mortality (NRM) and 5 deaths due to sinusoidal obstruction syndrome (SOS) / veno-occlusive disease (VOD). To improve upon the safety/efficacy profile of INO, the study was then amended to fractionate the dose of INO and administer a dose of 0.8 mg/m 2 on day 1 and 0.5 mg/m 2 on day 8 and 15, given every 3–4 weeks, with the rationale that lower dose and more frequent schedules of INO may improve anti-ALL efficacy (which is determined primarily by the area under the curve) while reducing toxicities (which is determined primarily by the peak level of INO). In a subsequent analysis after treating 90 total patients (49 at the original schedule and 41 at the new schedule), the response rates and survival outcomes were similar [ 11 ]. However, the new dosing schedule appeared safer and resulted in lower rates of fever, hypotension and hyperbilirubinemia. The rate of SOS/VOD was also lower with the new schedule (7% versus 17% with the previous schedule), which may have been driven by the fractionated dosing as well as better understanding of the SOS/VOD risk with INO, leading to a reduced use of alkylating agents in HSCT preparative regimens.

The safety and efficacy of INO was later confirmed with a phase I/II multicenter study that evaluated INO in a similar population of adults with relapsed or refractory ALL (Table  1 ) [ 12 ]. This study also evaluated divided, weekly doses of INO (ranging from 1.2 mg/m 2 to 1.8 mg/m 2 per cycle) given for up to 6 cycles. The recommended phase II dose was 1.8 mg/m 2 per cycle, with the dose reduced to 1.6 mg/m 2 once CR/CRi was achieved. Seventy-two patients were treated, including 78% in salvage 2 or beyond and approximately one-third who had undergone previous allogeneic HSCT. The CR/CRi rate was 68% (including CR in 32%), and the median OS was 7.4 months. One-third of patients received a subsequent allogeneic HSCT, and there were 4 cases of SOS/VOD (6% total).

Phase III study (INO-VATE)

Efficacy and safety outcomes.

Based on the promising safety and efficacy data from the 2 prior clinical studies of INO in B-cell ALL, the INO-VATE study was designed as pivotal trial to compare INO to conventional chemotherapy in adults with relapsed or refractory CD22-positive B-cell ALL (Table  1 ) [ 1 ]. Three hundred and twenty-six patients were randomized 1:1 to INO or combination chemotherapy (either fludarabine, cytarabine and granulocyte-stimulating factor [FLAG], cytarabine plus mitoxantrone, or high-dose cytarabine). Given the superior safety observed with weekly dosing, INO was given at a dose of 0.8 mg/m 2 on day 1 and 0.5 mg/m 2 on days 8 and 15, for up to 6 cycles. The median age was 47 years in both arms, and 32% of patients in the INO arm and 36% in the control arm were in second salvage. INO resulted in a significantly higher rate of CR/CRi than did conventional chemotherapy (80.7% [95% confidence interval (CI), 72.1–87.7%] vs. 29.4% [95% CI, 21.0–38.8%], respectively; P  < 0.001). Superior responses with INO were observed across all subgroups, with the exception of patients with t(4;11), although the number of patients was small. Among responders, INO was also associated with significantly higher rates of MRD negativity by multiparameter flow cytometry (78.4% vs. 28.1%, respectively; P  < 0.001) and higher rates of subsequent HSCT (41% vs. 11%, respectively; P  < 0.001). Driven by the higher rates of response and HSCT realization, INO resulted in significantly better median OS (7.7 months [95% CI, 6.0 to 9.2] vs. 6.7 months [95% CI, 4.9 to 8.3]; P  = 0.04). While the numerical improvement in median OS was marginal, the greatest benefit to INO was observed in the long-term survival outcomes, where INO more than doubled the 2-year OS rate compared with chemotherapy (23% vs. 10%, respectively). Febrile neutropenia and thrombocytopenia were more common in the control group, while liver-related adverse events were more common with INO. The SOS/VOD rate with INO and chemotherapy were 11% and 1%, respectively. Based on the substantial improvement in both response rates and OS, the FDA approved INO in August 2017 for the treatment of adults with relapsed/refractory B-cell ALL.

Subgroups analyses, including transplant outcomes

Following the initial publication of the INO-VATE study, several subgroup analyses of the trial population have been published. These analyses have highlighted important considerations for the use of INO, including its good activity irrespective of bone marrow blast percentage, extramedullary involvement, or CD22 expression, and its activity in Philadelphia chromosome (Ph)-positive ALL [ 13 , 14 , 15 ]. INO is associated with a higher rate of HSCT realization, which is the most significant predictor of OS following INO therapy by multivariate analysis [ 16 ]. Among patients in the INO-VATE study who received INO and achieved CR/CRi, those who underwent subsequent allogeneic had the best outcomes (median OS 12.6 months and 2-year OS rate 39% versus median OS 7.1 months and 2-year OS rate 13% in non-transplanted). However, subsequent transplant is associated with higher risk of SOS/VOD after INO (23% versus 9% in non-transplanted patients), which contributes to INO-related non-relapse mortality. Proper patient selection for INO and mitigation strategies are therefore imperative to prevent this important potential copmlication. Similar post-transplant findings were observed in a pooled analysis of 2 INO studies, where patients who underwent allogeneic HSCT following INO had a post-HSCT median OS of 9.2 months and 2-year post-HSCT OS rate of 41% [ 17 ]. The overall rate of SOS/VOD among transplanted patients across these 2 studies was 18%.

Pooled analyses from multiple INO studies have been used to better understand the risk for SOS/VOD, which is a severe and potential toxicity with INO treatment. Across these studies, the predictors for the development of SOS/VOD include: older age, the use of double alkylator preparative regimens for HSCT, elevated pretreatment transaminases and/or bilirubin, more cycles and higher cumulative doses of INO, and multiple prior ALL therapies, especially prior HSCT [ 1 , 18 , 19 , 20 ]. Subsequent consensus guidelines have been developed to mitigate these risks. Important considerations to prevent the risk of SOS/VOD in patients receiving INO include: proper selection of patients (e.g. avoiding in patients were severe underlying hepatic dysfunction, avoiding dual alkylator conditioning regimens in transplanted patients, limiting INO to a cumulative dose of 2.7 to 3.6 mg/m 2 in patients proceeding to allogeneic HSCT, use of high dose steroids at the first sign of liver dysfunction, and distancing the last dose of INO from time of HSCT [ 21 ]. Ursodiol prophylaxis 300 mg three times daily should be considered for all patients receiving INO, although there is no clear role for defibrotide as prophylaxis, even for high-risk patients [ 22 ].

