Probiotic supplementation during pregnancy for vaginal microbiota improvement and pathogen clearance: a systematic review and meta-analysis

Probiotic supplementation during pregnancy for vaginal microbiota improvement and pathogen clearance: a systematic review and meta-analysis | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 21 November 2025 V1 Latest version Share on Probiotic supplementation during pregnancy for vaginal microbiota improvement and pathogen clearance: a systematic review and meta-analysis Authors : Zimo Liu 0009-0005-3344-2969 , Roujie Huang , Tianshu Sun , and Lan Zhu 0000-0003-4018-5030 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.176371046.65903691/v1 Published Acta Obstetricia et Gynecologica Scandinavica Version of record Peer review timeline 577 views 182 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Abstract Background: Pregnancy is associated with susceptibility to vaginal dysbiosis, including Group B Streptococcus (GBS), bacterial vaginosis (BV), and vulvovaginal candidiasis (VVC). Probiotic supplementation has emerged as a potential strategy to restore vaginal microecology, yet its effectiveness during pregnancy remains uncertain. Objective: To evaluate whether probiotic supplementation during pregnancy improves vaginal microbiota health and facilitates clearance of GBS, BV, and VVC. Searching Strategy: We systematically searched PubMed, Embase, Cochrane CENTRAL, and Web of Science from inception to 16 April 2025. Selection Criteria: Eligible studies were randomised or non-randomised studies comparing probiotic supplementation with placebo or no treatment in pregnant women, reporting outcomes related to vaginal microbiota, pathogen colonisation, or infection resolution. Data Collection and Analysis: Two reviewers independently screened studies, extracted data, and assessed risk of bias using the Cochrane ROB-1 tool. Meta-analyses were performed for primary outcomes, with subgroup analyses by infection type, timing, and duration of intervention. Main Results: Eighteen studies (n=3,705) were included. Overall, probiotics did not significantly improve vaginal microbiota outcomes (OR 1.13, 95% CI 0.94–1.36; I 2 =16%). A significant reduction in GBS colonisation was observed (OR 1.38, 95% CI 1.08–1.76; I 2 =2%). No significant effects were found for BV (OR 0.91) or VVC (OR 0.65). Subgroup analysis indicated greater efficacy in interventions initiated during the third trimester or lasting ≤4 weeks, though interaction tests were not significant. Conclusions: Probiotic supplementation in pregnancy may reduce GBS colonisation but shows limited benefit for BV, VVC, or obstetric outcomes. Standardised probiotic regimens and harmonised diagnostic frameworks are needed. Funding: Supported by the CAMS Innovation Fund for Medical Sciences (2025-I2M-XHZY-005), the Natural Science Foundation of Beijing Municipality (L232074), and the National High Level Hospital Clinical Research Funding (2022-PUMCH-C-060; 2022-PUMCH-D-003). Key words: Probiotics, Cervicovaginal microbiome, Group B Streptococcus, Bacterial vaginosis, Vulvovaginal candidiasis. Probiotic supplementation during pregnancy for vaginal microbiota improvement and pathogen clearance: a systematic review and meta-analysis Zimo Liu 1, 2 , Roujie Huang 1, 2 , Tianshu Sun 2, 3* , Lan Zhu 1, 2* 1 Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric & Gynecologic Diseases, State Key Laboratory of Common Mechanism Research for Major Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China 2 State Key Laboratory of Complex, Severe, and Rare Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China 3 Clinical Biobank, Center for Biomedical Technology, Institute of Clinical Medicine, National Science and Technology Key Infrastructure on Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China * Correspondence: Dr. Tianshu Sun, Address: Shuaifuyuan No. 1, Dongcheng District, Beijing 100730, China Email: [email protected] Telephone details: +86 13001210076 Dr. Lan Zhu, Address: Shuaifuyuan No. 1, Dongcheng District, Beijing 100730, China Email: [email protected] Telephone details:+86 13911714696 Abstract Background: Pregnancy is associated with susceptibility to vaginal dysbiosis, including Group B Streptococcus (GBS), bacterial vaginosis (BV), and vulvovaginal candidiasis (VVC). Probiotic supplementation has emerged as a potential strategy to restore vaginal microecology, yet its effectiveness during pregnancy remains uncertain. Objective: To evaluate whether probiotic supplementation during pregnancy improves vaginal microbiota health and facilitates clearance of GBS, BV, and VVC. Searching Strategy: We systematically