Hypertension has been estimated to complicate 5% of all pregnancies and 11% of first pregnancies, half of these being associated with pre-eclampsia, and accounting for up to 40,000 maternal deaths annually (Villar 2003). Pre-eclampsia is defined as high blood pressure and proteinuria occurring after the 20th week of pregnancy.
In general, pre-eclampsia is considerably more prevalent in low-income than in high-income communities. Two striking exceptions have been identified. More than 50 years ago, a low prevalence of pre-eclampsia was reported from Ethiopia where the diet, among other features, contained high levels of calcium (Hamlin 1952). The observation in 1980 that Mayan Indians in Guatemala, who traditionally soaked their corn in lime before cooking, had a low incidence of pre-eclampsia and eclampsia (Belizan 1980), stimulated interest in the concept that the link between poverty and pre-eclampsia might be dietary calcium deficiency.
Subsequent epidemiological, clinical and laboratory studies linking pre-eclampsia to calcium deficiency have been outlined in a Cochrane review (Hofmeyr 2014).
Low dietary calcium intake is also associated with hypertension in the general population (Centeno 2009). A systematic review of randomised trials showed a small reduction in systolic and diastolic blood pressure with dietary and non-dietary calcium supplementation (Griffith 1999). Systolic blood pressure was reduced by -1.44 mm Hg (95% confidence interval (CI) -2.20 to -0.68; P < .001) and diastolic blood pressure by -0.84 mm Hg (95% CI -1.44 to -0.24; P < .001). Low dietary calcium intake is also considered a risk factor for osteoporosis, renal stones, increased body mass index, insulin resistance and colorectal cancer (Centeno 2009).
The hypothesis that calcium supplementation during pregnancy might reduce the incidence of pre-eclampsia was tested in several randomised trials commencing in the late 1980s.
The World Health Organization (WHO) conducted a randomised trial of calcium supplementation among low calcium intake pregnant women from 2001 to 2003 (Villar 2006). Results from this trial showed that although 1.5 g calcium/day supplement did not prevent pre-eclampsia, it reduced its severity, maternal morbidity, and neonatal mortality. Supplementation in this trial was only during later pregnancy, starting before the 20th week of pregnancy. This trial was included (along with other randomised trials of calcium supplementation during pregnancy) in the Cochrane review by Hofmeyr 2014. The results showed that calcium supplementation of at least 1 g daily, commencing around mid-pregnancy, was associated with a modest reduction in pre-eclampsia, and notably a reduction in its severe manifestations, particularly among women at increased risk, or with low dietary calcium intake. A review of lower dose calcium supplementation (mainly 500 mg/day in the second half of pregnancy), with or without other supplements, including small trials of variable quality also found a reduction in pre-eclampsia (nine trials, 2234 women, risk ratio (RR) 0·38, 95% CI 0·28 to 0.52) (Hofmeyr 2014a).
WHO has recommended that in populations where dietary calcium intake is low, pregnant women receive 1.5 to 2 g elemental calcium daily, particularly those at increased risk of pre-eclampsia (women with one or more of the following risk factors: obesity, previous pre-eclampsia, diabetes, chronic hypertension, renal disease, autoimmune disease, nulliparity, advanced maternal age, adolescent pregnancy and conditions leading to hyperplacentation and large placentas such as in twin pregnancy) (http://www.who.int/nutrition/publications/micronutrients/guidelines/calcium_supplementation/en/index.html).
Description of the condition
The hypertensive disorders of pregnancy include chronic hypertension, gestational hypertension, pre-eclampsia/eclampsia and unclassified hypertension.
Pre-eclampsia is defined as high blood pressure and proteinuria occurring for the first time after 20 weeks' gestation.
Gestational hypertension is defined as diastolic blood pressure > 90 mmHg on two occasions four hours apart, or > 110 mmHg once, and/or systolic blood pressure > 140 mmHg on two occasions four hours apart, or > 160 mmHg once, after 20 weeks’ gestation.
Gestational proteinuria is defined as 2+ or more on urine dipstix, or > 300 mg/24 hours, or > 500 mg/L or urinary protein/creatinine ratio > 0.034, after 20 weeks’ gestation.
failure of cytotrophoblast invasion to remodel uterine spiral arterioles to low-resistance vessels;
impaired uteroplacental blood flow;
syncytiotrophoblast oxidative stress and oversecretion of anti-angiogenic and pro-inflammatory factors from the ischaemic placenta;
widespread maternal endothelial dysfunction with vasoconstriction and renal dysfunction.
This sequence of events has been suggested to be a precursor particularly of early onset pre-eclampsia (Redman 2014).
