https://orcid.org/0009-0003-6262-7220
Figures
Abstract
Objective
To develop a novel Target Product Profile (TPP) outlining the minimum and optimal requirements of probiotics targeting the maternal gut microbiome, create a research and development (R&D) pipeline of maternal microbiome interventions, and identify the highest potential probiotic candidates matching TPP criteria.
Design
A mixed-methods study including in-depth interviews, an international survey, and online public consultation, with systematic R&D pipeline development.
Methods
Stakeholder feedback from 23 interviews and 32 survey responses was analyzed to revise the TPP. A systematic search of databases (Adis Insight, ClinicalTrials.gov, WHO ICTRP, Ovid MEDLINE, and relevant grant databases) identified drugs, supplements, and biologics targeting the maternal gut microbiome. Probiotic candidates were matched against key TPP criteria to identify promising options for future research.
Main Outcome Measures
Stakeholder consensus (≥75% agreement) on TPP variables and identification of high-potential probiotic candidates.
Results
The TPP met consensus for most of the 20 variables: 16 for minimum and 14 for optimal targets. Interviews raised issues concerning indication, target population, diagnostic requirements, and efficacy outcomes. Of 38 candidates identified in the maternal microbiome pipeline (2000–2023), eight were probiotics, with one high-potential candidate (Vivomixx) and two medium-potential candidates (Lactobacillus spp. and Bifidobacterium spp.) identified.
Citation: Mills K, Tan J, Guneratne T, Keir L, Goldstein M, Ventola C, et al. (2025) Maternal gut microbiome interventions to improve maternal and perinatal health outcomes: Target product profile expert consensus and pipeline analysis. PLoS One 20(7): e0321543. https://doi.org/10.1371/journal.pone.0321543
Editor: Zaky A. Zaky, Beni-Suef University, EGYPT
Received: December 17, 2024; Accepted: March 7, 2025; Published: July 2, 2025
Copyright: © 2025 Mills et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: The research was funded by the Bill & Melinda Gates Foundation (Grant INV-038938). J.P.V. is supported by an Australian National Health and Medical Research Council Emerging Leadership Investigator Grant (Grant GNT1194248). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Maternal gut microbiome conditions have been associated with adverse pregnancy outcomes [1,2]. While this relationship is complex and not yet entirely understood, with limited prevalence data available, it is hypothesised that pregnant women in settings with poor sanitation, high pathogen exposure, and chronic infections may be more likely to have environmental enteric dysfunction (EED) [3–12]. EED is characterised by gastrointestinal dysbiosis and chronic low-grade inflammation in the small intestine, caused by subclinical enteropathogen infection [13]. This leads to altered gut morphology and impaired barrier function, resulting in poor macro/micronutrient absorption capacity [13]. Maternal EED appears to increase the likelihood of stillbirth, miscarriage, foetal growth restriction, preterm birth, small-for-gestational-age babies, and poor neonatal outcomes [14].
The use of microbial interventions targeting the maternal gut microbiome to address EED is an active research area; currently, no specific treatments are clinically recommended for EED in pregnant women or the general population [2,15]. Much of the current research on EED focusses on children, particularly in relation to stunting and diarrhea [1,16,17]. Probiotics, defined as “live microorganisms which when administered in adequate amounts confer a health benefit on the host”, can be used as a potential therapy to target the maternal gut microbiome [18]. Probiotics may be regulated in two ways – as supplements for general health benefits or as drugs to treat a specific condition or disease [19]. If probiotics were able to resolve or mitigate EED in pregnancy, this could theoretically optimise maternal nutritional absorption and lead to improved maternal and newborn health outcomes.
The Accelerating Innovation for Mothers (AIM) project, established in 2020, seeks to encourage investment in research and development (R&D) to address the lack of efficacious and accessible medicines and technologies for pregnancy-related conditions. To achieve this we adopted a multi-faceted approach, including development of the first target product profiles (TPPs) for maternal medicines, diagnostics and devices [20,21], and creating comprehensive pipelines of maternal medicines, diagnostics and devices R&D pipelines [22]. TPPs guide R&D stakeholders – such as donors, researchers, developers, manufacturers, innovators and regulators – to better accelerate their R&D efforts by defining the clinical and public health requirements for novel medical products [23,24]. We have also assessed candidates in these R&D pipelines against criteria in TPPs to identify high-potential medicines, diagnostics and devices on which to focus future R&D efforts to meet the needs of pregnant women with these conditions [25–27].
Currently, no TPPs or comprehensive R&D pipelines exist for maternal gut microbiome interventions. This study aimed to 1) develop the first TPP for maternal gut microbiome-altering drugs and supplements, specifically probiotics, to elicit improvements in maternal outcomes, 2) create an R&D pipeline of these interventions in clinical or preclinical development between 2000–2023, and 3) compare candidates in the clinical R&D pipeline to the TPP to identify the most promising candidates for further research.
Methods
Target product profile development
We prepared a study protocol for TPP development guided by the process outlined by Lewin et al [28], and informed by our previous TPPs for medicines for preeclampsia [20] and preterm birth [21] (Fig 1). The study protocol was reviewed and approved by the Alfred Ethics Committee for Human Research (project number 32/23).
Previous TPP templates from the AIM project, the World Health Organization (WHO) and other international organisations were reviewed to determine what criteria to include [20,21,29,30]. An initial TPP draft was developed based on extensive literature reviews and discussions with maternal health and microbial interventions subject matter experts. Subsequently, we conducted a comprehensive stakeholder mapping process to ensure diverse participation from ten key stakeholder groups: obstetricians, midwives/nurses, academic researchers, dieticians/nutritionists, antenatal care/nutrition programme managers, biotech and nutraceutical manufacturers, consumer representatives, guideline panel members, procurement experts, and international health agency/organisation staff. Systematic identification and snowball sampling were used to identify stakeholders (S2 Table).
International stakeholder survey.
An international online stakeholder survey was conducted between 20th August and 9th October 2023 using the survey platform Qualtrics [31]. Respondents rated their agreement with the intended use case scenario and characteristics for each variable (minimum and optimistic) using a 5-point Likert scale. Free-text comments could also be added. The survey and invitation email were available in English, French and Spanish.
