Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems.

BACKGROUND: Pre-eclampsia and eclampsia are common causes of serious morbidity and death. Calcium supplementation may reduce the risk of pre-eclampsia, and may help to prevent preterm birth. This is an update of a review last published in 2014. OBJECTIVES: To assess the effects of calcium supplementation during pregnancy on hypertensive disorders of pregnancy and related maternal and child outcomes. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (18 September 2017), and reference lists of retrieved studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs), including cluster-randomised trials, comparing high-dose calcium supplementation (at least 1 g daily of calcium) during pregnancy with placebo. For low-dose calcium we included quasi-randomised trials, trials without placebo, trials with cointerventions and dose comparison trials. DATA COLLECTION AND ANALYSIS: Two researchers independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. Two researchers assessed the evidence using the GRADE approach. MAIN RESULTS: We included 27 studies (18,064 women). We assessed the included studies as being at low risk of bias, although bias was frequently difficult to assess due to poor reporting and inadequate information on methods.High-dose calcium supplementation (≥ 1 g/day) versus placeboFourteen studies examined this comparison, however one study contributed no data. The 13 studies contributed data from 15,730 women to our meta-analyses. The average risk of high blood pressure (BP) was reduced with calcium supplementation compared with placebo (12 trials, 15,470 women: risk ratio (RR) 0.65, 95% confidence interval (CI) 0.53 to 0.81; I² = 74%). There was also a reduction in the risk of pre-eclampsia associated with calcium supplementation (13 trials, 15,730 women: average RR 0.45, 95% CI 0.31 to 0.65; I² = 70%; low-quality evidence). This effect was clear for women with low calcium diets (eight trials, 10,678 women: average RR 0.36, 95% CI 0.20 to 0.65; I² = 76%) but not those with adequate calcium diets. The effect appeared to be greater for women at higher risk of pre-eclampsia, though this may be due to small-study effects (five trials, 587 women: average RR 0.22, 95% CI 0.12 to 0.42). These data should be interpreted with caution because of the possibility of small-study effects or publication bias. In the largest trial, the reduction in pre-eclampsia was modest (8%) and the CI included the possibility of no effect.The composite outcome maternal death or serious morbidity was reduced with calcium supplementation (four trials, 9732 women; RR 0.80, 95% CI 0.66 to 0.98). Maternal deaths were no different (one trial of 8312 women: one death in the calcium group versus six in the placebo group). There was an anomalous increase in the risk of HELLP syndrome in the calcium group (two trials, 12,901 women: RR 2.67, 95% CI 1.05 to 6.82, high-quality evidence), however, the absolute number of events was low (16 versus six).The average risk of preterm birth was reduced in the calcium supplementation group (11 trials, 15,275 women: RR 0.76, 95% CI 0.60 to 0.97; I² = 60%; low-quality evidence); this reduction was greatest amongst women at higher risk of developing pre-eclampsia (four trials, 568 women: average RR 0.45, 95% CI 0.24 to 0.83; I² = 60%). Again, these data should be interpreted with caution because of the possibility of small-study effects or publication bias. There was no clear effect on admission to neonatal intensive care. There was also no clear effect on the risk of stillbirth or infant death before discharge from hospital (11 trials, 15,665 babies: RR 0.90, 95% CI 0.74 to 1.09).One study showed a reduction in childhood systolic BP greater than 95th percentile among children exposed to calcium supplementation in utero (514 children: RR 0.59, 95% CI 0.39 to 0.91). In a subset of these children, dental caries at 12 years old was also reduced (195 children, RR 0.73, 95% CI 0.62 to 0.87).Low-dose calcium supplementation (< 1 g/day) versus placebo or no treatmentTwelve trials (2334 women) evaluated low-dose (usually 500 mg daily) supplementation with calcium alone (four trials) or in association with vitamin D (five trials), linoleic acid (two trials), or antioxidants (one trial). Most studies recruited women at high risk for pre-eclampsia, and were at high risk of bias, thus the results should be interpreted with caution. Supplementation with low doses of calcium reduced the risk of pre-eclampsia (nine trials, 2234 women: RR 0.38, 95% CI 0.28 to 0.52). There was also a reduction in high BP (five trials, 665 women: RR 0.53, 95% CI 0.38 to 0.74), admission to neonatal intensive care unit (one trial, 422 women, RR 0.44, 95% CI 0.20 to 0.99), but not preterm birth (six trials, 1290 women, average RR 0.83, 95% CI 0.34 to 2.03), or stillbirth or death before discharge (five trials, 1025 babies, RR 0.48, 95% CI 0.14 to 1.67).High-dose (=/> 1 g) versus low-dose (< 1 g) calcium supplementationWe included one trial with 262 women, the results of which should be interpreted with caution due to unclear risk of bias. Risk of pre-eclampsia appeared to be reduced in the high-dose group (RR 0.42, 95% CI 0.18 to 0.96). No other differences were found (preterm birth: RR 0.31, 95% CI 0.09 to 1.08; eclampsia: RR 0.32, 95% CI 0.07 to 1.53; stillbirth: RR 0.48, 95% CI 0.13 to 1.83). AUTHORS' CONCLUSIONS: High-dose calcium supplementation (≥ 1 g/day) may reduce the risk of pre-eclampsia and preterm birth, particularly for women with low calcium diets (low-quality evidence). The treatment effect may be overestimated due to small-study effects or publication bias. It reduces the occurrence of the composite outcome 'maternal death or serious morbidity', but not stillbirth or neonatal high care admission. There was an increased risk of HELLP syndrome with calcium supplementation, which was small in absolute numbers.The limited evidence on low-dose calcium supplementation suggests a reduction in pre-eclampsia, hypertension and admission to neonatal high care, but needs to be confirmed by larger, high-quality trials.

