1. Objectives

To assess the effect of calcium supplementation on maternal, fetal and neonatal outcomes (other than for preventing or treating hypertension), including adverse effects

2. How studies were identified

The following databases were searched in September 2014:

• Cochrane Pregnancy and Childbirth Group’s Trials Register
• CENTRAL (The Cochrane Library 2014)
• MEDLINE
• Embase

3. Criteria for including studies in the review

3.1 Study type

Randomized controlled trials, including cluster-randomized trials

3.2 Study participants

Pregnant women

(Trials including multiple pregnancies were excluded due to the effect that multiple pregnancies may have on the outcomes of interest, such as preterm birth)

3.3 Interventions

Calcium supplementation during pregnancy compared to placebo or no treatment

3.4 Primary outcomes

Maternal outcomes

• Preterm birth <37 weeks’ gestation

Infant outcomes

• Low birth weight <2500 g

Maternal secondary outcomes included preterm birth <34 weeks’ gestation, weight gain, bone mineral density, leg cramps, backache, tetany, fracture, duration of breastfeeding, tremor, paraesthesia, admission to an intensive care unit, death, mode of delivery (not a pre-specified outcome), and postpartum haemorrhage (not a pre-specified outcome). Fetal and neonatal secondary outcomes included stillbirth or fetal death (fetus died >20 weeks’ gestation or during labour and delivery), neonatal death (death in first 28 days of life), perinatal mortality (stillbirth and neonatal death), admission to a neonatal intensive care unit, birth weight, birth length, head circumference, intrauterine growth restriction, neonatal bone mineral density, osteopenia, rickets, and fracture. Adverse outcomes included side effects of calcium supplementation, compliance, satisfaction, urinary stones, urinary tract infection, nephrocalcinosis, impaired renal function, and maternal anaemia

4. Main results

4.1 Included studies

Twenty-five randomized controlled trials were included in the review, with 23 of these studies, enrolling 18,587 women, contributing data for analysis

• Sample size ranged from 23 to 8325 women
• Three trials enrolled only adolescent pregnant women, two trials included only women of low socioeconomic position, one study recruited women who had lived at an altitude of 2800 m for ≥1 year, and one study enrolled normotensive women with positive roll-over angiotensin tests
• Calcium carbonate was the most common supplement (17 of 23 trials), others included calcium gluconate, calcium lactate and combined calcium; 14 trials supplemented with high dose calcium >1000 mg/day
• Five trials initiated supplementation before 20 weeks’ gestation, 11 trials began from 20 weeks’ gestation, and in the remaining trials timing of initiation was not specified

4.2 Study settings

• Argentina (2 trials), Australia, China, Colombia, Ecuador (2 trials), Gambia (2 trials), Guatemala, India (4 trials), Iran (3 trials), Mexico, the United States of America (6 trials), and multi-country (Argentina, Egypt, India, Peru, South Africa, Viet Nam)
• Studies were conducted in antenatal care settings
• The largest trial included in this review recruited women from populations consuming <600 mg of calcium per day (multi-country trial)

4.3 Study settings

How the data were analysed
Calcium supplementation was compared to placebo or no treatment. For studies with multiple treatment arms, the placebo group was divided equally between the treatment arms for comparison to avoid double counting. Dichotomous data were summarized using risk ratios (RR) with corresponding 95% confidence intervals (CI), and mean differences (MD) with 95% CI were used for continuous data. Where substantial heterogeneity (I²>30%) was detected, random effects models were used to pool the data if an overall summary was considered meaningful. In addition, subgroup analyses were performed to explore sources of heterogeneity. The following subgroup analyses were performed for primary outcomes:

• Preterm birth <37 weeks’ gestation by dose of calcium (low dose <1000 mg/day versus high dose ≥1000 mg/day)
• Preterm birth <37 weeks’ gestation by timing of supplement initiation (<20 weeks’ gestation versus ≥20 weeks’ gestation)
• Preterm birth <37 weeks’ gestation by type of calcium (gluconate versus carbonate)
• Low birth weight <2500 g by timing of supplement initiation (<20 weeks’ gestation versus ≥20 weeks’ gestation)
• Low birth weight <2500 g by type of calcium (gluconate versus carbonate)

Results
Maternal outcomes
Preterm birth <37 weeks’ gestation
In pooled analysis of 13 trials, calcium supplementation had no effect on preterm birth <37 weeks’ gestation in comparison to no treatment or placebo (RR 0.86, 95% CI [0.70 to 1.05], 13 trials/16,139 women). Subgroup analysis revealed an apparent difference between low and high dose calcium trials (p=0.008 for subgroup differences); however, results did not become statistically significant in separate analyses of either subgroup. Sensitivity analysis excluding trials at risk of allocation concealment bias produced a statistically significant effect in favour of calcium supplementation (RR 0.80, 95% CI [0.65 to 0.99], p=0.038; 11 trials/15,379 women).