Survey invitations were sent to maternal and perinatal health professionals and stakeholders from ten key groups (S2 Table). Efforts were made to ensure respondent diversity in location, gender, and professional role. The survey was also distributed through clinician-researcher networks and email distribution lists. The survey link was anonymous, and recipients were encouraged to forward it to other relevant stakeholders, so an exact response rate cannot be calculated. Consensus for any variable was pre-defined as at least 75% of respondents either agreeing or strongly agreeing.
In-depth stakeholder interviews and public consultation.
In parallel with the stakeholder survey, we conducted in-depth, one-on-one interviews with key stakeholders. Diverse perspectives were ensured by sampling participants from each of the ten stakeholder groups, as well as a range of respondents from different geographical location, country income level, and gender (S2 and S3 Tables). These interviews sought feedback on the draft TPP, focusing on background information, use-case scenario, and variable characteristics (minimum and optimal). A semi-structured guide was used, with interviews emphasising variables relevant to the expertise and perspective of each interviewee.
Between 24th July and 11th September 2023, we invited 109 stakeholders to participate, with 23 agreeing to take part. Stakeholders were contacted via email and provided with a copy of the TPP to review prior to the interview. Conducted via Zoom or Teams by an AIM project researcher (KM), each interview lasted up to 60 minutes and was conducted in English. Informed consent was obtained at the beginning of each interview, including consent to record the interviews to supplement notes captured during the interview. The draft TPP was also made available online between 20th August and 9th October 2023 via the Burnet Institute and Concept Foundation websites for public comment. Feedback was requested to be shared via email with the research team.
Synthesis, analysis and finalisation.
Stakeholder interview outputs were analysed using qualitative content analysis to identify major and minor issues, and key themes were summarised [32]. Additionally, barriers to effective product development or implementation were identified. Leveraging our previous experience in TPP development, directed content analysis was used to establish an initial coding framework and summative content analysis for counting and comparison of major and minor issues. Excel spreadsheets were used to collate and categorise all major and minor feedback for analysis.
Survey responses were analysed to determine whether consensus was reached for each variable. Written comments, especially on variables that did not reach consensus, were reviewed. Variables that did not meet consensus or with strong disagreement from interviews were discussed and modified in the TPP by the research team. All findings informed revisions to the draft TPP, including changes to the use case scenario (Box 1). The final draft was reviewed by the AIM project team before finalisation and publication (S1 Table).
Box 1. Final use case scenario in the TPP for probiotic interventions targeting the maternal gut microbiome
A probiotic supplement or drug that targets the maternal gut microbiome in pre-conception, pregnancy and/or lactation. The product should impact at least one of the following: maternal gut and systemic inflammation, gut permeability, pathogen burden or microbiome composition or functions that are linked to maternal (e.g., gestational diabetes, hypertension, obesity, preeclampsia, maternal infection) and/or infant (e.g., small for gestational age, preterm birth, low birth weight, sepsis, necrotising enterocolitis, wasting, stunting) outcomes. Interventions should be affordable, and self-administered non-invasively.
R&D pipeline development
The pipeline mapping strategy was designed to capture all drugs, dietary supplements and biologic candidates targeting the maternal gut microbiome in preclinical and clinical development. This approach, detailed in previous publications [25,27,33,34], involved a systematic search of relevant databases to identify all relevant candidates – this included Adis Insight, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP), Ovid MEDLINE and several grant databases. To be included, candidates had to meet the following inclusion criteria: a) intended to prevent or treat maternal EED; b) specifically tested in, indicated for or targeted for use in pregnant women and/or within the postpartum period; c) indicated for improvement of maternal outcomes or neonatal outcomes; d) either in active discovery/preclinical or clinical development now, or have been in development at one point between 2000 and 2023, or approved and registered for clinical use and/or used currently in clinical treatment (off-label); and e) either entirely new entities, existing/repurposed/label extensions, or new formulations or dosing of existing/registered products. Eligible candidates were compiled into a pipeline database summarising key information on each candidate, including product type, stage of R&D development, and an overview of trials conducted (S4 Table; https://www.policycuresresearch.org/maternal-health-pipeline/). Candidate profiles could also be filtered by a range of characteristics including active/inactive status, repurposed/new, and clinical use status.
Identifying high-potential candidates within the R&D pipeline
To evaluate the potential of R&D pipeline candidates based on the TPP, we applied an agnostic, systematic matching approach [25,26]. We used eight key variables from the TPP as ranking criteria for all probiotic candidates in clinical development (S5 Table). These variables were deemed most important for real-world implementation, informed by our previous TPP matching studies [25,26]. TPP matching was conducted by two independent reviewers (KM, TG), with any differences resolved through discussion with a third reviewer (AM). Preclinical candidates were not matched due to limited available information at this early stage of development.
Candidates were assigned a numerical score indicating the degree of alignment with each TPP variable. Variables such as efficacy and safety were accorded higher weighting (S5 Table). Matching scores were visually presented with candidates classified as meeting optimal criteria (dark green), meeting minimum criteria (light green), partially meeting minimum criteria (yellow), not meeting minimum criteria (red), or not yet known (grey). This systematic evaluation allowed classification of candidates as high, medium, or low potential based on available evidence.
Results
Target product profile development
Survey and public consultation.
Thirty-two survey responses were received, across all WHO geographical regions (S3 Table) – Western Pacific (15; 46.9%), Europe (6; 18.8%), the Americas (5; 15.6%), Africa (3; 9.4%), South-East Asia (2; 6.3%), and Eastern Mediterranean (1; 3.1%). There was gender diversity among the survey respondents – 20 women (63%), 11 men (34%), and 1 preferring to self-describe their gender (3%). Respondents included academic researchers (18; 50.0%), nurses/midwives (5; 13.9%), obstetricians (4; 11.1%), international health agency or organisation staff (4; 11.1%), international guideline panel member (1; 2.8%), staff of microbiome or nutritional product companies (1; 2.8%), maternity health services manager (1; 2.8%), and other (2; 5.6%). One respondent disclosed a potential commercial or financial conflict of interest.