Combination therapies with INO for relapsed/refractory ALL

While single-agent INO therapy represents a therapeutic advance for patients with relapsed/refractory ALL, it is not curative for most patients when given as monotherapy, with < 20% of patients achieving long-term survival [ 16 ]. Research efforts have therefore been focused on combination therapies of INO with chemotherapy and/or other novel agents such as blinatumomab, with the goal of deepening response and further improving survival outcomes (Table  2 ). At MD Anderson Cancer Center, a regimen of mini-hyper-CVD (dose-reduced hyperfractionated cyclophosphamide, vincristine and dexamethasone alternating with dose-reduced methotrexate and cytarabine) in combination with INO was studied in relapsed/refractory Ph-negative B-cell ALL. Figure  2 shows the evolution of this regimen over the past decade. INO was originally given on day 3 of cycles 1–4 at a dose of 1.8 mg/m 2 in cycle 1 and 1.3 mg/m 2 in cycles 2–4 (cumulative dose of 5.7 mg/m 2 ) and then was later reduced to 1.3 mg/m 2 in cycle 1 and 1 mg/m 2 in cycles 2–4 (cumulative dose of 4.3 mg/m 2 ) in an effort to reduce the risk of SOS/VOD (Fig.  2 A) [ 23 ]. Among 59 patients treated, the overall response rate was 78%, with 82% of responders achieving MRD negativity by flow cytometry. Response rates were particularly encouraging in first salvage, where the overall response rate was 91%. The SOS/VOD rate was 15% using this single-dose regimen, which was similar to the 17% rate observed in the initial phase II study using a similar dosing strategy [ 10 ]. The median OS was 11 months, and the 1-year OS rate was 46%. The survival outcomes were compared to historical data with INO monotherapy using an inverse probability of treatment weighing analysis, which suggested that the combination therapy was superior to expectations with INO monotherapy.

Evolution of the hyper-CVD and inotuzumab ozogamicin ± blinatumomab regimen at MD Anderson Cancer Center. A .) Hyper-CVD plus inotuzumab ozogamicin, B .) Hyper-CVD plus inotuzumab ozogamicin with sequential blinatumomab, C .) “Dose dense” hyper-CVD, inotuzumab ozogamicin and blinatumomab

This study was then amended to further reduce and fractionate the dose of INO, add blinatumomab, and mandate ursodiol prophylaxis (Fig.  2 B) [ 24 ]. The purpose of these changes was two-fold: to deepen response with the addition of blinatumomab and to mitigate the risk of SOS/VOD by reducing the dose of INO and by increasing the interval between the last dose of INO and allogeneic HSCT. In this new design, patients received 4 cycles of mini-hyper-CVD plus INO, followed by 4 cycles of blinatumomab, and then a maintenance phase of blocks of POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone) alternating with blinatumomab. INO was reduced to 0.6 mg/m 2 on day 2 and 0.3 mg/m 2 on day 8 in cycle 1 and 0.3 mg/m 2 on days 2 and 8 in cycles 2–4 (cumulative dose of 2.7 mg/m 2 ). In the most recent published analysis of the mini-hyper-CVD, INO ± blinatumomab regimen (with blinatumomab given to patients #68+), 110 patients have been treated [ 25 ]. The overall response rate was 83%, and 82% of responders achieved MRD negativity by flow cytometry. The median OS was 17 months, and the 3-year OS rate was 40%. Outcomes were best for those treated in first salvage, where the median OS was 31 months, and the 3-year OS rate was 49%. In a landmark analysis, there was no benefit for receipt of subsequent allogeneic HSCT (3-year OS 54% for both groups). The SOS/VOD rate was also observed to be lower after the amendment to reduce and fractionate INO and add blinatumomab (2% vs. 13% with the previous design; P  = 0.05). These data highlight that SOS/VOD can be substantially mitigated with use of lower doses of INO without compromising efficacy.

The mini-hyper-CVD, INO and blinatumomab regimen has now been amended to administer to deliver all agents beginning in cycle 1 (Fig.  2 C). In the latest study design, 6 cycles of “dose-dense” mini-hyper-CVD, INO and blinatumomab are given, followed by POMP/blinatumomab maintenance in non-transplanted patients. In each cycle, blinatumomab is started on day 4 (i.e. once the mini-hyper-CVD chemotherapy has been delivered) and continues through day 21 of each cycle, followed by a 7-day break before beginning the next cycle. To date, 15 patients with relapsed/refractory ALL have been treated with this regimen. All patients responded, with 92% achieving flow MRD negativity (77% after 1 cycle) [ 26 ]. High rates of early response have also been observed in a retrospective analysis of this regimen in both newly diagnosed and relapsed/refractory patients [ 27 ]. Among patients with newly diagnosed or MRD-positive ALL, 10/11 (91%) achieved MRD negativity at a level of 10 − 6 by next-generation sequencing, an endpoint shown to be associated with superior outcomes in ALL [ 28 , 29 ]. The deep and rapid MRD negative responses with the dose-dose mini-hyper-CVD, INO and blinatumomab regimen are encouraging, and this regimen is also now being evaluated in older adults with newly diagnosed B-cell ALL.

Combination therapies with INO for newly diagnosed ALL

Older adults.

