What is the issue?
We wanted to know if giving women calcium as a supplement before pregnancy or during early pregnancy would help pregnant women avoid pre-eclampsia, high blood pressure, and other serious health problems during pregnancy. We wanted to know if these supplements could improve pregnancy, and birth for the baby, as well.
Why is this important?
Women can develop high blood pressure and have protein in their urine after the twentieth week of pregnancy; this condition is known as pre-eclampsia. Many women, particularly those in low-income countries, do not have enough calcium in their diets. Giving these women extra calcium during the second half of pregnancy has been shown to reduce their risk of having high blood pressure and protein in the urine, and other related problems, such as convulsions, stroke, blood-clotting problems, fluid in the lungs, kidney failure, or even death. It is important to know if taking extra calcium before pregnancy and in early pregnancy can reduce the number of women who develop blood pressure problems during pregnancy, and related complications.
We searched for randomised controlled studies that looked at the effect of taking extra calcium before or early in pregnancy on the number of women who developed pre-eclampsia.
What evidence did we find?
We searched the medical literature in July 2018 and found one relevant clinical trial. This trial included 1355 women who had previously had pre-eclampsia, who lived in Argentina, South Africa, and Zimbabwe.
The trial compared pregnant women who had daily calcium with women who had placebo (a dummy tablet) until 20 weeks of pregnancy, when all women switched to having daily calcium until birth. We had some concerns about the evidence from this trial, because nearly a quarter of the women who were enrolled were lost to follow-up, and we do not know whether they went on to become pregnant. Overall, while the results suggested that some women may benefit from calcium supplements, the findings included the possibility that the calcium didn't make a difference. Calcium may have helped some pregnant women avoid either losing the pregnancy or developing blood pressure problems, but we need more studies to be really confident that this effect was due to calcium. Calcium may have made little or no difference to whether pregnant women had other serious health conditions during pregnancy, such as: maternal admission to intensive care, blood pressure problems (pre-eclampsia, severe pre-eclampsia, eclampsia), placental separation from the uterus (placental abruption), or death. For babies, calcium may have had little or no impact on whether they were of low birthweight, of poor condition at birth, or required intensive care. The results did not clearly indicate the impact of calcium on whether babies died either before or after the birth, or needed to be admitted to neonatal intensive care for more than 24 hours.
What does this mean?
We need more research to decide whether or not calcium before pregnancy or during early pregnancy helps women avoid high blood-pressure and other related problems.
Further research is needed to confirm whether initiating calcium supplementation pre- or in early pregnancy is associated with a reduction in adverse pregnancy outcomes for mother and baby. Research could also address the acceptability of the intervention to women, which was not covered by this review update.
The single included study suggested that calcium supplementation before and early in pregnancy may reduce the risk of women experiencing the composite outcome pre-eclampsia or pregnancy loss at any gestational age, but the results are inconclusive for all other outcomes for women and babies. Therefore, current evidence neither supports nor refutes the routine use of calcium supplementation before conception and in early pregnancy.
To determine the overall benefit of calcium supplementation commenced before or in early pregnancy, the effects found in the study of calcium supplementation limited to the first half of pregnancy need to be added to the known benefits of calcium supplementation in the second half of pregnancy.
Further research is needed to confirm whether initiating calcium supplementation pre- or in early pregnancy is associated with a reduction in adverse pregnancy outcomes for mother and baby. Research could also address the acceptability of the intervention to women, which was not covered by this review update.
The hypertensive disorders of pregnancy include pre-eclampsia, gestational hypertension, chronic hypertension, and undefined hypertension. Pre-eclampsia is considerably more prevalent in low-income than in high-income countries. One possible explanation for this discrepancy is dietary differences, particularly calcium deficiency. Calcium supplementation in the second half of pregnancy reduces the serious consequences of pre-eclampsia, but has limited effect on the overall risk of pre-eclampsia. It is important to establish whether calcium supplementation before, and in early pregnancy (before 20 weeks' gestation) has added benefit. Such evidence could count towards justification of population-level interventions to improve dietary calcium intake, including fortification of staple foods with calcium, especially in contexts where dietary calcium intake is known to be inadequate. This is an update of a review first published in 2017.
To determine the effect of calcium supplementation, given before or early in pregnancy and for at least the first half of pregnancy, on pre-eclampsia and other hypertensive disorders, maternal morbidity and mortality, and fetal and neonatal outcomes.
We searched the Cochrane Pregnancy and Childbirth Trials Register (31 July 2018), PubMed (13 July 2018), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP; 31 July 2018), and reference lists of retrieved studies.
Eligible studies were randomised controlled trials (RCT) of calcium supplementation, including women not yet pregnant, or women in early pregnancy. Cluster-RCTs, quasi-RCTs, and trials published as abstracts were eligible, but we did not identify any.
Two review authors independently assessed trials for inclusion and risk of bias, extracted data, and checked them for accuracy. They assessed the quality of the evidence for key outcomes using the GRADE approach.
Calcium versus placebo
We included one study (1355 women), which took place across multiple hospital sites in Argentina, South Africa, and Zimbabwe. Most analyses were conducted only on 633 women from this group who were known to have conceived, or on 579 who reached 20 weeks' gestation; the trial was at moderate risk of bias due to high attrition rates pre-conception. Non-pregnant women with previous pre-eclampsia received either calcium 500 mg daily or placebo, from enrolment until 20 weeks' gestation. All participants received calcium 1.5 g daily from 20 weeks until birth.
Primary outcomes: calcium supplementation commencing before conception may make little or no difference to the risk of pre-eclampsia (69/296 versus 82/283, risk ratio (RR) 0.80, 95% confidence interval (CI) 0.61 to 1.06; low-quality evidence). For pre-eclampsia or pregnancy loss or stillbirth (or both) at any gestational age, calcium may slightly reduce the risk of this composite outcome, however the 95% CI met the line of no effect (RR 0.82, 95% CI 0.66 to 1.00; low-quality evidence). Supplementation may make little or no difference to the severe maternal morbidity and mortality index (RR 0.93, 95% CI 0.68 to 1.26; low-quality evidence), pregnancy loss or stillbirth at any gestational age (RR 0.83, 95% CI 0.61 to 1,14; low-quality evidence), or caesarean section (RR 1.11, 95% CI 0.96 to 1,28; low-quality evidence).
Calcium supplementation may make little or no difference to the following secondary outcomes: birthweight < 2500 g (RR 1.00, 95% CI 0.76 to 1.30; low-quality evidence), preterm birth < 37 weeks (RR 0.90, 95% CI 0.74 to 1.10), early preterm birth < 32 weeks (RR 0.79, 95% CI 0.56 to 1.12), and pregnancy loss, stillbirth or neonatal death before discharge (RR 0.82, 95% CI 0.61 to 1.10; low-quality evidence), no conception, gestational hypertension, gestational proteinuria, severe gestational hypertension, severe pre-eclampsia, severe pre-eclamptic complications index. There was no clear evidence on whether or not calcium might make a difference to perinatal death, or neonatal intensive care unit admission for > 24h, or both (RR 1.11, 95% CI 0.77 to 1.60; low-quality evidence).
It is unclear what impact calcium supplementation has on Apgar score < 7 at five minutes (RR 0.43, 95% CI 0.15 to 1.21; very low-quality evidence), stillbirth, early onset pre-eclampsia, eclampsia, placental abruption, intensive care unit admission > 24 hours, maternal death, hospital stay > 7 days from birth, and pregnancy loss before 20 weeks' gestation.