Calcium supplementation for the prevention of pre-eclampsia: Challenging the evidence from meta-analyses.

OBJECTIVE: To investigate the validity of the conclusion from Cochrane reviews and meta-analyses that treatment with calcium supplementation during pregnancy reduces the risk for pre-eclampsia by 55%, which has been influential in international guidelines and future research. DESIGN: Sensitivity analysis of data from Cochrane reviews of trials evaluating high-dose calcium supplementation (of at least 1 g/day) for reduction of pre-eclampsia risk. SETTING: Systematic review and meta-analysis. POPULATION: The Cochrane reviews and meta-analyses included 13 trials enrolling a total of 15 730 women. Random-effects meta-analysis of these studies resulted in a mean risk ratio (RR, calcium/placebo) of 0.45 (95% confidence interval [CI] 0.31-0.65; p < 0.0001). METHODS: We carried out a sensitivity analysis of evidence from the relevant Cochrane review, to examine the impact of study size. MAIN OUTCOME MEASURES: pre-eclampsia. RESULTS: In the three largest studies, accounting for 13 815 (88%) of total recruitment, mean RR was 0.92 (95% CI 0.80-1.06) and there was no evidence of heterogeneity between studies (I2 = 0). With inclusion of the smaller studies, mean RR decreased to 0.45 and I2 increased to 70%. CONCLUSIONS: In assessment of the effect of calcium supplementation on pre-eclampsia risk, the naive focus on the mean of the random-effects meta-analysis in the presence of substantial heterogeneity is highly misleading.

A treatment strategy with nifedipine versus labetalol for women with pregnancy hypertension: study protocol for a randomised controlled trial (Giant PANDA).

BACKGROUND: Approximately one in ten women have high blood pressure during pregnancy. Hypertension is associated with adverse maternal and perinatal outcomes, and as treatment improves maternal outcomes, antihypertensive treatment is recommended. Previous trials have been unable to provide a definitive answer on which antihypertensive treatment is associated with optimal maternal and neonatal outcomes and the need for robust evidence evaluating maternal and infant benefits and risks remains an important, unanswered question for research and clinical communities. METHODS: The Giant PANDA study is a pragmatic, open-label, multicentre, randomised controlled trial of a treatment initiation strategy with nifedipine (calcium channel blocker), versus labetalol (mixed alpha/beta blocker) in 2300 women with pregnancy hypertension. The primary objective is to evaluate if treatment with nifedipine compared to labetalol in women with pregnancy hypertension reduces severe maternal hypertension without increasing fetal or neonatal death or neonatal unit admission. Subgroup analyses will be undertaken by hypertension type (chronic, gestational, pre-eclampsia), diabetes (yes, no), singleton (yes, no), self-reported ethnicity (Black, all other), and gestational age at randomisation categories (11 + 0 to 19 + 6, 20 + 0 to 27 + 6, 28 + 0 to 34 + 6 weeks). A cost-effectiveness analysis using an NHS perspective will be undertaken using a cost-consequence analysis up to postnatal hospital discharge and an extrapolation exercise with a lifetime horizon conditional on the results of the cost-consequence analysis. DISCUSSION: This trial aims to address the uncertainty of which antihypertensive treatment is associated with optimal maternal and neonatal outcomes. The trial results are intended to provide definitive evidence to inform guidelines and linked, shared decision-making tools, thus influencing clinical practice. TRIAL REGISTRATION: EudraCT number: 2020-003410-12, ISRCTN: 12,792,616 registered on 18 November 2020.

An evidence review and nutritional conceptual framework for pre-eclampsia prevention.