Comparison of clinical outcomes in peripartum cardiomyopathy and age-matched dilated cardiomyopathy: A 15-year nationwide population-based study in Asia.

Peripartum cardiomyopathy (PPCM), often classified as a form of dilated cardiomyopathy (DCM), is the myocardial dysfunction that occurs in late pregnancy and through the first few postpartum months.The aim of this study is to investigate the differences in the clinical outcomes of PPCM and DCM.Electronic medical records from 1997 to 2011 were retrieved from the Taiwan National Health Insurance Research Database. Patients with PPCM were compared with age- and clinical characteristics-matched patients with DCM. Primary outcomes were 1- and 3-year heart failure (HF) readmission, cardiac death, all-cause mortality, and major adverse cardiovascular events. Secondary outcomes were myocardial infarction, new onset of dialysis, heart transplant, and cerebrovascular accident. Follow-up period was divided into "within the first year" and "after the first year."A total of 527,979 patients (253,166 females) were hospitalized with a principal diagnosis of HF during 1997 to 2011 period. After excluding patients aged <18 and >50 years, patients with other forms of HF, and those with a history of cerebrovascular accidents or coronary artery disease, 797 patients with PPCM and 1267 patients with DCM were evaluated. Propensity score matching yielded 391 patients in each group. Patients with DCM had a significantly worse prognosis compared to those with PPCM for all primary and secondary outcomes at the 1- and 3-year follow-ups. After 1 year, the HF readmission rate did not significantly differ between the 2 diseases, suggesting that HF medications should be aggressively instituted in patients with PPCM.This is the first study to directly compare the clinical outcomes between age-matched patients with PPCM and DCM. Patients with PPCM had a significantly better prognosis across all cardiovascular endpoints compared to patients with DCM.

Burden of arrhythmias in peripartum cardiomyopathy: Analysis of 9841 hospitalizations.