The online survey met the 75% or more consensus threshold for the majority of the 20 TPP variables – 16 for minimum and 14 for optimal targets (Fig 2). Agreement was less than 75% for both minimum and optimal targets for three variables – companion diagnostics, treatment adherence and volume estimates. The clinical endpoint variable did not meet consensus for the minimum target only. Consensus was not met for the optimal target of target population, clinical monitoring, and expected financing sources. Written comments explained rationales for disagreement on these variables. No responses were received via the online public consultation webpages.
Stakeholder interviews.
In-depth interviews were conducted with 23 expert stakeholders (16 females and 7 males), representing various WHO regions (five from Africa, five from the Americas, five from South-East Asia, three from Europe, three from Western Pacific and two from Eastern Mediterranean) – 57% from low- or middle-income countries and 43% from high-income countries (S3 Table). Interview participants were included from all ten key stakeholder groups.
Findings from both the survey and interviews were broadly aligned. Major themes included discussions on indication and target population, with consensus that interventions should focus on population rather than individual level due to a current lack of EED diagnostics. This was also reflected in several survey comments. Key population-level risk factors such as poor sanitation, high environmental pathogen burden and recurrent infections were highlighted for targeting populations for probiotic supplements. However, unlike probiotic supplements, probiotic drugs would remain specifically indicated for EED at the individual level. Several interviewees noted the importance of including overweight or obese women, as well as those who are undernourished.
Most interviewees expressed disagreement with initial iterations of the efficacy outcomes which focused solely on measures of gut inflammation, noting the complexities of EED pathogenesis and lack of consensus on a validated diagnostic test. Many stakeholders were uncertain regarding what constituted a clinically significant difference in EED, given the incomplete state of current knowledge on how a healthy gut microbiome should be defined, as well as variations in gut microbiome composition across populations.
Minor themes included consideration of prebiotics or synbiotics (a combination of prebiotics and probiotics) in the background information, and basing volume estimations on the prevalence of risk factors for EED (such as poor water, sanitation and hygiene, and undernutrition), rather than EED incidence, which is currently not known. Two interviewees raised concerns about the safety of probiotic use in pregnant women, based on a 2021 Cochrane review [35] that reported a potentially increased risk of pre-eclampsia in overweight and obese women taking probiotics.
Finalisation of Target Product Profile.
The author group refined the indication to distinguish between probiotic supplements for gut health and probiotic drugs for treating EED. The target population was amended to a population-level focus in settings with increased risk of EED. Clinical efficacy outcomes were expanded to include systematic inflammatory markers, reduced enteropathogen abundance, improved pregnancy or birth outcomes, improved breastmilk composition, and improved infant growth or health outcomes. Probiotic supplements no longer required diagnostic testing, whereas this remained a requirement for probiotic drugs. A label claim variable was added in place of clinical endpoint for licensure, as this was deemed more relevant, and the treatment adherence variable was removed. Volume estimates were updated to reflect the population-level focus of the TPP, replacing individual EED diagnosis. Full details of the final TPP can be found in S1 Table.
Mapping and analysis of the R&D maternal microbiome medicines pipeline
Between 2000 and 2023, 38 candidates were identified as part of the complete maternal microbiome interventions pipeline (S6 Table). None of the 38 candidates were approved for use for maternal gut microbiome-related indications. Most (30; 79%) were in active development, with evidence of R&D activity within the last three years, while the remaining eight candidates (21%) were inactive (Fig 3). Of the 38 candidates, twelve (32%) were in the discovery or preclinical phase, two (5%) in Phase I, 23 (60%) in Phase II, none (0%) in Phase III, and one (3%) (a fermented soy and dairy product) was not specified. Eleven candidates (29%), most of which were traditional fermented foods, were ‘region specific’ – that is, originating from a specific country or geographical region. Nearly all candidates (32; 84%) were repurposed rather than new biological or chemical entities.
Nearly half (18; 47%) were microbial interventions, followed by bioactive compounds (17 candidates (45%); glycans, polyphenols, fatty acids or microbial metabolites), and small-molecule drugs (3 candidates (8%)) (Fig 4). Of the 18 microbial interventions, nine were fermented foods, eight were probiotic supplements and one was a faecal microbiota transplant. Details of the eight probiotic candidates can be found in Table 1.
Target product profile matching of candidates
Seven of the eight probiotic supplements were in clinical development and thus were matched against key TPP variables. These candidates included one in Phase I and six in Phase II. None had efficacy evidence, as no trials in pregnant women with or at risk of EED had been completed; one trial involving women with EED was ongoing [36]. Among these candidates, one was assessed as high potential, two as medium potential and four as low potential (S5 Table).
The high potential candidate was Vivomixx, consisting of eight probiotic strains. This candidate met either minimum or optimal characteristics for six variables – target population, target country, companion diagnostic, clinical monitoring, safety and format/administration. A Phase II trial is ongoing in Senegal with 76 pregnant women with EED [36]. Additionally, a completed study in Denmark including 49 obese pregnant women (not tested for EED) investigated the effects of this formulation on gestational weight gain and maternal glucose homeostasis [37]. However, the study concluded larger trials are needed to evaluate pregnancy-related outcomes. There is currently insufficient information to assess the remaining key variables (efficacy and stability).
Two candidates were ranked as medium potential. Lactobacillus spp. met optimal characteristics for three variables – target country, format/administration, and stability – and partially met the minimum criteria for target population. This was due to evidence from two clinical trials in pregnant women, with one completed (but no published results available) in Sweden [38] and one ongoing in Ghana [39]. Bifidobacterium spp. met optimal characteristics for four variables, including target country, safety, formulation/administration, and stability. This was based on evidence available from two clinical trials exploring Bifidobacterium spp., both of which investigated strain transfer from pregnant women to infants – one completed in Ireland [40] and one ongoing in China [41].
