Association between calcium supplementation and gestational hypertension, and preeclampsia: A Meta-analysis of 26 randomized controlled trials.

BACKGROUND: Pre-eclampsia and eclampsia are common causes of morbidity and mortality, especially in low-income countries. Reducing adverse outcomes associated with hypertensive disorders of pregnancy has been the ultimate priority in recent years. We aim to evaluate the association between calcium supplementation and preeclampsia and gestational hypertension risk among pregnant women. METHODS: A systematic literature search was performed in electronic databases from inception to 15th July 2023, including only randomized controlled trials. Odds ratio (OR) were, and their corresponding 95% confidence interval (95% CI). RESULTS: A total of 26 studies with 20,038 patients (10,003 patients with calcium supplements and 10,035 patients with placebo group) were included in the analysis. The Pooled analysis of primary outcome shows that calcium supplements reduce the risk of preeclampsia by 49% (OR, 0.51(95%CI: 0.40-0.66), P<0.001), and reduce the risk of gestational hypertension by 30% (OR, 0.70 (95%CI: 0.58-0.85)), P<0.001) compared to placebo. There was a trend of lower incidence of preterm delivery (OR, 0.88 (95%CI: 0.71-1.09), P=0.23), labor induction (OR, 0.90 (95%CI: 0.78-1.03), P=0.13), small for gestational age (OR, 0.70 (95% CI:0.37-1.32), P = 0.27), low birth weight (OR, 0.96 (95%CI: 0.86-1.08), P=0.53), perinatal mortality (OR, 0.88 (95%CI: 0.72-1.09), P=0.24), and maternal mortality (OR, 0.48 (95%CI: 0.12-1.84), P=0.28) among calcium supplementation group compared with the placebo group, however, statistical signifance was not achieved. CONCLUSION: This study shows that calcium supplements are associated with a significant reduction in the risk of preeclampsia and gestational hypertension and a trend toward better maternal and fetal-related outcomes.

Clinical efficacy of low-dose aspirin combined with calcium in preventing preeclampsia: A systematic review and meta-analysis.

OBJECTIVE: This systematic review and meta-analysis aimed to evaluate the clinical effectiveness of low-dose aspirin combined with calcium supplements for the prevention of preeclampsia. METHODS: China National Knowledge Infrastructure, VIP, Wanfang, PubMed, EMBASE, and Cochrane Library databases were searched from inception until December 2022. Randomized controlled trials investigating the preventive use of aspirin in combination with calcium supplementation for preeclampsia in high-risk pregnant women were included. The quality of the literature was evaluated, and a meta-analysis was conducted using RevMan 5.3 software to analyze the clinical efficacy of low-dose aspirin combined with calcium supplementation in preventing preeclampsia. RESULTS: Seven randomized controlled trials were included in this meta-analysis, and compared with the control group, the experimental group had lower incidence rates of preeclampsia with gestational hypertension (odds ratios [OR]: 0.17, 95% confidence interval [CI]: 0.11-0.28), preeclampsia (OR: 0.20, 95% CI: 0.10-0.37), gestational hypertension (OR: 0.15, 95% CI: 0.07-0.31), preterm birth (OR: 0.26, 95% CI: 0.16-0.44), postpartum hemorrhage (OR: 0.15, 95% CI: 0.08-0.27), and fetal growth restriction (OR: 0.16, 95% CI: 0.08-0.33). CONCLUSION: Compared with aspirin alone, low-dose aspirin combined with calcium supplementation was more effective in preventing preeclampsia, reduced the risk of preterm birth and postpartum hemorrhage, and promoted fetal growth. This intervention has clinical value and should be considered for high-risk pregnant women.

Calcium supplementation for the prevention of hypertensive disorders of pregnancy: current evidence and programmatic considerations.