Several studies are also evaluating INO in patients with newly diagnosed ALL. Most of these efforts have focused on its use in older adults, a group with poor tolerance to conventional chemotherapy and with historical long-term OS rates of only 20% [ 31 , 32 ]. Ongoing trials exploring INO in the frontline setting are shown in Table  3 , and a summary of available trial data of INO-based regimens in older adults with ALL is shown in Table  4 . At MD Anderson Cancer Center, the same mini-hyper-CVD plus INO regimen previously described was also studied in patients ≥ 60 years of age with newly diagnosed Ph-negative B-cell ALL [ 32 ]. Initially, 52 patients with a median age of 68 years were treated. The overall response rate was 98%, with 96% of patients achieving MRD negativity by flow cytometry. These high rates of response translated to encouraging long-term survival with 3-year progression-free survival (PFS) and OS rates of 49% and 56%, respectively. As with the relapsed/refractory study, this regimen was later amended to use lower, fractionated doses of INO (cumulative dose 2.7 mg/m 2 ), add blinatumomab and mandate ursodiol prophylaxis. A total of 80 older patients have been treated with the mini-hyper-CVD, INO ± blinatumomab regimen (patients #50 + treated with the updated regimen) [ 33 ]. Twelve patients (15%) have relapsed, and the 5-year PFS and OS rates are 44% and 46%, respectively. These outcomes compare favorably to the historical 5-year OS rate of approximately 20% when chemotherapy alone is used. The superiority of the mini-hyper-CVD, INO and blinatumomab regimen as compared with dose-reduced hyper-CVAD in a similar older population was confirmed in a propensity score analysis [ 34 ].

Despite the improvement over historical expectations, toxicity is still a significant concern with this regimen. Overall, 35 patients (44%) died in remission (including 9 from myelodysplastic syndrome or acute myeloid leukemia, 8 from infection and 5 from SOS/VOD). The risk of death in remission was higher in patients ≥ 70 years of age (accounting for 85% of deaths in remission), resulting in age-dependent survival outcomes (median OS 75 months, 47 months, and 35 months for patients 60–64, 65–69 and ≥ 70 years of age, respectively). Due to the specific risks related to the chemotherapy backbone (e.g. secondary myeloid malignancy and infection), patients ≥ 70 years of age will now receive INO and blinatumomab only, without the mini-hyper-CVD backbone. A similar approach has been evaluated in the Alliance A041703 study [ 35 ]. In this trial, patients ≥ 60 years of age with newly diagnosed Ph-negative B-cell ALL received induction with fractionated INO at 1.8 mg/m 2 in cycle 1 and 1.5 mg/m 2 in cycle 2, followed by consolidation with blinatumomab for 4–5 cycles. Among 33 patients treated, the overall response rate was 96% (85% after INO induction), and the 1-year OS rate was 84%. Longer term follow-up will be needed to confirm the durability of these responses.

Several other INO-based frontline regimens are being evaluated in older adults with newly diagnosed ALL. In the INITIAL-1 study, patients > 55 years of age with newly diagnosed Ph-negative B-cell ALL received induction with 3 cycles of dexamethasone plus INO (1.8 mg/m 2 in cycle 1 and 1.5 mg/m 2 in cycles 2–3), followed by 6 cycles of age-adjusted chemotherapy as consolidation/maintenance. 37 Forty-three patients were treated with a median age of 64 years (range, 56–80 years). All patients achieved CR/CRi, with 71% achieving MRD negativity at a sensitivity of 10 − 4 after the 3 cycles of INO induction. The 3-year event-free survival (EFS) and OS rates were 55% and 73%, respectively, and there was only 1 case of non-fatal SOS/VOD. The EWALL-INO study also enrolled a similar population of patients and treated them with 2 cycles of induction consisting of INO, vincristine and dexamethasone (induction 1) and INO, cyclophosphamide and dexamethasone (induction 2), followed by 6 cycles of age-adjusted consolidation and then POMP maintenance [ 37 ]. Overall, 131 patients were treated, and the CR/CRi rate after 2 cycles of induction was 90%. The estimated 2-year OS rate was 54%. Taken together, these studies show that frontline INO-based therapy is safe and effective in older adults with B-cell ALL. Building on the promising experience with the mini-hyper-CVD and INO regimen from MD Anderson, the Alliance A042001 is a randomized phase II study evaluating mini-hyper-CVD plus INO versus dose-adjusted hyper-CVAD in older adults (≥ 50 years of age) with newly diagnosed B-cell ALL [ 38 ]. No data are yet available, and this study is ongoing.

Younger adults

Combination approaches using INO are also being explored in younger adults with newly diagnosed ALL. At MD Anderson, we developed a protocol of hyper-CVAD plus blinatumomab, which has now been amended to add INO. The hyper-CVAD plus blinatumomab regimen consists of 4 cycles of hyper-CVAD, followed by 4 cycles of blinatumomab, and then POMP and blinatumomab maintenance. In the first 38 patients treated, all patients responded, with 97% becoming MRD negative by flow cytometry. This translated to encouraging 3-year relapse-free survival (RFS) and OS rates of 73% and 81%, respectively [ 39 ]. An additional 37 patients have now been treated with the addition of INO (0.3 mg/m 2 on day 1 and 8 of cycles 2, 4, 6 and 8; cumulative dose of 2.4 mg/m 2 ) [ 41 ]. With a median follow-up of 22 months, only 3 relapses have been observed. The estimated 2-year RFS and OS rates of 88% and 100%, respectively. The initial data with the addition of INO are encouraging and suggest a potential benefit with the routine use of INO in younger patients with newly diagnosed Ph-negative B-cell ALL.

Of note, the Alliance A041501 was a randomized study that also evaluated the addition of INO to standard chemotherapy (CALGB 10,403 backbone) in newly diagnosed B-cell ALL. This study was suspended due to toxicity concerns with the combination regimen, possibly related to the use of multiple hepatoxic agents in this regimen (e.g. INO and asparaginase). The lack of success of this study highlights the need for rationale combinations with INO and to avoid overlapping toxicities.

Other investigational applications of INO in ALL

Ino for mrd-positive disease.

In the INO-VATE study, INO was associated with a flow MRD negativity rate of 63% among responders [ 41 ] and provided support for the evaluation of INO for MRD-positive B-cell ALL. In a phase II study, 26 patients with MRD-positive ALL were enrolled and treated with INO at a dose of 0.6 mg/m 2 and 0.3 mg/m 2 on days 1 and 8, respectively, of cycle 1 and 0.3 mg/m 2 on day 1 and 8 of cycles 2-6 [ 42 ]. Sixteen patients (62%) had Ph-positive ALL and also received a BCR::ABL1 TKI (predominantly ponatinib). The MRD negativity response at a sensitivity of 10 − 4 was 69%, which translated to a 2-year OS rate of 60%. In another study from GIMEMA, INO was evaluated in 20 patients with MRD-positive B-cell ALL. Eleven of 20 patients (55%) achieved MRD response < 10 − 4 [ 44 ]. These encouraging data support the further of evaluation of INO as an MRD-directed therapy in ALL and also provide support for its continued evaluation in the frontline setting to induce deep, MRD-negative remissions.

