Two Randomized Trials of Low-Dose Calcium Supplementation in Pregnancy.
Dwarkanath P, Muhihi A, Sudfeld CR, Wylie BJ, Wang M, Perumal N, Thomas T, Kinyogoli SM, Bakari M, Fernandez R, Raj JM, Swai NO, Buggi N, Shobha R, Sando MM, Duggan CP, Masanja HM, Kurpad AV, Pembe AB, Fawzi WW
- DOI
- 10.1056/NEJMoa2307212
- Record issued
- 2026-08-16
- 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/ecee61d0-b1e2-4a84-a75d-40b298d397a4 is authoritative.
How this rating was calculated
- StatisticsImpossible or misreported statistic−1★
- StatisticsPrinted percentage does not match its own count (capped)−0.25★
- ReportingData & code availability partially met−0.25★
A demonstrable critical failure caps the rating at the minimum, regardless of the deductions above.
- 01Significance claim does not survive recomputationdemonstrable
Noninferiority p-value for preeclampsia in India trial (RR 0.84, 95% CI 0.68-1.03) vs margin 1.54
“relative risk, 0.84; 95% confidence interval [CI], 0.68 to 1.03”
- 02Printed percentage does not match its own count
0.04% does not match the reported count 1/4475
“1/4475 (<0.1)”
Table 3Find in source
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.
The paper reports two well-designed randomized noninferiority trials with strong methodology, clear reporting, and appropriate ethical approvals. The main weaknesses are a vague data sharing statement and a potential statistical inconsistency in a key noninferiority p-value that warrants verification.
Both reviewers agreed on study type (interventional) and on most dimensions. The statistical analysis dimension was downgraded from pass to warn based on the deterministic statistics check, which found one inconsistent p-value. The data code availability warning is based on the vague data sharing statement.
Numerical inconsistencies
1 finding · worst mediumValues 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.
- Printed percentage does not match its own countRecomputed
Recomputed 2 tests: 1 consistent, 1 inconsistent (1 change significance at p<.05); 2 via agent-written checks. 1 printed percentage that does not match its own count.
- PERCENT0.04% does not match the reported count 1/4475
“1/4475 (<0.1)”
Table 3Find in source
- CONSISTENTreported p > .100 · recomputed p = .273Reviewers 1, 2Noninferiority p-value for preterm birth in Tanzania trial (RR 1.07, 95% CI 0.95-1.21) vs margin 1.16
“relative risk, 1.07; 95% CI, 0.95 to 1.21”
Taken as given: The CI is two-sided 95%.; The RR is on a log scale.; The noninferiority margin is 1.16.Method: Computed p-value from RR and CI using normal approximation on log scale, one-sided for noninferiority.How we recomputed it: pCI(1.07, 0.95, 1.21, 1)
Overstated conclusions
1 finding · worst criticalConclusions 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.
- Significance claim flips when recomputedRecomputed
- SIGNIFICANCE OVERSTATEDINCONSISTENTreported p < .001 · recomputed p = .100Reviewers 1, 2Noninferiority p-value for preeclampsia in India trial (RR 0.84, 95% CI 0.68-1.03) vs margin 1.54Reported as statistically significant, but recomputing from the paper’s own numbers gives p ≥ 0.05 — the result may not be significant as claimed.
“relative risk, 0.84; 95% confidence interval [CI], 0.68 to 1.03”
Taken as given: The CI is two-sided 95%.; The RR is on a log scale.; The noninferiority margin is 1.54.Method: Computed p-value from RR and CI using normal approximation on log scale, one-sided for noninferiority.How we recomputed it: pCI(0.84, 0.68, 1.03, 1)
3 major claims checked against the paper's own evidence: all adequately supported.
- supportedReviewers 1, 2Low-dose calcium supplementation was noninferior to high-dose with respect to preeclampsia in both trials.The presented relative risks and confidence intervals are within the noninferiority margin in both trials.Evidence: India: RR 0.84 (0.68-1.03); Tanzania: RR 1.10 (0.88-1.36), both with upper bounds below 1.54.
“In these two trials, low-dose calcium supplementation was noninferior to high-dose calcium supplementation with respect to the risk of preeclampsia.”
AbstractFind in source - supportedReviewers 1, 2Low-dose calcium was noninferior for preterm birth in India but not in Tanzania.The India trial's upper CI (0.98) is below the margin (1.16), while Tanzania's upper CI (1.21) exceeds it.Evidence: India: RR 0.89 (0.80-0.98); Tanzania: RR 1.07 (0.95-1.21).
“It was noninferior with respect to the risk of preterm live birth in the trial in India but not in the trial in Tanzania.”