searched PubMed, Embase, Cochrane CENTRAL, and Web of Science from inception to 16 April 2025. Selection Criteria: Eligible studies were randomised or non-randomised studies comparing probiotic supplementation with placebo or no treatment in pregnant women, reporting outcomes related to vaginal microbiota, pathogen colonisation, or infection resolution. Data Collection and Analysis: Two reviewers independently screened studies, extracted data, and assessed risk of bias using the Cochrane ROB-1 tool. Meta-analyses were performed for primary outcomes, with subgroup analyses by infection type, timing, and duration of intervention. Main Results: Eighteen studies (n=3,705) were included. Overall, probiotics did not significantly improve vaginal microbiota outcomes (OR 1.13, 95% CI 0.94–1.36; I²=16%). A significant reduction in GBS colonisation was observed (OR 1.38, 95% CI 1.08–1.76; I²=2%). No significant effects were found for BV (OR 0.91) or VVC (OR 0.65). Subgroup analysis indicated greater efficacy in interventions initiated during the third trimester or lasting ≤4 weeks, though interaction tests were not significant. Conclusions: Probiotic supplementation in pregnancy may reduce GBS colonisation but shows limited benefit for BV, VVC, or obstetric outcomes. Standardised probiotic regimens and harmonised diagnostic frameworks are needed. Funding: Supported by the CAMS Innovation Fund for Medical Sciences (2025-I2M-XHZY-005), the Natural Science Foundation of Beijing Municipality (L232074), and the National High Level Hospital Clinical Research Funding (2022-PUMCH-C-060; 2022-PUMCH-D-003). Key words: Probiotics, Cervicovaginal microbiome, Group B Streptococcus, Bacterial vaginosis, Vulvovaginal candidiasis. Introduction Probiotic therapy has emerged as a promising strategy for modulating the human microbiota across diverse clinical settings. Earlier studies have demonstrated that probiotics can restore vaginal microecology and mitigate pathogenic infections, thereby influencing clinical outcomes. 1, 2 Mechanistically, probiotics appear to act through several complementary pathways: competitive exclusion of pathogens, 3 re-establishment of Lactobacillus -dominant flora, 4 production of antimicrobial metabolites such as lactic acid and bacteriocins, 5 and modulation of local immune responses. 6, 7 These processes may attenuate inflammation, reinforce epithelial barrier integrity, and enhance ecosystem resilience. 8 Targeted probiotic interventions represents a biologically plausible and potentially scalable strategy for promoting vaginal health. Increasing attention has been directed toward the vaginal microbiome in pregnancy and its implications for both maternal and neonatal health. Rising estrogen and progesterone levels promote glycogen accumulation in the vaginal epithelium, fostering robust lactobacilli proliferation. 9 Yet this glycogen-rich milieu also supports adherence and overgrowth of opportunistic pathogens including Candida species 10 and Group B Streptococcus (GBS), 11 placing pregnant women at heightened risk of vulvovaginal candidiasis (VVC) and GBS colonization. Reported prevalence estimates reach approximately 50% for VVC 12 and 8.7–25% for GBS. 13-15 Pregnancy further induces a state of mucosal immune tolerance, diminishing pathogen clearance. 16 Constrained antimicrobial options during gestation compound this vulnerability. Dysbiosis involving Gardnerella vaginalis , Candida albicans, or GBS has been linked to adverse obstetric outcomes, including preterm birth, 17 chorioamnionitis, 18 and neonatal sepsis. 19 Identifying safe and effective alternatives to antibiotics is therefore a clinical priority. Approaches that restore Lactobacillus dominance and suppress pathogenic colonisation may reduce antibiotic use and support maternal wellbeing. To date, probiotic research in pregnancy has largely focused on metabolic or immunological endpoints—such as gestational diabetes mellitus, 20 pre-eclampsia 21 , and offspring atopy 22 such as allergic sensitisation, 23 underscoring that microbial interventions can influence systemic health. By contrast, comparatively little attention has been directed toward vaginal infections, despite their central role in reproductive tract homeostasis. A 2022 systematic review by Menichini et al. synthesised five RCTs on probiotics for GBS decolonisation, 24 but did not include more recent trials nor outcomes related to BV or VVC. Consequently, the broader therapeutic potential of probiotics for vaginal health in pregnancy remains inadequately characterised. This systematic review and meta-analysis addresses this gap by integrating newly published evidence and expanding examined outcome range. Our objective was to provide an updated, comprehensive synthesis of probiotic supplementation during pregnancy, evaluating its capacity to prevent or resolve GBS, BV, and VVC, and to restore vaginal microbial homeostasis across gestation. 