Supplementary calcium in prevention of pre-eclampsia. Nutritional factors and rest reduce pregnancy-induced hypertension and pre-eclampsia in positive roll-over test primigravidas. A randomized prospective comparison of nifedipine and bed rest versus bed rest alone in the management of preeclampsia remote from term. Trial of calcium to prevent preeclampsia. Calcium supplementation and the risk of preeclampsia in Ecuadorian pregnant teenagers. The efficacy and fetal-maternal cardiovascular effects of transdermal glyceryl trinitrate in the prophylaxis of pre-eclampsia and its complications: a randomized double-blind placebo-controlled trial. Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial. World Health Organization randomized trial of calcium supplementation among low calcium intake pregnant women. Calcium supplementation in nulliparous women for the prevention of pregnancy-induced hypertension, preeclampsia and preterm birth: an Australian randomized trial. FRACOG and the ACT Study Group.
To study the effect of calcium supplementation on reduction of pre-eclampsia in Iranian women at high risk of pre-eclampsia.
                Thirty pregnant women at high risk of developing pre-eclampsia were randomized to 2 g of daily calcium and placebo. Subjects and investigators were blinded to treatment allocation. The inclusion criteria were positive rollover test, having at least one risk factor for pre-eclampsia, between 28 and 32 weeks of pregnancy, and blood pressure less than 140/90 (mm Hg). Exclusion criteria were having any chronic condition. Pre-eclampsia was defined as systolic/diastolic blood pressure over 140/90 plus proteinuria. All the subjects were followed up to delivery.
                A sevenfold reduction in the occurrence of pre-eclamsia were seen among the calcium group compared with the placebo group (7 out of 15 developed pre-eclampsia in control group vs. 1 out of 15 in calcium group, P=0.014). No major effect on pregnancy induced hypertension was seen (66% in placebo and 76% in calcium group developed hypertension) but the onset of hypertension was delayed 3 weeks in the calcium group. A longer duration of pregnancy was seen in calcium than placebo (mean+/-S.D.=37+/-2 for calcium and 34+/-2 for placebo, P<0.05). Infants born to the calcium group, on average, were 552 g heavier than infants born to the placebo group, P<0.05.
                Calcium supplementation is beneficial for preventing pre-eclampsia among Iranian women at high risk of developing pre-eclampsia. The possibility of reducing pregnancy-induced hypertension and preeclampsia in primigravidas with low doses of nutritional factors and relative rest in the left lateral position was investigated in a randomized controlled, double-blind trial.
                Seventy-four normotensive women at 28-29 weeks' gestation, judged to be at risk of PIH or pre-eclampsia because they presented with a mean blood pressure of 80 mmHg or higher and a positive roll-over test, were studied. The treatment protocol was received by 37 women and the other 37 women received standard antenatal control until delivery.
                Twenty-nine (78.3%) women in the control group developed PIH and/or pre-eclampsia, as opposed to only 4 (10.8%) cases in the treatment group (P < 0.001). There were no adverse effects of treatment in mothers or in infants.
                This protocol reduces PIH and pre-eclampsia in primigravidas judged to be at risk of hypertension. Further studies are required to evaluate prostacyclin and prostaglandin E2 changes. The objective of our study was to test the hypothesis that treatment with nifedipine for mild preeclampsia remote from term reduces the number of days of maternal hospitalization and improves pregnancy outcome.
                A total of 200 patients at 26 to 36 weeks' gestation were randomly allocated to treatment with either bed rest alone (n = 100) or bed rest in combination with nifedipine (n = 100).
                Patients receiving nifedipine had significantly lower systolic (p < 0.0001) and diastolic (p < 0.0001) blood pressures during therapy. Severe hypertension as an indication for delivery was significantly (p < 0.05) more frequent in the bed-rest-alone group. The two study groups had similar average days of maternal hospitalization (12.6 +/- 7.9 vs 12.3 +/- 10.3) and pregnancy prolongation (22.3 +/- 13.5 vs 22.5 +/- 15.7). There were no differences between groups with respect to birth weight, incidences of small-for-gestational-age infants and preterm birth, number of days spent in special care unit, or cord blood gas measurement.
                Nifedipine therapy for preeclampsia reduces maternal blood pressure but does not reduce number of days of maternal hospitalization or improve perinatal outcome. Previous trials have suggested that calcium supplementation during pregnancy may reduce the risk of preeclampsia. However, differences in study design and a low dietary calcium intake in the populations studied limit acceptance of the data.
                We randomly assigned 4589 healthy nulliparous women who were 13 to 21 weeks pregnant to receive daily treatment with either 2 g of elemental calcium or placebo for the remainder of their pregnancies. Surveillance for preeclampsia was conducted by personnel unaware of treatment-group assignments, using standardized measurements of blood pressure and urinary protein excretion at uniformly scheduled prenatal visits, protocols for monitoring these measurements during the hospitalization for delivery, and reviews of medical records of unscheduled outpatient visits and all hospitalizations.