AbstractFind in source - supportedReviewers 1, 2Meta-analyses of the two trials showed no material difference between low-dose and high-dose for primary outcomes.The paper states meta-analyses were consistent with no difference, though details are in supplementary materials.Evidence: Fixed- and random-effects meta-analyses did not indicate a difference.
“Fixed- and random-effects meta-analyses of the outcomes in the two trials did not indicate a difference between the 500-mg group and 1500-mg group with regard to the risks of preeclampsia, preterm birth, and the secondary and safety outcomes.”
ResultsFind in source
Efficacy claim is anchored to an adequate endpoint and a meaningful effect.
- ADEQUATESurrogate endpointThe primary outcomes are preeclampsia and preterm birth, which are hard clinical outcomes, not surrogate biomarkers. The efficacy claim is based on these clinical endpoints.
“The two primary outcomes were preeclampsia and preterm birth”
- ADEQUATEEffect sizeThe effect sizes are reported as relative risks with confidence intervals and are anchored to noninferiority margins. For preeclampsia, the relative risks were 0.84 (95% CI, 0.68 to 1.03) in India and 1.10 (95% CI, 0.88 to 1.36) in Tanzania, both within the noninferiority margin of 1.54. For preterm birth, the relative risk in India was 0.89 (95% CI, 0.80 to 0.98) within the margin of 1.16, but in Tanzania it was 1.07 (95% CI, 0.95 to 1.21) exceeding the margin. The clinical meaningfulness is established by the noninferiority design and predefined margins.
“The cumulative incidence of preeclampsia was 3.0% in the 500-mg group and 3.6% in the 1500-mg group in the India trial (relative risk, 0.84; 95% confidence interval [CI], 0.68 to 1.03) and 3.0% and 2.7%, respectively, in the Tanzania trial (relative risk, 1.10; 95% CI, 0.88 to 1.36) — findings consistent with the noninferiority of the lower dose in both trials.”
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 WHO recommendations and placebo-controlled trials showing high-dose calcium reduces preeclampsia and preterm birth, and notes implementation barriers. It acknowledges limitations of prior low-dose trials (small sample sizes) and states the hypothesis that low-dose may be as efficacious as high-dose. The rationale links the premise to the study objectives.
“Calcium supplementation in pregnancy has been recommended by the World Health Organization (WHO) since 2011 to reduce the risk of preeclampsia in populations with low dietary calcium intake.”
“Trials of low-dose calcium supplementation of less than 1000 mg per day in pregnancy, most of which evaluated a single 500-mg calcium supplement per day as compared with placebo and have had relatively small sample sizes, have generally shown a magnitude of reduction in the risks of preeclampsia and preterm birth similar to that seen in the trials of high-dose supplementation.”
“We hypothesized that low-dose calcium supplementation in pregnancy may be as efficacious as high-dose supplementation with respect to the incidence of preeclampsia and preterm birth.”
“Calcium supplementation in pregnancy has been recommended by the World Health Organization (WHO) since 2011 to reduce the risk of preeclampsia in populations with low dietary calcium intake.”
“We hypothesized that low-dose calcium supplementation in pregnancy may be as efficacious as high-dose supplementation with respect to the incidence of preeclampsia and preterm birth.”
“Trials of low-dose calcium supplementation of less than 1000 mg per day in pregnancy, most of which evaluated a single 500-mg calcium supplement per day as compared with placebo and have had relatively small sample sizes, have generally shown a magnitude of reduction in the risks of preeclampsia and preterm birth similar to that seen in the trials of high-dose supplementation.”
Randomization used computer-generated block randomization stratified by clinic, with allocation concealment via prelabeled blister packs. Blinding was double-blind with identical tablets. Power analysis was performed for each trial with stated assumptions. Inclusion/exclusion criteria are clearly defined. The analysis population (ITT and per-protocol) is pre-specified, addressing outlier handling. Controls are inherent in the comparator arm. Independent replication is not applicable for a single pivotal trial.
“The assignment sequence for each trial was generated by a statistician not otherwise involved in the trial by means of a computer-generated list of participant identification numbers with block randomization, stratified according to trial clinic.”
“All the calcium and placebo tablets were identical in appearance, taste, and smell and were packaged in indistinguishable blister packs.”
“Assuming a randomization ratio of 1:1, a one-sided test with a type I error of 0.05, and a 10% incidence of loss to follow-up or missing outcome data, we planned to enroll 11,000 pregnant participants in each trial.”
“The assignment sequence for each trial was generated by a statistician not otherwise involved in the trial by means of a computer-generated list of participant identification numbers with block randomization, stratified according to trial clinic.”
