Abstract
Introduction
Pre-eclampsia (raised blood pressure and proteinuria) complicates 2% to 8% of pregnancies, and increases morbidity and mortality in the mother and child. Pre-eclampsia is more common in older women, women with a high body mass index, and women with multiple pregnancy. Pre-eclampsia risk is also increased in women with underlying medical conditions, particularly conditions associated with microvascular disease.
Methods and outcomes
We conducted a systematic overview, aiming to answer the following clinical questions: Does oral calcium supplementation during pregnancy reduce the risk and/or severity of pre-eclampsia? What are the effects of preventive calcium supplements pre-conception in women at risk of pre-eclampsia? We searched: Medline, Embase, The Cochrane Library, and other important databases up to November 2014 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review).
Results
At this update, searching of electronic databases retrieved 109 studies. After deduplication and removal of conference abstracts, 55 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 30 studies and the further review of 25 full publications. Of the 25 full articles evaluated, one update of a previously included systematic review was added. We performed a GRADE evaluation for seven PICO combinations.
Conclusions
In this systematic overview, we categorised the efficacy for three interventions based on information about the effectiveness and safety of calcium supplementation used to prevent pre-eclampsia, both during pregnancy and pre-conception, and different doses of calcium supplementation versus each other during pregnancy.
Key Points
Pre-eclampsia (raised blood pressure and proteinuria) complicates 2% to 8% of pregnancies, and increases morbidity and mortality in the mother and child.
Pre-eclampsia is more common in older women, women with a high body mass index, and women with multiple pregnancy. Pre-eclampsia risk is also increased in women with underlying medical conditions, particularly conditions associated with microvascular disease (e.g., chronic hypertension, diabetes, renal disease, and autoimmune conditions).
Despite countless studies, few therapies have been found to reduce the risk of developing pre-eclampsia. The use of low-dose aspirin has been shown to be one such therapy. For this update, we have focused on evidence from RCTs and systematic reviews of RCTs on the effect of calcium supplementation on the risk and/or severity of pre-eclampsia.
The use of calcium supplementation during pregnancy reduces the risk of pre-eclampsia and pre-term birth compared with placebo. It also seems to reduce maternal mortality/serious morbidity.
However, there was no difference in the incidence of eclampsia, placental abruption, caesarean section, stillbirth or neonatal death, or low birth weight (birth weight <2500 g), or need for further maternal or neonatal interventions or intensive care, in the calcium supplementation group.
The beneficial effect of calcium supplementation is particularly marked in those women with a low-calcium diet.
We found no systematic review or RCT evidence for different doses of calcium supplements versus each other or for pre-conceptual calcium supplementation.
Clinical context
General background
Pre-eclampsia (raised blood pressure and proteinuria) complicates 2% to 8% of pregnancies, and increases morbidity and mortality in the mother and child. It is more common in older women, women with a high body mass index, and women with multiple pregnancy. Pre-eclampsia risk is also increased in women with underlying medical conditions, particularly conditions associated with microvascular disease (e.g., chronic hypertension, diabetes, renal disease, and autoimmune conditions).
Focus of the review
Despite countless studies, few therapies have been found to reduce the risk of developing pre-eclampsia. The use of low-dose aspirin has been shown to be one such therapy and is now advocated by the National Institute for Health and Care Excellence (NICE) in women considered at high risk of developing pre-eclampsia. Less evidence is available for calcium supplementation and, therefore, this therapy has been chosen as a focus for this overview.
Comments on evidence
This overview indicates that the use of calcium supplementation does reduce the risk of pre-eclampsia, pre-term birth, and the composite outcome of maternal death or severe morbidity. Although most trials in the systematic review were of good quality, they included only nulliparous or primiparous women and were conducted largely in the US and South America, with most women classified at low risk of pre-eclampsia and with low dietary calcium. While not necessarily applicable to the UK population, this evidence supports the use of calcium supplementation in women with low-calcium diets and those at higher risk of pre-eclampsia. The timing of starting these supplements and the adherence to the high doses used, which are often unpalatable and unacceptable to women, needs further research.
Search and appraisal summary
The update literature search for this overview was carried out from the date of the last search, February 2010, to November 2014. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the overview, please see the Methods section. Searching of electronic databases retrieved 109 studies. After deduplication and removal of conference abstracts, 55 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 30 studies and the further review of 25 full publications. Of the 25 full articles evaluated, one update of a previously included systematic review was added.
Additional information
The evidence has led to the World Health Organisation recommending calcium supplementation of 1.5 to 2.0 g daily for pregnant women with low-calcium diets.
