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Kaimen Rigor review

IVF versus ICSI in patients without severe male factor infertility: a randomized clinical trial.

Berntsen S, Zedeler A, Nøhr B, Rønn Petersen M, Grøndahl ML, Andersen LF, Løssl K, Løkkegaard E, Englund AL, Vestergaard Gabrielsen A, Prætorius L, Behrendt-Møller I, Langhoff Thuesen L, Vomstein K, Petri Lauritsen M, Ivanoska Trajcevski A, Frøding Skipper D, Westergaard D, Pinborg A, Svarre Nielsen H, la Cour Freiesleben N

DOI: 10.1038/s41591-025-03621-x
Record issued: 2026-08-15
Engine: 7.39.0
Exported: 2026-09-22

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/05073aa1-5099-474e-b7eb-ffcfc054f8a0 is authoritative.

Kaimen Rigor review

Kaimen Rigor reviewed

1 / 5

Critical — a demonstrable failure

Interventional Study

Critical

High-priority

How this rating was calculated

Started at 5★ — deductions

StatisticsImpossible or misreported statistic ×2−2★
IntegrityIntegrity concern ×2−1★
CitationsCitations & links (capped) ×8−1★
StatisticsPrinted percentage does not match its own count (capped) ×4−0.25★

Citations & links are capped at −1★ combined, however many are flagged.

A demonstrable critical failure caps the rating at the minimum, regardless of the deductions above.

Model-reported confidence: moderateReviewer agreement: lowEngine: 7.39.0Source: full text

Biggest issues2 demonstrable

01Printed percentage does not match its own countdemonstrable
criticalArithmeticrecomputedFull detail
68.5% does not match the reported count 242/414
“242/414 (68.5%)”
Find in source
02Printed percentage does not match its own countdemonstrable
criticalArithmeticrecomputedFull detail
2.9% does not match the reported count 3/179
“3/179 (2.9%)”
Find in source
03Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
16.4% does not match the reported count 67/414
“67/414 (16.4%)”
Find in source
04Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
5.3% does not match the reported count 10/193
“10/193 (5.3%)”
Find in source
05Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
2.1% does not match the reported count 4/179
“4/179 (2.1%)”
Find in source
06Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
1.3% does not match the reported count 3/179
“3/179 (1.3%)”
Find in source

Findings by category

301ArithmeticNumerical inconsistencies 102OverreachOverstated conclusions 03AuthenticityNone found 04DisclosureNone found 105AvailabilityBroken references and links 06Copyedit6 minor suggestions

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 multicenter RCT comparing ICSI versus c-IVF, with strong ethical approvals, detailed biological variable reporting, and a concrete data availability statement. The main weaknesses are the open-label design, lack of explicit CONSORT reporting, and some statistical inconsistencies that could not be fully verified.

All three reviewers agreed on study type (interventional). The synthesis weighed the reviewers' divergent ratings, with specific evidence from the statistics verification component (6/9 inconsistent recomputations) and copyedit issues (denominator errors) influencing the final statuses. N/A dimensions were excluded from scoring.

Numerical inconsistencies

3 findings · worst critical

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.

Summary statistic impossible for the stated N (GRIM/GRIMMER)Recomputed
Printed percentage does not match its own countRecomputed
Internal contradictions in the reported numbersAssessed

Recomputed 3 tests: 3 consistent, 0 inconsistent; 3 via agent-written checks. 2 reported summary statistics mathematically impossible for the stated N (PERCENT). 4 printed percentages that do not match their own count.

Numeric forensics— values impossible for the reported sample size

PERCENT
16.4% does not match the reported count 67/414
“67/414 (16.4%)”
Find in source
PERCENT
68.5% does not match the reported count 242/414
“242/414 (68.5%)”
Find in source
PERCENT
2.9% does not match the reported count 3/179
“3/179 (2.9%)”
Find in source
PERCENT
5.3% does not match the reported count 10/193
“10/193 (5.3%)”
Find in source
PERCENT
2.1% does not match the reported count 4/179
“4/179 (2.1%)”
Find in source
PERCENT
1.3% does not match the reported count 3/179
“3/179 (1.3%)”
Find in source

Agent-written checks— recomputed from reported CIs / ratios by code the agent wrote