BACKGROUND: Peripartum cardiomyopathy (PPCM) is associated with significant morbidity and mortality. Arrhythmogenic causes of death have been implicated in a significant number of patients. However, there is a dearth of systematic studies evaluating the burden of arrhythmias in PPCM. METHODS: We used the Healthcare Utilization Project, Nationwide Inpatient Sample database (2007-2012) and identified 9841 hospitalizations for women aged ≥18years with a primary diagnosis of PPCM. Frequency of arrhythmias, utilization of electrophysiologic procedures, length of stay, hospitalization costs and outcomes associated with arrhythmias were determined. RESULTS: Mean age was 30.05±6.69years. Arrhythmias were present in 18.7% of hospitalized PPCM cohort. Ventricular tachycardia was the most common arrhythmia and was noted in 4.2%. Approximately 2.2% of cases experienced cardiac arrest. Electrical cardioversion was performed in 0.3%, Catheter ablation in 1.9%, PPM implantation in 3.4% and ICD in 6.8% of hospitalizations for PPCM with arrhythmias. In-hospital mortality was 3-times more frequent in arrhythmia cohort (2.1% vs. 0.7%). Hospitalization costs were significantly higher in PPCM with arrhythmias. Elixhauser comorbidity score (adjusted OR:1.10; 95%CI:1.02-1.18; p=0.016), in-hospital mortality (adjusted OR:2.35; 95%CI:1.38-4.02; p=0.002), cardiogenic shock (adjusted OR:2.61; 95%CI:1.44-4.72; p=0.002), utilization of balloon pump (adjusted OR:13.4; 95%CI: 2.55-70.53; p<0.001), Swan-Ganz catheterization (adjusted OR:3.12; 95%CI:1.21-8.06; p=0.019), and coronary angiography (adjusted OR:1.79; 95%CI:1.19-2.70; p=0.005) were significantly associated with arrhythmias in PPCM. CONCLUSIONS: Arrhythmias were present in 18.7% of PPCM related hospitalizations. Morbidity, in-hospital mortality, length of inpatient stay, hospitalization costs and cardiac procedure utilization were significantly higher in the arrhythmia cohort.

Congenital Heart Disease and Reproductive Risk: An Overview for Obstetricians, Cardiologists, and Primary Care Providers.

Patients with congenital heart disease have improved survival rates, and most patients are now expected to survive into adulthood. This improved survival has resulted in increasing numbers of women with congenital heart disease who are of childbearing age. This patient population requires specialized advice on contraception and pregnancy risk. Understanding the unique challenges this population presents is key to providing appropriate care.

Maternal hypotension during fetoscopic surgery: incidence and its impact on fetal survival outcomes.

In this retrospective cohort study, we aimed to determine the incidence of intraoperative maternal hypotension during fetoscopic surgery for twin-twin transfusion syndrome (TTTS) and to evaluate the impact of intraoperative hypotension on fetal survival. A total of 328 TTTS patients with recipient twin cardiomyopathy who underwent fetoscopic surgery under epidural anesthesia were included. The exposure of interest was maternal medical therapy with nifedipine for the treatment of fetal cardiomyopathy. We found that intraoperative hypotension occurred in 53.4% (175/328 patients). There was no statistically significant difference in incidence of hypotension between nifedipine exposure and nonexposure groups (54.8% versus 50.8%, P = 0.479). However, the nifedipine exposure group received a statistically significant higher dose of phenylephrine (7.04 ± 6.38 mcg/kg versus 4.70 ± 4.14 mcg/kg, P = 0.018) and higher doses of other vasopressor, as counted by number of treatments (6.06 ± 4.58 versus 4.96 ± 3.42, P = 0.022). There were no statistically significant differences in acute fetal survival rate (within 5 days) and fetal survival rate at birth between hypotensive and nonhypotensive patients. We concluded that preoperative exposure to nifedipine resulted in increased intraoperative maternal vasopressor requirement during fetoscopic surgery under epidural anesthesia. In patients who had intraoperative maternal hypotension, there was no correlation between the presence of maternal hypotension and postoperative fetal survival.

Hypertensive emergencies of pregnancy.