About this condition
Definition
Hypertension in pregnancy is defined as blood pressure greater than 140 mmHg systolic or 90 mmHg diastolic occurring twice and at least 4 hours apart. Hypertension during pregnancy may be classified[1] as: Chronic hypertension known hypertension before pregnancy or raised blood pressure before 20 weeks' gestation. It may be essential hypertension or, less commonly, secondary to an underlying disease.[2] Gestational hypertension new-onset raised blood pressure, without evidence of other complications of pre-eclampsia. Pre-eclampsia new or worsening hypertension usually after 20 weeks' gestation, in association with new or worsening proteinuria; other maternal organ dysfunction (notably renal, liver, haematological, or neurological); and/or evidence of fetal growth restriction. This may be de novo or superimposed on chronic hypertension. White coat hypertension diagnosed by evidence of hypertension during clinic visits but demonstration of normal blood pressure, ideally using 24-hour ambulatory BP monitoring (ABPM), in the first half of pregnancy.
Incidence/ Prevalence
Pregnancy-induced hypertension affects 10% of pregnancies, and pre-eclampsia complicates 2% to 8% of pregnancies.[3] Eclampsia occurs in about 1/2000 deliveries in resource-rich countries.[4] In resource-poor countries, estimates of the incidence of eclampsia vary from 1/100 to 1/1700.[5] [6]
Aetiology/ Risk factors
The aetiology of pre-eclampsia is only partially understood. It is likely to be multifactorial, and may result from deficient placental implantation during the first half of pregnancy.[7] Pre-eclampsia is more common among women with multiple pregnancy, obesity, or older age and among women with medical conditions associated with microvascular disease (such as diabetes, hypertension, and autoimmune conditions).[8] [9] One systematic review found that the risk of pre-eclampsia is increased in women with a previous history of pre-eclampsia (RR 7.19, 95% CI 5.85 to 8.83) and in those with antiphospholipid antibodies (RR 9.72, 95% CI 4.34 to 21.75), pre-existing diabetes (RR 3.56, 95% CI 2.54 to 4.99), multiple (twin) pregnancy (RR 2.93, 95% CI 2.04 to 4.21), nulliparity (RR 2.91, 95% CI 1.28 to 6.61), family history (RR 2.90, 95% CI 1.70 to 4.93), raised blood pressure (diastolic 80 mm Hg or greater) at booking (RR 1.38, 95% CI 1.01 to 1.87), raised body mass index before pregnancy (RR 2.47, 95% CI 1.66 to 3.67) or at booking (RR 1.55, 95% CI 1.28 to 1.88), or maternal age 40 years or older (RR 1.96, 95% CI 1.34 to 2.87, for multiparous women). The review reported that other factors that increase the risk are: an interval of 10 years or more since a previous pregnancy; autoimmune disease; renal disease; and chronic hypertension.[10] Cigarette smoking seems to be associated with a lower risk of pre-eclampsia, but this potential benefit is outweighed by an increase in adverse outcomes such as low birth weight, placental abruption, and perinatal death.[11] Predictive tests Risk assessment using the risk factors discussed above is advocated by NICE at the booking visit to help risk-stratify women. Other investigations during pregnancy are used widely in clinical practice. A systematic review of the accuracy of 27 predictive tests for pre-eclampsia found that some seemed to have high specificity, but at the expense of compromised sensitivity.[12] The review reported that tests with specificity of more than 90% were: body mass index greater than 34, alpha-fetoprotein, and uterine artery Doppler (bilateral notching). The review found that the only Doppler test with a sensitivity of more than 60% was resistance index and combinations of indices. It also found that a few tests not commonly seen in routine practice (kallikreinuria and SDS-PAGE proteinuria) potentially have both high sensitivity and specificity, but these require further investigation.[12] Most recently, commercially available assays for plasma placentally derived growth factor (PlGF) have become available. In women with suspected pre-term pre-eclampsia, low (<fifth centile) plasma PlGF has high sensitivity and negative predictive value for pre-eclampsia within 14 days and is better than other currently used tests.[13]
Prognosis
The outcome of pregnancy in women with late-onset pregnancy-induced hypertension alone is similar to that for normotensive pregnancies.[8] [14] However, once pre-eclampsia develops, morbidity and mortality increase for both mother and child. For example, perinatal mortality for women with severe pre-eclampsia is double that for normotensive women.[8] Perinatal outcome is worse with early gestational hypertension.[8] [14] [15] Perinatal mortality also increases in women with severe essential hypertension.[16]
Aims of intervention
To delay or prevent the development of pre-eclampsia and/or reduce the severity of pre-eclampsia, to improve outcomes for women and their babies.
Outcomes
For the woman: mortality; morbidity (such as renal failure, coagulopathy, cardiac failure, liver failure, placental abruption, and stroke); development of pre-eclampsia (rates of severe hypertension, rates of pre-eclampsia, proteinuria, and hypertension); seizures (includes eclampsia); need for further interventions (caesarean section); use of resources (such as dialysis, ventilation, admission to intensive care, or length of stay); adverse effects. For the child: mortality, intrauterine growth restriction, preterm birth, and morbidity (such as intraventricular haemorrhage, respiratory distress syndrome, or asphyxia, small for gestational age); measures of infant and child development (such as cerebral palsy or significant learning disability); use of resources (such as admission to a special care nursery, ventilation, length of stay in hospital, and special needs in the community); adverse effects.