                Calcium supplementation did not significantly reduce the incidence or severity of preeclampsia or delay its onset. Preeclampsia occurred in 158 of the 2295 women in the calcium group (6.9 percent) and 168 of the 2294 women in the placebo group (7.3 percent) (relative risk, 0.94; 95 percent confidence interval, 0.76 to 1.16). There were no significant differences between the two groups in the prevalence of pregnancy-associated hypertension without preeclampsia (15.3 percent vs. 17.3 percent) or of all hypertensive disorders (22.2 percent vs. 24.6 percent). The mean systolic and diastolic blood pressures during pregnancy were similar in both groups. Calcium did not reduce the numbers of preterm deliveries, small-for-gestational-age births, or fetal and neonatal deaths; nor did it increase urolithiasis during pregnancy.
                Calcium supplementation during pregnancy did not prevent preeclampsia, pregnancy-associated hypertension, or adverse perinatal outcomes in healthy nulliparous women. To determine whether increased calcium intake (2 g/day) in pregnancy is effective in reducing the risk of preeclampsia in pregnant teenagers.
                The present study was a prospective, randomized, double-blind, controlled clinical trial. Two hundred sixty teenaged pregnant girls attending the Hospital Gíneco-Obstétrico Isidro Ayora in Quito, Ecuador, were included. Selection criteria were age less than 17.5 years, nulliparity, first prenatal visit before 20 weeks' gestation, and residency in Quito (2800-m altitude). We used a table of random numbers to assign 125 girls to receive 2000 mg of elemental calcium daily, beginning at 20 weeks of gestation and continuing until delivery; 135 women in the control group received a placebo. Blood pressure (BP) was measured twice every 4 weeks until delivery and at 48 hours after delivery. The diagnosis of preeclampsia was defined as BP greater than 140/90 mmHg on at least two occasions more than 6 hours apart and proteinuria greater than 30 mg/dL (over one cross by dipstick on two occasions 4-24 hours apart).
                The average daily calcium intake in this population was approximately 51% of the Recommended Dietary Allowance. Calcium supplementation was associated with a significantly decreased risk of preeclampsia (risk reduction 12.35%; P < .001), with 3.2% (n = 4) developing preeclampsia in the treatment group versus 15.5% (n = 21) in the placebo group. Moreover, calcium supplementation led to a reduction in systolic BP of 9.1 mmHg and in diastolic BP of 6.0 mmHg.
                These results suggest that calcium supplementation during pregnancy in populations with low calcium intake is a safe, effective, and inexpensive preventive measure that significantly reduces the risk of preeclampsia. Pre-eclampsia continues to be a major cause of maternal and perinatal mortality. A disorder of the nitric oxide system is implicated in the pathogenesis of this condition and preliminary studies have suggested a possible therapeutic role for nitric oxide donors in women with established pre-eclampsia. The aim of this study was to determine whether pre-eclampsia and its complications could be prevented by the long-term use of nitric oxide donors in a group of women identified to be at risk on the basis of abnormal uterine artery Doppler measurements.
                We enrolled 40 healthy normotensive women at high risk of pre-eclampsia selected on the basis of abnormal uterine artery Doppler waveforms at 24-26 weeks of gestation. Women were randomly allocated to receive transdermal glyceryl trinitrate 5 mg-patches or equivalent placebo patches in a double-blind randomized study. The primary outcome measures were pre-eclampsia, fetal growth restriction, preterm delivery or small for gestational age/fetal growth restriction rates. Patches were worn daily from recruitment for 10 weeks or until delivery.
                The primary outcomes were not significantly different in the placebo compared to the glyceryl trinitrate group. However, survival analysis of adverse events with gestation in both groups showed a significantly reduced risk of an adverse event in the glyceryl trinitrate group (p = 0.004), equating to a 73% reduction in hazard. There was no difference in maternal systolic and diastolic blood pressure, mean uterine artery resistance index and fetal umbilical and middle cerebral artery pulsatility indices between the groups.
                Low-dose prophylactic transdermal glyceryl trinitrate commenced late in the second trimester did not reduce the incidence of pre-eclampsia, preterm delivery or fetal growth restriction, but may increase the likelihood of a complication-free pregnancy. Transdermal glyceryl trinitrate (5 mg/day) did not affect maternal cardiovascular, uterine artery or fetal arterial Doppler parameters. Oxidative stress has been implicated in the pathophysiology of pre-eclampsia. This randomised controlled trial investigated the effect of supplementation with vitamins C and E in women at increased risk of the disorder on plasma markers of vascular endothelial activation and placental insufficiency and the occurrence of pre-eclampsia.