INO for Ph + ALL

INO is active in relapsed/refractory Ph-positive ALL and achieves a CR/CRi rate of 73% and median OS of 8.7 months, which are similar to the findings from the broader population of the INO-VATE study [ 14 ]. In a phase I/II study, INO was combined with bosutinib in patients with relapsed/refractory Ph-positive ALL who did not harbor a T315I mutation [ 44 ]. Among 18 patients (16 with Ph-positive ALL and 2 with CML in lymphoid blast phase), the CR/CRi rate was 83%, with 56% achieving a complete molecular response. The median OS was 13.5 months, which appears superior to expectations with INO as monotherapy.

INO as post-transplant maintenance

INO has been evaluated as post-transplant maintenance in a phase I study of patients with CD22-positive ALL and high-risk for relapse [ 45 ]. INO doses of 0.3 mg/m 2 to 0.6 mg/m 2 were administered once per cycle for up to 12 cycles. The MTD was 0.6 mg/m 2 . Among 18 treated patients, no cases of SOS/VOD were observed. With a median follow-up of 18.1 months, only 2 relapses were observed, and the 1-year PFS and OS rates were 89% and 94%, respectively. This study suggests that low-dose INO can be safely administered in the peri-transplant setting and may also be helpful in preventing relapse in high-risk patients.

Sequencing of INO with CAR T-cell therapy

In clinical practice, INO is commonly given prior to CAR T-cell therapy, either as a salvage regimen and as bridging therapy. However, the data are mixed regarding whether prior INO exposure impacts the effectiveness of CAR T-cells [ 46 , 47 , 48 ]. Some studies in children have suggested that prior INO—including INO as bridging therapy—did not impact response rates or long-term outcomes following tisagenlecleucel, as compared with historical expectations [ 46 , 47 ]. However, in the ZUMA-3 study of brexucabtagene autoleucel in adult patients, those with prior INO exposure had numerically lower CR/CRi rates (59% with prior INO exposure versus 77% without prior INO exposure) and inferior OS (median OS 8.8 months and 47.0 months, respectively) [ 48 ]. Future studies evaluating the optimal sequencing of INO with other available therapies—including blinatumomab and CD19 CAR T-cells—and the use of INO as bridging therapy prior to CAR T-cell therapy are needed.

Conclusions

Along with the blinatumomab and CAR T-cells, the clinical development of INO has been a major contributor to improving outcomes of adult ALL over the past decade [ 49 ]. While INO has been shown to be more effective than conventional cytotoxic chemotherapy in relapsed/refractory B-cell ALL, its greatest potential is as combination therapy in both the frontline and salvage settings. When used along with low-dose chemotherapy and blinatumomab in relapsed/refractory ALL, a 3-year OS rate > 50% has been observed, even in non-transplanted patients. Similarly, very encouraging outcomes have been observed with INO in newly diagnosed B-cell ALL, whether combined with chemotherapy, blinatumomab or both. Over the course of these studies, the INO dose has been modified, with some studies suggesting that lower, fractionated doses of INO can be highly effective and may also reduce the risk of SOS/VOD, which is one of the feared potential toxicities of INO. Studies continue to expand the potential applications of INO, including its use for MRD-positive disease, combination with BCR::ABL1 tyrosine kinase inhibitors, and its use in low doses as post-transplant maintenance. Many of these ongoing research efforts seek to explore alternative dosing strategies of INO. New translational research is also seeking to understand the mechanisms of resistance to INO, which may help to inform future rational drug combinations [ 50 , 51 , 52 , 53 ]. The FDA approval of INO in 2017 marked a major milestone that paved the way for these important studies, but it is imperative to note that this was just one step in the clinical development of INO. The research that has followed in the years since the INO-VATE study highlight a truism in oncology: that regulatory approval of a drug is often only the beginning of its true clinical development and innovation.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

Acute lymphoblastic leukemia

Confidence interval

Chronic myeloid leukemia

Complete remission

Complete remission with incomplete hematologic recovery

Event-free survival

Food and Drug Administration

Hematopoietic stem cell transplantation

Inotuzumab ozogamicin

Dose-attenuated hyperfractionated cyclophosphamide, vincristine and dexamethasone alternating with methotrexate and cytarabine

Measurable residual disease

Maximum tolerated dose

Non-relapse mortality

Overall survival

Progression-free survival

Philadelphia chromosome

6-mercaptopurine, vincristine, methotrexate, and prednisone

Relapse-free survival

Sinusoidal obstruction syndrome

Tyrosine kinase inhibitor

Veno-occlusive disease

Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia. N Engl J Med. 2016;375:740–53.

Article   CAS   PubMed   PubMed Central   Google Scholar  

DiJoseph JF, Armellino DC, Boghaert ER, et al. Antibody-targeted chemotherapy with CMC-544: a CD22-targeted immunoconjugate of calicheamicin for the treatment of B-lymphoid malignancies. Blood. 2004;103:1807–14.

Article   CAS   PubMed   Google Scholar  

DiJoseph JF, Goad ME, Dougher MM, et al. Potent and specific antitumor efficacy of CMC-544, a CD22-targeted immunoconjugate of calicheamicin, against systemically disseminated B-cell lymphoma. Clin Cancer Res. 2004;10:8620–9.

DiJoseph JF, Dougher MM, Kalyandrug LB, et al. Antitumor efficacy of a combination of CMC-544 (inotuzumab ozogamicin), a CD22-targeted cytotoxic immunoconjugate of calicheamicin, and rituximab against Non-hodgkin’s B-cell lymphoma. Clin Cancer Res. 2006;12:242–9.

de Vries JF, Zwaan CM, De Bie M, et al. The novel calicheamicin-conjugated CD22 antibody inotuzumab ozogamicin (CMC-544) effectively kills primary pediatric acute lymphoblastic leukemia cells. Leukemia. 2012;26:255–64.