2. Method This systematic review and meta-analysis was conducted in accordance with the PRISMA 2020 guidelines. 25 We included RCTs evaluating the effects of probiotic interventions on vaginal infections during pregnancy. Eligible studies assessed outcomes using Nugent scoring, microscopy, culture-based methods, molecular diagnostics, or symptomatology. We excluded studies involving non-pregnant or non-human populations, those lacking comparator groups, and those without extractable data. Only full-text, peer-reviewed articles were included. 2.1 Search Strategy A comprehensive search of PubMed, Embase, Cochrane CENTRAL, and Web of Science was conducted from database inception to 16 April 2025. Search strategies combined MeSH terms with relevant free-text keywords and were adapted to the syntax and indexing of each database. Filters were applied, where appropriate, to restrict results to RCTs, cohort studies, and case–control studies (see Appendix S1). We also searched ClinicalTrials.gov and the WHO ICTRP for ongoing or unpublished trials, and screened reference lists of included articles and relevant reviews. Searches were limited to English-language publications. All retrieved records were imported into EndNote, and duplicates were removed. Two reviewers (Z.L. and R.H.) independently screened titles and abstracts using predefined criteria, followed by full-text assessment. Discrepancies were resolved by discussion or consultation with a third reviewer (T.S.). A PRISMA flow diagram summarising the selection process is shown in Figure 1. 2.2 Data Collection Process Data were extracted independently by two reviewers using a standardised form. Extracted variables included study characteristics, setting, participant demographics (age, gestational age, BMI, ethnicity), intervention details (strain, route, dose, frequency, and duration), comparator type, and outcome measures. The primary outcome was maintenance of a healthy vaginal microecology, defined as GBS decolonisation or clinical resolution of BV or VVC. Secondary outcomes included gestational age at delivery and preterm birth. All reported time points and quantitative indicators were extracted. When required, study authors were contacted for clarification. For studies with multiple reports, the most complete dataset was used. All assumptions regarding incomplete data were documented. 2.3 Risk of Bias Assessment Risk of bias was independently assessed by two reviewers (Z.L. and R.H.) using the Cochrane ROB-1 tool and the Jadad scale. Domains evaluated included random sequence generation, allocation concealment, blinding, attrition, reporting, and other biases. Each domain was rated as low, unclear, or high risk. Risk-of-bias figures were generated using RevMan 5.4. 2.4 Statistic Methods For dichotomous outcomes—such as improvement in vaginal microecology or preterm birth—risk ratios (RRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. For continuous outcomes, including gestational age, mean differences (MDs) with 95% CIs were used. Where necessary, effect estimates were derived from raw data; medians and ranges were used to approximate means and standard deviations when required. Studies were synthesised according to outcome type, probiotic strain, gestational age at initiation, intervention timing, and geographic region. Meta-analyses were conducted using fixed-effect models, with pooled estimates reported as ORs or MDs with 95% CIs. Heterogeneity was assessed using the I² statistic. Where meta-analysis was not feasible, findings were reported narratively. All analyses were performed using RevMan 5.4. 2.5 Certainty of evidence The certainty of evidence for primary outcomes—clearance or resolution of GBS colonisation, BV, and VVC was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. 27 We assessed risk of bias, inconsistency, indirectness, imprecision, and publication bias, assigning an overall rating of high, moderate, low, or very low. Two reviewers (Z.L. and R.H.) conducted assessments independently using GRADEpro, with disagreements resolved by a third reviewer (T.S.). 3. Results A total of 574 records were identified through database searching (PubMed: 67; Cochrane Library: 39; Embase: 119; Web of Science: 349). After removing duplicates, 421 unique records were screened for eligibility. Of these, 365 were excluded based on title and abstract review. Following full-text assessment of 56 articles, 38 were excluded for not meeting the inclusion criteria. Ultimately, 18 studies were included in the review, comprising 17 RCTs and one non-randomized comparative study. The PRISMA study selection flow diagram is presented in Figure 1. 