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.

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.

Early prenatal use of a multivitamin diminishes the risk for inadequate vitamin D status in pregnant women: results from the Maternal-Infant Research on Environmental Chemicals (MIREC) cohort study.

BACKGROUND: Reports on the adequacy of vitamin D status of pregnant women are not available in Canada. OBJECTIVES: The objectives of this study were to examine vitamin D status across pregnancy and identify the correlates of vitamin D status of pregnant women in Canada. METHODS: Pregnant women (≥18 years) from 6 provinces (2008-2011) participating in a longitudinal cohort were studied. Sociodemographic data, obstetrical histories, and dietary and supplemental vitamin D intakes were surveyed. Plasma 25-hydroxyvitamin D (25OHD) was measured using an immunoassay standardized to LC-MS/MS from samples collected during the first (n = 1905) and third trimesters (n = 1649) and at delivery (n = 1543). The proportion of women with ≥40 nmol/L of plasma 25OHD (adequate status) was estimated at each time point, and factors related to achieving this cut point were identified using repeated-measures logistic regression. Differences in 25OHD concentrations across trimesters and at delivery were tested a using repeated-measures ANOVA with a post hoc Tukey's test. RESULTS: In the first trimester, 93.4% (95% CI: 92.3%-94.5%) of participants had 25OHD ≥40 nmol/L. The mean plasma 25OHD concentration increased from the first to the third trimester and then declined by delivery (69.8 ± 0.5 nmol/L, 78.6 ± 0.7 nmol/L, and 75.7 ± 0.7 nmol/L, respectively; P < 0.0001). A lack of multivitamin use early in pregnancy reduced the odds of achieving 25OHD ≥40 nmol/L (ORadj = 0.33; 95% CI: 0.25-0.42) across all time points. Factors associated with not using a prenatal multivitamin included multiparity (ORadj = 2.08; 95% CI: 1.42-3.02) and a below-median income (ORadj = 1.39; 95% CI: 1.02-1.89). CONCLUSIONS: The results from this cohort demonstrate the importance of early multivitamin supplement use to achieve an adequate vitamin D status in pregnant women.

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).

The International Federation of Gynecology and Obstetrics (FIGO) initiative on pre-eclampsia: A pragmatic guide for first-trimester screening and prevention.