Most low- and middle-income countries present suboptimal intakes of calcium during pregnancy and high rates of mortality due to maternal hypertensive disorders. Calcium supplementation during pregnancy is known to reduce the risk of these disorders and associated complications, including preeclampsia, maternal morbidity, and preterm birth, and is, therefore, a recommended intervention for pregnant women in populations with low dietary calcium intake (e.g., where ≥25% of individuals in the population have intakes less than 800 mg calcium/day). However, this intervention is not widely implemented in part due to cost and logistical issues related to the large dose and burdensome dosing schedule (three to four 500-mg doses/day). WHO recommends 1.5-2 g/day but limited evidence suggests that less than 1 g/day may be sufficient and ongoing trials with low-dose calcium supplementation (500 mg/day) may point a path toward simplifying supplementation regimens. Calcium carbonate is likely to be the most cost-effective choice, and it is not necessary to counsel women to take calcium supplements separately from iron-containing supplements. In populations at highest risk for preeclampsia, a combination of calcium supplementation and food-based approaches, such as food fortification with calcium, may be required to improve calcium intakes before pregnancy and in early gestation.

Maternal mortality reduction: a need to focus actions on the prevention of hypertensive disorders of pregnancy.

Maternal mortality (MM) reflects one of the most striking global health inequalities. Global figures of MM fell significantly from 1990 to 2017. The reduction was largely due to a 70% fall in haemorrhages, and a limited (18.2%) improvement in hypertensive disorders of pregnancy (HDP). If this trend continues, by 2021 HDP will be the main cause of global MM.MM reductions due to haemorrhage is reassuring, however MM due to HDP show a more complex situation as early detection of HDP requires regular contact of pregnant women with the health system. In order to reduce MM due to HDP, population wide preventive actions such as low dose aspirin and adequate calcium intake are required, especially in areas where women have little contact with the health systems.Calcium supplementation for women with low calcium intake has reduced the risk of pre-eclampsia, with further reductions starting daily supplementation with 500 mg of calcium preconceptionally, however adherence to supplementation is limited.To reduce global inequities in calcium intake and consequently in the HDP, food fortification seem to be an attractive strategy to achieve an increase of calcium intake.

Effects of prenatal micronutrients supplementation timing on pregnancy-induced hypertension: Secondary analysis of a double-blind randomized controlled trial.

In this secondary analysis of data from a double-blind randomized controlled trial (clinicaltrials.gov identifier: NCT00133744) of micronutrient supplementation (multiple micronutrients [MMN], iron-folic acid [IFA] and folic acid [FA] alone), we examined the potential modifying effect of gestational age at enrolment on the association of antenatal supplementation and pregnancy-induced hypertension (PIH). We included 18,775 nulliparous pregnant women with mild or no anaemia who were enrolled at 20 weeks of gestation or earlier from five counties of northern China. Women were randomly assigned to receive daily FA, IFA or MMN from enrolment until delivery. We used logistic regression to evaluate the association between PIH and timing of micronutrient supplementation. The incidence of PIH was statistically significantly lower among women who began MMN supplementation before 12 gestational weeks compared with women who began MMN supplementation at 12 weeks or later (RR = 0.74, 95% CI: 0.60-0.91). A similar protective effect was observed for both early-onset (<28 weeks, RR 0.45, 0.21-0.96) and late-onset of PIH (≥28 weeks, RR 0.77, 0.63-0.96). No statistically significant association was observed between PIH occurrence and timing of supplementation for FA or IFA. Maternal MMN supplementation and antenatal enrolment during the first trimester of pregnancy appeared to be of importance in preventing both early- and late-onset of PIH.

Design of the Pregnancy REmote MOnitoring II study (PREMOM II): a multicenter, randomized controlled trial of remote monitoring for gestational hypertensive disorders.

