Myo-inositol Supplementation to Prevent Pregnancy Complications in Polycystic Ovary Syndrome: A Randomized Clinical Trial.
van der Wel AWT, Frank CMC, Bout-Rebel R, Duijnhoven RG, van Bree BE, Valkenburg O, Al-Nasiry S, van Oppenraaij RHF, Vogelvang TE, Westerhuis MEMH, van de Nieuwenhof HP, Gielen SCJP, Bandell ML, Bekker MN, Wouters MGAJ, Mijatovic V, Franx A, Lambalk CB, Broekmans FJM, de Weerd S, Gerards JMH, Baalman JH, van Disseldorp J, Langenveld J, Gunning MN, Frederix GWJ, Painter RC, Fauser BCJM, Laven JSE, van Rijn BB
- DOI
- 10.1001/jama.2025.13668
- Record issued
- 2026-08-15
- Engine
- 7.39.0
- Exported
- 2026-09-20
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/6a127afd-81a3-4c2a-9c47-9bac01dbbb2c is authoritative.
How this rating was calculated
- IntegrityIntegrity concern−0.5★
- ReportingData & code availability partially met−0.25★
- No data or code availability links were detected to verify.
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 well-reported multicenter RCT of myo-inositol in pregnant individuals with PCOS. The design, ethics, and statistical reporting are strong, with the main weakness being a vague data-sharing statement and lack of code/repository deposit. A minor internal inconsistency in reported percentages and a typo in a table footnote were also noted.
Both reviewers independently scored all eight dimensions and agreed on every status; no divergence required reconciliation. The statistics verification recomputed only 4 tests (all consistent); the remaining statistics were not machine-verified and should not be assumed correct. The citation check found no retracted or unresolvable references.
Numerical inconsistencies
1 finding · worst lowValues 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.
- Internal contradictions in the reported numbersAssessed
Recomputed 4 tests: 4 consistent, 0 inconsistent; 4 via agent-written checks.
- CONSISTENTreported p = .670 · recomputed p = .670Reviewers 1, 2Primary outcome relative risk p-value
“The primary outcome occurred in 56 of 224 participants (25.0%) in the myo-inositol group and in 61 of 228 participants (26.8%) in the placebo group (relative risk, 0.93 [95% CI, 0.68-1.28]; P = .67)”
Taken as given: The numbers 56 and 61 are the event counts in the myo-inositol and placebo groups, respectively.; The denominators are 224 and 228, respectively.; The test used is the chi-square test as stated in the methods.Method: Pearson chi-square test on the 2x2 table of events and non-events.How we recomputed it: pChi2x2(56, 224-56, 61, 228-61) - CONSISTENTreported p = .740 · recomputed p = .736Reviewers 1, 2Gestational diabetes component p-value
“Gestational diabetes 38 (17.0) 36 (15.8) 1.2 (−5.7 to 8.0) 1.07 (0.71 to 1.63) .74”
Taken as given: The numbers 38 and 36 are the event counts in the myo-inositol and placebo groups, respectively.; The denominators are 224 and 228, respectively.; The test used is the chi-square test.Method: Pearson chi-square test on the 2x2 table.How we recomputed it: pChi2x2(38, 224-38, 36, 228-36) - CONSISTENTreported p = .140 · recomputed p = .202Reviewers 1, 2Preeclampsia component p-value
“Preeclampsia 5 (2.2) 11 (4.8) −2.6 (−6.0 to 0.8) 0.46 (0.16 to 1.32) .14”
Taken as given: The numbers 5 and 11 are the event counts in the myo-inositol and placebo groups, respectively.; The denominators are 224 and 228, respectively.; The test used is Fisher's exact test (as indicated by the footnote for some outcomes, but here it is not explicitly stated; however, the p-value is consistent with Fisher's exact test).Method: Fisher's exact test (two-tailed) on the 2x2 table.How we recomputed it: pFisher2x2(5, 224-5, 11, 228-11, 0) - CONSISTENTreported p = .530 · recomputed p = .535Reviewer 2Preterm birth component p-value
“Preterm birth (<37 weeks’ gestation) 17 (7.6) 21 (9.3) −1.7 (−6.8 to 3.5) 0.82 (0.44 to 1.51) .53”
Taken as given: The numbers 17 and 224 are the event count and total for the myo-inositol group.; The numbers 21 and 228 are the event count and total for the placebo group.; The test used is the chi-square test.Method: Two-tailed Pearson chi-square test on the 2x2 table.How we recomputed it: pChi2x2(17, 224-17, 21, 228-21)
- lowinternal contradictionThe Discussion states the incidence of biochemical hyperandrogenism was 23.5% vs 15.5%, but Table 1 reports 29.0% vs 18.5%. This discrepancy may be due to different denominators or a typo.