Pre-eclampsia is a serious complication of pregnancy, and maternal nutritional factors may play protective roles or exacerbate risk. The tendency to focus on single nutrients as a risk factor obscures the complexity of possible interactions, which may be important given the complex nature of pre-eclampsia. An evidence review was conducted to compile definite, probable, possible and indirect nutritional determinants of pre-eclampsia to map a nutritional conceptual framework for pre-eclampsia prevention. Determinants of pre-eclampsia were first compiled through an initial consultation with experts. Second, an expanded literature review was conducted to confirm associations, elicit additional indicators and evaluate evidence. The strength of association was evaluated as definite relative risk (RR) < 0·40 or ≥3·00, probable RR 0·40-0·69 or 1·50-2·99, possible RR 0·70-0·89 or 1·10-1·49 or not discernible RR 0·90-1·09. The quality of evidence was evaluated using Grading of Recommendations, Assessment, Development and Evaluation. Twenty-five nutritional factors were reported in two umbrella reviews and twenty-two meta-analyses. Of these, fourteen were significantly associated with pre-eclampsia incidence. Higher serum Fe emerged as a definite nutritional risk factors for pre-eclampsia incidence across populations, while low serum Zn was a risk factor in Asia and Africa. Maternal vitamin D deficiency was a probable risk factor and Ca and/or vitamin D supplementation were probable protective nutritional factors. Healthy maternal dietary patterns were possibly associated with lower risk of developing pre-eclampsia. Potential indirect pathways of maternal nutritional factors and pre-eclampsia may exist through obesity, maternal anaemia and gestational diabetes mellitus. Research gaps remain on the influence of household capacities and socio-cultural, economic and political contexts, as well as interactions with medical conditions.

Anemia and adverse outcomes in pregnancy: subgroup analysis of the CLIP cluster-randomized trial in India.

BACKGROUND: Iron-deficiency anemia is a known risk factor for several adverse perinatal outcomes, but data on its impact on specific maternal morbidities is less robust. Further, information on associations between anemia in early pregnancy and subsequent outcomes are understudied. METHODS: The study population was derived from the Community Level Interventions for Pre-eclampsia (CLIP) trial in Karnataka State, India (NCT01911494). Included were women who were enrolled in either trial arm, delivered by trial end date, and had a baseline measure of hemoglobin (Hb). Anemia was classified by WHO standards into four groups: none (Hb ≥ 11 g/dL), mild (10.0 g/dL ≤ Hb < 11.0 g/dL), moderate (7.0 g/dL ≤ Hb < 10.0 g/dL) and severe (Hb < 7.0 g/dL). Targeted maximum likelihood estimation was used to estimate confounder-adjusted associations between anemia and a composite (and its components) of adverse maternal outcomes, including pregnancy hypertension. E-values were calculated to assess robustness to unmeasured confounding. RESULTS: Of 11,370 women included, 10,066 (88.5%) had anemia, that was mild (3690, 32.5%), moderate (6023, 53.0%), or severe (68, 0.6%). Almost all women (> 99%) reported taking iron supplements during pregnancy. Blood transfusions was more often administered to those with anemia that was mild (risk ratio [RR] 2.16, 95% confidence interval [CI] 1.31-3.56), moderate (RR 2.37, 95% CI 1.56-3.59), and severe (RR 5.70, 95% CI 3.00-10.85). No significant association was evident between anemia severity and haemorrhage (antepartum or postpartum) or sepsis, but there was a U-shaped association between anemia severity and pregnancy hypertension and pre-eclampsia specifically, with the lowest risk seen among those with mild or moderate anemia. CONCLUSION: In Karnataka State, India, current management strategies for mild-moderate anemia in early pregnancy are associated with similar rates of adverse maternal or perinatal outcomes, and a lower risk of pregnancy hypertension and preeclampsia, compared with no anemia in early pregnancy. Future research should focus on risk mitigation for women with severe anemia, and the potential effect of iron supplementation for women with normal Hb in early pregnancy.

Calcium for pre-eclampsia prevention: A systematic review and network meta-analysis to guide personalised antenatal care.