BACKGROUND: Observational data from the retrospective, non-randomized Pregnancy REmote MOnitoring I (PREMOM I) study showed that remote monitoring (RM) may be beneficial for prenatal observation of women at risk for gestational hypertensive disorders (GHD) in terms of clinical outcomes, health economics, and stakeholder perceptions. PREMOM II is a prospective, randomized, multicenter follow-up study that was performed to explore these promising results. METHODS: After providing written consent, 3922 pregnant women aged ≥18 years who are at increased risk of developing GHD will be randomized (1:1:1 ratio) to (a) conventional care (control group), (b) a patient self-monitoring group, and (c) a midwife-assisted RM group. The women in each group will be further divided (1:1 ratio) to evaluate the outcomes of targeted or non-targeted (conventional) antihypertensive medication. Women will be recruited in five hospitals in Flanders, Belgium: Ziekenhuis Oost-Limburg, Universitaire Ziekenhuis Antwerpen, Universitaire Ziekenhuis Leuven, AZ Sint Jan Brugge-Oostende, and AZ Sint Lucas Brugge. The primary outcomes are: (1) numbers and types of prenatal visits; (2) maternal outcomes; (3) neonatal outcomes; (4) the applicability and performance of RM; and (5) compliance with RM and self-monitoring. The secondary outcomes are: (1) cost-effectiveness and willingness to pay; (2) patient-reported outcome measures (PROMS) questionnaires on the experiences of the participants; and (3) the maternal and perinatal outcomes according to the type of antihypertensive medication. Demographic, and maternal and neonatal outcomes are collected from the patients' electronic records. Blood pressure and compliance rate will be obtained from an online digital coordination platform for remote data handling. Information about the healthcare-related costs will be obtained from the National Coordination Committee of Belgian Health Insurance Companies (Intermutualistisch Agentschap). PROMS will be assessed using validated questionnaires. DISCUSSION: To our knowledge, this is the first randomized trial comparing midwife-assisted RM and self-monitoring of prenatal blood pressure versus conventional management among women at increased risk of GHD. Positive results of this study may lead to a practical framework for caregivers, hospital management, and payers to introduce RM into the prenatal care programs of high-risk pregnancies. TRIAL REGISTRATION: This study was registered on clinicaltrials.gov , identification number NCT04031430. Registered 24 July 2019, https://clinicaltrials.gov/ct2/show/NCT04031430?cond=premom+ii&draw=2&rank=1 .

Açaí (Euterpe oleracea Mart) seed extract protects against maternal vascular dysfunction, hypertension, and fetal growth restriction in experimental preeclampsia.

Objective: To investigate whether Euterpe oleracea Mart. (açaí) seed extract (ASE) prevents maternal cardiovascular changes and intrauterine growth restriction (IUGR) in experimental preeclampsia (PE).Methods: ASE administration (200 mg/kg/day) during mid to late pregnancy in a rat model of L-NAME-induced PE.Results: ASE impaired the maternal hypertension and microalbuminuria as well as the lower fetal and placental weight in experimental PE. ASE also prevented the maternal vascular dysfunction and lipoperoxidation in this model.Conclusion: ASE protected against maternal cardiovascular changes and IUGR in the L-NAME-induced PE. The protective effect of ASE may be partly explained by its antioxidant property.

Nutraceuticals and Hypertensive Disorders in Pregnancy: The Available Clinical Evidence.

The aim of the present critical review is to summarize the available clinical evidence supporting the use of some dietary supplements that have been shown to lower blood pressure in hypertensive pregnant women. A systematic search strategy was carried out to identify trials in MEDLINE (National Library of Medicine, Bethesda, Maryland, MD, USA; January 1980 to September 2019) and the Cochrane Register of Controlled Trials (The Cochrane Collaboration, Oxford, UK). The terms 'nutraceuticals', 'dietary supplements', 'pregnancy', 'pre-eclampsia', 'clinical trial', and 'human' were incorporated into an electronic search strategy. The references of the identified studies and review articles were reviewed to look for additional studies of interest. We preferably selected papers that reported recent comprehensive reviews or meta-analysis, or original clinical trials of substances with blood pressure-lowering or vascular protective effect in pregnancy. There is a relative body of evidence that supports the use of calcium, vitamin D, folic acid, and resveratrol in preventing the development of hypertensive disorders in pregnancy, and evidence supporting drug treatment too. Further clinical research is advisable to identify the dosage and timing of the supplementation, the group of women that might benefit the most from this approach, and the nutraceuticals with the best cost-effectiveness and risk-benefit ratio for widespread use in clinical practice.

Efficacy of n-3 fatty acids supplementation on the prevention of pregnancy induced-hypertension or preeclampsia: A systematic review and meta-analysis.

