Vitamin D supplementation before in vitro fertilisation in women with polycystic ovary syndrome: multicentre, double blind, placebo controlled, randomised clinical trial.
Hu KL, Liao T, Wu Q, Ma X, Cao Y, Tan J, Tian L, Wang J, Yin J, Liu Y, Zhao J, Zhao S, Li M, Cai L, Liu FT, Gan K, Xu Y, Wang Y, Cai J, Zheng B, Ma Y, Ma Q, Zheng J, Pu X, Zhang H, Hao C, Xie Q, Zhang C, Jiang L, Zhang S, Yan L, Meng Q, Li W, Mol BW, Li R, Wang R, Zhang D, VitD-PCOS trial group
- DOI
- 10.1136/bmj-2025-087438
- Record issued
- 2026-08-15
- Engine
- 7.39.0
- Exported
- 2026-09-21
Prepared by Alpha1. This document is confidential: it is intended for the recipient it was shared with and must not be redistributed. The live record at alpha1science.com/verify/ada8a36b-6b09-4ad1-8efa-433bd7f0b647 is authoritative.
How this rating was calculated
Started at 5★ — no deductions. Nothing the checks ran surfaced a material problem.
- Statistics were not checked: no recomputable values were found in this text — no test statistic reported with its degrees of freedom, no effect estimate printed with both a 95% CI and a p-value, and no percentage printed with both its count and its denominator.
- The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 6 reported means were read, and their group size is not stated where the values are printed (this source has no machine-readable table structure). These checks need the count the mean was averaged over, so none was performed.
This Kaimen Rigor review uses Kaimen Rigor reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.
This is a well-conducted and transparently reported multicentre RCT of vitamin D supplementation in women with PCOS undergoing IVF. The design, ethics, statistical reporting, and data availability are all exemplary, with no major rigor gaps identified.
Both reviewers independently scored all dimensions as pass with high confidence, and no divergence was found. The study is a human interventional trial, so several checklist items (e.g., species, housing, cell lines) were correctly marked not applicable. The statistics verification component checked 0 tests due to the reporting style (effect sizes with CIs rather than test statistics), so no independent recomputation was possible; this is a coverage limitation, not a finding of correctness.
Numerical inconsistencies
None foundValues that contradict each other or are impossible for the stated sample: recomputed p-values and test statistics, GRIM/GRIMMER checks on summary numbers, percentages against their own counts, totals against their parts, and estimates against their own confidence intervals.
Checked — nothing surfaced.
Overstated conclusions
None foundConclusions that reach past what the paper's own results support — including a significance claim that no longer holds when the statistic is recomputed, and efficacy resting on an unvalidated surrogate endpoint.
Checked — nothing surfaced.
4 major claims checked against the paper's own evidence: all adequately supported.
- supportedReviewers 1, 2Vitamin D supplementation increases serum 25-OHD levels.The trial shows a significant increase in serum 25-OHD levels on trigger day, supporting this claim.Evidence: Adjusted mean difference 13.6, 95% CI 10.9 to 16.3
“On the day of triggering, the serum 25-OHD level was significantly higher in the vitamin D group than in the placebo group (32.3±11.2 v 18.2±7.6 ng/mL, adjusted mean difference 13.6, 95% confidence interval 10.9 to 16.3).”
AbstractFind in source - supportedReviewers 1, 2Vitamin D supplementation does not improve live birth rates.The primary outcome shows no significant difference between groups, supporting the claim of no improvement.Evidence: Adjusted risk ratio 1.03, 95% CI 0.91 to 1.18
“226 (52.0%) live births occurred in the vitamin D group and 216 (50.2%) in the placebo group (adjusted risk ratio 1.03, 95% confidence interval 0.91 to 1.18).”
AbstractFind in source - supportedReviewers 1, 2The trial was adequately powered to detect a 10% difference in live birth rate.The sample size calculation and the observed event rates support adequate power for the prespecified effect size.Evidence: Sample size calculation and discussion of observed placebo rate
“Our trial (n=865) was still adequately powered to detect a 10% point difference in live birth rate, even though a higher live birth rate in the control group (50.2%) was observed.”
LimitationsFind in source - supportedReviewers 1, 2No interaction between baseline vitamin D levels and treatment effect on live birth.The interaction test was not significant, supporting the claim.Evidence: Interaction P=0.731
“No interaction was observed between baseline vitamin D levels and treatment effect on live birth (interaction P=0.731).”
Results ¶5Find in source
Efficacy claim is anchored to an adequate endpoint and a meaningful effect.
- N/ASurrogate endpointThe primary outcome is live birth, a hard clinical outcome, not a surrogate.