Hypertension is commonly encountered in pregnancy and has both maternal and fetal effects. Acute hypertensive crisis most commonly occurs in severe preeclampsia and is associated with maternal stroke, cardiopulmonary decompensation, fetal decompensation due to decreased uterine perfusion, abruption, and stillbirth. Immediate stabilization of the mother including the use of intervenous antihypertensives is required and often delivery is indicated. With appropriate management, maternal and fetal outcomes can be excellent.

Quantifying the fall in mortality associated with interventions related to hypertensive diseases of pregnancy.

BACKGROUND: In this paper we review the evidence of the effect of health interventions on mortality reduction from hypertensive diseases in pregnancy (HDP). We chose HDP because they represent a major cause of death in low income countries and evidence of effect on maternal mortality from randomised studies is available for some interventions. METHODS: We used four approaches to review the evidence of the effect of interventions to prevent or treat HDP on mortality reduction from HDP. We first reviewed the Cochrane Library to identify systematic reviews and individual trials of the efficacy of single interventions for the prevention or treatment of HDP. We then searched the literature for articles quantifying the impact of maternal health interventions on the reduction of maternal mortality at the population level and describe the approaches used by various authors for interventions related to HDP. Third, we examined levels of HDP-specific mortality over time or between regions in an attempt to quantify the actual or potential reduction in mortality from HDP in these regions or over time. Lastly, we compared case fatality rates in women with HDP-related severe acute maternal morbidity with those reported historically in high income countries before any effective treatment was available. RESULTS: The Cochrane review identified 5 effective interventions: routine calcium supplementation in pregnancy, antiplatelet agents during pregnancy in women at risk of pre-eclampsia, Magnesium sulphate (MgS04) for the treatment of eclampsia, MgS04 for the treatment of pre-eclampsia, and hypertensive drugs for the treatment of mild to moderate hypertension in pregnancy.We found 10 studies quantifying the effect of maternal health interventions on reducing maternal mortality from HDP, but the heterogeneity in the methods make it difficult to draw uniform conclusions for effectiveness of interventions at various levels of the health system. Most authors include a health systems dimension aimed at separating interventions that can be delivered at the primary or health centre level from those that require hospital treatment, but definitions are rarely provided and there is no consistency in the types of interventions that are deemed effective at the various levels.The low levels of HDP related mortality in rural China and Sri Lanka suggest that reductions of 85% or more are within reach, provided that most women give birth with a health professional who can refer them to higher levels of care when necessary. Results from studies of severe acute maternal morbidity in Indonesia and Bolivia also suggest that mortality in women with severe pre-eclampsia or eclampsia in hospital can be reduced by more than 84%, even when the women arrive late. CONCLUSIONS: The increasing emphasis on the rating of the quality of evidence has led to greater reliance on evidence from randomised controlled trials to estimate the effect of interventions. Yet evidence from randomised studies is often not available, the effects observed on morbidity may not translate in to mortality, and the distinction between efficacy and effectiveness may be difficult to make. We suggest that more use should be made of observational evidence, particularly since such data represent the actual effectiveness of packages of interventions in various settings.

Hypotensive resuscitation combined with polydatin improve microcirculation and survival in a rabbit model of uncontrolled hemorrhagic shock in pregnancy.