The efficacy of n-3 fatty acids supplementation on the prevention of pregnancy-induced hypertension or preeclampsia remains unclear. The aim of study was to examine the effect of supplementation with EPA, and/or DHA, and/or ALA during pregnancy on the pregnancy-induced hypertension or preeclampsia. A systematic search was performed on Scopus, PubMed, Web of Science (WoS), Cochrane Library, and Google scholar, which covered the period between 1991 and 2018. The clinical trials with any control groups (i.e. placebo or other supplementation) were selected. The whole process of meta-analysis and data analysis was done using Comprehensive Meta-Analysis (Version 2.0, Biostat). The searched keywords were: "Fatty Acids, Omega-3", "n-3 Polyunsaturated Fatty Acid" "Eicosapentaenoic Acid", "Docosahexaenoic Acids", "n-3 Polyunsaturated Fatty Acid", "n-3 PUFAs", "alpha-Linolenic Acid", "fish oil", "Nuts", "nutrient", or their synonyms "pregnancy induced hypertension" and preeclampsia. In addition, some key journals, according to Scopus report and the references of the original and review articles, were manually searched for possible related studies. The meta-analysis of the 14 comparisons demonstrated that n-3 fatty acids supplementation played a protective role against the risk of preeclampsia (RR, 0.82; 95% CI, 0.70-0.97; p = 0.024; I2 = 19.0%). The analysis of the 10 comparisons revealed that n-3 fatty acid supplements for pregnant women did not mitigate the risk of pregnancy-induced hypertension (RR, 0.98; 95% CI, 0.90-1.07; p = 0.652; I2 = 0%). The n-3 fatty acid supplements are an effective strategy to prevent the incidence of preeclampsia in women with low-risk pregnancies.

The effect of folic acid throughout pregnancy among pregnant women at high risk of pre-eclampsia: A randomized clinical trial.

BACKGROUND: Pre-eclampsia is a serious hypertension disease that occurs during pregnancy. Folic acid (FA) supplementation has been reported to reduce pre-eclampsia risk in pregnant women. Here, we aimed to assess whether treatment of high doses of FA in pregnant women with high pre-eclampsia risk could prevent the onset of pre-eclampsia. METHODS: We conducted a randomized clinical trial in 1576 women who had pre-eclampsia or eclampsia in their last pregnancy and had a pregnancy plan. Subjects were randomized into two groups. The low dose (LD) group (n = 788) received 0.4 mg of FA daily from the first 3 months of pregnancy until the entire pregnancy, and the high dose (HD) group (n = 788) received 4 mg of FA per day. We followed up the subjects until production. RESULTS: The plasma homocysteine (homocysteine) and FA levels were significantly higher in the HD group that in the LD group. Severe gestational hypertension, early onset pre-eclampsia (<32 weeks' gestation), severe pre-eclampsia, and newborns' Apgar score <7 at 5 min were remarkably decreased in the HD group compared with the LD group. Further, the incidence of pre-eclampsia was reduced in the HD group with compliance >50%. CONCLUSION: This study has provided evidence that a high dosage of FA supplement from 3 months before pregnancy until the entire pregnancy reduces the recurrent pre-eclampsia.

Can Women's Lives be saved from Hypertensive Disorders during Pregnancy? Experiences of South African Midwives.

A qualitative, descriptive phenomenological research design was conducted to explore and describe the experiences of midwives on the management of women diagnosed with hypertensive disorders during pregnancy in rural areas of Limpopo Province, South Africa. Non-probability sampling was used to select eighteen (18) midwives from primary health care facilities of Mopani and Vhembe districts in Limpopo Province. Data was collected through in-depth interview and analysed using eight steps of Tesch's open coding method. Ethical considerations were adhered to by ensuring confidentiality, anonymity, privacy and signing of informed consent by participants. Measures to ensure trustworthiness; credibility, transferability, dependability and lastly, confirmability were ensured. Findings of this study revealed three themes (with sub-themes) namely; management of pregnant women diagnosed with hypertensive disorders, support experienced when managing complications, challenges experienced by midwives when managing hypertensive disorders during pregnancy. In conclusion, poor support came up very strongly as a factor influencing good management of hypertensive disorders in pregnancy. Recruitment of more midwives that will support each other during management of pregnant women with hypertensive disorders is recommended.

Risk factors and potential protective factors of pregnancy-induced hypertension in China: A cross-sectional study.