Four probiotics combinations (Lactobacillus and Bifidobacterium – combined, Probiotic combination – four unspecified strains, Probiotic combination – unspecified strains, and Probiotics and LC-PUFA – combined, unspecified strains) were ranked as low potential candidates. Lactobacillus and Bifidobacterium – combined met optimal characteristics for two variables – format/administration and stability – and partially met for target country. Data exists from two clinical trials for this candidate, with a study in the US not yet publishing results, and a study in China being halted due to recruitment difficulties [42,43]. All other variables had insufficient information available to assess. The remaining three low potential candidates had only one clinical trial registered each [44–46], and no published results were available.
Discussion
Main findings
We have developed the first R&D pipeline and publicly available TPP for interventions targeting the maternal gut microbiome. Using a mixed-methods approach with inputs from a diverse international sample of stakeholders, our study found agreement among participants for most TPP variables. Participants largely agreed that 1) to be effective, probiotic interventions should be implemented at a population level unless an appropriate diagnostic test for EED is developed; 2) there should be a special focus on low-resource settings where the burden of EED is likely greatest; 3) the safety of any product must be guaranteed before implementation and scale-up; 4) product stability without any need for cold chain is required; and 5) products must be affordable, particularly in low- and middle-income countries (LMICs). Additionally, stakeholders believed that a broader set of clinical efficacy outcomes is required in future research, given the diversity of health effects that may be associated with targeting the maternal gut microbiome [47]. The R&D pipeline for candidate medicines targeting the maternal gut microbiome found few candidates overall. However, despite the early stage of R&D for this condition, of the candidates identified a high proportion were active, reflecting increasing interest in this field in recent years. Eight out of 38 candidates were probiotics, and only one of these is currently being investigated in a clinical trial specifically for EED in pregnant women.
Interpretation, in light of known evidence
Stakeholder feedback was dominated by whether the intervention should target women with EED specifically or be applied population-wide. This reflects the current challenge in diagnosing EED due to the absence of an agreed, validated diagnostic test for pregnant women [48]. While an intestinal biopsy via endoscopy is the gold standard for diagnosing EED, it is not recommended during pregnancy due to potential safety concerns [49,50]. Ideally, a non-invasive diagnostic test would be developed to test pregnant women for EED, however achieving this will require innovative R&D advancements. Many nutritional deficiencies during pregnancy are addressed with population-level strategies, in part due to diagnostic challenges. For example, calcium supplementation for pregnant women in settings with low dietary calcium intake to prevent hypertensive disorders, and folic acid intake to reduce risk of neural tube defects [51], are both population-level health strategies, as opposed to testing and treating individual women for deficiencies. This approach removes the need for individual diagnostics but leads to a degree of over-treatment in those who are not deficient. Additionally, different approaches would be required for designing interventions at the individual-level compared to population-level. Much of the EED research to date has focused on population-level probiotic interventions targeting the gut microbiome of infants and children, particularly relating to treating diarrheal disease and growth stunting [1,52,53]. Studies have shown potential benefits of probiotics in infants and children with EED for these conditions [54–56], suggesting similar population-level approaches could be effective for pregnant women at risk of EED.
Overall, the pipeline of maternal gut microbiome candidates is small when compared to other maternal health conditions, such as pre-eclampsia and preterm labour/birth [25,26], with limited evidence available for all candidates [57]. However, analysis of this novel pipeline demonstrates there is a growing interest in this area of research. Despite the overall low number of candidates, there are a proportionately higher number of active candidates for maternal gut microbiome compared to other pregnancy-related conditions. Two-thirds of the candidates in the maternal gut microbiome pipeline commenced R&D within the previous five years, and almost 95% of R&D for all candidates began in the last ten years. The surge in R&D in recent years reflects an increased interest in the maternal gut microbiome that is likely to continue into the future.
Currently, the prevalence of EED in the general population and pregnant women is not known, in part due to the diagnostic barriers [12]. Despite limited diagnostics for EED, studies conducted in children with diarrheal disease and stunting show very high EED rates in populations with poor sanitation, high pathogen burden and chronic infections [1,52,53]. Although EED may not be regarded as a high-priority maternal condition like pre-eclampsia or postpartum haemorrhage (PPH), its impact on the gut microbiome likely influences the effectiveness of numerous interventions aimed at improving maternal outcomes. The detrimental effect of EED on the gut microbiome can reduce the absorption of critical nutrients, potentially undermining the efficacy of nutritional supplements such as iron, folic acid, and calcium, all of which are recommended for pregnant women [14,58]. This malabsorption can exacerbate general undernutrition and multi-nutrient deficiencies during pregnancy, in turn further affecting maternal outcomes. For example, anaemia, which is exacerbated by poor nutrient absorption, can increase the risk of PPH [59]. Therefore, if probiotics targeting the maternal gut microbiome prove effective in addressing EED, they could also prevent various pregnancy-related conditions and improve newborn and infant outcomes.
Clinical and research implications
The complexity of the gut microbiome, influenced by factors such as nutrition and the environment [60], suggests that probiotics are unlikely to be a ‘silver bullet’ intervention that resolves all gut microbiome-related issues. A multifaceted public health approach, combining interventions such as probiotics (and pre- or post-biotics), alongside nutritional and environmental interventions will likely be more effective and sustainable in altering gut microbiome composition [61]. Additionally, as there is a vast diversity of probiotics with many different strains and combinations of strains [62], as well as different target mechanisms (e.g., inflammation vs pathogen suppression), the efficacy of probiotics is both strain-specific and disease-specific [63]. This indicates no single probiotic strain would effectively address all pregnancy-related conditions. Individualised analysis of the gut microbiome to develop personalised treatments is being explored outside of the maternal health space and may help to address this challenge [64]. Further evidence, including through basic research, is needed to identify the most promising strains or combinations for improving a range of maternal, foetal and newborn outcomes.
Importantly, gut microbiome composition differs across geographical regions and ethnicities [65–67]. A greater understanding of these differences is essential for developing region- or population-specific probiotic products. Notably, nearly all trials identified in the pipeline, as well as most preclinical studies, were conducted in high-income countries, highlighting a significant gap in understanding the impact of probiotics across diverse population groups. In addition, the gut microbiome undergoes changes during pregnancy [47,68,69]. Should an effective probiotic product be discovered, formative research would be needed in diverse contexts to understand local feasibility and acceptability, facilitating effective implementation.