Additional outcomes
No evidence of a statistically significant difference between treatment and control groups was found for preterm birth <34 weeks’ gestation (RR 1.04, 95% CI [0.80 to 1.36], 4 trials/5669 women), maternal weight gain (MD -29.46 g/week, 95% CI [-119.80 to 60.89], 3 trials/404 women), bone mineral density (1 trial/273 women), maternal death (RR 0.29, 95% CI [0.06 to 1.38], 2 trials/8974 women), admission to an intensive care unit (RR 0.84, 95% CI [0.66 to 1.07], 1 trial/8312), or mode of delivery (vaginal: RR 1.01, 95% CI [0.99 to 1.03], 8 trials/6916 women; instrumental: RR 0.89, 95% CI [0.66 to 1.20], 2 trials/675 women; caesarean section: RR 0.99, 95% CI [0.89 to 1.10], 9 trials/7440 women). No other secondary outcomes were reported on in the included studies.

Adverse outcomes
For the side effects maternal cholestatic jaundice, gastrointestinal symptoms, gall stones, headache, vomiting, backache, swelling, genitourinary complaints, dyspepsia, and abdominal pain, there were no statistically significant differences between treatment groups. No significant difference between groups was found for urinary tract infection (RR 0.95, 95% CI [0.69 to 1.30], 3 trials/1743 women), urinary stones (RR 1.11, 95% CI [0.48 to 2.54], 3 trials/13,419 women), renal colic (RR 1.67, 95% CI [0.40 to 6.99], 1 trial/8312 women), impaired renal function (RR 0.91, 95% CI [0.51 to 1.64], 1 trial/4589 women), or maternal anaemia (RR 1.04, 95% CI [0.90 to 1.22], 1 trial/1098 women).

Fetal and neonatal outcomes
Low birth weight <2500 g
Overall, calcium supplementation in comparison to placebo or no treatment had no statistically significant effect on the incidence of low birth weight <2500 g (RR 0.93, 95% CI [0.81 to 1.07], 6 trials/14,162 women). In subgroup analysis according to initiation of supplement use, in studies beginning before 20 weeks’ gestation the difference remained non-significant (RR 0.98, 95% CI [0.94 to 1.03], 3 trials/13,425 women). However, for studies beginning from 20 weeks’ gestation, the risk of low birth weight was reduced by 59% (RR 0.41, 95% CI [0.23 to 0.73], p=0.0024; 3 trials/737 women). No studies reporting on low birth weight used low dose calcium supplements <1000 mg/day.

Additional outcomes
Birth weight was statistically significantly greater by 56.4 g among neonates whose mothers had received calcium supplementation in comparison to those whose mothers had not (95% CI [13.6 to 99.3 g], p=0.0099; 21 trials/9202 women), however heterogeneity was high (I²=74%). Neonatal total body and tibial bone mineral density was reported to be improved with calcium supplementation (data not shown). No statistically significant differences between treatment groups were observed for perinatal mortality (RR 0.87, 95% CI [0.72 to 1.06], 8 trials/15,785 women), stillbirth or fetal death (RR 0.91, 95% CI [0.72 to 1.14], 6 trials/15,269 women), admission to a neonatal intensive care unit (RR 1.05, 95% CI [0.94 to 1.18], 4 trials/14,062), birth length (MD -0.09 cm, 95% CI [-0.25 to 0.06], 7 trials/6389 women), head circumference (MD -0.09 cm, 95% CI [-0.36 to 0.18], 3 trials/460 women), or intrauterine growth restriction (RR 0.83, 95% CI [0.61 to 1.13], 6 trials/1701 women). No data were available for other fetal and neonatal secondary outcomes.

5. Additional author observations*

The methodological quality of the included trials was good, with 17 of the 25 studies at low risk of allocation concealment bias. The outcomes preterm birth <37 weeks’ gestation, low birth weight <2500 g, and preterm birth <34 weeks’ gestation were judged to be of moderate quality using GRADE quality of evidence criteria. In addition, trials were conducted in a range of settings, increasing the generalizability of the findings.

Overall, the evidence summarized in this review does not support the use of calcium supplementation for the prevention of preterm birth or low birth weight. While mean birth weight was greater with calcium supplementation, the difference was small and the heterogeneity was high between studies.

In a previous Cochrane systematic review (Hofmeyr et al., Cochrane Database of Systematic Reviews 2014, Issue 6. DOI: 10.1002/14651858.CD001059.pub4), preterm birth was reduced with calcium supplementation. This discrepancy between reviews may be explained by differing inclusion criteria and sample sizes. Large, multicentre, high-quality trials are therefore needed to determine the effect of calcium supplementation during pregnancy on preterm birth. In addition, few long-term data on outcomes such as osteoporosis currently exist.