A cross-sectional study was conducted to the reported factors and assesses possible protective factors for pregnancy-induced hypertension (PIH) in China. The data of pregnant women who delivered between October 2016 and September 2017 were collected from a birth registry. The primary outcome was the occurrence of PIH. Secondary outcomes were delivery before 34 gestational weeks and other adverse obstetric outcomes of PIH. Among the 99 535 women enrolled, 5731 women (5.8%) developed PIH. BMI had a positive correlation with the primary and two secondary outcomes (adjusted OR = 2.05, 2.56, 1.87, respectively, for overweight; adjusted OR = 4.44, 3.90, and 2.63, respectively, for obesity). Otherwise, calcium supplementation during pregnancy was a potential protective factor for those outcomes (adjusted OR = 0.87, 0.14, and 0.44, respectively). These results provide a basis for PIH prevention strategy in the Chinese public health sector. Calcium supplementation and lowering the BMI might have the potential benefit on reducing the prevalence of PIH in selected women.

Supplementation of folic acid in pregnancy and the risk of preeclampsia and gestational hypertension: a meta-analysis.

OBJECTIVES: We aimed to systematically assess the relationship between folic acid supplementation in pregnancy and risk of preeclampsia and gestational hypertension. METHODS: The relevant studies were included by retrieving the Embase, PubMed and Cochrane library databases. Data extraction was conducted by two investigators independently. The risk ratio (RR) and 95% confidence interval (CI) were used as effect indexes to evaluate the relationship between folic acid supplementation and risk of gestational hypertension or preeclampsia. A subgroup analysis was performed according to the supplementation patterns of folic acid. The homogeneity of the effect size was tested across the studies, and publication biases were examined. RESULTS: In total, 13 cohort studies and 1 randomized controlled trial study was included, containing 160,562 and 149,320 women with and without folic acid supplementation during pregnancy. Pooled results showed that risk of gestational hypertension was not associated with the supplementation of folic acid. However, folic acid supplementation during pregnancy could significantly reduce the risk of preeclampsia. Moreover, the results of subgroup analysis showed that the decreased preeclampsia risk was associated with supplementation of multivitamins containing folic acid rather than folic acid alone. CONCLUSIONS: Our findings indicate that the supplementation of multivitamins containing folic acid during pregnancy could significantly lower preeclampsia risk.

Magnesium Supplementation and Blood Pressure in Pregnancy: A Double-Blind Randomized Multicenter Study.

OBJECTIVE: To investigate the effect of magnesium (Mg) supplementation in healthy pregnant women for prevention of blood pressure increase. Secondary outcomes were comparison of biomarkers for hypertensive disorders and labour and fetal outcomes between the groups. METHODS: Two hundred nulliparous healthy pregnant women were double-blind randomized to receive Mg daily or placebo. RESULTS: There were no differences in blood pressure increase. However, among the Mg-treated women, there was a significant negative correlation between increase in blood levels of magnesium and increase in systolic blood pressure (p = 0.042). Magnesium supplementation seems to be safe for both mother and infant. CONCLUSION: Magnesium supplementation in healthy first-time pregnant women is not to be recommended for prevention of blood pressure increase. Supplementation in risk pregnancies needs to be further investigated. The study is listed on the ISRCTN registry with study ID 13890849.

Systematic Review of Vitamin D and Hypertensive Disorders of Pregnancy.

This narrative systematic review evaluates growing evidence of an association between low maternal vitamin D status and increased risk of hypertensive disorders. The inclusion of interventional, observational, and dietary studies on vitamin D and all hypertensive disorders of pregnancy is a novel aspect of this review, providing a unique contribution to an intensively-researched area that still lacks a definitive conclusion. To date, trial evidence supports a protective effect of combined vitamin D and calcium supplementation against preeclampsia. Conflicting data for an association of vitamin D with gestational hypertensive disorders in observational studies arises from a number of sources, including large heterogeneity between study designs, lack of adherence to standardized perinatal outcome definitions, variable quality of analytical data for 25-hydroxyvitamin D (25(OH)D), and inconsistent data reporting of vitamin D status. While evidence does appear to lean towards an increased risk of gestational hypertensive disorders at 25(OH)D concentrations <50 nmol/L, caution should be exercised with dosing in trials, given the lack of data on long-term safety. The possibility that a fairly narrow target range for circulating 25(OH)D for achievement of clinically-relevant improvements requires further exploration. As hypertension alone, and not preeclampsia specifically, limits intrauterine growth, evaluation of the relationship between vitamin D status and all terms of hypertension in pregnancy is a clinically relevant area for research and should be prioritised in future randomised trials.

The Association between Dietary Vitamin C/E and Gestational Hypertensive Disorder: A Case-Control Study.