“All the calcium and placebo tablets were identical in appearance, taste, and smell and were packaged in indistinguishable blister packs.”
“Assuming a randomization ratio of 1:1, a one-sided test with a type I error of 0.05, and a 10% incidence of loss to follow-up or missing outcome data, we planned to enroll 11,000 pregnant participants in each trial.”
Sex is reported (all pregnant women), and since both sexes are not applicable, sex_justified is not applicable. Age is reported in categories, and health status is indicated by baseline characteristics such as BMI, hemoglobin, and blood pressure. Demographics include education, wealth, and age. Species/strain and housing are not applicable for human trials.
“nulliparous pregnant women”
“nulliparous pregnant women”
The paper states that protocols were approved by institutional review boards and that participants provided written informed consent. Regulatory compliance is implied by adherence to standard care and mention of a data safety monitoring board. The specific IRB names are not given, but the statement is adequate for a trial report.
“The protocols of the trials were approved by institutional review boards.”
“who provided written informed consent”
“A data and safety monitoring board oversaw the trial.”
“The protocols of the trials were approved by institutional review boards.”
“who provided written informed consent”
“All the participants in India and Tanzania received standard-care antenatal and postpartum services that were aligned with the country-specific antenatal care guidelines.”
The calcium supplement is described as 500 mg elemental calcium as calcium carbonate, manufactured by Influx Healthcare. The dose and regimen are specified. Statistical software (SAS 9.4) is identified. No antibodies, cell lines, or other bench reagents are used.
“The 500-mg calcium supplementation group received one tablet that contained 500 mg of elemental calcium as calcium carbonate and two placebo tablets each day”
“Influx Healthcare (in Maharashtra, India) manufactured the tablets for both trials.”
“Statistical analyses were performed with the use of SAS software, version 9.4 (SAS Institute).”
“The 500-mg calcium supplementation group received one tablet that contained 500 mg of elemental calcium as calcium carbonate and two placebo tablets each day”
“Influx Healthcare (in Maharashtra, India) manufactured the tablets for both trials.”
“Statistical analyses were performed with the use of SAS software, version 9.4 (SAS Institute).”
Tests are named (log-binomial, GEE, Poisson). Assumptions are handled by design (e.g., GEE for multiple gestations). Exact p-values are reported for noninferiority. Effect sizes with CIs are reported. Software is identified. Data presentation includes per-group n and CIs. Mathematical plausibility checks are not applicable for large-N continuous outcomes.
“Log-binomial models were used to estimate the relative risk of preeclampsia between the 500-mg group and the 1500-mg group.”
“relative risk, 0.84; 95% confidence interval [CI], 0.68 to 1.03”
“Log-binomial models were used to estimate the relative risk of preeclampsia between the 500-mg group and the 1500-mg group.”
“relative risk, 0.84; 95% confidence interval [CI], 0.68 to 1.03”
The paper mentions a data sharing statement is available with the full text, but the specific mechanism is not described in the provided text. No repository deposit or accession numbers are mentioned. Code sharing is not applicable as no custom code is described.
“A data sharing statement provided by the authors is available with the full text of this article at NEJM.org”
“A data sharing statement provided by the authors is available with the full text of this article at NEJM.org”
Trial registration numbers are provided. Methods are detailed enough for replication. Limitations are discussed. Conclusions are proportional to the evidence. Funding and COI are disclosed. Reporting guideline adherence is implied by NEJM standards but not explicitly stated.
“Our trials have some limitations.”
“Supported by a grant (OPP1172660) from the Bill and Melinda Gates Foundation.”
“Our trials have some limitations. The two trials used the best obstetrical estimate for gestational age on the basis of the reported last menstrual period and fetal ultrasonography; however, we cannot rule out some measurement error and misclassification for preterm birth.”
“Supported by a grant (OPP1172660) from the Bill and Melinda Gates Foundation.”
Registered (2 IDs: ClinicalTrials.gov, Clinical Trials Registry – India). Reporting guideline cited: CARE.
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 24 references by DOI: 1 verified — 23 no DOI (shown, not verified).