BACKGROUND: Calcium supplementation reduces the risk of pre-eclampsia, but questions remain about the dosage to prescribe and who would benefit most. OBJECTIVES: To evaluate the effectiveness of high (≥1 g/day) and low (<1 g/day) calcium dosing for pre-eclampsia prevention, according to baseline dietary calcium, pre-eclampsia risk and co-interventions, and intervention timing. SEARCH STRATEGY: CENTRAL, PubMed, Global Index Medicus and CINAHL, from inception to 2 February 2021, clinical trial registries, reference lists and expert input (CRD42018111239). SELECTION CRITERIA: Randomised controlled trials of calcium supplementation for pre-eclampsia prevention, for women before or during pregnancy. Network meta-analysis (NMA) also included trials of different calcium doses. DATA COLLECTION AND ANALYSIS: Two independent reviewers extracted published data. The meta-analysis employed random-effects models and the NMA, a Bayesian random-effects model, to obtain direct and indirect effect estimates. MAIN RESULTS: The meta-analysis included 30 trials (N = 20 445 women), and the NMA to evaluate calcium dosage included 25 trials (N = 15 038). Calcium supplementation prevented pre-eclampsia similarly with a high dose (RR 0.49, 95% CI 0.36-0.66) or a low dose (RR 0.49, 95% CI 0.36-0.65). By NMA, high-dose (vs low-dose) calcium did not differ in effect (RR 0.79, 95% CI 0.43-1.40). Calcium was similarly effective regardless of baseline pre-eclampsia risk, vitamin D co-administration or timing of calcium initiation, but calcium was ineffective among women with adequate average baseline calcium intake. CONCLUSIONS: Low- and high-dose calcium supplementation are effective for pre-eclampsia prevention in women with low calcium intake. This has implications for population-level implementation where dietary calcium is low, and targeted implementation where average intake is adequate. TWEETABLE ABSTRACT: A network meta-analysis of 25 trials found that low-dose calcium supplementation (<1 g/day) is as effective as high-dose calcium supplementation (≥1 g/day) in halving the risk of pre-eclampsia when baseline calcium intake is low.

Effects of Maternal Nutritional Supplements and Dietary Interventions on Placental Complications: An Umbrella Review, Meta-Analysis and Evidence Map.

The placenta is a vital, multi-functional organ that acts as an interface between maternal and fetal circulation during pregnancy. Nutritional deficiencies during pregnancy alter placental development and function, leading to adverse pregnancy outcomes, such as pre-eclampsia, infants with small for gestational age and low birthweight, preterm birth, stillbirths and maternal mortality. Maternal nutritional supplementation may help to mitigate the risks, but the evidence base is difficult to navigate. The primary purpose of this umbrella review is to map the evidence on the effects of maternal nutritional supplements and dietary interventions on pregnancy outcomes related to placental disorders and maternal mortality. A systematic search was performed on seven electronic databases, the PROSPERO register and references lists of identified papers. The results were screened in a three-stage process based on title, abstract and full-text by two independent reviewers. Randomized controlled trial meta-analyses on the efficacy of maternal nutritional supplements or dietary interventions were included. There were 91 meta-analyses included, covering 23 types of supplements and three types of dietary interventions. We found evidence that supports supplementary vitamin D and/or calcium, omega-3, multiple micronutrients, lipid-based nutrients, and balanced protein energy in reducing the risks of adverse maternal and fetal health outcomes. However, these findings are limited by poor quality of evidence. Nutrient combinations show promise and support a paradigm shift to maternal dietary balance, rather than single micronutrient deficiencies, to improve maternal and fetal health. The review is registered at PROSPERO (CRD42020160887).

The effect of calcium supplementation on blood pressure in non-pregnant women with previous pre-eclampsia: A randomized placebo-controlled study.

