Calcium for Pre-Eclampsia Prevention (CPEP)
Condition: Cardiovascular Diseases; Eclampsia; Heart Diseases; HELLP Syndrome; Hypertension; Pre-Eclampsia; Pregnancy Toxemias; Vascular Diseases
MeSH terms: Toxemia; Eclampsia; Pre-Eclampsia; HELLP Syndrome; Cardiovascular Diseases; Heart Diseases; Vascular Diseases
Study type: Interventional
Phase: Phase 3

Summary: 
      To evaluate the efficacy of 2 grams per day of oral calcium supplementation in reducing the
      combined incidence of hypertensive disorders of pregnancy: pre-eclampsia, eclampsia, and the
      HELLP Syndrome (hypertension, thrombocytopenia, hemolysis, and abnormal liver function). The
      National Institute of Child Health and Human Development (NICHD) initiated the trial in 1991,
      with joint funding provided by the National Heart, Lung, and Blood Institute in fiscal years
      1992, 1993, and 1995.
    

Detailed description: 
      BACKGROUND:

      A considerable body of data has associated lower blood pressures with higher levels of
      dietary calcium. Epidemiologic studies, laboratory evaluations, and clinical trials have also
      indicated that the incidence of hypertensive disorders of pregnancy is affected similarly by
      calcium intake. A meta-analysis of five controlled clinical trials of calcium supplementation
      in pregnancy suggested a significant reduction in proteinuric pre-eclampsia of 46 percent.
      Several of the trials, however, suffered from 'pitfalls' in the diagnosis of pre-eclampsia,
      including lack of blinding, uncertain definition of endpoints, and unknown techniques of
      measurement. Most trials have not assessed the role of dietary nutrients or the possibility
      that a subgroup with low baseline urinary calcium may benefit most from calcium
      supplementation. In no trial has the potential for increased risk of kidney stones in the
      treatment group been examined systematically. Moreover, the daily schedule for administration
      of calcium, has generally not been reported. There was a great need, therefore, to evaluate
      the efficacy of calcium supplementation for the prevention of pre-eclampsia in a large
      multicenter controlled clinical trial. The trial considered the role of dietary nutrients,
      establish whether treatment is beneficial only for those with low baseline urinary calcium,
      conduct systematic surveillance for urolithiasis, and employ standardized terminology,
      techniques of measurement, and diagnostic criteria. The NHLBI provided funding to NICHD for
      three years by means of an Intraagency Agreement (Y01HC20154).

      DESIGN NARRATIVE:

      Randomized, double-blind, multicenter. Healthy nulliparous patients were randomly assigned to
      receive either 2 grams of supplemental calcium daily ((n = 2,295) or placebo (n = 2,294) in a
      double-blind study. Study tablets were administered beginning from 13 to 21 completed weeks
      of gestation and continued until the termination of pregnancy. Eligible patients entered a
      run-in period of 6 to 14 days to exclude highly noncompliant subjects. During the run-in,
      obstetrical ultrasound was performed if it had not been obtained previously, and blood was
      drawn for serum calcium and creatinine. Follow-up visits were scheduled every four weeks
      through the 29th week of gestation, then every two weeks through the 35th week, and weekly
      thereafter. Blood pressure and urine-protein were obtained at each clinic visit, during labor
      and delivery, and during the first 24 hours postpartum. Primary endpoints included
      pregnancy-associated hypertension, pregnancy-associated proteinuria, pre-eclampsia,
      eclampsia, or hypertension. Other endpoints included placental abruption, cerebral hemorrhage
      or thrombosis, elevated liver enzymes, acute renal failure, and disseminated intravascular
      coagulation. Surveillance was conducted for renal calculi. Recruitment began in May 1992 and
      ended in March 1995. Follow-up was completed in October of 1995. Data analysis continued
      through March 2000 under the NICHD contract N01HD13121.
    

Intervention name(s): calcium; dietary supplements
Intervention type(s): Drug; Behavioral
Intervention MeSH terms: Calcium
Masking: Double
Primary purpose: Prevention