Article   PubMed   Google Scholar  

Dijoseph JF, Dougher MM, Armellino DC, Evans DY, Damle NK. Therapeutic potential of CD22-specific antibody-targeted chemotherapy using inotuzumab ozogamicin (CMC-544) for the treatment of acute lymphoblastic leukemia. Leukemia. 2007;21:2240–5.

Advani A, Coiffier B, Czuczman MS, et al. Safety, pharmacokinetics, and preliminary clinical activity of inotuzumab ozogamicin, a novel immunoconjugate for the treatment of B-cell non-hodgkin’s lymphoma: results of a phase I study. J Clin Oncol. 2010;28:2085–93.

Dang NH, Ogura M, Castaigne S, et al. Randomized, phase 3 trial of inotuzumab ozogamicin plus rituximab versus chemotherapy plus rituximab for relapsed/refractory aggressive B-cell non-hodgkin lymphoma. Br J Haematol. 2018;182:583–6.

Dang NH, Ogura M, Castaigne S, et al. Randomized, phase 3 trial of inotuzumab ozogamicin plus rituximab (R-InO) versus chemotherapy for relapsed/refractory aggressive B-cell non-hodgkin lymphoma (B-NHL). J Clin Oncol. 2014;32:8529.

Article   Google Scholar  

Kantarjian H, Thomas D, Jorgensen J, et al. Inotuzumab ozogamicin, an anti-CD22–calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study. Lancet Oncol. 2012;13:403–11.

Kantarjian H, Thomas D, Jorgensen J, et al. Results of inotuzumab ozogamicin, a CD22 monoclonal antibody, in refractory and relapsed acute lymphocytic leukemia. Cancer. 2013;119:2728–36.

DeAngelo DJ, Stock W, Stein AS, et al. Inotuzumab ozogamicin in adults with relapsed or refractory CD22-positive acute lymphoblastic leukemia: a phase 1/2 study. Blood Adv. 2017;1:1167–80.

DeAngelo DJ, Advani AS, Marks DI, et al. Inotuzumab ozogamicin for relapsed/refractory acute lymphoblastic leukemia: outcomes by disease burden. Blood Cancer J. 2020;10:81.

Article   PubMed   PubMed Central   Google Scholar  

Stock W, Martinelli G, Stelljes M, et al. Efficacy of inotuzumab ozogamicin in patients with Philadelphia chromosome-positive relapsed/refractory acute lymphoblastic leukemia. Cancer. 2021;127:905–13.

Kantarjian HM, Stock W, Cassaday RD, et al. Inotuzumab Ozogamicin for Relapsed/Refractory Acute Lymphoblastic Leukemia in the INO-VATE trial: CD22 Pharmacodynamics, Efficacy, and Safety by Baseline CD22. Clin Cancer Res. 2021;27:2742–54.

Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019;125:2474–87.

Marks DI, Kebriaei P, Stelljes M, et al. Outcomes of allogeneic stem cell transplantation after Inotuzumab Ozogamicin treatment for relapsed or refractory Acute Lymphoblastic Leukemia. Biol Blood Marrow Transpl. 2019;25:1720–9.

Article   CAS   Google Scholar  

Kantarjian HM, DeAngelo DJ, Advani AS, et al. Hepatic adverse event profile of inotuzumab ozogamicin in adult patients with relapsed or refractory acute lymphoblastic leukaemia: results from the open-label, randomised, phase 3 INO-VATE study. Lancet Haematol. 2017;4:e387–98.

Mohty M, Malard F, Abecassis M, et al. Sinusoidal obstruction syndrome/veno-occlusive disease: current situation and perspectives-a position statement from the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transpl. 2015;50:781–9.

Kebriaei PSR, Wallis W, et al. P739: predictive factors for developing veno-occlusive disease in patients with acute lymphoblastic leukemia treated with inotuzumab ozogamicin followed by allogeneic hematopoietic stem cell transplantation. Haematologica. 2017;102:299.

Google Scholar  

Kebriaei P, Cutler C, de Lima M, et al. Management of important adverse events associated with inotuzumab ozogamicin: expert panel review. Bone Marrow Transpl. 2018;53:449–56.

Giglio F, Xue E, Greco R, et al. Defibrotide Prophylaxis of Sinusoidal obstruction syndrome in adults treated with Inotuzumab Ozogamicin prior to hematopoietic stem cell transplantation. Front Oncol. 2022;12:933317.

Jabbour E, Ravandi F, Kebriaei P, et al. Salvage Chemoimmunotherapy with Inotuzumab Ozogamicin Combined with Mini-Hyper-CVD for patients with relapsed or refractory Philadelphia chromosome-negative Acute Lymphoblastic Leukemia: a phase 2 clinical trial. JAMA Oncol. 2018;4:230–4.

Jabbour E, Sasaki K, Short NJ, et al. Long-term follow-up of salvage therapy using a combination of inotuzumab ozogamicin and mini-hyper-CVD with or without blinatumomab in relapsed/refractory Philadelphia chromosome-negative acute lymphoblastic leukemia. Cancer. 2021;127:2025–38.

Kantarjian H, Haddad FG, Jain N, et al. Results of salvage therapy with mini-hyper-CVD and inotuzumab ozogamicin with or without blinatumomab in pre-B acute lymphoblastic leukemia. J Hematol Oncol. 2023;16:44.

Haddad F, Jabbour E, Nasnas C et al. S119: COMBINATION OF MINI-HYPER-CVD AND INOTUZUMAB (INO) FOLLOWED BY BLINATUMOMAB (BLINA) CONSOLIDATION IN PATIENTS WITH RELAPSED/REFRACTORY (R/R) ACUTE LYMPHOBLASTIC LEUKEMIA (ALL): A PHASE II TRIAL. Hemasphere 2023;7.

Short NJ, Jabbour E, Jamison T et al. Dose-dense Mini-Hyper-CVD, Inotuzumab Ozogamicin and Blinatumomab achieves Rapid MRD-Negativity in Philadelphia chromosome-negative B-cell Acute Lymphoblastic Leukemia. Clinical Lymphoma, Myeloma and Leukemia.

