Author Affiliations: Division of Epidemiology, Statistics, and Prevention Research, National Institute of Child Health and Development, Bethesda, Md.
Context A recent meta-analysis found calcium supplementation to be highly effective
in preventing preeclampsia but a large National Institutes of Health trial
(Calcium for Preeclampsia Prevention [CPEP]) found no risk reduction due to
calcium in healthy nulliparous women.
Objectives To resolve discrepancies between the results of the meta-analysis and
the CPEP trial and to assess the role of effect heterogeneity in the discrepancies.
Data Sources Literature search of English-language articles published prior to July
10, 1997, the date of publication of the CPEP trial, using MEDLINE and by
a manual search of bibliographies of published articles.
Study Selection Trials were included if they reported data on preeclampsia and calcium
supplementation. Fourteen trials were systematically evaluated for differences
in study design and patient populations. One trial was excluded because its
results were reported after publication of the major CPEP results.
Data Extraction The sample size and number of subjects who developed preeclampsia in
the calcium supplementation group vs a control group were recorded and analyzed
on an intent-to-treat basis. Each author independently extracted the data.
Data Synthesis Substantial heterogeneity existed across trials (P=.001). After stratifying studies by the presence of a placebo-controlled
group and by high-risk and low-risk populations, the conclusions of the meta-analysis
of placebo-controlled trials enrolling a low-risk population (relative risk,
0.79; 99% confidence interval, 0.44-1.42; P=.30)
were compatible with the conclusions of the CPEP trial that calcium supplementation
does not prevent preeclampsia in healthy nulliparous women. In contrast, the
data implied a strong beneficial calcium effect (relative risk, 0.19; 99%
confidence interval, 0.08-0.46; P=.001) in healthy
high-risk subject populations. However, only 225 women were analyzed and because
of inconsistent data, these results remain equivocal.
Conclusions Further studies are needed to establish the efficacy of calcium for
preeclampsia prevention in healthy high-risk populations. A single summary
measure does not adequately describe the findings of a meta-analysis when
the observed effects in individual studies differ substantially. In such settings
the primary focus should be to identify and incorporate pertinent covariates
that reduce heterogeneity and allow for optimum treatment strategies.
DerSimonian R, Levine RJ. Resolving Discrepancies Between a Meta-analysis and a Subsequent Large Controlled Trial. JAMA. 1999;282(7):664-670. doi:10.1001/jama.282.7.664