3.1 Characteristics of the Included Studies A total of 18 studies comprising 3,705 participants were included, with geographic representation spanning five continents: Asia (n = 7), 28-34 Europe (n = 5), 35-39 North America (n = 4), 40-43 Oceania (n = 1), 44 and Africa (n = 1). 45 At enrolment, four studies included a total of 282 participants who were positive for GBS. 29, 30, 35, 44 Three studies recruited women diagnosed with vulvovaginal infections (VVI), including one with BV, 42 one with VVC, 28 and one with a recent history of BV or VVC. 34 One additional studies enrolled participants whose baseline vaginal discharge exhibited a Nugent score = 4. 38 One study specifically included women presenting with vaginal symptoms but without detectable microbial colonisation. 31 The gestational age at enrolment ranged from 10 to 37 weeks across the included studies. Fifteen studies compared probiotics with placebo controls, 24, 28, 29, 31, 32, 34-37, 40-45 while three employed no-treatment control arms. 30, 33, 38 Three trials evaluated single-strain probiotic formulations—two using Lactobacillus species, 30, 38 and one using Clostridium . 33 The remaining 15 studies investigated multi-strain formulations, including four that combined Lactobacillus and Bifidobacterium species. 24, 28, 29, 31, 32, 34-37, 40-45 Across all studies, 27 distinct probiotic strains were assessed: 19 Lactobacillus , 5 Bifidobacterium , 2 Streptococcus , and 1 Clostridium strain. The most frequently administered formulation was the combination of Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14, which was evaluated in eight studies involving a total of 1,225 participants. 29, 36, 37, 40, 42-45 The probiotic dose typically ranged from 10⁷ to 10⁹ colony-forming unit (CFU)/mL. All interventions were administered orally, except for one study that employed a vaginal route. 38 With respect to outcomes, 9 of the 18 studies reported on GBS clearance, 24, 29, 30, 33, 35, 40, 41, 43, 44 8 studies examined BV remission, 31, 32, 34, 36-38, 42, 45 and 3 studies assessed the therapeutic effect on VVC. 28, 31, 34 The timing of outcome assessment varied across studies. In three trials, outcomes were measured immediately following completion of the intervention period. 32, 44, 45 Four studies assessed outcomes at the time of delivery, 29-31, 34 while one study conducted evaluation nearest prenatal visit after intervention. 36 The remaining studies reported outcomes during the third trimester of gestation, 28, 33, 35, 37, 39-43 except one measured between week 20 to week 22. 38 3.2 Risk of Bias The risk of bias for all included studies was assessed using the ROB-1 tool and is summarized in Figure 2 (Jadad Score shown in Figure S1). The majority of studies were judged to have an overall low risk of bias. The primary source of high risk was identified in the study by Lai et al. 33 which reported on GBS clearance. This study exhibited both selection and performance biases due to the absence of randomisation and blinding; participants were allowed to self-select into intervention or control arms, resulting in markedly unequal group sizes (299 vs. 1,277). In seven studies, blinding procedures—whether of participants, clinicians, or outcome assessors—were either not implemented or not reported. 30-32, 38, 40-42 Moreover, potential confounding variables such as antibiotic use during pregnancy, sexual activity, vaginal hygiene practices, and hormonal status were not accounted for in the study design or explicitly reported. 3.3 Vaginal Infection Eradication BV cure was defined as a Nugent score <4. VVC resolution was defined as the absence of symptoms or pathogenic Candida on microscopic examination. GBS decolonization was defined as a negative culture result. Among the 18 studies reporting relevant outcomes, the vast majority (16/18) did not demonstrate a statistically significant effect of probiotic administration on vaginal microbiota restoration. 28, 30-32, 34-45 Two studies specifically evaluating the effect of probiotics on GBS elimination reported statistically significant differences, with ORs (95% CI) of 1.52 (1.03, 2.23) 33 and 3.42 (1.37, 8.55), 29 respectively. Seven additional studies reported favorable but non-significant trends toward microbial improvement. 