Methods
Search strategy BMJ Clinical Evidence search and appraisal date November 2014. Databases used to identify studies for this systematic overview include: Medline 1966 to November 2014, Embase 1980 to November 2014, The Cochrane Database of Systematic Reviews 2014, issue 11 (1966 to date of issue), the Database of Abstracts of Reviews of Effects (DARE), and the Health Technology Assessment (HTA) database. Inclusion criteria Study design criteria for inclusion in this systematic overview were systematic reviews and RCTs published in English, at least single-blinded, of any number of individuals, of whom more than 80% were followed up. There was no minimum length of follow-up. We excluded all studies described as 'open', 'open label', or not blinded unless blinding was impossible. BMJ Clinical Evidence does not necessarily report every study found (e.g., every systematic review). Rather, we report the most recent, relevant, and comprehensive studies identified through an agreed process involving our evidence team, editorial team, and expert contributors. Evidence evaluation A systematic literature search was conducted by our evidence team, who then assessed titles and abstracts, and finally selected articles for full text appraisal against inclusion and exclusion criteria agreed a priori with our expert contributors. In consultation with the expert contributors, studies were selected for inclusion and all data relevant to this overview extracted into the benefits and harms section of the review. In addition, information that did not meet our pre-defined criteria for inclusion in the benefits and harms section may have been reported in the 'Further information on studies' or 'Comment' sections (see below). Adverse effects All serious adverse effects, or those adverse effects reported as statistically significant, were included in the harms section of the overview. Pre-specified adverse effects identified as being clinically important were also reported, even if the results were not statistically significant. Although BMJ Clinical Evidence presents data on selected adverse effects reported in included studies, it is not meant to be, and cannot be, a comprehensive list of all adverse effects, contraindications, or interactions of included drugs or interventions. A reliable national or local drug database must be consulted for this information. Comment and Clinical guide sections In the Comment section of each intervention, our expert contributors may have provided additional comment and analysis of the evidence, which may include additional studies (over and above those identified via our systematic search) by way of background data or supporting information. As BMJ Clinical Evidence does not systematically search for studies reported in the Comment section, we cannot guarantee the completeness of the studies listed there or the robustness of methods. Our expert contributors add clinical context and interpretation to the Clinical guide sections where appropriate. Structural changes this update At this update, we have removed the following previously reported questions: What are the effects of preventive interventions in women at risk of pre-eclampsia? What are the effects of interventions in women who develop mild to moderate hypertension during pregnancy? What are the effects of interventions in women who develop severe pre-eclampsia or very high blood pressure during pregnancy? What is the best choice of anticonvulsant for women with eclampsia? We have added the following questions: Does oral calcium supplementation during pregnancy reduce the risk and/or severity of pre-eclampsia? What are the effects of preventive calcium supplements pre-conception in women at risk of pre-eclampsia? Data and quality To aid readability of the numerical data in our overviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). BMJ Clinical Evidence does not report all methodological details of included studies. Rather, it reports by exception any methodological issue or more general issue that may affect the weight a reader may put on an individual study, or the generalisability of the result. These issues may be reflected in the overall GRADE analysis. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table.
GRADE Evaluation of interventions for Pre-eclampsia: reducing the risk with calcium supplements.
| Important outcomes | Child development, Development of pre-eclampsia, Morbidity, Mortality, Need for further interventions, Preterm birth, Seizures, Use of resources | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| Does oral calcium supplementation during pregnancy reduce the risk and/or severity of pre-eclampsia? | |||||||||
| 11 at most (15,665 at most) | Mortality | Calcium supplementation versus placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for use of a composite outcome for maternal mortality |
| 11 (15,275) | Preterm birth | Calcium supplementation versus placebo | 4 | 0 | 0 | 0 | 0 | High | |
| 9 (14,883) | Morbidity | Calcium supplementation versus placebo | 4 | 0 | 0 | 0 | 0 | High | |
| 13 (15,730) | Development of pre-eclampsia | Calcium supplementation versus placebo | 4 | 0 | 0 | 0 | +1 | High | Effect-size point added for RR <0.5 |
| 3 (13,425) | Seizures | Calcium supplementation versus placebo | 4 | 0 | 0 | 0 | 0 | High | |
| 8 (15,234) | Need for further interventions | Calcium supplementation versus placebo | 4 | 0 | 0 | 0 | 0 | High | |
| 4 (13,406) | Use of resources | Calcium supplementation versus placebo | 4 | 0 | 0 | 0 | 0 | High | |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
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