A case-control study of 10,228 gestational women was conducted in Lanzhou, China, between 2010 and 2012. This study aimed to evaluate the associations between the risk of gestational hypertensive disorders and dietary intake of vitamin C/E. Among this study's participants, 5.41% (n=553) were diagnosed with gestational hypertensive disorders. Of these disorders, 69.44% (n=384) were preeclampsia and 30.56% (n=169) were considered to be gestational hypertension. After adjustment for confounding variables and other relevant dietary nutrients, no association was found between the risk of gestational hypertensive disorders and dietary intake of vitamin C, vitamin E, copper or manganese before or during pregnancy. However, zinc and selenium intake was associated with the decrease risk of gestational hypertensive disease during different stages of pregnancy (p<0.05). Gestational dietary intake of zinc and selenium can significantly decrease the risk of gestational hypertensive disorders. No association was found between gestational hypertensive disorders and vitamin C, vitamin E, copper or manganese intake.

Folic acid supplement use and the risk of gestational hypertension and preeclampsia.

BACKGROUND: Hypertensive disorders of pregnancy are among the leading causes of maternal morbidity and mortality. Studies suggest that the use of folic acid may lower the risk of hypertensive disorders in pregnant women. AIM: The aim of this study was to assess the effects of timing and duration of folic acid-containing supplement use on the risk for gestational hypertension and preeclampsia. METHODS: Exposures and outcomes data were obtained through interviews and review of participant's medical records from the MotherToBaby cohort studies across the United States and Canada. Demographics, medical history, lifestyle factors, substance use, and fetal sex were assessed as potential confounders. Unadjusted and adjusted risks for gestational hypertension and preeclampsia were examined using odds ratios and 95% confidence intervals. FINDINGS: 3247 women were included in the study. Compared to non-supplement use, early and late supplement use were not significantly associated with the development of gestational hypertension or preeclampsia. The odds of developing gestational hypertension and preeclampsia were significantly reduced as the duration of folic acid-containing supplement use increased. CONCLUSION: Findings from this study suggest that the use of folic acid-containing supplements may mitigate the risk for gestational hypertension and preeclampsia.

Calcium supplementation commencing before or early in pregnancy, or food fortification with calcium, for preventing hypertensive disorders of pregnancy.