30, 35, 36, 40-43 Notably, none of the included studies documented any adverse impact of probiotics on the vaginal microbiota. Meta-analysis of the 18 included studies indicated a modest, non-significant trend toward improved vaginal microbiota outcomes with probiotic use during pregnancy (OR = 1.13, 95% CI 0.94–1.36; I² = 16%) (Figure 3). Subgroup analysis suggested potential effect modification across populations (interaction P = 0.04), indicating that the efficacy of probiotic interventions may vary by clinical context (Figure 4). A consistent and statistically significant benefit was observed in studies targeting GBS colonisation (OR = 1.38, 95% CI 1.08–1.76; I² = 2%; 9 studies; 2,572 participants) (Figure 4). This was accessed to have a moderate certatinty of evidence (Table S1). In contrast, no significant benefit was observed in studies addressing BV (OR = 0.91, 95% CI 0.67–1.24; I² = 0%; 8 studies; 1,055 participants) or VVC (OR = 0.65, 95% CI 0.32–1.32; I² = 0%; 3 studies; 225 participants) (Figure 4). The certainty of evidence was rated as low for the effect of probiotics on BV amelioration and very low for VVC curation, primarily due to concerns regarding imprecision and, in the case of VVC, indirectness and limited sample size (Table S1). Visual inspection of the funnel plot for GBS decolonisation suggested no substantial asymmetry, indicating a low risk of publication bias for this outcome (Figure S2). Further subgroup analyses were conducted to explore the impact of intervention timing, treatment duration, and probiotic formulation ( Lactobacillus vs. combination with Bifidobacterium ). Significant effects were observed among trials initiating treatment in the third trimester (≥28 weeks’ gestation) (OR = 1.42, 95% CI 1.08–1.87; I² = 21%) (Figure S3) and in those with treatment duration ≤4 weeks (OR = 1.41, 95% CI 1.06–1.87; I² = 29%) (Figure S4). However, interaction tests between the two comparator subgroups did not reach statistical significance ( P = 0.09 and P = 0.10, respectively), indicating no clear evidence of differential effects across these groups. Due to limited reporting, ethnicity-based subgroup analysis was not performed; only 8 studies reported participant ethnicity, and none presented infection-related outcomes stratified by ethnic group. 3.4 Secondary Outcomes 3.4.1 Gestational Age at Delivery Fifteen studies comprising 3,315 participants reported gestational age at delivery as a continuous outcome. 29-36, 38-43, 45 The pooled analysis demonstrated a non-significant difference between the probiotic and control groups (MD = 0.20 weeks, 95% CI –0.18 to 0.58), with substantial heterogeneity observed across studies (I² = 90%) (Figure S5). Notably, two smaller trials reported statistically significant prolongation of gestation following probiotic use: one with 320 participants (MD = 3.50 weeks, 95% CI 2.90–4.10) 36 and another with 109 participants (MD = 0.65 weeks, 95% CI 0.17–1.13). 43 The high degree of heterogeneity suggests considerable variability in study populations, probiotic formulations, or timing of intervention, warranting cautious interpretation of the aggregated estimate. The certainty of evidence regarding the effect of probiotics on gestational age at delivery is very low, due to considerable heterogeneity across studies and substantial imprecision in the effect estimate (Table S1). 3.4.2 Preterm Birth Preterm birth was evaluated in 10 studies comprising 1,523 participants. 31, 34-40, 42, 45 The meta-analysis yielded an OR of 0.84 (95% CI 0.56–1.28), indicating no statistically significant association between probiotic supplementation and reduced risk of preterm delivery (Figure S6). Between-study heterogeneity was minimal (I² = 0%), reflecting consistent effect estimates across trials. Collectively, the available evidence does not support a protective role of probiotics against preterm birth in this population. The certainty of evidence was rated as low, due to serious imprecision in the effect estimate (Table S1). 3.4.3 Vulvovaginal Symptom Amelioration Two studies assessed the effect of probiotic intervention on the relief of vulvovaginal symptoms. One trial employed a symptom severity scoring scale. 28 However, quantitative data were not reported in a form suitable for inclusion in meta-analysis. The other study, involving 47 participants, reported a non-significant trend toward symptom improvement in the probiotic group compared with controls (OR = 0.36, 95% CI 0.08–1.63). 34 Given the limited number of studies and extractable data, no definitive conclusion can be drawn regarding the efficacy of probiotics in alleviating vulvovaginal symptoms. 