                283 women were identified as being at increased risk of pre-eclampsia by abnormal two-stage uterine-artery doppler analysis or a previous history of the disorder and were randomly assigned vitamin C (1000 mg/day) and vitamin E (400 IU/day) or placebo at 16-22 weeks' gestation. Plasma markers of endothelial activation (plasminogen-activator inhibitor 1 [PAI-1]) and placental dysfunction (PAI-2) were measured every month until delivery. Pre-eclampsia was assessed by the development of proteinuric hypertension. Analyses were done by intention to treat, and in the cohort who completed the study.
                Supplementation with vitamins C and E was associated with a 21% decrease in the PAI-1/PAI-2 ratio during gestation (95% CI 4-35, p=0.015). In the intention-to-treat cohort, pre-eclampsia occurred in 24 (17%) of 142 women in the placebo group and 11 (8%) of 141 in the vitamin group (adjusted odds ratio 0.39 [0.17-0.90], p=0.02). In the cohort who completed the study (81 placebo group, 79 vitamin group), the odds ratio for pre-eclampsia was 0.24 (0.08-0.70, p=0.002).
                Supplementation with vitamins C and E may be beneficial in the prevention of pre-eclampsia in women at increased risk of the disease. Multicentre trials are needed to show whether vitamin supplementation affects the occurrence of pre-eclampsia in low-risk women and to confirm our results in larger groups of high-risk women from different populations. The purpose of this trial was to determine whether calcium supplementation of pregnant women with low calcium intake reduces preeclampsia and preterm delivery.
                Randomized placebo-controlled, double-blinded trial in nulliparous normotensive women from populations with dietary calcium < 600 mg/d. Women who were recruited before gestational week 20 received supplements (1.5 g calcium/d or placebo) throughout pregnancy. Primary outcomes were preeclampsia and preterm delivery; secondary outcomes focused on severe morbidity and maternal and neonatal mortality rates.
                The groups comprised 8325 women who were assigned randomly. Both groups had similar gestational ages, demographic characteristics, and blood pressure levels at entry. Compliance were both 85% and follow-up losses (calcium, 3.4%; placebo, 3.7%). Calcium supplementation was associated with a non-statistically significant small reduction in preeclampsia (4.1% vs 4.5%) that was evident by 35 weeks of gestation (1.2% vs 2.8%; P = .04). Eclampsia (risk ratio, 0.68: 95% CI, 0.48-0.97) and severe gestational hypertension (risk ratio, 0.71; 95% CI, 0.61-0.82) were significantly lower in the calcium group. Overall, there was a reduction in the severe preeclamptic complications index (risk ratio, 0.76; 95% CI, 0.66-0.89; life-table analysis, log rank test; P = .04). The severe maternal morbidity and mortality index was also reduced in the supplementation group (risk ratio, 0.80; 95% CI, 0.70-0.91). Preterm delivery (the neonatal primary outcome) and early preterm delivery tended to be reduced among women who were < or = 20 years of age (risk ratio, 0.82; 95% CI, 0.67-1.01; risk ratio, 0.64; 95% CI, 0.42-0.98, respectively). The neonatal mortality rate was lower (risk ratio, 0.70; 95% CI, 0.56-0.88) in the calcium group.
                A 1.5-g calcium/day supplement did not prevent preeclampsia but did reduce its severity, maternal morbidity, and neonatal mortality, albeit these were secondary outcomes. A multicentre, randomized controlled double-blind trial in 5 maternity hospitals in Australia assessed the effect of a daily supplement of calcium (1.8g oral calcium or an oral placebo) taken daily until delivery, from less than 24 weeks' gestation, on the frequency of pregnancy-induced hypertension, preeclampsia and preterm birth (< 37 weeks' gestation) in 456 nulliparas with a singleton pregnancy. Treatment with calcium reduced the risk of preeclampsia (relative risk 0.44 [95% CI, 0.21-0.90], p = 0.02) and the risk of preterm birth (relative risk 0.44 [95% CI, 0.21-0.90], p = 0.02). No significant differences were seen between the 2 groups in the frequency of pregnancy-induced hypertension, although the study only had statistical power to detect large differences in this outcome. An updated systematic review of the 9 randomized trials of calcium supplementation in pregnancy shows a significant reduction in the risk of hypertension and preeclampsia although no effect on preterm birth. Calcium supplementation during pregnancy reduced the risk of preeclampsia and preterm birth in this nulliparous population. The available evidence for systematic review of all the randomized trials of calcium supplementation shows benefit in reducing the risk of hypertension and preeclampsia.
Daily rest, with or without nutrient supplementation, may reduce the risk of pre-eclampsia for women with normal blood pressure, although the reported effect may reflect bias and/or random error rather than a true effect. There is no information about outcomes such as perinatal mortality and morbidity, maternal morbidity, women's views, adverse effects, and costs. Current evidence is insufficient to support recommending rest or reduced activity to women for preventing pre-eclampsia and its complications. Whether women rest during pregnancy should therefore be a matter of personal choice.