Short NJ, Kantarjian H, Ravandi F, et al. High-sensitivity next-generation sequencing MRD assessment in ALL identifies patients at very low risk of relapse. Blood Adv. 2022;6:4006–14.

Kotrová M, Koopmann J, Trautmann H, et al. Prognostic value of low-level MRD in adult acute lymphoblastic leukemia detected by low- and high-throughput methods. Blood Adv. 2022;6:3006–10.

Sive JI, Buck G, Fielding A, et al. Outcomes in older adults with acute lymphoblastic leukaemia (ALL): results from the international MRC UKALL XII/ECOG2993 trial. Br J Haematol. 2012;157:463–71.

O’Brien S, Thomas DA, Ravandi F, Faderl S, Pierce S, Kantarjian H. Results of the hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone regimen in elderly patients with acute lymphocytic leukemia. Cancer. 2008;113:2097–101.

Kantarjian H, Ravandi F, Short NJ, et al. Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2018;19:240–8.

Jabbour E, Short NJ, Senapati J, et al. Mini-hyper-CVD plus inotuzumab ozogamicin, with or without blinatumomab, in the subgroup of older patients with newly diagnosed Philadelphia chromosome-negative B-cell acute lymphocytic leukaemia: long-term results of an open-label phase 2 trial. Lancet Haematol. 2023;10:e433–44.

Jabbour EJ, Sasaki K, Ravandi F, et al. Inotuzumab ozogamicin in combination with low-intensity chemotherapy (mini-HCVD) with or without blinatumomab versus standard intensive chemotherapy (HCVAD) as frontline therapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukemia: a propensity score analysis. Cancer. 2019;125:2579–86.

Wieduwilt MJ, Yin J, Kour O, et al. Chemotherapy-free treatment with inotuzumab ozogamicin and blinatumomab for older adults with newly diagnosed, Ph-negative, CD22-positive, B-cell acute lymphoblastic leukemia: Alliance A041703. J Clin Oncol. 2023;41:7006.

Stelljes M, Raffel S, Alakel N et al. Inotuzumab Ozogamicin as induction therapy for patients older than 55 years with Philadelphia chromosome-negative B-Precursor ALL. J Clin Oncol 2023:Jco2300546.

Chevallier P, Leguay T, KIM R, et al. Fractionated Inotuzumab Ozogamicin combined with low-intensity chemotherapy in older patients with newly diagnosed CD22 + Philadelphia chromosome (Ph)-Negative B-Cell precursor (BCP) Acute Lymphoblastic Leukemia (ALL): results of the EWALL-INO Study. Blood. 2022;140:6114–6.

Muffly L. ALLIANCE A042001: a Randomized Clinical Trial to determine whether inotuzumab + Mini-HyperCVD will replace HyperCVAD as Frontline Treatment in older adult ALL. The Hematologist 2023;20.

Jabbour E, Short NJ, Jain N, et al. Hyper-CVAD and sequential blinatumomab for newly diagnosed Philadelphia chromosome-negative B-cell acute lymphocytic leukaemia: a single-arm, single-centre, phase 2 trial. Lancet Haematol. 2022;9:e878–85.

Nguyen D, Kantarjian HM, Short NJ, et al. Updated results from a phase II study of Hyper-CVAD, with or without Inotuzumab Ozogamicin, and sequential blinatumomab in patients with newly diagnosed B-Cell Acute Lymphoblastic Leukemia. Blood. 2023;142:4245.

Jabbour E, Gökbuget N, Advani A, et al. Impact of minimal residual disease status in patients with relapsed/refractory acute lymphoblastic leukemia treated with inotuzumab ozogamicin in the phase III INO-VATE trial. Leuk Res. 2020;88:106283.

Jabbour EJ, Haddad FG, Short NJ et al. Phase II study of inotuzumab ozogamicin for measurable residual disease in acute lymphoblastic leukemia in remission. Blood. 2024;143(5):417–21.

Marconi G, Piciocchi A, Chiaretti S, et al. Gimema ALL2418: interim analysis of a phase Iia Study of Feasibility and Effectiveness of Inotuzumab Ozogamicin in Adult patients with B-Cell Acute Lymphoblastic Leukemia with positive minimal residual disease before any hematopoietic stem cell transplantation. Blood. 2022;140:6119–21.

Jain N, Maiti A, Ravandi F, et al. Inotuzumab ozogamicin with bosutinib for relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia or lymphoid blast phase of chronic myeloid leukemia. Am J Hematol. 2021;96:1000–7.

Metheny L, Sobecks RM, Cho C et al. A multicenter study of posttransplant low-dose inotuzumab ozogamicin to prevent relapse of acute lymphoblastic leukemia. Blood Adv 2024.

Rubinstein JD, Breese EH, Krupski MC et al. The Choice of Either Conventional Chemotherapy or Inotuzumab Ozogamicin as Bridging Regimen Does Not Appear To Impact Clinical Response to CD19-Directed CAR-T Therapy in Pediatric B-ALL. Transplantation and Cellular Therapy, Official Publication of the American Society for Transplantation and Cellular Therapy. 2023;29:311.e1-.e7.

Ceolin V, Brivio E, van Tinteren H, et al. Outcome of chimeric antigen receptor T-cell therapy following treatment with inotuzumab ozogamicin in children with relapsed or refractory acute lymphoblastic leukemia. Leukemia. 2023;37:53–60.

Shah BD, Cassaday RD, Park JH, et al. Impact of prior therapies and subsequent transplantation on outcomes in adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia treated with brexucabtagene autoleucel in ZUMA-3. J Immunother Cancer. 2023;11:e007118.

Jabbour E, Short NJ, Jain N, et al. The evolution of acute lymphoblastic leukemia research and therapy at MD Anderson over four decades. J Hematol Oncol. 2023;16:22.

Wintering A, Ishiyama K, Tamaki S, et al. CD22low/Bcl-2high expression identifies poor response to inotuzumab ozogamicin in relapsed/refractory acute lymphoblastic leukemia. Blood Adv. 2023;7:251–5.