4. Discussion 4.1 Main Findings This systematic review and meta-analysis synthesises current evidence on probiotic supplementation during pregnancy for treating vaginal infections and restoring vaginal microecology. Although the pooled effect for overall infection improvement did not reach statistical significance (OR = 1.13, 95% CI 0.94–1.36), subgroup analyses revealed meaningful benefits in specific contexts. Probiotics significantly enhanced GBS decolonisation (OR = 1.38, 95% CI 1.08–1.76), a clinically relevant finding given the implications of intrapartum GBS for neonatal morbidity. By contrast, no significant improvements were observed for BV or VVC. A small, non-significant prolongation in gestational age was detected (MD = 0.20 weeks), though high heterogeneity (I² = 90%) limits interpretation. Two smaller trials reported substantial extensions in gestation, Gille et al. demonstrated a MD of 3.50 weeks (95% CI: 2.90–4.10), 36 and Sharpe et al. reported a MD of 0.65 weeks (95% CI: 0.17–1.13), 43 suggesting possible context-specific benefits, while pooled analyses showed no reduction in preterm birth risk (OR = 0.84, 95% CI 0.56–1.28). Evidence for symptom relief in VVIs was sparse and inconsistent. Subgroup analyses indicated that probiotic efficacy may depend on timing and duration, with trials initiating supplementation in the third trimester or lasting ≤4 weeks showing more pronounced effects. However, interaction tests did not confirm differential efficacy between subgroups. Only one trial used vaginal administration, limiting insight into the relative merits of local versus systemic delivery. Overall, the findings suggest that probiotics may confer microbiological benefits in pregnancy—particularly for GBS decolonisation—while broader clinical utility remains uncertain. 4.2 Strengths and Limitations This review provides the first comprehensive synthesis focusing specifically on probiotic use for vaginal microbiota modulation and infection clearance during pregnancy. Unlike prior reviews centred on metabolic 20, 21 or offspring-related outcomes, 22, 23 our analysis foregrounds the reproductive microenvironment, an area of considerable clinical relevance but limited prior synthesis. The evidence base is relatively robust: most included studies were well-designed RCTs, and heterogeneity for the primary outcome was low (I² = 16%), supporting the reliability of pooled estimates. Several limitations should be noted. First, although the majority of studies were RCTs, one study was at high risk of bias, 33 and seven did not adequately describe blinding, 30-32, 38, 40-42 introducing potential performance and detection bias. Second, methodological heterogeneity was substantial. Variations in probiotic strains, timing of initiation, and treatment duration may have influenced effect estimates. Third, outcome sampling time points varied widely. In four studies, vaginal samples were collected weeks to months after intervention 35, 36, 38, 42 —up to a median of 19 weeks in one trial 35 —potentially obscuring transient microbial changes. Fourth, only one trial used intravaginal probiotics, limiting generalisability to oral formulations and preventing direct comparisons between routes. 38 Finally, outcome definitions were inconsistent: BV defined by Nugent score, 31, 32, 34, 36-38, 42, 45 VVC by microscopy, 31, 34 and GBS by culture 29, 33, 35, 39-41, 43, 44 or PCR. 30 The lack of standardised, validated diagnostic criteria highlights the need for harmonised ecological and clinical endpoints in future research. 4.3 Interpretations, in light of other evidence Across all outcomes, the clearest evidence of probiotic efficacy was observed for GBS decolonisation. This finding is consistent with mechanistic data showing that specific Lactobacillus strains can competitively inhibit GBS adhesion, modulate local immune responses, and reduce epithelial invasion. 46, 47 Given the broad implementation of intrapartum antibiotic prophylaxis (IAP) to prevent early-onset GBS disease, 48, 49 probiotics may offer a complementary, non-antibiotic approach to reduce GBS burden prior to labour. 50 Reliance on IAP is effective but not without consequence. Prospective studies show that intrapartum antibiotics disrupt neonatal gut and oral microbiota—reducing Bacteroides and Bifidobacterium while increasing Enterococcus and Staphylococcus —with alterations persisting for months. 51-54 Evidence also suggests a higher incidence of neonatal infections following IAP exposure. 55 These concerns strengthen interest in microbiome-sparing alternatives, such as probiotics, which could reduce antibiotic use without compromising neonatal safety. 