CONSISTENTreported p = .240 · recomputed p = .209Reviewer 2
Primary outcome risk ratio p-value from CI
“The CLBR was 43.2% (179/414) in the ICSI group and 47.3% (193/408) in the c-IVF group, yielding a risk ratio of 0.91 (95% confidence interval, 0.79–1.06).”
Find in source
Taken as given: The risk ratio is 0.91 with 95% CI 0.79-1.06.; The CI is two-sided at 95%.; The p-value is for the null hypothesis RR=1.
Method: Two-sided p-value derived from the log-risk ratio and its standard error from the CI.
How we recomputed it: pCI(0.91, 0.79, 1.06, 1)
CONSISTENTreported p = .240 · recomputed p = .209Reviewer 3
Primary outcome CLBR risk ratio p-value
“CLBR | 179/414 (43.2%) | 193/408 (47.3%) | −0.04 (−0.11 to 0.03) | 0.91 (0.79–1.06) | 0.24”
Find in source
Taken as given: The risk ratio is 0.91 with 95% CI 0.79-1.06.; The p-value is two-sided from a Wald test on the log risk ratio.
Method: Recomputed p-value from the reported risk ratio and 95% CI using the normal approximation.
How we recomputed it: pCI(0.91, 0.79, 1.06, 1)
CONSISTENTreported p = .440 · recomputed p = .412Reviewer 3
Total fertilization failure p-value
“TFF | 20/414 (4.8%) | 15/408 (3.7%) | 1.29 (0.68–2.54) | 0.44”
Find in source
Taken as given: The counts are 20 events out of 414 in ICSI group and 15 out of 408 in c-IVF group.; The p-value is from a chi-square test (or equivalent) for the 2x2 table.
Method: Recomputed p-value using Pearson's chi-square test on the 2x2 table.
How we recomputed it: pChi2x2(20, 414-20, 15, 408-15)

lowinternal contradiction
In Table 3, the footnote for c-IVF group says 'One spontaneous pregnancy occurred in the c-IVF group but is not included in this table' but the text says two spontaneous pregnancies in the c-IVF group.
“d One spontaneous pregnancy occurred in the c-IVF group but is not included in this table.”
Table 3Find in source
lowinternal contradiction
In Table 2, the row 'Participants with no embryo transfer' shows 67/414 for the c-IVF group, but the c-IVF group has 408 participants. This appears to be a typographical error.
“Participants with no embryo transfer | 87/414 (21.0%) | 67/414 (16.4%)”
Table 2Find in source

Overstated conclusions

1 finding · worst low

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

7 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.

partialReviewers 2, 3
ICSI may be associated with reduced live birth in younger women (≤32 years).
This is a secondary analysis with a significant interaction, but it was not pre-specified and may be exploratory.
Evidence: Extended Data Fig. 1 shows a negative effect in younger women; number needed to harm = 9.
“The secondary analysis showed a negative effect of ICSI compared to c-IVF on younger women (≤32 years of age; Extended Data Fig. ).”
Results ¶5Find in source
supportedReviewers 2, 3
ICSI does not improve CLBR compared to c-IVF in patients without severe male factor infertility.
The primary outcome analysis shows a risk ratio of 0.91 (95% CI 0.79-1.06), which is not statistically significant, supporting the claim of non-superiority.
Evidence: Primary outcome CLBR: 43.2% vs 47.3%, RR 0.91 (95% CI 0.79-1.06), p=0.24.
“These findings demonstrate that ICSI does not improve CLBR compared to c-IVF and support c-IVF as the preferred first-line treatment for patients with normal or nonseverely decreased sperm quality.”
AbstractFind in source
supportedReviewer 2
c-IVF should be the preferred first-line treatment for patients without severe male factor infertility.
The non-superiority of ICSI, combined with cost and resource considerations, supports this recommendation.
Evidence: Primary outcome non-significant; discussion of cost-effectiveness.
“C-IVF is safe, straightforward and gentle on both oocytes and sperm, making it more cost-effective and resource-efficient in first-cycle patients compared to ICSI.”
DiscussionFind in source
supportedReviewers 2, 3
ICSI should be reserved for severe male factor infertility.
The study did not include severe male factor patients, but the lack of benefit in non-severe cases supports reserving ICSI for severe cases.
Evidence: Study population excluded severe male factor; results show no benefit in non-severe cases.
“ICSI should be reserved for severe male factor infertility.”
AbstractFind in source
supportedReviewer 2
Fertilization rates are higher with c-IVF than ICSI.
The fertilization rate per oocyte retrieved was significantly higher in the c-IVF group (58.1% vs 53.5%, p≤0.001).
Evidence: Table 4: Fertilization rate per oocyte retrieved 53.5% vs 58.1%, p≤0.001.
“The fertilization rate (two pronuclei (2PN)) per oocyte retrieved was substantially lower in the ICSI group than in the c-IVF group (53.5% (1,940/3,628) versus 58.1% (1,983/3,412); P ≤ 0.001; Table ).”
Results ¶2Find in source
supportedReviewer 3
c-IVF should be the preferred first-line treatment for patients with normal or nonseverely decreased sperm quality.
The non-superiority of ICSI, combined with cost and resource considerations, supports this recommendation.
Evidence: Primary outcome and discussion of cost-effectiveness.
“support c-IVF as the preferred first-line treatment for patients with normal or nonseverely decreased sperm quality.”
AbstractFind in source
supportedReviewer 3
Fertilization rate per oocyte retrieved is lower with ICSI than with c-IVF.
The reported fertilization rates (53.5% vs 58.1%) with a p-value ≤0.001 support this claim.
Evidence: Table 4: Fertilization rate per oocyte retrieved 53.5% vs 58.1%, p≤0.001.
“The fertilization rate (two pronuclei (2PN)) per oocyte retrieved was substantially lower in the ICSI group than in the c-IVF group (53.5% (1,940/3,628) versus 58.1% (1,983/3,412); P ≤ 0.001; Table ).”
Results ¶2Find in source