BACKGROUND: Pre-eclampsia is considerably more prevalent in low- than high-income countries. One possible explanation for this discrepancy is dietary differences, particularly calcium deficiency. Calcium supplementation in the second half of pregnancy reduces the serious consequences of pre-eclampsia and is recommended by the World Health Organization (WHO) for women with low dietary calcium intake, but has limited effect on the overall risk of pre-eclampsia. It is important to establish whether calcium supplementation before and in early pregnancy has added benefit. Such evidence would be justification for population-level fortification of staple foods with calcium. OBJECTIVES: To determine the effect of calcium supplementation or food fortification with calcium, commenced before or early in pregnancy and continued at least until mid-pregnancy, on pre-eclampsia and other hypertensive disorders, maternal morbidity and mortality, as well as fetal and neonatal outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Trials Register (10 August 2017), PubMed (29 June 2017), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (10 August 2017) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials of calcium supplementation or food fortification which include women of child bearing age not yet pregnant, or in early pregnancy. Cluster-RCTs, quasi-RCTs and trials published in abstract form only would have been eligible for inclusion in this review but none were identified. Cross-over designs are not appropriate for this intervention.The scope of this review is to consider interventions including calcium supplementation with or without additional supplements or treatments, compared with placebo or no intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. MAIN RESULTS: This review is based on one RCT (involving 60 women) which looked at calcium plus additional supplements versus control. The women (who had low antioxidant status) were in the early stages of pregnancy. We did not identify any studies where supplementation commenced pre-pregnancy. Another RCT comparing calcium versus placebo is ongoing but not yet complete. We did not identify any studies looking at any of our other planned comparisons. Calcium plus antioxidants and other supplements versus placeboWe included one small study (involving 60 women with low antioxidant levels) which was conducted in an academic hospital in Indondesia. The study was at low risk of bias for all domains with the exception of selective reporting, for which it was unclear. Women in the intervention group received calcium (800 mg) plus N-acetylcysteine (200 mg), Cu (2 mg), Zn (15 mg), Mn (0.5 mg) and selenium (100 mcg) and vitamins A (1000 IU), B6 (2.2 mg), B12 (2.2 mcg), C (200 mg), and E (400 IU) versus the placebo control group of women who received similar looking tablets containing iron and folic acid. Both groups received iron (30 mg) and folic acid (400 mcg). Tablets were taken twice daily from eight to 12 weeks of gestation and then throughout pregnancy.The included study found that calcium supplementation plus antioxidants and other supplements may slightly reduce pre-eclampsia (gestational hypertension and proteinuria) (risk ratio (RR) 0.24, 95% confidence interval (CI) 0.06 to 1.01; low-quality evidence), but this is uncertain due to wide confidence intervals just crossing the line of no effect, and small sample size. It appears that earlypregnancy loss before 20 weeks' gestation (RR 0.06, 95% CI 0.00 to 1.04; moderate-quality evidence) may be slightly reduced by calcium plus antioxidants and other supplements, but this outcome also has wide confidence intervals, which just cross the line of no effect. Very few events were reported under the composite outcome, severe maternal morbidity and mortality index and no clear difference was seen between groups (RR 0.36, 95% CI 0.04 to 3.23; low-quality evidence). However, the included study observed a reduction in the composite outcome pre-eclampsia and/or pregnancy loss at any gestational age (RR 0.13, 95% CI 0.03 to 0.50; moderate-quality evidence), and pregnancy loss/stillbirth at any gestational age (RR 0.06, 95% CI 0.00 to 0.92; moderate-quality evidence) in the calcium plus antioxidant/supplement group.Other outcomes reported (placental abruption, severe pre-eclampsia and preterm birth (less than 37 weeks' gestation)) were too infrequent for meaningful analysis. No data were reported for the outcomes caesarean section, birthweight < 2500 g, Apgar score less than seven at five minutes, death or admission to neonatal intensive care unit (ICU), or pregnancy loss, stillbirth or neonatal death before discharge from hospital. AUTHORS' CONCLUSIONS: The results of this review are based on one small study in which the calcium intervention group also received antioxidants and other supplements. Therefore, we are uncertain whether any of the effects observed in the study were due to calcium supplementation or not. The evidence in this review was graded low to moderate due to imprecision. There is insufficient evidence on the effectiveness or otherwise of pre- or early-pregnancy calcium supplementation, or food fortification for preventing hypertensive disorders of pregnancy.Further research is needed to determine whether pre- or early-pregnancy supplementation, or food fortification with calcium is associated with a reduction in adverse pregnancy outcomes such as pre-eclampsia and pregnancy loss. Such studies should be adequately powered, limited to calcium supplementation, placebo-controlled, and include relevant outcomes such as those chosen for this review.There is one ongoing study of calcium supplementation alone versus placebo and this may provide additional evidence in future updates.

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.

Dimethylesculetin ameliorates maternal glucose intolerance and fetal overgrowth in high-fat diet-fed pregnant mice via constitutive androstane receptor.

The constitutive androstane receptor (CAR) has been reported to decrease insulin resistance along with obesity. 6,7-dimethylesculetin (DE) is an active component of Yin Zhi Huang which is a traditional Asian medicine used to treat neonatal jaundice via CAR. In this study, we examined whether DE could affect the expression of gluconeogenic and lipogenic genes via human CAR pathway using human HepG2 cells in vitro. We also studied whether DE treatment during pregnancy could prevent maternal hypertension, glucose intolerance and hyperlipidemia, and fetal overgrowth in high-fat diet (HFD)-induced obese pregnant mice. Dimethylesculetin suppressed the mRNA expression of gluconeogenic genes, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, and lipogenic genes, sterol regulatory element-binding protein 1 and stearoyl-CoA desaturase 1, and enhanced CAR-mediated transcription. Blocking the CAR-mediated pathway abolished the effect of DE in vitro. DE treatment during pregnancy could prevent maternal hypertension, glucose intolerance and hyperlipidemia, and fetal overgrowth in HFD-induced obese pregnant mice in vivo. Our data indicate that DE might be a potential therapeutic agent for obese pregnant patients with insulin resistance through CAR to prevent the perinatal outcomes such as preeclampsia, gestational diabetes, and macrosomia. Further analysis of possible complications and side effects using animal models is required.