- NO DOIGlobal and regional estimates of preeclampsia and eclampsia: a systematic reviewNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIGlobal, regional, and national levels of maternal mortality, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIPreeclampsiaNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIGlobal, regional, national, and selected subnational levels of stillbirths, neonatal, infant, and under-5 mortality, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIWHO recommendations on antenatal care for a positive pregnancy experienceNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOICalcium supplementation during pregnancy for preventing hypertensive disorders and related problemsNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIIntegrating calcium into antenatal iron-folic acid supplementation in Ethiopia: women’s experiences, perceptions of acceptability, and strategies to support calcium supplement adherenceNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIShould all pregnant women take calcium supplements in Nepal? GRADE evidence to policy assessmentNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOINon-inferiority of low-dose compared to standard high-dose calcium supplementation in pregnancy: study protocol for two randomized, parallel group, noninferiority trials in India and TanzaniaNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOINational guidelines for calcium supplementation during pregnancy and lactationNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIHypertension in pregnancy: report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in PregnancyNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIHypertensive disorders of pregnancy: case definitions & guidelines for data collection, analysis, and presentation of immunization safety dataNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIInternational standards for newborn weight, length, and head circumference by gestational age and sex: the Newborn Cross-Sectional Study of the INTERGROWTH-21st ProjectNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOICalcium nitake and healthNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOICalcium supplementation during pregnancy may reduce preterm delivery in high-risk populationsNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIEffects of calcium supplementation on uteroplacental and fetoplacental blood f low in low-calcium-intake mothers: a randomized controlled trialNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIGlobal inequities in dietary calcium intake during pregnancy: a systematic review and meta-analysisNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIDietary reference intakes for calcium and vitamin DNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIPrepregnancy and early pregnancy calcium supplementation among women at high risk of pre-eclampsia: a multicentre, double-blind, randomised, placebo-controlled trialNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIComparative effectiveness of prophylactic strategies for preeclampsia: a network meta-analysis of randomized controlled trialsNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIThe impact of medication regimen factors on adherence to chronic treatment: a review of literatureNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOISources of variance in 24-hour dietary recall data: implications for nutrition study design and interpretationNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIRisk factors and effective management of preeclampsiaNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
1 data/code link checked; 1 live.
- datahttps://clinicaltrials.gov/ct2/show/NCT03350516LIVEHTTP 200Resolves, but the content could not be matched to the paper.
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 consistency, clarity.
- MINORconsistencyAbstract“ClinicalTrials.gov (https://ClinicalTrials.gov) number, NCT03350516 (https://clinicaltrials.gov/ct2/show/NCT03350516)”→ Use consistent capitalization for ClinicalTrials.gov.Inconsistent capitalization of the URL.
- MINORclarityMethods, Statistical Analysis“Our protocol did not include a plan to adjust for the two primary efficacy outcomes in each trial, but we applied a Bonferroni correction to account for multiplicity (one-sided alpha of 0.025).”→ Clarify that the Bonferroni correction was applied post hoc.The sentence could be clearer about the timing of the correction.
The published work is generally robust, but readers should weigh the potential statistical inconsistency in the noninferiority p-value for the India trial. The authors should consider issuing a correction or providing additional clarification on the data sharing statement.
- 1.CRITICALstatisticsResolve the statistics inconsistency that flips a significance claim: Recomputed 2 tests: 1 consistent, 1 inconsistent (1 change significance at p<.05); 2 via agent-written checks. 1 printed percentage that does not match its own count.Demonstrable critical failure — blocks the verdict from passing.
- 2.HIGHstatisticsRe-verify the noninferiority p-value for preeclampsia in the India trial (reported p=0.001) against the reported RR (0.84) and CI (0.68-1.03); the recomputed p-value is 0.0998, which is inconsistent.A demonstrable inconsistency in a key result could undermine the noninferiority conclusion and warrants correction or clarification.
- 3.HIGHdata codeExpand the data sharing statement in the manuscript to specify the mechanism for data access (e.g., data access committee, repository) and conditions, rather than only referring to a statement available at NEJM.org.A vague data sharing statement is insufficient for a clinical trial and may not meet journal or funder requirements.
- 4.HIGHreportingExplicitly state adherence to a reporting guideline such as CONSORT in the Methods or a separate section.Explicitly naming the reporting guideline improves transparency and helps readers assess completeness.
- 5.MEDIUMethicsAdd the specific IRB names and protocol numbers to the Ethics section.Providing specific IRB details strengthens the ethics approval statement and aids verification.
- 6.MEDIUMdata codeConsider depositing de-identified aggregate data or statistical analysis code in a public repository and include accession numbers.Depositing data and code enhances reproducibility and transparency, which is increasingly expected for clinical trials.
- 7.LOWcopyeditStandardize capitalization of 'ClinicalTrials.gov' in the Abstract and throughout the manuscript.Consistent capitalization improves professionalism and avoids minor inconsistencies.
- 8.LOWcopyeditClarify in the Methods, Statistical Analysis section that the Bonferroni correction was applied post hoc.Clarifying the timing of the correction avoids ambiguity about whether it was pre-specified.
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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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.
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