Description of the intervention
Previous studies and reviews have focused on calcium supplementation during pregnancy. In most studies, calcium supplementation was administered from around 20 weeks of pregnancy, the rationale being to cover the period during which pre-eclampsia is manifest. As set out below, this may be too late to interrupt early pregnancy events which are precursors of pre-eclampsia. This review will focus on interventions to improve calcium intake in early pregnancy. This may be achieved by means of calcium supplementation given to women before or very early in pregnancy and during at least the first half of pregnancy, or food fortification with calcium at an individual or community level.
The possibility of harm from calcium supplementation needs to be considered. Calcium supplementation (but not dietary calcium) has been associated with myocardial infarction risk in the Heidelberg study, an observation at risk of confounding (Li 2012); 1.5 g calcium/day during pregnancy may cause rebound postnatal bone demineralisation (an unexpected finding among multiple trial outcomes assessed) (Jarjou 2010); and an earlier review identified an unexpected increase in the syndrome of haemolysis, elevated liver enzymes and low platelets (HELLP) following calcium supplementation (Hofmeyr 2014), perhaps through the antihypertensive effect of calcium masking the evolution of mild pre-eclampsia into HELLP syndrome (Hofmeyr 2007).
Calcium may be administered in the form of carbonate, citrate, lactate or gluconate, which have good bioavailability. The 19th Expert Committee on the Selection and Use of Essential Medicines recommended the listing of oral solid dosage forms of calcium, providing 500 mg of elemental calcium per dose. http://www.who.int/medicines/EC19uneditedReport.pdf
Food fortification would involve the addition of calcium to staple foods that are low in calcium, such as maize or wheat.
How the intervention might work
Hofmeyr 2008 conducted a randomised trial nested within the large WHO trial of calcium supplementation (1.5 g daily from at least 20 weeks’ gestation) in pregnant women with low dietary calcium intake (Villar 2006) and the nested trial failed to demonstrate an effect of calcium supplementation on biochemical measures commonly elevated in pre-eclampsia: serum urate, platelet count, and urine protein/creatinine ratio.
The lack of effect on proteinuria is consistent with the findings of the main WHO trial (Villar 2006), in which there was a statistically non-significant reduction in pre-eclampsia (8312 women, RR 0.92, 95% CI 0.75 to 1.13) and severe pre-eclampsia (8302 women, RR 0.74, 95% CI 0.48 to 1.15), but no reduction in proteinuria (8312 women, RR for proteinuria 1.01, 95% CI 0.88 to 1.15). Proteinuria is a hallmark of pre-eclampsia, and a predictor of adverse maternal outcome (von Dadelzsen 2004).
To reconcile the evidence from the systematic review for reduced pre-eclampsia with calcium supplementation (Hofmeyr 2014), with the absence of evidence of an effect on proteinuria and other markers for pre-eclampsia, we proposed the hypothesis that calcium supplementation in the second half of pregnancy reduces blood pressure and thus the diagnosis and severe manifestations of pre-eclampsia, without a significant effect on the underlying pathology (Hofmeyr 2008).
This hypothesis also serves to explain another anomaly identified in the systematic review: whereas pre-eclampsia was reduced overall by 22% (12 trials, 15,206 women; RR 0.78, 95% CI 0.68 to 0.89) and the composite outcome ‘maternal death or severe morbidity’ was reduced by 20% (five trials, 9734 women, RR 0.80, 95% CI 0.65 to 0.97), HELLP syndrome was increased 2.7 times with calcium supplementation (two trials, 12,901 women, RR 2.67, 95% CI 1.05 to 6.82) (Hofmeyr 2014). If calcium supplementation in the second half of pregnancy reduces only blood pressure, this would reduce the diagnosis and some of the hypertension-related complications of pre-eclampsia, while the effects on other organ systems, such as the endothelium, platelets and liver might continue for a longer time in the calcium supplementation group in which fewer early deliveries for hypertension would take place.
The second anomaly requiring explanation is the modest effect of calcium supplementation in late pregnancy on pre-eclampsia, in contrast to the striking epidemiological differences in populations with good and poor dietary calcium. Deficient dietary calcium before and during early pregnancy may place populations at risk for pre-eclampsia, and the potential to reverse this effect by supplementation in later pregnancy may be limited (Hofmeyr 2008).
Based on the epidemiological association of pre-eclampsia with low dietary calcium and the current understanding of pre-eclampsia as having its origins in early pregnancy events, it is hypothesised that calcium supplementation in early pregnancy may reduce the risk of pre-eclampsia (Hofmeyr 2008).
Why it is important to do this review
The benefits of calcium supplementation in the second half of pregnancy in the prevention of severe pre-eclampsia and other severe morbidity have been proven by systematic reviews. However, there is no evidence to prove or disprove the potential benefits of pre- and early pregnancy calcium supplementation or food fortification in preventing pre-eclampsia. Evidence for such an effect would create the opportunity to have a major impact on pre-eclampsia at a population level, for example by food fortification with calcium among communities at risk. There has not to our knowledge been a previous systematic review on this subject.