56, 57 The absence of significant benefits for BV and VVC likely reflects a mismatch between probiotic mechanisms and the pathophysiology of these infections. BV involves a collapse of Lactobacillus dominance and the emergence of anaerobic, biofilm-forming consortia. 58, 59 Conventional probiotic strains lack biofilm-disrupting activity and do not interfere with the quorum-sensing pathways that stabilise BV-associated communities. 60 Without the capacity to penetrate or dismantle biofilm matrices, probiotic colonisation alone may be insufficient to restore eubiosis. VVC pathogenesis is shaped by Candida albicans ’ transition from yeast to hyphal form, 61 a process amplified by pregnancy-related increases in estrogen and glycogen and by immunotolerance at mucosal surfaces. 62-64 Probiotic strains exert only modest antifungal effects and do not inhibit hyphal transformation or produce fungicidal metabolites at concentrations achievable in vivo. Thus, Candida’s ecological and immunological advantages in pregnancy may eclipse the modest modulatory capacity of probiotics unless coupled with targeted antifungal or anti-biofilm interventions. 65 Altogether, these mechanistic constraints suggest that while probiotics hold theoretical promise, their therapeutic impact on BV and VVC during pregnancy may be inherently limited unless strain selection and delivery methods are specifically tailored to address the ecological and immunological barriers presented by these infections. The route of administration may also shape efficacy. Oral probiotics must survive gastrointestinal passage, reach the lower genital tract in sufficient quantities, and overcome systemic dilution. This may explain their more established utility in metabolic and immune modulation. In contrast, intravaginal administration allows direct mucosal adherence, enhanced biofilm formation by beneficial lactobacilli, 66, 67 and localized production of lactic acid, hydrogen peroxide, and bacteriocins. 68-70 The single intravaginal trial in this review reported favourable outcomes, underscoring the need for further head-to-head comparisons of oral and vaginal delivery using harmonized strains and dosing regimens. 38 Efficacy may also be context-dependent. Many trials recruited unselected populations, diluting potential effects in women without dysbiosis. Targeted enrolment of women with confirmed BV, VVC, or GBS colonisation may yield clearer microbiological and clinical signals. Our subgroup findings further indicate that late-pregnancy (≥28 weeks) or short-duration regimens (≤4 weeks) may align better with the temporal dynamics of microbial change during pregnancy. Several biological and methodological factors may underlie these findings. Late gestation is characterised by increased mucosal stability 71, 72 and heightened estrogen-driven Lactobacillus proliferation, 73 potentially providing a more receptive ecological niche for probiotic colonisation. Shorter interventions may also reduce behavioural confounding and improve adherence. These findings underscore the importance of intervention timing and duration in optimizing probiotic-based strategies for vaginal microbiota modulation and suggest that targeted, time-sensitive applications may offer maximal clinical benefit with minimal burden. Finally, current diagnostic approaches do not capture the ecological complexity of the vaginal microbiome. 74-76 Emerging evidence shows substantial diversity across populations, with community state type (CST) IV—marked by high richness and BV-associated anaerobes—commonly observed even in asymptomatic women. 77 Advances in PCR-based molecular methods and next-generation sequencing (NGS) now enable more precise microbial profiling. 78-80 Yet only a minority of included studies used molecular diagnostics, 37, 39, 41, 42, 45 and none evaluated changes in CSTs or functional microbial activity. An ecology-based framework incorporating community composition, diversity indices, and functional signatures is needed to evaluate the true impact of probiotics on vaginal health. 5. Conclusion This systematic review and meta-analysis provides the most comprehensive synthesis to date on probiotic use during pregnancy for improving vaginal microbiota and reducing pathogen-associated colonisation. Although overall effects were modest, subgroup analyses showed a consistent benefit for GBS decolonisation, particularly with late-pregnancy, short-duration regimens. Heterogeneity in strains, timing, administration routes, and diagnostic criteria highlights the need for standardised, ecology-based protocols. Probiotics may represent a safe, non-antibiotic adjunct for supporting vaginal health, especially in settings of GBS over-intervention. Further rigorously designed trials are required to define optimal