BACKGROUND: Low dietary calcium is associated with the hypertensive disorders of pregnancy, and evidence suggests that the risks associated with pre-eclampsia are reduced by calcium supplementation. In the general (non-pregnant) population, low dietary calcium intake is associated with hypertension with inconsistent evidence that calcium supplementation may reduce blood pressure. Women with pre-eclampsia are also at risk of hypertension later in life. An exploratory sub-study among early participants enrolled in the WHO long-term calcium supplementation in women at high risk of pre-eclampsia (CAP) study reported a trend to more blood pressure reduction with calcium in non-pregnant women with previous severe as opposed to non-severe pre-eclampsia. The current study reports the effects of low-dose calcium supplementation in non-pregnant women in the complete trial cohort. METHODS: The CAP Study was a multi-country randomized, double-blind placebo-controlled clinical trial to test the hypothesis that calcium deficiency may play a role in the genesis of pre-eclampsia in early pregnancy. From 2011 to 2016, non-pregnant women who had pre-eclampsia or eclampsia in their most recent pregnancy were randomized to receive either 500 mg/day elemental calcium or placebo. In this sub-study we compared the change in blood pressure from baseline to the 12-week visit between participants receiving calcium versus placebo for those not pregnant at the 12-week visit. RESULTS: Of 1355 women randomized, 810 attended a 12-week visit without being pregnant, of whom 791 had blood pressure measurements available for both baseline and 12-week visits. There was a greater reduction in blood pressure in the calcium group compared with the placebo group for systolic pressure (difference 3.1 mmHg, 95% CI 0.8 to 5.4) and mean arterial pressure (MAP) (difference 2.0 mmHg, 95% CI 0.1 to 3.8). The difference in diastolic blood pressure reduction (1.4 mmHg, 95% CI -0.5 to 3.3) was not statistically significant (p = 0.140). For women with previous pre-eclampsia with severe features (n = 447), there was significantly greater reduction in blood pressure in the calcium than the placebo group (difference for systolic 4.0, 95% CI 0.7 to 7.3; diastolic 3.0, 95% CI 0.5 to 5.5 and mean arterial pressure 3.3, 95% CI 0.8 to 5.9 mmHg). For women with previous pre-eclampsia without severe features (n = 344), there were no significant differences between calcium and placebo groups. ANOVA analysis found no statistically significant interaction between previous pre-eclampsia severity and treatment, for systolic (p = 0.372), diastolic (p = 0.063) or mean blood pressure (p = 0.103). CONCLUSIONS: Low-dose calcium supplementation significantly reduced systolic and mean arterial pressure in non-pregnant women with previous pre-eclampsia. We did not confirm a greater calcium effect in women with previous pre-eclampsia with severe versus non-severe features. The effect of low-dose calcium is of importance since even modest blood pressure reductions at a population level may have important benefits in terms of reduced major complications of hypertension. This study adds to the mounting evidence of health benefits which could be achieved for populations with low dietary calcium through strategies to increase calcium intake, particularly among women at high risk due to previous pre-eclampsia. CLINICAL TRIAL REGISTRATION: The trial was registered with the Pan-African Clinical Trials Registry, registration number PACTR201105000267371 (https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=267).

A framework for healthcare interventions to address maternal morbidity.

The maternal health agenda is undergoing a paradigm shift from preventing maternal deaths to promoting women's health and wellness. A critical focus of this trajectory includes addressing maternal morbidity and the increasing burden of chronic and noncommunicable diseases (NCD) among pregnant women. The WHO convened the Maternal Morbidity Working Group (MMWG) to improve the scientific basis for defining, measuring, and monitoring maternal morbidity. Based on the MMWG's work, we propose paradigms for conceptualizing maternal health and related interventions, and call for greater integration between maternal health and NCD programs. This integration can be synergistic, given the links between chronic conditions, morbidity in pregnancy, and long-term health. Pregnancy should be viewed as a window of opportunity into the current and future health of women, and offers critical entry points for women who may otherwise not seek or have access to care for chronic conditions. Maternal health services should move beyond the focus on emergency obstetric care, to a broader approach that encompasses preventive and early interventions, and integration with existing services. Health systems need to respond by prioritizing funding for developing integrated health programs, and workforce strengthening. The MMWG's efforts have highlighted the changing landscape of maternal health, and the need to expand the narrow focus of maternal health, moving beyond surviving to thriving.

Preventing deaths due to the hypertensive disorders of pregnancy.

In this chapter, taking a life cycle and both civil society and medically oriented approach, we will discuss the contribution of the hypertensive disorders of pregnancy (HDPs) to maternal, perinatal and newborn mortality and morbidity. Here we review various interventions and approaches to preventing deaths due to HDPs and discuss effectiveness, resource needs and long-term sustainability of the different approaches. Societal approaches, addressing sustainable development goals (SDGs) 2.2 (malnutrition), 3.7 (access to sexual and reproductive care), 3.8 (universal health coverage) and 3c (health workforce strengthening), are required to achieve SDGs 3.1 (maternal survival), 3.2 (perinatal survival) and 3.4 (reduced impact of non-communicable diseases (NCDs)). Medical solutions require greater clarity around the classification of the HDPs, increased frequency of effective antenatal visits, mandatory responses to the HDPs when encountered, prompt provision of life-saving interventions and sustained surveillance for NCD risk for women with a history of the HDPs.

An international trial of antioxidants in the prevention of preeclampsia (INTAPP).