Key research questions remain to facilitate the development of a probiotic product that meets the parameters of the TPP. Given the clinical efficacy of probiotics on maternal, foetal and infant outcomes is not yet known for all candidates in the pipeline, efficacy trials are required before these candidates can be considered for treating EED. To date, systematic reviews have found no benefits of probiotics during pregnancy [70–72], though available evidence is limited, much of which is low certainty. Additionally, safety data are critical. While the safety of probiotic use during pregnancy has generally been shown,[73] a Cochrane review found an increased risk of pre-eclampsia in overweight and obese pregnant women with probiotic use compared to placebo (RR 1.85, 95% CI 1.04 to 3.29; 4 studies, 955 women; high‐certainty evidence)[35]. In contrast, a 2024 systematic review found no evidence of increased pre-eclampsia risk with probiotic use during pregnancy [70]. Future trials should measure and minimise potential harms.
Despite the current lack of trial evidence on the effects of probiotics on pregnancy-related outcomes, and a dearth of trials in pregnant women with EED, there is considerable interest in this field [47]. There are efforts underway to develop a diagnostic test suitable for use during pregnancy, with a range of different technologies being explored [1,5,74,75]. Biomarkers are particularly promising - many potential biomarkers are being explored for use in EED diagnostics [74,76–79]. Ideally, an EED diagnostic test would be simple to use, non-invasive, available at point-of-care in antenatal settings and affordable. This would allow treatment interventions to be targeted to the individual woman, rather than requiring population-wide strategies. As an emerging and complex area, where much is still not fully understood, creating a rigorous and structured approach to research into EED in pregnant women will help to focus efforts on the highest potential areas [47,80]. This TPP, R&D pipeline and candidate matching approach can better guide all stakeholders involved and provide rigour and structure to this field of research.
Strengths and limitations
This is the first TPP developed for interventions targeting the maternal gut microbiome. Systematic stakeholder mapping ensured diverse participants and views were obtained, in terms of geographical location, expertise and gender. This diversity, including strong representation from LMICs, ensures a balanced set of stakeholder perspectives and relevance of these outputs across various contexts. The R&D pipeline is the first database of its kind, mapping pre-clinical and clinical candidates for maternal microbiome interventions. Our TPP matching used a systematic, drug-agnostic approach, meaning high-potential candidates can be identified in an evidence-informed, unbiased fashion.
The current R&D pipeline is small, particularly in comparison to similar pipelines for other maternal health conditions [81]. Additionally, references to specific genus, such as Lactobacillus spp., encompasses all species within that genus. As clinical effects of probiotics are species- and strain-specific, this generalisation limits the ability to extrapolate results across different species or strains within the genus. One challenge was finding enough participants with experience in maternal microbiome interventions. For example, no responses were received through the public consultation webpage. As an emerging field, there are relatively few individuals working in this disease area. To counteract this, we contacted many stakeholders through systematic identification methods. However, it is possible that additional responses may have led to differing agreement levels for some variables. Unlike some other published TPPs, we conducted a single round of interviews. However, given the feedback we received, and the degree of consensus amongst stakeholders, we do not consider that further rounds would significantly impact these findings. Considering the rapidly evolving nature of this field, it may be necessary to update the TPP and R&D pipeline in future to reflect ongoing innovation and developments.
Conclusions
Development of this novel TPP showed agreement amongst diverse stakeholders as to most characteristics a probiotic intervention targeting the maternal gut microbiome should have. The TPP will assist in guiding key stakeholders working in maternal microbiome research to develop, trial and administer probiotic interventions that are accessible, affordable and effective for pregnant women globally. We identified one high- and two medium-potential probiotic candidates in the R&D pipeline. However, the lack of information available on candidates due to the emerging nature of clinical research into probiotics targeting the maternal microbiome suggests further evidence is needed. This combined method of TPP development, pipeline analysis, and candidate matching will inform and guide future research in probiotic interventions targeting the maternal gut microbiome.
Supporting information
S1 Table. Target Product Profile for Microbial Interventions (Probiotics) during pre-conception, pregnancy, and lactation to promote maternal health.
https://doi.org/10.1371/journal.pone.0321543.s001
(PDF)
S2 Table. Strategies to identify stakeholders from each group.
https://doi.org/10.1371/journal.pone.0321543.s002
(DOCX)
S3 Table. Distribution of stakeholders by WHO global region and gender.
https://doi.org/10.1371/journal.pone.0321543.s003
(DOCX)
S5 Table. TPP candidates with matching weights and scoring definitions.
https://doi.org/10.1371/journal.pone.0321543.s005
(DOCX)
S6 Table. Maternal microbiome interventions pipeline.
https://doi.org/10.1371/journal.pone.0321543.s006
(DOCX)
References
- 1. Lauer JM, Duggan CP, Ausman LM, Griffiths JK, Webb P, Agaba E, et al. Biomarkers of maternal environmental enteric dysfunction are associated with shorter gestation and reduced length in newborn infants in Uganda. Am J Clin Nutr. 2018;108(4):889–96. pmid:30247538
- 2. Di Simone N, Santamaria Ortiz A, Specchia M, Tersigni C, Villa P, Gasbarrini A, et al. Recent Insights on the Maternal Microbiota: Impact on Pregnancy Outcomes. Front Immunol. 2020;11:528202. pmid:33193302
- 3. Montoro-Huguet MA, Belloc B, Domínguez-Cajal M. Small and Large Intestine (I): Malabsorption of Nutrients. Nutrients. 2021;13(4):1254. pmid:33920345
- 4. Jandhyala SM, Talukdar R, Subramanyam C, Vuyyuru H, Sasikala M, Nageshwar Reddy D. Role of the normal gut microbiota. World J Gastroenterol. 2015;21(29):8787–803. pmid:26269668
- 5. Tickell KD, Atlas HE, Walson JL. Environmental enteric dysfunction: a review of potential mechanisms, consequences and management strategies. BMC Med. 2019;17(1):181. pmid:31760941
- 6. George CM, Oldja L, Biswas SK, Perin J, Lee GO, Ahmed S, et al. Fecal Markers of Environmental Enteropathy are Associated with Animal Exposure and Caregiver Hygiene in Bangladesh. Am J Trop Med Hyg. 2015;93(2):269–75. pmid:26055734
- 7. Wang AZ, Shulman RJ, Crocker AH, Thakwalakwa C, Maleta KM, Devaraj S, et al. A Combined Intervention of Zinc, Multiple Micronutrients, and Albendazole Does Not Ameliorate Environmental Enteric Dysfunction or Stunting in Rural Malawian Children in a Double-Blind Randomized Controlled Trial. J Nutr. 2017;147(1):97–103. pmid:27807040
- 8. Mbuya MNN, Humphrey JH. Preventing environmental enteric dysfunction through improved water, sanitation and hygiene: an opportunity for stunting reduction in developing countries. Matern Child Nutr. 2016;12(1):106–20. pmid:26542185
- 9. Exum NG, Lee GO, Olórtegui MP, Yori PP, Salas MS, Trigoso DR, et al. A Longitudinal Study of Household Water, Sanitation, and Hygiene Characteristics and Environmental Enteropathy Markers in Children Less than 24 Months in Iquitos, Peru. Am J Trop Med Hyg. 2018;98(4):995–1004. pmid:29436350
- 10. Abou-Seri H, Abdalgaber M, Zahran F. Enteric parasitic infections: From environmental enteric dysfunction to gut microbiota and childhood malnutrition. Parasitologists United Journal. 2022;15(3):216–23.