strains, dosing strategies, delivery routes, and target populations. Abbreviations GBS, Group B Streptococcus VVC, vulvovaginal candidiasis RCT, randomized clinical trial BV, bacterial vaginosis MeSH, Medical Subject Headings WHO, World Health Organization ICTRP, International Clinical Trials Registry Platform ROB-1, Cochrane Risk of Bias RR, risk ratio OR, odds ratio CI, confidence interval MD, mean difference GRADE, Grading of Recommendations Assessment, Development and Evaluation VVI, vulvovaginal infection CFU, colony-forming unit PCR, polymerase chain reaction IAP, intrapartum antibiotic prophylaxis CST, community state type NGS, next-generation sequencing Acknowledgements We extend our sincere gratitude to all the faculty members of the Evidence-Based Medicine and Systematic Review Program at Peking Union Medical College Hospital for their generous guidance and insightful instruction, which greatly informed the development of this review. Conflicts of Interest None declared. Ethics Statement Not applicable. Author Contributions Z.L. was involved in the conception and planning of the study and writing the protocol. T.S. and L.Z. provided expert methodological support for the systematic review and meta-­analysis. Z.L. and R.H. undertook the search and screen, and assessments of the included studies. Z.L. wrote the initial manuscript draft, with all authors providing review and feedback. Data Availability Statement The data that support the findings of this study are available from the corresponding author upon reasonable request. Supporting Information Additional supporting information may be found in the Supporting Information section at the end of the article. Figure S1-S6. Summary of analytic results on probiotics’ efficiency on pregnant women. Table S1. Summary of findings and certainty of evidence. Appendix S1. Search terms and filters. Funding This work was supported by the CAMS Innovation Fund for Medical Sciences (CIFMS) (Grant No. 2025-I2M-XHZY-005); the Natural Science Foundation of Beijing Municipality (Grant No. L232074); and the National High Level Hospital Clinical Research Funding (Grant Nos. 2022-PUMCH-C-060 and 2022-PUMCH-D-003). References 1. Liu HF, Yi N. A systematic review and meta-analysis on the efficacy of probiotics for bacterial vaginosis. Eur Rev Med Pharmacol Sci. 2022 Jan;26(1):90-8.2. Zeng X, An R, Li H, Zhang Y. Improved treatment of vulvovaginal candidiasis with Clotrimazole plus probiotic Lacidophilin Vaginal Capsules: A prospective, real-world study. Medicine. 2023;102(1):e32664.3. Asadi A, Lohrasbi V, Abdi M, Mirkalantari S, Esghaei M, Kashanian M, et al. The probiotic properties and potential of vaginal Lactobacillus spp. isolated from healthy women against some vaginal pathogens. Letters in Applied Microbiology. 2022;74(5):752-64.4. Liu Y, Zhao X, Wu F, Chen J, Luo J, Wu C, et al. 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Hong KH, Hong SK, Cho SI, Ra E, Han KH, Kang SB, et al. Analysis of the Vaginal Microbiome by Next-Generation Sequencing and Evaluation of its Performance as a Clinical Diagnostic Tool in Vaginitis. Ann Lab Med. 2016 Sep;36(5):441-9. Supplementary Material File (figures.docx) Download 3.44 MB File (tables.docx) Download 54.50 KB Information & Authors Information Version history V1 Version 1 21 November 2025 Peer review timeline Published Acta Obstetricia et Gynecologica Scandinavica Version of Record 28 Apr 2026 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords antenatal care general obstetrics infectious disease: microbiology maternal physiology meta-analysis substance misuse in pregnancy Authors Affiliations Zimo Liu 0009-0005-3344-2969 Peking Union Medical College Hospital Department of Obstetrics and Gynecology View all articles by this author Roujie Huang Peking Union Medical College Hospital Department of Obstetrics and Gynecology View all articles by this author Tianshu Sun Peking Union Medical College Hospital State Key Laboratory of Complex Severe and Rare Diseases View all articles by this author Lan Zhu 0000-0003-4018-5030 [email protected] Peking Union Medical College Hospital Department of Obstetrics and Gynecology View all articles by this author Metrics & Citations Metrics Article Usage 577 views 182 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Zimo Liu, Roujie Huang, Tianshu Sun, et al. Probiotic supplementation during pregnancy for vaginal microbiota improvement and pathogen clearance: a systematic review and meta-analysis. Authorea . 21 November 2025. DOI: https://doi.org/10.22541/au.176371046.65903691/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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