“The primary outcome was live birth after the first embryo transfer.”
- ADEQUATEEffect sizeThe primary outcome is live birth, a hard clinical outcome. The effect size is reported as an adjusted risk ratio of 1.03 (95% CI 0.91 to 1.18), indicating no significant difference. The study was powered to detect a 10% absolute difference, and the confidence interval excludes a large benefit, but the result is clinically meaningful as a null finding.
“226 (52.0%) live births occurred in the vitamin D group and 216 (50.2%) in the placebo group (adjusted risk ratio 1.03, 95% confidence interval 0.91 to 1.18).”
Data authenticity concerns
None foundAn adversarial read for patterns associated with data that may not be genuine: results that look too clean, implausibly large effects, duplicated data or images, and methods that do not match the results reported.
Checked — nothing surfaced.
Reporting gaps
None foundRequired detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.
Checked — nothing surfaced.
The paper cites prior studies and a meta-analysis, acknowledges conflicting evidence, and identifies limitations of existing trials (small sample sizes, short durations, single-centre design). The rationale linking vitamin D deficiency to PCOS and IVF outcomes is well articulated, and the study aims to address these gaps.
“Evidence on vitamin D supplementation in women with infertility is conflicting. A meta-analysis based on nine randomised controlled trials and three cohort studies suggested increased clinical pregnancy rates in women with vitamin D supplementation. However, the largest included trial (630 participants) did not show improvement in clinical pregnancy rates with a single high dose bolus (600 000 IU) of vitamin D before IVF.”
“Existing randomised controlled trials in general infertility populations are limited by small sample sizes, short intervention durations, single centre design, and insufficient follow-up time.”
“Therefore, we conducted a multicentre, randomised, double blind, placebo controlled trial to evaluate the effects of supplementing vitamin D (4000 IU daily) for up to about 12 weeks (up to 90 days) before IVF on live birth rates in women with PCOS.”
“Existing randomised controlled trials in general infertility populations are limited by small sample sizes, short intervention durations, single centre design, and insufficient follow-up time.”
“Therefore, we conducted a multicentre, randomised, double blind, placebo controlled trial to evaluate the effects of supplementing vitamin D (4000 IU daily) for up to about 12 weeks (up to 90 days) before IVF on live birth rates in women with PCOS.”
Randomization used a computer-generated list with variable block sizes, stratified by centre, and allocation was concealed. Blinding was double-blind with identical placebo. Sample size calculation was provided with assumptions. Inclusion/exclusion criteria were specified. The modified intention-to-treat and per-protocol populations were defined, and missing data handling was described. Outlier handling is not explicitly mentioned but is not a standard requirement for a clinical trial.
“Randomisation was conducted using a computer generated list, with variable block sizes of two, four, or six, stratified by study centre. This list was prepared by an independent statistician not involved in participant recruitment and data analysis, and it was not accessible to investigators or recruiting staff at any centre.”
“Placebo capsules, composed of pharmaceutical grade gelatin, glycerin, and purified water, were identical in size, colour, appearance, and packaging to the vitamin D capsules. Participants and trial investigators were unaware of the treatment allocation, except for the two researchers who labelled the containers.”
“To show or refute a 10% increase in the live birth rate in the vitamin D treatment group (48%), a total of 768 participants were required (power 80% and type I error rate 5%).”
“Randomisation was conducted using a computer generated list, with variable block sizes of two, four, or six, stratified by study centre.”
“Participants and trial investigators were unaware of the treatment allocation, except for the two researchers who labelled the containers.”
“To show or refute a 10% increase in the live birth rate in the vitamin D treatment group (48%), a total of 768 participants were required (power 80% and type I error rate 5%).”
The study reports age, BMI, duration of infertility, PCOS phenotype, and serum 25-OHD levels. Sex is female by design (PCOS), so sex_justified is not applicable. Demographics are reported in Table 1. Species/strain and housing are not applicable as this is a human trial.
“Age (years), mean (SD)* | 29.4 (3.6) | 29.4 (3.5) | | Body mass index, median (IQR)† | 24.2 (21.6-27.2) | 23.8 (21.5-26.6)”
“PCOS phenotype**†† | | Type A | 143 (32.9) | 135 (31.4) | | Type B | 4 (0.9) | 6 (1.4) | | Type C | 17 (3.9) | 12 (2.8) | | Type D | 259 (59.5) | 266 (61.9)”
“Age (years), mean (SD)* | 29.4 (3.6) | 29.4 (3.5)”
The study was approved by the Ethics Committee of Women's Hospital of Zhejiang University (IRB-20200035-R) and by each centre's ethics committee. Informed consent was obtained from participants. Regulatory compliance is implied through adherence to ethical standards, though not explicitly named.