- 11. Gabain IL, Ramsteijn AS, Webster JP. Parasites and childhood stunting - a mechanistic interplay with nutrition, anaemia, gut health, microbiota, and epigenetics. Trends Parasitol. 2023;39(3):167–80. pmid:36707340
- 12. Crane RJ, Jones KDJ, Berkley JA. Environmental enteric dysfunction: an overview. Food Nutr Bull. 2015;36(1):S76-87. pmid:25902619
- 13. Moya-Alvarez V, Sansonetti PJ. Understanding the pathways leading to gut dysbiosis and enteric environmental dysfunction in infants: the influence of maternal dysbiosis and other microbiota determinants during early life. FEMS Microbiol Rev. 2022;46(3):fuac004. pmid:35088084
- 14. Cowardin C, Syed S, Iqbal N, et al. Environmental enteric dysfunction: gut and microbiota adaptation in pregnancy and infancy. Nature. 2023;20:223–37.
- 15. Hitch TCA, Hall LJ, Walsh SK, Leventhal GE, Slack E, de Wouters T, et al. Microbiome-based interventions to modulate gut ecology and the immune system. Mucosal Immunol. 2022;15(6):1095–113. pmid:36180583
- 16. Gizaw Z, Yalew A, Bitew B, et al. Stunting among children aged 24–59 months and associations with sanitation, enteric infections, and environmental enteric dysfunction in rural northwest Ethiopia. Scientific Reports. 2022;12.
- 17. Budge S, Parker AH, Hutchings PT, Garbutt C. Environmental enteric dysfunction and child stunting. Nutr Rev. 2019;77(4):240–53. pmid:30753710
- 18. Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, et al. Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol. 2014;11(8):506–14. pmid:24912386
- 19. Cordaillat-Simmons M, Rouanet A, Pot B. Live biotherapeutic products: the importance of a defined regulatory framework. Exp Mol Med. 2020;52(9):1397–406. pmid:32908212
- 20. Mcdougall AR, Tuttle A, Goldstein M, Ammerdorffer A, Gülmezoglu AM, Vogel JP. Target product profiles for novel medicines to prevent and treat preeclampsia: An expert consensus. PLOS Glob Public Health. 2022;2(11):e0001260. pmid:36962694
- 21. McDougall ARA, Tuttle A, Goldstein M, Ammerdorffer A, Aboud L, Gülmezoglu AM, et al. Expert consensus on novel medicines to prevent preterm birth and manage preterm labour: Target product profiles. BJOG. 2024;131(1):71–80. pmid:36209501
- 22. Ammerdorffer A, McDougall ARA, Tuttle A, Rushwan S, Chinery L, Vogel JP, et al. The drug drought in maternal health: an ongoing predicament. Lancet Glob Health. 2024;12(7):e1174–83. pmid:38876763
- 23. Tyndall A, Du W, Breder CD. Regulatory watch: The target product profile as a tool for regulatory communication: advantageous but underused. Nat Rev Drug Discov. 2017;16(3):156. pmid:28209989
- 24.
Food and Drug Administration. Guidance for Industry and Review Staff Target Product Profile — A Strategic Development Process Tool (Draft Guidance). 2007.
- 25. McDougall ARA, Hastie R, Goldstein M, Tuttle A, Tong S, Ammerdorffer A, et al. Systematic evaluation of the pre-eclampsia drugs, dietary supplements and biologicals pipeline using target product profiles. BMC Med. 2022;20(1):393. pmid:36329468
- 26. McDougall ARA, Hastie R, Goldstein M, Tuttle A, Ammerdorffer A, Gülmezoglu AM, et al. New medicines for spontaneous preterm birth prevention and preterm labour management: landscape analysis of the medicine development pipeline. BMC Pregnancy Childbirth. 2023;23(1):525. pmid:37464260
- 27. Lim S, McDougall ARA, Goldstein M, Tuttle A, Hastie R, Tong S, et al. Analysis of a maternal health medicines pipeline database 2000-2021: New candidates for the prevention and treatment of fetal growth restriction. BJOG. 2023;130(6):653–63. pmid:36655375
- 28. Lewin SR, Attoye T, Bansbach C, Doehle B, Dubé K, Dybul M, et al. Multi-stakeholder consensus on a target product profile for an HIV cure. Lancet HIV. 2021;8(1):e42–50. pmid:33271125
- 29.
WHO. Target Product Profiles [cited 2022 7 November]. Available from: https://www.who.int/observatories/global-observatory-on-health-research-and-development/analyses-and-syntheses/target-product-profile/who-target-product-profiles#:~:text=A%20target%20product%20profile%20(TPP,safety%20and%20efficacy%2Drelated%20characteristics.