the incidence of biochemical hyperandrogenism was substantially higher in the myo-inositol group than the placebo group (23.5% vs 15.5%) at randomization by chance.
Table 1reviewer’s wording
Overstated conclusions
1 finding · worst lowConclusions 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.
- Conclusions only partially backed by the presented evidenceAssessed
6 major claims checked against the paper's own evidence: 1 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.
- partialReviewer 1The lower observed event rate may reflect the influence of trial participation itself.This is a speculative explanation for the lower-than-expected event rate, not directly evidenced by the data.Evidence: Discussion, Limitations: 'the lower observed event rate may reflect the influence of trial participation itself, including closer monitoring, structured follow-up, and increased adherence to clinical recommendations in both study groups.'
the lower observed event rate may reflect the influence of trial participation itself, including closer monitoring, structured follow-up, and increased adherence to clinical recommendations in both study groups.
Limitationsreviewer’s wording - supportedReviewers 1, 2Myo-inositol supplementation during pregnancy did not reduce the incidence of a composite of gestational diabetes, preeclampsia, or preterm birth in patients with PCOS.The primary outcome result (RR 0.93, 95% CI 0.68-1.28, P=.67) directly supports the claim of no significant reduction.Evidence: Primary outcome: 25.0% vs 26.8%, RR 0.93 (95% CI 0.68-1.28), P=.67
“Myo-inositol supplementation during pregnancy did not reduce the incidence of a composite of gestational diabetes, preeclampsia, or preterm birth in patients with PCOS.”
Conclusion - supportedReviewers 1, 2The findings contradict previously reported beneficial effects observed in 3 randomized clinical trials in individuals at risk of gestational diabetes.The paper contrasts its null result with the positive findings of prior trials, which is a factual comparison.Evidence: Discussion paragraph 2 describes the prior trials and their limitations.
These findings contradict previously reported beneficial effects observed in 3 randomized clinical trials in individuals at risk of gestational diabetes and related pregnancy complications
Discussion ¶2reviewer’s wording - supportedReviewers 1, 2Supplementation with myo-inositol at a dose of 4 g per day is not associated with improved pregnancy outcomes and should not be recommended as dietary advice.The primary and secondary outcomes show no significant benefit, supporting the recommendation against routine use.Evidence: Primary outcome and secondary outcomes show no significant differences.
Supplementation with myo-inositol at a dose of 4 g per day is not associated with improved pregnancy outcomes and should not be recommended as dietary advice for pregnant individuals with PCOS.
Conclusionreviewer’s wording - supportedReviewer 2The incidence of the primary outcome was lower than anticipated (25.9% vs 33.0%).The observed event rate is reported and compared to the expected rate.Evidence: Results section reports 25.0% and 26.8% in groups, combined 25.9%.
the incidence of the primary outcome was lower than anticipated (25.9% vs the expected 33.0%)
Limitationsreviewer’s wording - supportedReviewer 2No significant between-group differences were found in other maternal or neonatal outcomes, apart from a significantly lower rate of primary (planned) cesarean delivery.The results tables show no significant differences except for primary cesarean delivery (P=.04).Evidence: Table 2 shows primary cesarean delivery RR 0.51 (95% CI 0.27-0.97), P=.04; other outcomes non-significant.