“This study was approved by the Ethics Committee in Women’s Hospital of Zhejiang University (IRB-20200035-R), followed by approval of ethics committees from each centre.”
“After giving informed consent, participants were randomly assigned 1:1 to receive vitamin D or placebo.”
“This study was approved by the Ethics Committee in Women’s Hospital of Zhejiang University (IRB-20200035-R), followed by approval of ethics committees from each centre.”
“After giving informed consent, participants were randomly assigned 1:1 to receive vitamin D or placebo.”
Vitamin D and placebo capsules are identified with manufacturer (Sinopharm Xingsha Pharmaceuticals) and dose. The vitamin D assay kit (DISIGNS Diagnostics) and LC-MS/MS system (SCIEX) are named. Statistical software (Stata 18.0) is identified. No antibodies, cell lines, or organisms are used.
“Vitamin D and placebo capsules were produced by a licensed pharmaceutical company (Sinopharm Xingsha Pharmaceuticals, Xiamen, China).”
“Serum concentrations of 25-OHD from all centres were measured using a well standardised isotope dilution liquid chromatography tandem mass spectrometry method with an automatic analyser (SCIEX Triple Quad 4500MD) using the vitamin D 200M Assay Kit (DISIGNS Diagnostics, China)”
“All analyses were performed using Stata 18.0 (StataCorp, USA).”
“Vitamin D and placebo capsules were produced by a licensed pharmaceutical company (Sinopharm Xingsha Pharmaceuticals, Xiamen, China).”
“using a well standardised isotope dilution liquid chromatography tandem mass spectrometry method with an automatic analyser (SCIEX Triple Quad 4500MD) using the vitamin D 200M Assay Kit (DISIGNS Diagnostics, China)”
“All analyses were performed using Stata 18.0 (StataCorp, USA).”
The paper reports adjusted risk ratios with 95% CIs for primary and secondary outcomes, which is the standard idiom for clinical trials. Exact p-values are not reported for most outcomes, but this is acceptable as the trial reports by estimation. Statistical tests are named (modified Poisson regression, random effects model). Software is identified. Data presentation includes CONSORT flowchart and tables with per-group n. Mathematical plausibility checks were not possible for most outcomes due to continuous data or lack of raw counts, but no inconsistencies were found.
“226 (52.0%) live births occurred in the vitamin D group and 216 (50.2%) in the placebo group (adjusted risk ratio 1.03, 95% confidence interval 0.91 to 1.18).”
“For unadjusted estimates, modified Poisson regression with a robust variance estimate was used. For adjusted estimates, a random effects model was used to account for centre effects.”
“For unadjusted estimates, modified Poisson regression with a robust variance estimate was used. For adjusted estimates, a random effects model was used to account for centre effects.”
“adjusted risk ratio 1.03, 95% confidence interval 0.91 to 1.18”
The data availability statement provides a concrete route: deidentified individual participant data and code are available at a DOI (https://doi.org/10.17605/OSF.IO/F9BC5). This is reported_and_adequate. Repository deposit and accession numbers are not applicable for patient-level data, but the DOI serves as a persistent identifier.
“Deidentified individual participant data, and the code for statistical analyses are available at: https://doi.org/10.17605/OSF.IO/F9BC5”
“Deidentified individual participant data, and the code for statistical analyses are available at: https://doi.org/10.17605/OSF.IO/F9BC5”
The trial is registered (NCT04082650). A CONSORT flowchart is included. Limitations are discussed in detail. Conclusions are proportional to the evidence. Funding and competing interests are declared.
“Trial registration ClinicalTrials.gov NCT04082650 (https://clinicaltrials.gov/ct2/show/NCT04082650)”
“The observed live birth rate in the placebo group (50.2%) substantially exceeded the prespecified assumption of 38%.”
“Funding: This study was supported by National Key Research and Development Program of China (2022YFC2703500, 2021YFC2700601, 2018YFC1005003), National Natural Science Foundation of China (U23A20404, 82394424).”
“Trial registration ClinicalTrials.gov NCT04082650”
“Fig 1 CONSORT (consolidated standards of reporting trials) flowchart.”
“The observed live birth rate in the placebo group (50.2%) substantially exceeded the prespecified assumption of 38%.”
Registered (1 ID: ClinicalTrials.gov). Reporting guideline cited: CONSORT.
Broken references and links
None foundReferences checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.
Checked — nothing surfaced.
Checked 35 references by DOI: 35 verified.