- 30. PATH. Target product profile 2023 [cited 2024 6 February]. Available from: https://www.path.org/search/?query=target±product±profile
- 31. QualtricsXM. 2023. Available from: https://www.qualtrics.com/au/
- 32. Hsieh H-F, Shannon SE. Three approaches to qualitative content analysis. Qual Health Res. 2005;15(9):1277–88. pmid:16204405
- 33. McDougall ARA, Goldstein M, Tuttle A, Ammerdorffer A, Rushwan S, Hastie R, et al. Innovations in the prevention and treatment of postpartum hemorrhage: Analysis of a novel medicines development pipeline database. Int J Gynaecol Obstet. 2022;158(1):31–9. pmid:35762804
- 34. Concept Foundation. Accelerating innovation for mothers: pipeline candidates Geneva, Switzerland: Concept Foundation; 2021. Available from: https://www.conceptfoundation.org/accelerating-innovation-for-mothers/aim-pipeline-candidates/
- 35. Davidson SJ, Barrett HL, Price SA, Callaway LK, Dekker Nitert M. Probiotics for preventing gestational diabetes. Cochrane Database Syst Rev. 2021;4(4):CD009951. pmid:33870484
- 36. Drame N, Dieye Y. Probiotic For the Improvement of Environmental Enteropathy in Pregnant Women in Senegal (PROFE-Sen) 2022. Available from: https://clinicaltrials.gov/study/NCT05501470
- 37. Halkjær SI, de Knegt VE, Lo B, Nilas L, Cortes D, Pedersen AE, et al. Multistrain Probiotic Increases the Gut Microbiota Diversity in Obese Pregnant Women: Results from a Randomized, Double-Blind Placebo-Controlled Study. Curr Dev Nutr. 2020;4(7):nzaa095. pmid:32617453
- 38. Jacobsson B. Lactobacillus Reuteri Feasibility Study on Probiotic Treatment and Perinatal Microbiome 2018. Available from: https://clinicaltrials.gov/study/NCT02693028
- 39. Kaali S. Probiotic supplementation among pregnant women in the third trimester 2021. Available from: https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=16076
- 40. Moore RL, Feehily C, Killeen SL, Yelverton CA, Geraghty AA, Walsh CJ, et al. Ability of Bifidobacterium breve 702258 to transfer from mother to infant: the MicrobeMom randomized controlled trial. Am J Obstet Gynecol MFM. 2023;5(7):100994. pmid:37142190
- 41. Tang H, Zhao J. Study on the dynamic changes of maternal and infant gut microbiota and the effect of probiotics on maternal and infant gut microbiota Chinese Clinical Trial Registry (ChiCTR). 2021. Available from: https://www.chictr.org.cn/showproj.html?proj=123854.
- 42. Hung-Chih L. Oral Probiotics to Allergic Pregnant Mother and Their Offspring to Prevent Allergic Disease 2022. Available from: https://clinicaltrials.gov/study/NCT03873792
- 43. Laurent L. Correlating Probiotic Dietary Supplements During Pregnancy With Maternal Microbiome Profiles 2019. Available from: https://clinicaltrials.gov/study/NCT03611647
- 44. Agustina R. Brain Probiotic and LC-PUFA Intervention for Optimum Early Life (BRAVE) 2022. Available from: https://clinicaltrials.gov/study/NCT03851120
- 45. Zhang Y. Probiotic Supplementation During Pregnancy in Preeclampsia High-risk Groups 2022. Available from: https://clinicaltrials.gov/study/NCT05554185
- 46. Hansen C. Characterisation of the Gut Microbiota in Term Infants After Maternal Supplementation of Probiotics 2022. Available from: https://clinicaltrials.gov/study/NCT04987593
- 47. Sinha T, Brushett S, Prins J, Zhernakova A. The maternal gut microbiome during pregnancy and its role in maternal and infant health. Curr Opin Microbiol. 2023;74:102309. pmid:37068462
- 48. Keusch G, Denno D, Black R, Duggan C, Guerrant R. Environmental enteric dysfunction: pathogenesis, diagnosis, and clinical consequences. Clin Infect Dis. 2014;59(4):207–12.
- 49. Shergill AK, Ben-Menachem T, Chandrasekhara V, Chathadi K, Decker GA, et al; ASGE Standard of Practice Committee. Guidelines for endoscopy in pregnant and lactating women. Gastrointest Endosc. 2012;76(1):18–24. pmid:22579258
- 50. Savas N. Gastrointestinal endoscopy in pregnancy. World J Gastroenterol. 2014;20(41):15241–52. pmid:25386072
- 51.
WHO. WHO recommendations on antenatal care for a positive pregnancy experience. Geneva; Switzerland: WHO; 2016.
- 52. Hossain M, Begum K, Rahman M, Parvez M, Mazumder R. Environmental enteric dysfunction and small intest. PLoS Negl Trop Dis. 2023;17(1).
- 53. Das R, Haque MA, Sobi RA, Sultana A-A, Khan MA, Gazi A, et al. Citrulline and kynurenine to tryptophan ratio: potential EED (environmental enteric dysfunction) biomarkers in acute watery diarrhea among children in Bangladesh. Sci Rep. 2023;13(1):1416. pmid:36697429
- 54. Nuzhat S, Hasan SMT, Palit P, Islam MR, Mahfuz M, Islam MM, et al. Effects of probiotic and synbiotic supplementation on ponderal and linear growth in severely malnourished young infants in a randomized clinical trial. Sci Rep. 2023;13(1):1845. pmid:36725893
- 55. Onubi O, Poobalan A, Dineen B, Marais D, McNeill G. Effects of probiotics on child growth: a systematic review. J Health Popul Nutr. 2015;34.
- 56. Szajewska H, Mrukowicz JZ. Probiotics in the treatment and prevention of acute infectious diarrhea in infants and children: a systematic review of published randomized, double-blind, placebo-controlled trials. J Pediatr Gastroenterol Nutr. 2001;33(2):S17-25. pmid:11698781
- 57.
Policy Cures Research. Maternal Health Medicines Pipeline [cited 2022 August 10]. Available from: https://www.policycuresresearch.org/maternal-health-pipeline/.