BACKGROUND: Obstetric hemorrhage remains a leading cause of maternal death internationally. Polydatin is an effective drug in ameliorating microcirculatory insufficiency and increasing survival rate in non-pregnant animal model of controlled hemorrhagic shock. In the present study, we investigated the effects of hypotensive resuscitation combined with Polydatin administration on microcirculation and survival rate in a clinically relevant model of uncontrolled hemorrhagic shock in pregnancy. MATERIALS AND METHODS: Twenty anesthetized New Zealand white rabbits at mid and late gestation were anesthetized, and an ear chamber was prepared to examine microvessels by intravital microscopy. Shock was induced by transecting a small artery in mesometrium, followed by blood withdrawal via the femoral artery to a mean arterial pressure (MAP) of 40-45 mm Hg. Animals were randomly divided into two groups (n=10 per group): 30 min after hemorrhage induction, hypotensive resuscitation with Ringer's solution to MAP of 60 mm Hg, followed by a single volume infusion of 4 mL/Kg of normal saline or Polydatin at 60 min after hemorrhage induction (group NS, PD). Finally all the animals received hemorrhage control and resuscitated with half of the heparinized shed blood and Ringer's solution to MAP of 80 mm Hg. RESULTS: At the end of resuscitation, compared with group NS, group PD showed significantly improved capillary perfusion as indicated by increased arteriole diameter [0.95±0.02 of baseline (PD), 0.71±0.05 of baseline (NS); P=0.000] and higher functional capillary density[95.3% ± 2.6% (PD), 57.2% ± 4.1% (NS); P=0.000]. Median survival time was significantly longer in group PD than that in group NS [4 d (PD), 2 d (NS); P=0.000]. CONCLUSIONS: On the basis of hypotensive resuscitation, Polydatin administration improved microcirculation and prolonged survival time in pregnant rabbit model of uncontrolled hemorrhagic shock.

Anticoagulant management of pregnancy following heart valve replacement in the United Kingdom, 1986-2002.

BACKGROUND AND AIM OF THE STUDY: Patients with mechanical heart valves require anticoagulation which is associated with significant maternal mortality (1-4%) and fetal complications (31%) in pregnancy. The study aim was to identify anticoagulant protocols and outcomes for pregnant women undergoing heart valve replacement (HVR) in the United Kingdom. METHODS: Women aged between 18 and 45 years and registered with the United Kingdom Heart Valve Registry (UKHVR) each completed a questionnaire, and their obstetric notes were reviewed. The data analyzed included valve type (mechanical, bioprosthetic, homograft), valve site (mitral, aortic, tricuspid, pulmonary), anticoagulation at confirmation of pregnancy, between 6-12 weeks and from 12 weeks to term, delivery, maternal and fetal outcomes, and cause of death. The summary statistics and a descriptive review of the findings are reported. RESULTS: Of 2,532 women eligible for the study, 922 responded. Among these women, 72 became pregnant, with 60 pregnancies in the mechanical valve (MV) group and 45 in the tissue valve (TV) group. Three anticoagulation regimes were used during early pregnancy: unfractionated heparin (UFH), low-molecular-weight heparin (LMWH) or warfarin. All women received warfarin in the second trimester and heparin for delivery. Live births were recorded in 30% of MV pregnancies and in 60% of TV pregnancies. Miscarriage rates differed markedly (37% MV versus 2% TV). Fetal outcome was poorest in the warfarin-only group, with embryopathy occurring at a dose level of 6 mg. The maternal outcomes did not differ significantly among groups. High-dose heparin during the first trimester and for delivery was effective for the majority of mechanical valves. CONCLUSION: The study results illustrate the diverse and uncertain manner in which UKHVR patients are managed during pregnancy. A national notification system would record much-needed prospective information on anticoagulation and pregnancy outcomes, thus aiding evidence-based management.

Calcium supplementation prevents pregnancy-induced hypertension by increasing the production of vascular nitric oxide.

Pregnancy-induced hypertension (PIH) remains a common cause of maternal and fetal morbidity and mortality. During the past 7 years, some progress has been made in the prevention of PIH. Specifically, clinical studies have shown that supplementation with calcium can significantly reduce the frequency of PIH, specially in populations with a low calcium intake. We have suggested that, in such a population, calcium supplementation is a safe and effective measure for reducing the frequency of PIH. Thus, the purpose of this article is to advance a hypothesis about the mechanism by which calcium supplementation reduces the risk of PIH. We propose that dietary calcium supplementation reduces the frequency of PIH by maintaining the serum ionized calcium level which is crucial for the production of endothelial nitric oxide, the increased generation of which maintains the vasodilatation that is characteristic of normal pregnancy.