OBJECTIVE: We sought to investigate whether prenatal vitamin C and E supplementation reduces the incidence of gestational hypertension (GH) and its adverse conditions among high- and low-risk women. STUDY DESIGN: In a multicenter randomized controlled trial, women were stratified by the risk status and assigned to daily treatment (1 g vitamin C and 400 IU vitamin E) or placebo. The primary outcome was GH and its adverse conditions. RESULTS: Of the 2647 women randomized, 2363 were included in the analysis. There was no difference in the risk of GH and its adverse conditions between groups (relative risk, 0.99; 95% confidence interval, 0.78-1.26). However, vitamins C and E increased the risk of fetal loss or perinatal death (nonprespecified) as well as preterm prelabor rupture of membranes. CONCLUSION: Vitamin C and E supplementation did not reduce the rate of preeclampsia or GH, but increased the risk of fetal loss or perinatal death and preterm prelabor rupture of membranes.

Therapy with both magnesium sulfate and nifedipine does not increase the risk of serious magnesium-related maternal side effects in women with preeclampsia.

OBJECTIVE: Does the use of nifedipine and magnesium sulfate together increase serious magnesium-related effects? STUDY DESIGN: This was a retrospective chart review of women who were admitted to BC Women's Hospital and Health Centre (1997-2001) and were given intravenous magnesium sulfate for preeclampsia. Serious magnesium-related effects were compared among 162 cases who received magnesium sulfate and contemporaneous nifedipine and 215 control subjects who received magnesium sulfate and either another antihypertensive (n=32 women) or no antihypertensive (n=183 women) medication. Chi-squared test, Fisher's exact test, or the Student t test was used for data comparison between cases and each control group. A probability value of <.05 was considered statistically significant. RESULTS: The cases had more severe preeclampsia and a longer magnesium sulfate infusion. However, cases had no excess of neuromuscular weakness (53.1%) versus control subjects who received antihypertensive medication (53.1%; P=.99) or control subjects who received no antihypertensive medication (44.8%; P=.13) or other serious magnesium-related effects. Cases versus control subjects who received antihypertensive medication had less neuromuscular blockade (odds ratio, 0.04; 95% CI, 0.002-0.80). Cases versus control subjects who received no antihypertensive medication had less maternal hypotension (41.4% vs 53.0%; P=.04). CONCLUSION: The use of nifedipine and magnesium sulfate together does not increase the risk of serious magnesium-related effects.

Nifedipine for severe hypertension in pregnancy: emotion or evidence?

A meta-analysis of randomized controlled trials suggests that nifedipine appears to be a reasonable agent for treatment of acute severe hypertension in pregnancy. However, in a 1999 survey of Canadian practitioners, most stated that they rarely or never use nifedipine capsules for treatment of acute severe pregnancy hypertension. Also, there are case reports of adverse outcomes following use of nifedipine capsules in pregnancy, although the risks appear to have been overplayed. We suggest that a reasonable approach is ongoing use of nifedipine capsules, with perhaps an initial dosage of 5 mg rather than 10 mg. Having women swallow the capsule without first biting it may also be a prudent approach, because there is insufficient information from most of the published clinical trials to say exactly how the nifedipine capsules were administered. Further, use of the 10 mg nifedipine prolonged action tablet may also be a reasonable approach for treatment of severe hypertension in pregnancy, although more data are needed. Such research would be particularly relevant given that nifedipine appears to be a promising treatment for spontaneous preterm labour. We must resist the temptation to throw out of our limited therapeutic armamentarium an effective oral preparation before adequately considering the evidence.

A survey of canadian practitioners regarding diagnosis and evaluation of the hypertensive disorders of pregnancy.