- 58. Tuncalp Ö, Rogers LM, Lawrie TA, Barreix M, Peña-Rosas JP, Bucagu M, et al. WHO recommendations on antenatal nutrition: an update on multiple micronutrient supplements. BMJ Glob Health. 2020;5(7):e003375. pmid:32732247
- 59. The WOMAN-2 trial collaborators. Maternal anaemia and the risk of postpartum haemorrhage: a cohort analysis of data from the WOMAN-2 trial. Lancet. 2023;11:e1249-59.
- 60. Hills RD Jr, Pontefract BA, Mishcon HR, Black CA, Sutton SC, Theberge CR. Gut Microbiome: Profound Implications for Diet and Disease. Nutrients. 2019;11(7):1613. pmid:31315227
- 61. Conlon M, Bird R. The impact of diet and lifestyle on gut microbiota and human health. Nutrients. 2014;7(1).
- 62. National Institutes of Health: Office of Dietary Supplements. Probiotics 2023. Available from: https://ods.od.nih.gov/factsheets/Probiotics-HealthProfessional/
- 63. McFarland LV, Evans CT, Goldstein EJC. Strain-specificity and disease-specificity of probiotic efficacy: a systematic review and meta-analysis. Front Med (Lausanne). 2018;5:124. pmid:29868585
- 64. Ratiner K, Ciocan D, Abdeen SK, Elinav E. Utilization of the microbiome in personalized medicine. Nat Rev Microbiol. 2024;22(5):291–308. pmid:38110694
- 65. Dwiyanto J, Hussain MH, Reidpath D, Ong KS, Qasim A, Lee SWH, et al. Ethnicity influences the gut microbiota of individuals sharing a geographical location: a cross-sectional study from a middle-income country. Sci Rep. 2021;11(1):2618. pmid:33514807
- 66. Prideaux L, Kang S, Wagner J, Buckley M, Mahar JE, De Cruz P, et al. Impact of ethnicity, geography, and disease on the microbiota in health and inflammatory bowel disease. Inflamm Bowel Dis. 2013;19(13):2906–18. pmid:24240708
- 67. Lu J, Zhang L, Zhai Q, Zhao J, Zhang H, Lee Y-K, et al. Chinese gut microbiota and its associations with staple food type, ethnicity, and urbanization. NPJ Biofilms Microbiomes. 2021;7(1):71. pmid:34489454
- 68. Gorczyca K, Obuchowska A, Kimber-Trojnar Ż, Wierzchowska-Opoka M, Leszczyńska-Gorzelak B. Changes in the Gut Microbiome and Pathologies in Pregnancy. Int J Environ Res Public Health. 2022;19(16):9961. pmid:36011603
- 69. Edwards S, Cunningham S, Dunlop A, Corwin E. The maternal gut microbiome during pregnancy. MCN Am J Matern Child Nurs. 2017;42(6):310–7.
- 70. McDougall A, Nguyen R, Nguyen P-Y, Allen C, Cheang S, Makama M, et al. The effects of probiotics administration during pregnancy on preeclampsia and associated maternal, fetal, and newborn outcomes: a systematic review and meta-analysis. Am J Obstet Gynecol MFM. 2024;6(4):101322. pmid:38447676
- 71. Jarde A, Lewis-Mikhael A-M, Moayyedi P, Stearns JC, Collins SM, Beyene J, et al. Pregnancy outcomes in women taking probiotics or prebiotics: a systematic review and meta-analysis. BMC Pregnancy Childbirth. 2018;18(1):14. pmid:29310610
- 72. Masulli M, Vitacolonna E, Fraticelli F, Della Pepa G, Mannucci E, Monami M. Effects of probiotic supplementation during pregnancy on metabolic outcomes: A systematic review and meta-analysis of randomized controlled trials. Diabetes Res Clin Pract. 2020;162:108111. pmid:32194215
- 73. Sheyholislami H, Connor KL. Are Probiotics and Prebiotics Safe for Use during Pregnancy and Lactation? A Systematic Review and Meta-Analysis. Nutrients. 2021;13(7):2382. pmid:34371892
- 74. Singh A, Ghosh S, Ward H, Manary MJ, Rogers BL, Rosenberg IH. Biomarkers of environmental enteric dysfunction are differently associated with recovery and growth among children with moderate acute malnutrition in Sierra Leone. Am J Clin Nutr. 2021;113(6):1556–64. pmid:33668048
- 75. Gora MJ, Sauk JS, Carruth RW, Gallagher KA, Suter MJ, Nishioka NS, et al. Tethered capsule endomicroscopy enables less invasive imaging of gastrointestinal tract microstructure. Nat Med. 2013;19(2):238–40. pmid:23314056
- 76. Kirby M, Lauer J, Muhini A. Biomarkers of environmental enteric dysfunction and adverse birth outcomes: an observational study among pregnant women living with HIV in Tanzania. eBioMedicine. 2022;84.
- 77. Hasan MM, Gazi MA, Das S, Fahim SM, Hossaini F, Khan A-R, et al. Gut biomolecules (I-FABP, TFF3 and lipocalin-2) are associated with linear growth and biomarkers of environmental enteric dysfunction (EED) in Bangladeshi children. Sci Rep. 2022;12(1):13905. pmid:35974137
- 78. Uddin MI, Hossain M, Islam S, Akter A, Nishat NS, Nila TA, et al. An assessment of potential biomarkers of environment enteropathy and its association with age and microbial infections among children in Bangladesh. PLoS One. 2021;16(4):e0250446. pmid:33886672
- 79. Vonaesch P, Winkel M, Kapel N, Nestoret A, Barbot-Trystram L. Putative biomarkers of environmental enteric disease fail to correlate in a cross-sectional study in two study sites in sub-Saharan Africa. Nutrients. 2022;14(16).
- 80. Brüssow H. Problems with the concept of gut microbiota dysbiosis. Microb Biotechnol. 2020;13(2):423–34. pmid:31448542
- 81. Policy Cures Research. Maternal Health Medicines Pipeline 2021 [cited 2022 28 October]. Available from: https://www.policycuresresearch.org/maternal-health-pipeline/