Efficacy claim is anchored to an adequate endpoint and a meaningful effect.

ADEQUATESurrogate endpoint
The primary outcome is cumulative live birth rate (CLBR), a hard clinical outcome, not a surrogate. The study directly measures live births, which is a validated clinical endpoint.
“The CLBR was 43.2% (179/414) in the ICSI group and 47.3% (193/408) in the c-IVF group, yielding a risk ratio of 0.91 (95% confidence interval, 0.79–1.06).”
Find in source
ADEQUATEEffect size
The effect size is reported as a risk ratio of 0.91 with a 95% CI including 1, indicating no statistically significant difference. The study was powered to detect a 10% absolute difference, and the observed difference is small and not clinically meaningful. The conclusion of non-superiority is based on the confidence interval crossing 1, which is an appropriate anchor for clinical meaningfulness in a superiority trial.
“The CLBR was 43.2% (179/414) in the ICSI group and 47.3% (193/408) in the c-IVF group, yielding a risk ratio of 0.91 (95% confidence interval, 0.79–1.06).”
Find in source

Data authenticity concerns

None found

An 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 found

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.

Checked — nothing surfaced.

Eight Dimensions8 pass

The introduction cites prior retrospective studies and two Asian RCTs, acknowledges the debate and lack of evidence for ICSI in non-male factor infertility, and clearly links the premise to the study's objective of comparing CLBR. Limitations of prior work (e.g., retrospective designs, use of cleavage-stage transfers) are addressed in the discussion.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 80% conf

The premise is well established with extensive citation of prior work, but the paper does not explicitly acknowledge weaknesses or limitations of the cited prior studies.

Evidence

paraphrase[Introduction, paragraph 2]

“Paraphrase: Recently, two randomized controlled trials (RCTs) conducted in Asia found no improvement in live birth rate after the first embryo transfer when comparing ICSI with c-IVF among couples with normal sperm parameters and those with nonsevere male factor infertility, respectively.”

“The CLBR is considered the most appropriate metric for evaluating the overall effectiveness of an ART treatment regimen”

Introduction ¶3Find in source

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise with adequate citation of prior work and a logical rationale for the study.

Evidence

“However, retrospective studies have failed to demonstrate any advantage of ICSI over c-IVF in terms of live birth rates in this patient group – .”

Introduction ¶2Find in source

“This European contribution provides new insights by focusing on key aspects—targeting first-cycle patients, emphasizing blastocyst transfers and elective single embryo transfers (eSET) to minimize multiple pregnancies and using cumulative live birth rate (CLBR) as the primary outcome measure.”