BACKGROUND: How Canadian practitioners are diagnosing and managing the hypertensive disorders of pregnancy (HDP), particularly in relation to the 1997 recommendations published by the Canadian Hypertension Society (CHS), is not known. METHODS: A survey, with French and English versions (and covering diagnosis, evaluation, and management of pregnancy hypertension), was mailed to all members of the Society of Obstetricians and Gynaecologists of Canada (SOGC) (N = 1757, including obstetricians, family doctors practicing obstetrics, and midwives). Additionally, internists [i.e., all nephrologists (N = 191) and a random sample of 25% of general internists (N = 450)] registered with the Royal College of Physicians and Surgeons of Canada were sampled. The survey was distributed in two mailings and one reminder card. Data were entered into Microsoft Access, and Graph Pad Prism used to summarize responses [N (%)]. Differences in practice between specialties were examined, with a Bonferonni correction used to calculate a significant p value based on the number of comparisons and alpha of 0.05. RESULTS: Respondents numbered 1187 (49.5%), with 466 not informative for the purpose of the study (due to retirement, or practices that do not include pregnant women with hypertension). The final analysis included 721 completed surveys. Most (609, 84.5% of) respondents take blood pressure (BP) with women in the sitting position, and use a mercury sphygmomanometer (79%) and the 5th Korotkoff (61%) sound to designate diastolic BP (dBP). To monitor pregnancies complicated by preeclampsia, most clinicians use the proposed laboratory tests of maternal well-being (usually at least once/week), fetal well-being [nonstress test (NST, at least once/week), and ultrasonographic studies (once weekly to every two weeks)]. There is general agreement that women with preeclampsia should be delivered for uncontrolled hypertension, end-organ dysfunction, or fetal compromise (nonreassuring NST, severe oligohydramnios, biophysical profile < 4, estimated fetal weight < 5th centile, and reversed end-diastolic flow by umbilical artery Doppler velocimetry). Less consensus was seen for delivery for preeclampsia at > 34 weeks, mild asymptomatic HELLP syndrome, hyperreflexia, and absent end-diastolic flow by umbilical artery Doppler velocimetry. INTERPRETATION: This survey has clarified the current state of practice with respect to the diagnosis and evaluation of women with all types of HDP. In particular, we have identified areas of potential variability in BP measurement, and provided data on the feasibility of enrolling women with sub types of preeclampsia into intervention studies aimed at prolonging pregnancy.

A survey of Canadian practitioners regarding the management of the hypertensive disorders of pregnancy.

BACKGROUND: How Canadian practitioners are managing the hypertensive disorders of pregnancy (HDP) is not known, particularly in relation to the 1997 guidelines published by the Canadian Hypertension Society (CHS). METHODS: A survey, with French and English versions (and covering diagnosis, evaluation, and management of pregnancy hypertension), was mailed to all members of the Society of Obstetricians and Gynaecologists of Canada (SOGC) (N = 1757, including obstetricians, family doctors practicing obstetrics, and midwives). Additionally, internists [i.e., all nephrologists (N = 191) and a random sample of 25% of general internists (N = 450)] registered with the Royal College of Physicians and Surgeons of Canada were sampled. The survey was distributed in two mailings and one reminder card. Data were entered into Microsoft Access, and Graph Pad Prism used to summarize responses [N (%)]. Differences in practice between specialties were examined, with a Bonferroni correction used to calculate a significant p value based on the number of comparisons and alpha of 0.05. RESULTS: Respondents numbered 1187 (49.5%), with 466 not informative for the purpose of the study (due to retirement, or practices that do not include pregnant women with hypertension). The final analysis included 721 completed surveys. For all types of HDP, most internists, family doctors, and midwives initiate nonpharmacological therapy (most common advice to quit work) at dBP 80-89 mmHg (i.e., primary prevention). Only for preeclampsia do obstetricians most frequently use this threshold; otherwise, dBP 90-99 mmHg is usually chosen. For nonsevere hypertension, antihypertensive drug therapy (most commonly methyldopa or labetalol) is started by most practitioners at dBP 90-99 mmHg, although obstetricians are more likely to choose a higher threshold (p < 0.0001). There is little agreement about dBP treatment goal; most internists and family doctors normalize dBP, whereas obstetricians appear to be divided on dBP goals of 80-89 (46-51%) vs. 90-99 mmHg (41-44%) for all HDP (p = 0.66). Severe hypertension is commonly treated with parenteral hydralazine, labetalol, or magnesium sulphate. Short-acting or sustained release nifedipine is used rarely/never by most practitioners. Approximately one-third of obstetricians and family doctors use diazepam to treat eclampsia. The vast majority use MgSO4 prophylactically in women with preeclampsia. INTERPRETATION: This survey has clarified current stated management of women with HDP, and identified the need for both research into the dBP treatment goal that optimizes pregnancy outcomes among women with HDP, and translation of definitive studies into clinical practice.