Every extracted reference resolved against Crossref/OpenAlex with no retraction flags.
1 data/code link checked; 1 live.
- dataOSFLIVEHTTP 200https://doi.org/10.17605/OSF.IO/F9BC5Resolves to OSF (data repository).
Copyediting
2 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 2 minor suggestions below.
2 copyedit issues flagged: mostly typo, consistency.
- MINORtypoAbstract, Results“226 (52.0%) live births occurred in the vitamin D group and 216 (50.2%) in the placebo group”→ Ensure consistent use of parentheses and spacing.Minor formatting inconsistency.
- MINORconsistencyAbstract, Results“226 (52.0%) live births occurred in the vitamin D group and 216 (50.2%) in the placebo group”→ Ensure consistent use of 'live births' vs 'live birth rate' throughout.Minor wording inconsistency.
The published work is robust and well-reported; an informed reader should weigh the minor copyedit inconsistencies and the lack of exact p-values for secondary outcomes, but these do not undermine the conclusions. No erratum or re-analysis is warranted based on this audit.
- 1.MEDIUMreportingIn the Abstract Results, standardize the formatting of percentages (e.g., '226 (52.0%)' vs '216 (50.2%)') to ensure consistent spacing and parentheses.Minor formatting inconsistency flagged by copyedit; fixing improves professional presentation.
- 2.MEDIUMreportingIn the Abstract and Results, ensure consistent use of 'live births' vs 'live birth rate' when referring to the primary outcome.Minor wording inconsistency flagged by copyedit; consistency aids clarity.
- 3.MEDIUMstatisticsConsider reporting exact p-values for secondary outcomes in the Results tables or text, in addition to confidence intervals.Facilitates future meta-analyses and allows readers to assess significance more precisely.
- 4.MEDIUMreportingAdd a statement in the Methods or Ethics section confirming adherence to the Declaration of Helsinki or other relevant regulatory frameworks.Strengthens the ethics reporting and aligns with common journal requirements.
- 5.MEDIUMreportingIn the CONSORT flowchart, provide a breakdown of the 11 participants excluded from the modified intention-to-treat analysis, with reasons.Enhances transparency about participant flow and exclusions.
- 6.MEDIUMstatisticsAdd a sensitivity analysis excluding participants with poor adherence to assess robustness of the primary result.Addresses potential confounding by adherence and strengthens the evidence.
- 7.MEDIUMreportingReport the results of the complete case analysis in the main text rather than only in supplementary materials.Provides a more complete picture of the data and addresses missing data concerns.
- 8.LOWreportingAdd a note in the Discussion on the generalizability of findings to non-Chinese populations.Acknowledges potential limitations in external validity.
- 9.LOWreportingProvide a plain language summary of the results for participants and the public.Improves accessibility and dissemination of trial findings.
- 10.LOWreportingConsider adding a statement about the data monitoring committee's role and any interim analyses in the Methods.Provides additional context on trial oversight.
- 11.LOWreportingProvide a more detailed description of the randomisation list generation and allocation concealment in the supplementary materials.Enhances reproducibility and transparency of the randomisation process.
The star rating is the report’s one-glance summary. Every paper starts at 5★ and loses stars for the concrete problems the review finds — so a rating is never a vague average, it’s a running total you can read line by line under “How this rating was calculated.”
- Reporting — 8 dimensionseach dimension that fully fails−½★
- each dimension partially met−¼★
- Statistics · Integrity · Claimseach serious problem−1★
- each medium problem−½★
- Citationseach retracted or unverifiable reference−¼★
- Copyeditonly when the manuscript needs a full edit−½★
The rating never drops below 1★, and a demonstrable critical failure (an impossible statistic, a proven ethics violation) caps it at 1★ on its own — so the stars can never look healthy when the verdict is CRITICAL.
The rating draws on a panel of agents. Three independent Kaimen Rigor reviewers grade the eight dimensions below across several independent passes (the shown verdict is their majority vote — steadier than any single run), isolate the paper’s major claims and check its own evidence backs them, and flag integrity concerns. Alongside them, a citation agent resolves every reference against Crossref, OpenAlex, and Retraction Watch; a statistics agent recomputes reported tests; and rule-based checks verify that declared data/code links actually resolve. Full text is required — an abstract-only submission is not analyzed.
Graded against NIH, MDAR, ARRIVE 2.0, CONSORT, EQUATOR, and RRID guidelines. A dimension that doesn’t apply to the study type is skipped, never penalized.
This Kaimen Rigor review is model-assisted and is not a substitute for formal expert review. It complements human evaluation by surfacing potential methodological concerns — verify each finding against the source.