Introduction ¶3Find in source

“These results are consistent with the outcomes of prior RCTs from other countries ,, , as well as large retrospective studies –, and a recently updated Cochrane systematic review and meta-analysis .”

Discussion ¶1Find in source

PASSReviewer 3· 90% conf

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

Evidence

“However, retrospective studies have failed to demonstrate any advantage of ICSI over c-IVF in terms of live birth rates in this patient group – .”

Introduction ¶2Find in source

“The CLBR is considered the most appropriate metric for evaluating the overall effectiveness of an ART treatment regimen – .”

Introduction ¶3Find in source

Randomization method (computer-generated, permuted blocks, stratified by site and age) and unit (participant) are clearly described. Blinding is not performed but a rationale is provided. Power analysis is reported with effect size, alpha, and power. Inclusion/exclusion criteria are pre-specified. Outlier handling is addressed via ITT and per-protocol analyses. Controls are inherent in the comparator arm. Independent replication is not applicable for a single pivotal trial.

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 85% conf

The trial is well-designed with adequate randomization, stratification, and a pre-specified primary outcome, but the lack of blinding and the timing of randomization (after the ovulation trigger) introduce potential performance bias.

Evidence

“For the randomization process, a statistician who was not involved in any other parts of the study devised a computer-generated randomization scheme, maintaining a 1:1 ratio between the two arms (c-IVF and ICSI). Randomization involved permuted blocks of varying sizes, ranging from 4 to 12. It was stratified by trial site and female age, categorized into the following three age groups: 18–25 years, 26–37 years and 38–42 years.”

MethodsFind in source

“The study was designed with no blinding of participants, clinicians or assessors.”

MethodsFind in source

“The primary outcome was the CLBR, defined as at least one live birth after completing an ART cycle”

MethodsFind in source

PASSReviewer 2· 95% conf

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

Evidence

MethodsFind in source

“The study was designed as a superiority trial with 80% power and a 5% significance level for a two-sided test, aiming to detect a 10% point difference in CLBR.”

Statistical analysisFind in source

“The study was designed with no blinding of participants, clinicians or assessors.”

MethodsFind in source

PASSReviewer 3· 95% conf

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

Evidence

“Randomization involved permuted blocks of varying sizes, ranging from 4 to 12. It was stratified by trial site and female age, categorized into the following three age groups: 18–25 years, 26–37 years and 38–42 years.”

MethodsFind in source

“The study was designed as a superiority trial with 80% power and a 5% significance level for a two-sided test, aiming to detect a 10% point difference in CLBR.”

Statistical analysisFind in source

“Eligible participants were women aged 18–42 years with no prior c-IVF or ICSI treatment and a body mass index of 18–35 mg m −2 .”

MethodsFind in source

The paper reports female age, BMI, ethnicity, and infertility cause, and male partner age, BMI, and detailed semen parameters. The study population is female participants and their male partners or sperm donors, so sex is inherent. Missing data are reported for several variables.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 90% conf

Biological variables are adequately reported for the female participants and male partners, with the exception of a few missing data points.

Evidence

“Table 1 Baseline characteristics (ITT analysis)”

Table 1Find in source

“Sperm characteristics were assessed from the sample used on the day of oocyte retrieval.”

Table 1Find in source

PASSReviewer 2· 90% conf

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

Evidence

“Age at inclusion, mean (s.d.) | 33.0 (4.6) | 33.5 (4.4)”

Table 1Find in source

paraphrase[Table 1]

“Ethnicity, n (%) | Europe, the Middle East or North Africa | 370/414 (89.4%) | 368/408 (90.2%)”

PASSReviewer 3· 90% conf

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

Evidence

“No sex or gender analysis was carried out, as the study population enrolled only female participants assigned female sex at birth and male partners or sperm donors, with a focus on their biological contributions to the outcomes.”

MethodsFind in source

“Age at inclusion, mean (s.d.) | 33.0 (4.6) | 33.5 (4.4)”

Table 1Find in source

paraphrase[Table 1]

“Ethnicity, n (%) | Europe, the Middle East or North Africa | 370/414 (89.4%) | 368/408 (90.2%)”

The study was approved by the Scientific Ethical Committee of the Capital Region of Denmark (H-19022201) and the Danish Knowledge Centre on Data Protection Compliance, and was performed in accordance with the Helsinki Declaration. Written informed consent was obtained from all participants. The trial was registered at ClinicalTrials.gov (NCT04128904).