Ryland GL, Barraclough A, Fong CY, et al. Inotuzumab ozogamicin resistance associated with a novel CD22 truncating mutation in a case of B-acute lymphoblastic leukaemia. Br J Haematol. 2020;191:123–6.

Zhao Y, Short NJ, Kantarjian HM et al. Genomic determinants of response and resistance to inotuzumab ozogamicin in B-cell ALL. Blood. 2024. (In press)

Luskin MR, Shimony S, Keating J, et al. A phase I study of Venetoclax in Combination with Inotuzumab Ozogamicin for Relapsed or Refractory ALL in adults. Blood. 2023;142:1509.

Download references

Acknowledgements

The authors wish to thank Lewis Nasr MD and Omer Karrar MD for their assistance with creation of tables and formatting of the manuscript.

This research is supported in part by the MD Anderson Cancer Center Leukemia SPORE CA100632, and the NIH/NCI Cancer Center Support Grant P30 CA016672.

Author information

Authors and affiliations.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Unit 428, 1515 Holcombe Boulevard, Houston, TX, 77030, USA

Nicholas J. Short, Elias Jabbour, Nitin Jain & Hagop Kantarjian

You can also search for this author in PubMed   Google Scholar

Contributions

N.J.S. wrote the first draft of the manuscript. All authors reviewed and edited the manuscript and approve of the final version.

Corresponding author

Correspondence to Nicholas J. Short .

Ethics declarations

Ethics approval and consent to participate.

Not applicable.

Consent for publication

Competing interests.

N.J.S. has served as consultant for Pfizer Inc., GSK, NKARTA, Autolus, and Sanofi, reports receiving research grants from Takeda Oncology, Astellas Pharma Inc., Xencor, Stemline Therapeutics, and NextCure, and has received honoraria from Adaptive Biotechnologies, Novartis, Amgen, Takeda Oncology, Pfizer Inc., Astellas Pharma Inc., Sanofi and BeiGene. E.J. reports receiving research grants and consultancy fees from AbbVie, Adaptive Biotechnologies, Amgen, Ascentage, Bristol Myers Squibb, Genentech, Incyte, Pfizer, and Takeda. N.J. reports receiving research grants from Pharmacyclics, AbbVie, Genentech, AstraZeneca, BMS, Pfizer, ADC Therapeutics, Cellectis, Adaptive Biotechnologies, Precision Biosciences, Fate Therapeutics, Kite/Gilead, Mingsight, Takeda, Medisix, Loxo Oncology, Novalgen, Dialectic Therapeutics, Newave, TransThera Sciences, Novartis, Carna Biosciences, Sana Biotechnology, Kisoji Biotechnology, and has received honoraria from Pharmacyclics, Janssen, AbbVie, Genentech, AstraZeneca, BMS, Adaptive Biotechnologies, Kite/Gilead, Precision Biosciences, Beigene, Cellectis, MEI Pharma, Ipsen, CareDX, MingSight, and Novalgen. H.K. reports receiving research grants from AbbVie, Agios, Amgen, Ariad, Astex, BMS, Cyclacel, Daiichi-Sankyo, Immunogen, Jazz Pharma, Novartis, Pfizer, Actinium, and Takeda.

Additional information

Publisher’s note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ . The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Cite this article.

Short, N.J., Jabbour, E., Jain, N. et al. Inotuzumab ozogamicin for the treatment of adult acute lymphoblastic leukemia: past progress, current research and future directions. J Hematol Oncol 17 , 32 (2024). https://doi.org/10.1186/s13045-024-01552-7

Download citation

Received : 26 January 2024

Accepted : 29 April 2024

Published : 11 May 2024

DOI : https://doi.org/10.1186/s13045-024-01552-7

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Antibody-drug conjugate
• Clinical trials
• Lymphoid diseases
• Immunotherapy

Journal of Hematology & Oncology

ISSN: 1756-8722

• General enquiries: [email protected]

Log in using your username and password

• Search More Search for this keyword Advanced search
• Latest content
• Current issue
• BMJ Journals More You are viewing from: Google Indexer

You are here

• Online First
• Pilot study on large language models for risk-of-bias assessments in systematic reviews: A(I) new type of bias?
• Article Text
• Article info
• Citation Tools
• Rapid Responses
• Article metrics

• http://orcid.org/0000-0001-7989-6994 Joseph Barsby 1 , 2 ,
• http://orcid.org/0000-0003-4417-0370 Samuel Hume 1 , 3 ,
• http://orcid.org/0000-0002-7679-9125 Hamish AL Lemmey 1 , 4 ,
• http://orcid.org/0000-0002-2867-7393 Joseph Cutteridge 5 , 6 ,
• http://orcid.org/0000-0001-8621-5165 Regent Lee 7 ,
• http://orcid.org/0000-0003-3795-6762 Katarzyna D Bera 3 , 7
• 1 Oxford Medical School , Oxford , UK
• 2 Newcastle Upon Tyne Hospitals NHS Foundation Trust , Newcastle Upon Tyne , UK
• 3 University of Oxford St Anne's College , Oxford , UK
• 4 University of Oxford Magdalen College , Oxford , UK
• 5 York and Scarborough Teaching Hospitals NHS Foundation Trust , York , UK
• 6 Hull University Teaching Hospitals NHS Trust , Hull , UK
• 7 Nuffield Department of Surgical Sciences , University of Oxford , Oxford , UK
• Correspondence to Dr Katarzyna D Bera, University of Oxford Nuffield Department of Surgical Sciences, Oxford, UK; katarzyna.bera{at}st-annes.ox.ac.uk

https://doi.org/10.1136/bmjebm-2024-112990

Statistics from Altmetric.com

Request permissions.

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

• Systematic Reviews as Topic

Risk-of-bias (RoB) assessment is used to assess randomised control trials for systematic errors. Developed by Cochrane, it is considered the gold standard of assessing RoB for studies included within systematic reviews, representing a key part of Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. 1 The RoB tool comprises six domains that may signify bias: random sequence generation, allocation concealment, blinding of participants and personnel, attrition bias, reporting bias and other potential biases. 2 This assessment is an integral component of evaluating the quality of evidence; however, it is a time-consuming and labour-intensive process.