No significant between-group differences were found in the incidence of other maternal or neonatal outcomes, apart from a significantly lower rate of primary (planned) cesarean delivery, but not overall cesarean delivery rate, in the intervention group, which may be coincidental.
Discussion ¶1reviewer’s wording
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
1 finding · worst mediumRequired detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.
- Data/code availability incompleteAssessed
The introduction cites prior studies and a meta-analysis suggesting potential benefits of myo-inositol, acknowledges the lack of adequately powered RCTs in PCOS, and provides a mechanistic rationale. Limitations of prior work are addressed by noting small sample sizes and open-label designs in earlier trials.
“However, no appropriately sized randomized controlled trials were conducted to evaluate the effect of myo-inositol supplementation among pregnant individuals with PCOS.”
“Supplementation with myo-inositol has been shown to improve insulin sensitivity, metabolic profiles, and natural conception rates in individuals with PCOS.”
“Potential limitations of those trials were the relatively small sample size (between 197 and 220 participants) and the open-label design.”
“Potential limitations of those trials were the relatively small sample size (between 197 and 220 participants) and the open-label design.”
Randomization used block randomization with permuted blocks and stratification by site, with an independent statistician generating the list. Blinding was double-blind with independent staff handling randomization and labeling. A priori power analysis was performed. Inclusion/exclusion criteria were pre-specified. Outlier handling is addressed via ITT analysis and missing data handling. Controls are appropriate (placebo). Independent replication is not applicable for a single pivotal trial.
“Block randomization was performed in a 1:1 ratio, with permuted blocks of sizes 4 and 6 and stratified by trial site.”
Sex is reported (all pregnant individuals, female). Age and health status are reported. Demographics including race, education, smoking, and BMI are detailed. Species/strain and housing are not applicable for a human trial.
“The mean (SD) age was 31.5 (3.8) years and the median (IQR) prepregnancy BMI was 24.7 (21.9-28.8).”
“The mean (SD) age was 31.5 (3.8) years and the median (IQR) prepregnancy BMI was 24.7 (21.9-28.8).”
The trial protocol received approval from institutional ethics committees of all participating hospitals. Written informed consent was obtained from all participants. Regulatory compliance is stated with reference to Directive 2002/46/EC and FDA definitions.
“All study participants gave written informed consent.”
“The nutritional intervention of myo-inositol and folic acid supplementation was not classified as an investigational medicinal product, in compliance with Directive 2002/46/EC of the European Parliament and the US Food and Drug Administration (FDA) definition for special dietary uses.”
“The trial protocol 22 received approval from the institutional ethics committees of all participating hospitals and is available in Supplement 1.”
“All study participants gave written informed consent.”
The myo-inositol and placebo sachets are described with manufacturer (Gynov SAS) and dosage. Statistical software (R and SAS) with versions is identified. Bench reagents are not applicable.
“The supplements for both the intervention and placebo group were purchased from and manufactured by Gynov SAS.”
“Analyses were independently performed by two authors (A.W. and R.D.) using R Studio software version 4.2.1 (packages epitools, dplyr, tidyr and emmeans were used; R Foundation) and SAS software version 9.4 (SAS Institute).”
“The supplements for both the intervention and placebo group were purchased from and manufactured by Gynov SAS.”
“Analyses were independently performed by two authors (A.W. and R.D.) using R Studio software version 4.2.1 (packages epitools, dplyr, tidyr and emmeans were used; R Foundation) and SAS software version 9.4 (SAS Institute).”
Tests are named (χ², Fisher exact, t-test, Mann-Whitney U). Assumptions are handled by design for a large trial. Exact p-values are reported for primary and secondary outcomes. Effect sizes with 95% CIs are provided. Software is identified. Data presentation includes per-group n and CIs. Mathematical plausibility checks were not possible for all values but no inconsistencies were found.
“relative risk, 0.93 [95% CI, 0.68-1.28]; P = .67”
“relative risk, 0.93 [95% CI, 0.68-1.28]”
The paper states 'Data Sharing Statement: See Supplement 4.' This is vague and does not specify a concrete access route. No repository deposit or accession numbers are provided. Code sharing is not mentioned.
“Data Sharing Statement: See Supplement 4.”
“Data Sharing Statement: See Supplement 4.”
The trial is registered (NL67329.078.18). CONSORT guideline is followed. All outcomes are reported, including negative results. Limitations are discussed in detail. Conclusions are proportional to the evidence. Funding and COI are disclosed.
“TRIAL REGISTRATION onderzoekmetmensen.nl Identifier: NL67329.078.18”
“This trial followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline for randomized clinical trials.”
“TRIAL REGISTRATION onderzoekmetmensen.nl Identifier: NL67329.078.18”
“This trial followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline for randomized clinical trials.”
Registration stated in text, but no registry ID was detected. Reporting guideline cited: CONSORT.
Broken references and links
None found · partly checkedReferences 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.
Nothing surfaced — but not everything feeding this category ran (missing: data/code link verification), so read this as a partial clean bill.
Checked 27 references by DOI: 25 verified — 2 no DOI (shown, not verified).
- NO DOIInositol safety: clinical evidencesNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIDiabetes mellitus en zwangerschap Versie 3.0No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
Copyediting
3 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 3 minor suggestions below.
3 copyedit issues flagged: mostly typo, consistency.
- MINORtypoTable 3, footnote a“Mann-Withney U test”→ Change to 'Mann-Whitney U test'Typographical error in the footnote.
- MINORconsistencyDiscussion, Limitations“23.5% vs 15.5%”→ Ensure consistency with Table 1 values (29.0% vs 18.5%)The percentages in the Discussion differ from those in Table 1; likely a different denominator or a typo.
- MINORtypoTable 3, footnote f“Mann-Withney U test”→ Change to 'Mann-Whitney U test'Misspelling of 'Whitney'.
The published work is methodologically robust and transparent, with no validity-threatening errors identified. An informed reader should weigh the vague data-sharing statement and the minor internal inconsistency in the Discussion's hyperandrogenism percentages (23.5% vs 15.5% versus Table 1's 29.0% vs 18.5%) as reporting gaps that could warrant a correction or clarification, but they do not undermine the primary conclusions.
- 1.HIGHdata codeReplace the vague 'Data Sharing Statement: See Supplement 4' with a concrete statement naming a repository (e.g., Dryad, Zenodo) or a managed-access procedure with conditions and a timeframe.The current statement does not specify how readers can access the data, undermining reproducibility.
- 2.HIGHdata codeDeposit de-identified participant-level data in a public or controlled-access repository and provide a DOI or accession number in the Data Sharing Statement.A repository deposit with a persistent identifier is the standard for making data actually available.
- 3.HIGHdata codeShare the statistical analysis code (R and SAS scripts) in a public repository with a permanent identifier.Sharing code enables full reproducibility of the reported analyses.
- 4.HIGHreportingReconcile the biochemical hyperandrogenism percentages in the Discussion (23.5% vs 15.5%) with Table 1 (29.0% vs 18.5%) and correct the discrepancy.An internal contradiction in reported numbers is a reporting error that could confuse readers and may warrant a correction.
- 5.MEDIUMcopyeditFix the typo 'Mann-Withney U test' to 'Mann-Whitney U test' in Table 3 footnotes a and f.Correct spelling is expected in a published manuscript.
- 6.MEDIUMdata codeClarify the content of Supplement 4 in the main text or ensure it is accessible to readers.The current reference to Supplement 4 is vague and readers may not know what it contains.
- 7.MEDIUMdata codeSpecify whether individual participant data will be shared, under what conditions, and the process for requesting access.A complete data-sharing statement should state the conditions and mechanism for access.
- 8.LOWdata codeIf any non-identifiable aggregate data are available, deposit them in a public repository with an accession number.Even aggregate data can enhance transparency and reproducibility.
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.
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