Sub-criteria

informed consentADEQUATE

iac الدايرهN/A

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethics approval and informed consent are clearly documented for this human RCT.

Evidence

“Approval for the study was obtained from the Scientific Ethical Committee of the Capital Region of Denmark (H-19022201) and the Danish Knowledge Centre on Data Protection Compliance.”

EthicsFind in source

“Couples/women who wished to participate in the study were asked to sign an informed consent form before enrollment.”

EthicsFind in source

PASSReviewer 2· 95% conf

Ethical approvals and consent are adequately reported.

Evidence

“Approval for the study was obtained from the Scientific Ethical Committee of the Capital Region of Denmark (H-19022201) and the Danish Knowledge Centre on Data Protection Compliance.”

MethodsFind in source

“Couples/women who wished to participate in the study were asked to sign an informed consent form before enrollment.”

MethodsFind in source

“The study was performed according to Danish Law and ethical principles in the Helsinki Declaration.”

MethodsFind in source

PASSReviewer 3· 95% conf

Ethical approvals and consent are adequately reported.

Evidence

“Approval for the study was obtained from the Scientific Ethical Committee of the Capital Region of Denmark (H-19022201) and the Danish Knowledge Centre on Data Protection Compliance.”

MethodsFind in source

“Couples/women who wished to participate in the study were asked to sign an informed consent form before enrollment.”

MethodsFind in source

“The study was performed according to Danish Law and ethical principles in the Helsinki Declaration.”

MethodsFind in source

The trial compares two fertilization techniques; the procedures are described in detail. Statistical software (R v4.2.2) and packages are identified. No antibodies, cell lines, or other bench reagents are applicable.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

The investigational product (ICSI) is adequately identified, and the statistical software is named; however, the specific culture media and other reagents are not fully specified.

Evidence

paraphrase[Methods, Oocyte insemination and embryo transfer]

“Oocyte insemination was performed by either ICSI or c-IVF, based on randomization, following standard procedures at the trial sites.”

paraphrase[Methods, Statistical analysis]

“All statistical analyses were performed using R (v4.2.2)”

PASSReviewer 2· 85% conf

The investigational product (ICSI vs c-IVF) is adequately described, and software is identified.

Evidence

“All statistical analysis was done using R (v4.2.2), using the packages sjPlot (v2.8.15) and marginal effects (v0.18.0).”

Statistical analysisFind in source

PASSReviewer 3· 90% conf

The investigational product (ICSI vs c-IVF) is adequately described, and software tools are identified.

Evidence

“Fertility treatment procedures adhered to established practices, encompassing ovarian stimulation, transvaginal ultrasound, ovulation triggering, insemination (ICSI or c-IVF), embryo culture, luteal phase support, embryo transfer and cryopreservation.”

MethodsFind in source

“All statistical analysis was done using R (v4.2.2), using the packages sjPlot (v2.8.15) and marginal effects (v0.18.0).”

Statistical analysisFind in source

Tests are named (Wald test, Mann-Whitney U). Assumptions are handled by design (GLM, non-parametric tests). Exact p-values are reported. Effect sizes with CIs are reported. Software is identified. Data presentation is adequate for a clinical trial (tables with n, percentages, CIs). Mathematical plausibility checks were not possible for most outcomes due to continuous data and large N, 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 (3) — the votes behind the verdict

WARNReviewer 1· 80% conf

The statistical analysis is generally well-reported with named tests, exact p-values, and effect estimates with confidence intervals, but the mathematical plausibility of several reported statistics could not be independently verified from the printed numbers.

Evidence

paraphrase[Methods, Statistical analysis]

“The primary analysis was performed using an intention-to-treat approach. ... The P values for binary variables were calculated using a Wald test, with effect estimates (β) and s.e. derived from a generalized linear model.”

paraphrase[Table 2, Results]

“The CLBR was 43.2% (179/414) in the ICSI group and 47.3% (193/408) in the c-IVF group (risk ratio = 0.91, 95% CI = 0.79–1.06; Table 2).”

PASSReviewer 2· 90% conf

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

Evidence

“The P values for binary variables were calculated using a Wald test, with effect estimates ( β ) and s.e. derived from a generalized linear model. The P values for continuous variables were calculated using a Mann–Whitney U test.”

Table 2Find in source

“The fertilization rate (two pronuclei (2PN)) per oocyte retrieved was substantially lower in the ICSI group than in the c-IVF group (53.5% (1,940/3,628) versus 58.1% (1,983/3,412); P ≤ 0.001; Table ).”

Results ¶2Find in source

“The CLBR was 43.2% (179/414) in the ICSI group and 47.3% (193/408) in the c-IVF group, yielding a risk ratio of 0.91 (95% confidence interval, 0.79–1.06).”

AbstractFind in source

PASSReviewer 3· 90% conf

Statistical analysis is rigorous with named tests, exact p-values, effect sizes with CIs, and appropriate data presentation.

Evidence

Table 2Find in source

“CLBR | 179/414 (43.2%) | 193/408 (47.3%) | −0.04 (−0.11 to 0.03) | 0.91 (0.79–1.06) | 0.24”

Table 2Find in source

paraphrase[Table 2]

“Risk ratio (95% CI) | 0.91 (0.79–1.06)”

The data availability statement provides a concrete route: controlled access via the Health Research Ethics Committees and GDPR compliance, with a review timeframe. Repository deposit and accession numbers are not applicable for identifiable patient data. Code sharing is not applicable as no custom code was developed.

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositN/A

data availability statementADEQUATE

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 80% conf

A data availability statement is present, but it describes only controlled access upon reasonable request, with no repository deposit or accession numbers.

Evidence

“Individual de-identified participant data will be available upon reasonable request.”

Data availabilityFind in source

absence[Data availability]

No data repository deposit or accession numbers are provided.

PASSReviewer 2· 90% conf

Data availability is adequately described with a concrete access route, and code availability is stated.

Evidence

“Individual de-identified participant data will be available upon reasonable request. Access will require approval from the Health Research Ethics Committees for the Capital Region of Denmark (H-19022201) and compliance with the General Data Protection Regulation. Requests can be directed to N.l.C.F. and will be reviewed within 4 weeks.”

Data availabilityFind in source

“No custom computational code or software was developed for this study.”

Data availabilityFind in source

PASSReviewer 3· 90% conf

Data availability is adequately described with a concrete access route, and code availability is stated.

Evidence

Data availabilityFind in source

“No custom computational code or software was developed for this study.”

Data availabilityFind in source

The trial is registered (NCT04128904). A reporting guideline is not explicitly mentioned but the paper follows CONSORT-like structure. All outcomes are reported, including negative results. Limitations are discussed. Conclusions are proportional. Funding and COI are disclosed.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineINADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 80% conf

The methods are detailed and reproducible, but the trial was not registered in a primary registry with a number, and no reporting guideline (CONSORT) is referenced.

Evidence

“ClinicalTrials.gov registration: NCT04128904 (https://clinicaltrials.gov/study/NCT04128904)”

DiscussionFind in source

paraphrase[Methods, ethics approval]

“The study was prospectively registered before the first participant was enrolled.”

paraphrase[Discussion]

“The study does have limitations. First, participants were randomized before oocyte retrieval, and there was no blinding, which introduces the possibility of performance bias.”

PASSReviewer 2· 95% conf

Reporting is transparent with trial registration, funding/COI statements, and proportional conclusions.

Evidence

“ClinicalTrials.gov registration: NCT04128904 (https://clinicaltrials.gov/study/NCT04128904) .”

AbstractFind in source

“However, the study does have limitations. First, participants underwent randomization before oocyte retrieval, and there was no blinding, introducing the possibility of performance bias.”

Discussion ¶4Find in source

“The preparation of the study was funded by Gedeon Richter (unrestricted grant to N.l.C.F.).”

AcknowledgementsFind in source

PASSReviewer 3· 95% conf

Reporting is transparent with trial registration, reporting guideline, complete outcome reporting, limitations, proportional conclusions, and funding/COI statements.

Evidence

“ClinicalTrials.gov registration: NCT04128904 (https://clinicaltrials.gov/study/NCT04128904) .”

AbstractFind in source

“Further information on research design is available in the linked to this article.”

AbstractFind in source

“However, the study does have limitations. First, participants underwent randomization before oocyte retrieval, and there was no blinding, introducing the possibility of performance bias.”

Discussion ¶4Find in source

Registered (1 ID: ClinicalTrials.gov). No reporting guideline cited.

ClinicalTrials.gov

NCT04128904

Broken references and links

1 finding · worst low

References 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.

References not resolvable to a published paperRecomputed

Checked 53 references by DOI: 44 verified — 8 DOI unresolved, 1 no DOI (shown, not verified).

UNRESOLVED10.1016/s0140-6736(21)00535-4
Intracytoplasmic sperm injection versus conventional in-vitro fertilisation in couples with infertility in whom the male partner has normal total sperm count and motility: an open-label, randomised controlled trial
Cited DOI does not resolve to any Crossref record.
UNRESOLVED10.1016/s0140-6736(24)00034-5
Intracytoplasmic sperm injection versus conventional in-vitro fertilisation for couples with infertility with non-severe male factor: a multicentre, open-label, randomised controlled trial
Cited DOI does not resolve to any Crossref record.
UNRESOLVED10.1016/s0140-6736(00)05121-5
Conventional in-vitro fertilisation versus intracytoplasmic sperm injection for the treatment of non-male-factor infertility: a randomised controlled trial
Cited DOI does not resolve to any Crossref record.
UNRESOLVED10.1007/s10815-005-9016-5
A prospective randomized trial of conventional in vitro fertilization versus intracytoplasmic sperm injection in unexplained infertility
Cited DOI does not resolve to any Crossref record.
UNRESOLVED10.1007/s10815-020-01996-1
The role of ICSI vs. conventional IVF for patients with advanced maternal age—a randomized controlled trial
Cited DOI does not resolve to any Crossref record.
UNRESOLVED10.1007/s10815-017-0966-1
Pre-implantation genetic diagnosis-should we use ICSI for all?
Cited DOI does not resolve to any Crossref record.
UNRESOLVED10.1186/s12958-021-00809-5
Should rescue ICSI be re-evaluated considering the deferred transfer of cryopreserved embryos in in-vitro fertilization cycles? A systematic review and meta-analysis
Cited DOI does not resolve to any Crossref record.
UNRESOLVED10.1186/s11689-020-09335-5
Risk of neurodevelopmental disorders in children born from different ART treatments: a systematic review and meta-analysis
Cited DOI does not resolve to any Crossref record.
NO DOI
Effect of sperm morphology on clinical outcome parameters in ICSI cycles
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).

2 data/code links checked; 2 live.

datahttps://clinicaltrials.gov/study/NCT04128904LIVEHTTP 200
Resolves, but the content could not be matched to the paper.
datahttps://clinicaltrials.gov/ct2/show/NCT04128904LIVEHTTP 200
Resolves, but the content could not be matched to the paper.

Copyediting

6 minor

Wording, consistency and formatting errors that need correcting before submission.

No major wording or formatting errors. 6 minor suggestions below.

6 copyedit issues flagged: mostly consistency, typo, clarity.

MINORconsistencyTable 2, row 'Participants with no embryo transfer'
“67/414 (16.4%)”
→ Should be 67/408 (16.4%) to match the c-IVF group denominator.
The denominator for the c-IVF group is 408, not 414.
MINORtypoTable 5, row 'Gestational hypertension'
“−6.31 −3 (−0.06 to 0.04)”
→ Likely meant '−6.31 × 10⁻³'.
Missing multiplication sign and exponent formatting.
MINORclarityMethods, Statistical analysis
“All secondary analyses, except for the per-protocol analysis, were defined postdata collection as outlined in the statistical analysis plan.”
→ Clarify that the statistical analysis plan was finalized before data analysis.
Potential ambiguity about pre-specification.
MINORtypoAbstract
“31 6 1939 1939–1948”
→ Remove stray numbers
Stray numbers appear in the abstract header.
MINORconsistencyTable 2
“Participants with no embryo transfer | 87/414 (21.0%) | 67/414 (16.4%)”
→ Change denominator to 408 for c-IVF group
The c-IVF group denominator is incorrectly listed as 414 instead of 408.
MINORclarityTable 5
“−6.31 −3 (−0.06 to 0.04)”
→ Use scientific notation consistently
The risk difference is written in an unusual format.

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is largely robust, but an informed reader should weigh the open-label design and the statistical inconsistencies flagged by the verification component. The copyedit issues (denominator errors, stray numbers) are minor but should be corrected in any erratum. The lack of explicit CONSORT reporting and the registration number not in Methods are reporting gaps that could be addressed in a correction.

1.
CRITICALstatistics
Correct or explain the statistically impossible value: PERCENT: 68.5% does not match the reported count 242/414
Demonstrable critical failure — blocks the verdict from passing.
2.
CRITICALstatistics
Correct or explain the statistically impossible value: PERCENT: 2.9% does not match the reported count 3/179
Demonstrable critical failure — blocks the verdict from passing.
3.
HIGHstatistics
In the statistical analysis section, clarify the discrepancies found in the recomputation of reported statistics (e.g., fertilization rates, percentages) by providing the exact denominators and raw data or correcting any typographical errors.
The statistics verification component found 6 of 9 recomputed tests inconsistent, which could indicate reporting errors that need correction.
4.
HIGHreporting
Add the ClinicalTrials.gov registration number (NCT04128904) to the Methods section, not just the abstract and discussion.
The registration number is a key transparency element that should be prominently reported in the Methods.
5.
HIGHreporting
Explicitly state adherence to the CONSORT reporting guideline in the Methods or Reporting Summary.
Referencing CONSORT strengthens reporting transparency and is expected for randomized trials.
6.
MEDIUMcopyedit
Correct the denominator error in Table 2 for the c-IVF group in the row 'Participants with no embryo transfer' (should be 67/408, not 67/414).
The copyedit pass flagged this as a consistency issue that could mislead readers.
7.
MEDIUMcopyedit
Fix the typo in Table 5 for 'Gestational hypertension' where the risk difference is written as '−6.31 −3 (−0.06 to 0.04)' — should be '−6.31 × 10⁻³'.
The unusual formatting is a typographical error that should be corrected for clarity.
8.
MEDIUMcopyedit
Remove stray numbers in the Abstract header ('31 6 1939 1939–1948').
The copyedit pass flagged stray numbers that appear to be a formatting error.
9.
MEDIUMreporting
Clarify the definition of the per-protocol population in the main text, not just in the figure legend.
Reviewer 2 suggested this to improve clarity for readers.
10.
MEDIUMdata code
Consider adding a data-sharing statement in the main text, even though the Data Availability section is adequate.
Reviewer 2 suggested this to make the data availability more prominent.
11.
MEDIUMstatistics
Report the exact p-value for the fertilization rate comparison instead of 'P ≤ 0.001'.
Reviewer 3 suggested this to improve precision.
12.
LOWreporting
Clarify the distinction between 'missing data' and 'unavailable data' in tables.
Reviewer 3 suggested this to avoid confusion.
13.
LOWreporting
Consider adding a statement about the availability of the statistical analysis plan (SAP) in a public repository.
Reviewer 3 suggested this to enhance transparency.
14.
LOWother
Clarify the internal contradiction regarding the number of spontaneous pregnancies in the c-IVF group (Table 3 footnote says one, text says two).
The integrity check flagged this as a low-severity internal contradiction that should be resolved.

Full text (71,998 chars)Analyzed: Aug 15, 2026

RigorReviewer 1

RigorReviewer 2

RigorReviewer 3

RigorPre-Submission Reviewer

CopyeditAgent Scribe

CitationsCitation Integrity

StatisticsStatistics Consistency

ReproducibilityLink verification (liveness + content)· no model (rule-based)

PreregistrationDeterministic check· no model (rule-based)

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.”

How stars are deducted

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.

The eight reporting dimensions

Scientific PremisePrior work, rationale, and how it addresses gaps.

Study Design & RigorRandomization, blinding, power, controls, replication.

Biological VariablesSex, age, species/strain, housing, demographics.

Ethical ApprovalsIRB/IACUC approval, informed consent, regulatory compliance.

Key ResourcesAntibodies, cell lines, organisms, software — identified with persistent IDs.

Statistical ReportingNamed tests, exact p-values, effect sizes, plausible summary stats.

Data & Code AvailabilityAvailability statements, repositories, accession numbers, shared code.

Reporting TransparencyMethods, registration, guidelines, outcomes, limitations, funding/COI.

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.

IVF versus ICSI in patients without severe male factor infertility: a randomized clinical trial.

DOI

10.1038/s41591-025-03621-x

Record issued

2026-08-15

Engine

7.39.0

Exported

2026-09-22