Large language models (LLMs) are a form of generative artificial intelligence (AI) trained on large volumes of data. ChatGPT is an LLM developed by OpenAI, capable of generating a wide variety of responses in response to user prompts. Concerns exist around the application of such AI tools in research, including ethical, copyright, plagiarism and cybersecurity risks. 3 However, LLMs are increasingly popular with investigators seeking to streamline analyses. Studies have begun investigating the potential role of LLMs in the RoB assessment process. 4 5 Given the flexibility and rapidly evolving nature of LLMs, our goal was to explore whether ChatGPT could be used to automate the RoB assessment process without sacrificing accuracy. This study offers an assessment of the applicability of LLMs in SRs as of December 2023.

This study sits within an SR (PROSPERO CRD420212479050). Two reviewers (SH and HALL) implemented RoB across n=15 full-length papers in portable document format (PDF) format ( table 1 ). Six domains were assessed independently alongside an added ‘overall assessment’ domain ranking each as high, low or unclear RoB. Alongside RoB assessment, reviewers recorded author name, DOI and publication year using a Microsoft Office form. Any conflicts were resolved by discussion, with a third reviewer (KDB) available for arbitration, although this was not required.

• View inline

List of included papers (n=15), numbered 1–15

In parallel, a fourth reviewer (JB) uploaded the same PDF files to ChatPDF.com, a plug-in powered by ChatGPT3.5 that facilitates the upload of PDF files for analysis by ChatGPT3.5. ChatGPT3.5 was prompted to assess the RoB within each paper through prompts pertaining to each of the six domains. Responses were recorded in a separate, but identical, Microsoft Office form. Reviewer 4 (JB) was blinded to the assessment of reviewers 1 and 2 throughout. JB then repeated this process using ChatGPT4.

Responses from decisions across all domains were compared considering percentage of concurrent decisions, opposite decisions and indeterminable decisions. All data were analysed and stored in Microsoft Excel. Gemini was trialled but was unable to perform a RoB assessment in its current form.

In total, n=105 decisions were undertaken by GPT3.5, GPT4 and human reviewers. ChatGPT3.5 was concurrent with human (gold standard) assessment in 41/105 (39.0%) decisions and disagreed on 10/105 (9.5%). ChatGPT4 agreed with human assessment on 34/105 (34.3%) decisions and disagreed on 15/105 (14.3%). Both ChatGPT3.5 and ChatGPT4 delivered an indeterminate response on 54/105 (51.4%) decisions. ChatGPT3.5 outperformed or matched the performance of ChatGPT4 in 6/7 (85.6%) domains (aside from selective reporting), with ChatGPT3.5 performing best in assessing sequence generation and completeness of data, with 8/15 (53.3%) concurrent with human assessment. ChatGPT4 performed best in assessing selective reporting, with 14/15 (93.3%) correct decisions. Results by domain are summarised in table 2 . Notably, GPT4 performed superiorly in one domain (selective reporting), returning a correct decision in 14/15 (93.3%) cases, while GPT3.5 was correct in 10/15 (66.7%) decisions.

Summary of risk-of-bias assessment outcome per domain assessed by ChatGPT3.5 and ChatGPT4 compared with human assessment

When assessing Karanikolas (2011) and Mann (1983), ChatGPT3.5 returned an assessment as ‘moderate’, and ‘low to moderate’, in the overall domain. Both were recorded as unclear as substitute. On one occasion, ChatGPT identified an author as ‘P. C. Weaver’, who is not an author on any included papers. When discussing Lastoria (2006), ChatGPT responded initially in Portuguese.

We explored the potential for ChatGPT as a tool for assessing RoB. Overall, ChatGPT demonstrated moderate agreement, and minor disagreement with gold standard (human) assessment. While encouraging, this suboptimal performance precludes us from recommending ChatGPT be used in real-world RoB assessment.

To emulate end-users, prompts were not standardised, and some questions were repeated to ensure accuracy. When responses were ‘moderate’, ChatGPT was prompted to reassess. Similarly, ChatGPT often declined to perform assessments, which required further prompting with alternate question structure or wording. When prompted to assess allocation concealment for Choksy (2006), ChatGPT summarised the process as follows: ‘randomisation was performed using a random number table and randomisation details were placed in sealed envelopes which were opened in the operating theatre’. Human assessment ranked this as low RoB, whereas ChatGPT ranked this as unclear stating ‘it [was] unclear whether these envelopes were opaque’, demonstrating a literal interpretation of the literature not seen in human assessment.

In this analysis, ChatGPT4 did not offer improvement on ChatGPT3.5 in any domain, aside from selective reporting. For selective reporting, ChatGPT4 returned a correct decision in 14/15 (93.3%) cases, and ChatGPT3.5 in 10/15 (66.7%). However, human assessment returned a decision of unclear on n=14/15 of these assessments. ChatGPT4’s inability to give a definitive assessment is perhaps best outlined by ChatGPT4’s response: ‘To make a definitive assessment, one would ideally compare the outcomes reported in the paper with those specified in the study’s protocol registration’. This could represent an improvement through appreciation of the wider context of a given paper.

Our findings have limitations: the sample size of included papers in this study was small and fairly homogenous. Additionally, we chose not to use standardised prompts. Prompt variability has been demonstrated to introduce output variability. 5 Future research could benefit from a larger and more diverse dataset, with standardised prompts to assess and improve consistency of responses.

Supplemental material

Ethics statements, patient consent for publication.

Not applicable.

Ethics approval

• McKenzie JE ,
• Bossuyt PM , et al
• Higgins JPT ,
• Altman DG ,
• Gøtzsche PC , et al
• Arshad HB ,
• Khan SU , et al
• Talukdar JR

Supplementary materials

Supplementary data.

This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

• Data supplement 1

X @scullingmonkey

Contributors Conception of study: JB and KDB. Data collection: JB, JC, KDB, SH, HALL. Data analysis: JB, JC and KDB. Data interpretation: JB, KDB and LR. Drafting of paper: JB, JC and KDB. Approval of final version: all authors. ChatGPT is the subject of this study and was only used as described in methods and results. ChatGPT was not used in analysing, drafting or rewriting of the paper.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests None declared.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

Read the full text or download the PDF: