Rigor Reviewed

Rigor-Reviewed Manuscript

Myo-inositol Supplementation to Prevent Pregnancy Complications in Polycystic Ovary Syndrome: A Randomized Clinical Trial.

Name: Αlpha¹ Rigor Record — Myo-inositol Supplementation to Prevent Pregnancy Complications in Polycystic Ovary Syndrome: A Randomized Clinical Trial.
Item: Myo-inositol Supplementation to Prevent Pregnancy Complications in Polycystic Ovary Syndrome: A Randomized Clinical Trial.
Rating: 96
Author: Αlpha¹

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

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Αlpha¹ Rigor Review — 4.25★ (Strong), 0 critical, 4 high issues for “Myo-inositol Supplementation to Prevent Pregnancy Complications in Polycystic Ovary Syndrome: A Randomized Clinical Trial.”

Links back to this Rigor Record.

Αlpha¹ Editorial

This rigor review was examined and confirmed by Αlpha¹ Editorial · August 15, 2026

Αlpha¹ Rigor Review

Rigor Reviewed

4.25 / 5

Strong — minor issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern−0.5★
ReportingData & code availability partially met−0.25★

Model-reported confidence: highReviewer agreement: highEngine: 7.39.0Source: full text

Not verified in this report

No data or code availability links were detected to verify.

Problems surfaced3 types

Numerical inconsistencies1

Values 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

Overstated conclusions1

Conclusions 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

Reporting gaps1

Required 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

This Αlpha¹ Rigor Review uses AI 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.

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.

Recomputed 4 tests: 4 consistent, 0 inconsistent; 4 via agent-written checks.

1 integrity concern flagged (0 high).

Reporting

Eight Dimensions7 pass · 1 warn

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.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a clear scientific premise with prior work cited and a logical rationale for the trial.

Evidence

direct quote[Introduction, paragraph 3]

“However, no appropriately sized randomized controlled trials were conducted to evaluate the effect of myo-inositol supplementation among pregnant individuals with PCOS.”

direct quote[Introduction, paragraph 2]

“Supplementation with myo-inositol has been shown to improve insulin sensitivity, metabolic profiles, and natural conception rates in individuals with PCOS.”

direct quote[Discussion, paragraph 2]

“Potential limitations of those trials were the relatively small sample size (between 197 and 220 participants) and the open-label design.”

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise with prior work cited, a logical rationale, and addresses limitations of prior research.

Evidence

paraphrase[Introduction, paragraph 3]

“Prior randomized trials of dietary myo-inositol supplementation during pregnancy have estimated a reduction in the risk for gestational diabetes of 52% to 60%... However, no appropriately sized randomized controlled trials were conducted to evaluate the effect of myo-inositol supplementation among pregnant individuals with PCOS.”

paraphrase[Introduction, paragraph 2]

“It is hypothesized from in vitro human studies that intracellular myo-inositol depletion contributes to the development of insulin resistance and thereby increases the pregnancy risks associated with PCOS.”

direct quote[Discussion, paragraph 2]

“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.

Sub-criteria

controlsADEQUATE

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The trial design is rigorous with adequate randomization, blinding, power analysis, and pre-specified criteria.

Evidence

direct quote[Methods, Trial Procedures]

“Block randomization was performed in a 1:1 ratio, with permuted blocks of sizes 4 and 6 and stratified by trial site.”

paraphrase[Methods, Trial Procedures]

“To maintain blinding for participants, physicians, and researchers, the randomization and labeling processes of the supplement sachets were conducted by an independent research staff member and an independent statistician.”

paraphrase[Methods, Statistical Analysis]

“a sample size of 464 participants (232 per study group) was estimated to provide 80% statistical power to detect a 35% relative risk reduction of the primary outcome between the myo-inositol group and the placebo group, at a 2-sided α level of 5%.”

PASSReviewer 2· 95% conf

The trial design is rigorous with adequate randomization, blinding, power analysis, and inclusion/exclusion criteria.

Evidence

paraphrase[Methods, Trial Procedures]

“A randomization list was generated using the software package ALEA. Block randomization was performed in a 1:1 ratio, with permuted blocks of sizes 4 and 6 and stratified by trial site.”

paraphrase[Methods, Trial Procedures]

paraphrase[Methods, Statistical Analysis]

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.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Biological variables are adequately reported for a human trial, including sex, age, and demographics.

Evidence

direct quote[Results, Patients]

“The mean (SD) age was 31.5 (3.8) years and the median (IQR) prepregnancy BMI was 24.7 (21.9-28.8).”

paraphrase[Results, Patients]

“The majority of participants reported White race (86.1%)”

PASSReviewer 2· 90% conf

Demographic and clinical characteristics are well reported, including age, race, BMI, and relevant comorbidities.

Evidence

direct quote[Results, Patients]

“The mean (SD) age was 31.5 (3.8) years and the median (IQR) prepregnancy BMI was 24.7 (21.9-28.8).”

paraphrase[Results, Patients]

“The majority of participants reported White race (86.1%), were nulliparous (66.0%), and conceived through assisted reproductive technology (67.5%).”

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.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethical approvals and consent are adequately documented.

Evidence

paraphrase[Methods, Trial Oversight]

“The trial protocol received approval from the institutional ethics committees of all participating hospitals”

direct quote[Methods, Trial Oversight]

“All study participants gave written informed consent.”

direct quote[Methods, Trial Oversight]

“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.”

PASSReviewer 2· 95% conf

Ethical approval and informed consent are adequately documented.

Evidence

direct quote[Methods, Trial Oversight]

“The trial protocol 22 received approval from the institutional ethics committees of all participating hospitals and is available in Supplement 1.”

direct quote[Methods, Trial Oversight]

“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.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational product is adequately identified, and software tools are named.

Evidence

direct quote[Methods, Trial Oversight]

“The supplements for both the intervention and placebo group were purchased from and manufactured by Gynov SAS.”

direct quote[Methods, Statistical Analysis]

“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).”

PASSReviewer 2· 90% conf

The investigational product (myo-inositol and placebo) is adequately identified, and statistical software is named.

Evidence

direct quote[Methods, Trial Procedures]

“The supplements for both the intervention and placebo group were purchased from and manufactured by Gynov SAS.”

direct quote[Methods, Statistical Analysis]

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.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Statistical methods are appropriate and well-reported, with exact p-values and effect sizes with CIs.

Evidence

paraphrase[Methods, Statistical Analysis]

“Between-group differences and relative risks for the primary outcome were assessed with the use of the χ2 test. Secondary outcomes were compared using the χ2 test, Fisher exact test, unpaired t test, or Mann-Whitney U test as appropriate.”

direct quote[Results, Primary Outcome]

“relative risk, 0.93 [95% CI, 0.68-1.28]; P = .67”

direct quote[Results, Primary Outcome]

“relative risk, 0.93 [95% CI, 0.68-1.28]”

PASSReviewer 2· 90% conf

Statistical methods are appropriate and well-reported, with exact p-values and effect sizes with confidence intervals.

Evidence

paraphrase[Methods, Statistical Analysis]

paraphrase[Results, Primary Outcome]

“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).”

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.

Sub-criteria

code sharingNOT REPORTED

accession numbersN/A

repository depositNOT REPORTED

data availability statementINADEQUATE

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 80% conf

Data availability statement is present but vague, and no repository deposit or code sharing is mentioned.

Evidence

direct quote[Article Information]

“Data Sharing Statement: See Supplement 4.”

WARNReviewer 2· 80% conf

A data sharing statement is present but vague, and no repository or code is provided.

Evidence

direct quote[Article Information]

“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.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Reporting is complete and transparent, with trial registration, CONSORT adherence, and limitations discussed.

Evidence

direct quote[Abstract, Trial Registration]

“TRIAL REGISTRATION onderzoekmetmensen.nl Identifier: NL67329.078.18”

direct quote[Methods, Trial Oversight]

“This trial followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline for randomized clinical trials.”

paraphrase[Discussion, Limitations]

“This trial has several limitations. First, 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.”

PASSReviewer 2· 95% conf

The manuscript is transparent with complete methods, trial registration, CONSORT adherence, and proportional conclusions.

Evidence

direct quote[Abstract, Trial Registration]

“TRIAL REGISTRATION onderzoekmetmensen.nl Identifier: NL67329.078.18”

direct quote[Methods, Trial Oversight]

“This trial followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline for randomized clinical trials.”

paraphrase[Discussion, Limitations]

3 copyedit issues flagged: mostly typo, consistency.

Checked 27 references by DOI: 25 verified — 2 no DOI (shown, not verified).

Reproducibility

Registration stated in text, but no registry ID was detected. Reporting guideline cited: CONSORT.

Αlpha¹ Rigor Action ItemsFinal pass before journal submission

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 code
Replace 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 code
Deposit 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 code
Share 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.
HIGHreporting
Reconcile 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.
MEDIUMcopyedit
Fix 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 code
Clarify 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 code
Specify 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 code
If 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.

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Myo-inositol Supplementation to Prevent Pregnancy Complications in Polycystic Ovary Syndrome: A Randomized Clinical Trial.

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DOI

10.1001/jama.2025.13668

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Issued Aug 15, 2026Engine 7.39.0

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