Pre­eclampsia (PE) is a multisystem disorder that typically affects 2%­5% of pregnant women and is one of the leading causes of maternal and perinatal morbidity and mortality, especially when the condition is of early onset. Globally, 76 000 women and 500 000 babies die each year from this disorder. Furthermore, women in low­resource countries are at a higher risk of developing PE compared with those in high­resource countries. Although a complete understanding of the pathogenesis of PE remains unclear, the current theory suggests a two­stage process. The first stage is caused by shallow invasion of the trophoblast, resulting in inadequate remodeling of the spiral arteries. This is presumed to lead to the second stage, which involves the maternal response to endothelial dysfunction and imbalance between angiogenic and antiangiogenic factors, resulting in the clinical features of the disorder. Accurate prediction and uniform prevention continue to elude us. The quest to effectively predict PE in the first trimester of pregnancy is fueled by the desire to identify women who are at high risk of developing PE, so that necessary measures can be initiated early enough to improve placentation and thus prevent or at least reduce the frequency of its occurrence. Furthermore, identification of an "at risk" group will allow tailored prenatal surveillance to anticipate and recognize the onset of the clinical syndrome and manage it promptly. PE has been previously defined as the onset of hypertension accompanied by significant proteinuria after 20 weeks of gestation. Recently, the definition of PE has been broadened. Now the internationally agreed definition of PE is the one proposed by the International Society for the Study of Hypertension in Pregnancy (ISSHP). According to the ISSHP, PE is defined as systolic blood pressure at ≥140 mm Hg and/or diastolic blood pressure at ≥90 mm Hg on at least two occasions measured 4 hours apart in previously normotensive women and is accompanied by one or more of the following new­onset conditions at or after 20 weeks of gestation: 1.Proteinuria (i.e. ≥30 mg/mol protein:creatinine ratio; ≥300 mg/24 hour; or ≥2 + dipstick); 2.Evidence of other maternal organ dysfunction, including: acute kidney injury (creatinine ≥90 µmol/L; 1 mg/dL); liver involvement (elevated transaminases, e.g. alanine aminotransferase or aspartate aminotransferase >40 IU/L) with or without right upper quadrant or epigastric abdominal pain; neurological complications (e.g. eclampsia, altered mental status, blindness, stroke, clonus, severe headaches, and persistent visual scotomata); or hematological complications (thrombocytopenia­platelet count <150 000/µL, disseminated intravascular coagulation, hemolysis); or 3.Uteroplacental dysfunction (such as fetal growth restriction, abnormal umbilical artery Doppler waveform analysis, or stillbirth). It is well established that a number of maternal risk factors are associated with the development of PE: advanced maternal age; nulliparity; previous history of PE; short and long interpregnancy interval; use of assisted reproductive technologies; family history of PE; obesity; Afro­Caribbean and South Asian racial origin; co­morbid medical conditions including hyperglycemia in pregnancy; pre­existing chronic hypertension; renal disease; and autoimmune diseases, such as systemic lupus erythematosus and antiphospholipid syndrome. These risk factors have been described by various professional organizations for the identification of women at risk of PE; however, this approach to screening is inadequate for effective prediction of PE. PE can be subclassified into: 1.Early­onset PE (with delivery at <34+0 weeks of gestation); 2.Preterm PE (with delivery at <37+0 weeks of gestation); 3.Late­onset PE (with delivery at ≥34+0 weeks of gestation); 4.Term PE (with delivery at ≥37+0 weeks of gestation). These subclassifications are not mutually exclusive. Early­onset PE is associated with a much higher risk of short­ and long­term maternal and perinatal morbidity and mortality. Obstetricians managing women with preterm PE are faced with the challenge of balancing the need to achieve fetal maturation in utero with the risks to the mother and fetus of continuing the pregnancy longer. These risks include progression to eclampsia, development of placental abruption and HELLP (hemolysis, elevated liver enzyme, low platelet) syndrome. On the other hand, preterm delivery is associated with higher infant mortality rates and increased morbidity resulting from small for gestational age (SGA), thrombocytopenia, bronchopulmonary dysplasia, cerebral palsy, and an increased risk of various chronic diseases in adult life, particularly type 2 diabetes, cardiovascular disease, and obesity. Women who have experienced PE may also face additional health problems in later life, as the condition is associated with an increased risk of death from future cardiovascular disease, hypertension, stroke, renal impairment, metabolic syndrome, and diabetes. The life expectancy of women who developed preterm PE is reduced on average by 10 years. There is also significant impact on the infants in the long term, such as increased risks of insulin resistance, diabetes mellitus, coronary artery disease, and hypertension in infants born to pre­eclamptic women. The International Federation of Gynecology and Obstetrics (FIGO) brought together international experts to discuss and evaluate current knowledge on PE and develop a document to frame the issues and suggest key actions to address the health burden posed by PE. FIGO's objectives, as outlined in this document, are: (1) To raise awareness of the links between PE and poor maternal and perinatal outcomes, as well as to the future health risks to mother and offspring, and demand a clearly defined global health agenda to tackle this issue; and (2) To create a consensus document that provides guidance for the first­trimester screening and prevention of preterm PE, and to disseminate and encourage its use. Based on high­quality evidence, the document outlines current global standards for the first­trimester screening and prevention of preterm PE, which is in line with FIGO good clinical practice advice on first trimester screening and prevention of pre­eclampsia in singleton pregnancy.1 It provides both the best and the most pragmatic recommendations according to the level of acceptability, feasibility, and ease of implementation that have the potential to produce the most significant impact in different resource settings. Suggestions are provided for a variety of different regional and resource settings based on their financial, human, and infrastructure resources, as well as for research priorities to bridge the current knowledge and evidence gap. To deal with the issue of PE, FIGO recommends the following: Public health focus: There should be greater international attention given to PE and to the links between maternal health and noncommunicable diseases (NCDs) on the Sustainable Developmental Goals agenda. Public health measures to increase awareness, access, affordability, and acceptance of preconception counselling, and prenatal and postnatal services for women of reproductive age should be prioritized. Greater efforts are required to raise awareness of the benefits of early prenatal visits targeted at reproductive­aged women, particularly in low­resource countries. Universal screening: All pregnant women should be screened for preterm PE during early pregnancy by the first­trimester combined test with maternal risk factors and biomarkers as a one­step procedure. The risk calculator is available free of charge at https://fetalmedicine.org/research/assess/preeclampsia. FIGO encourages all countries and its member associations to adopt and promote strategies to ensure this. The best combined test is one that includes maternal risk factors, measurements of mean arterial pressure (MAP), serum placental growth factor (PLGF), and uterine artery pulsatility index (UTPI). Where it is not possible to measure PLGF and/or UTPI, the baseline screening test should be a combination of maternal risk factors with MAP, and not maternal risk factors alone. If maternal serum pregnancy­associated plasma protein A (PAPP­A) is measured for routine first­trimester screening for fetal aneuploidies, the result can be included for PE risk assessment. Variations to the full combined test would lead to a reduction in the performance screening. A woman is considered high risk when the risk is 1 in 100 or more based on the first­trimester combined test with maternal risk factors, MAP, PLGF, and UTPI. Contingent screening: Where resources are limited, routine screening for preterm PE by maternal factors and MAP in all pregnancies and reserving measurements of PLGF and UTPI for a subgroup of the population (selected on the basis of the risk derived from screening by maternal factors and MAP) can be considered. Prophylactic measures: Following first­trimester screening for preterm PE, women identified at high risk should receive aspirin prophylaxis commencing at 11­14+6 weeks of gestation at a dose of ~150 mg to be taken every night until 36 weeks of gestation, when delivery occurs, or when PE is diagnosed. Low­dose aspirin should not be prescribed to all pregnant women. In women with low calcium intake (<800 mg/d), either calcium replacement (≤1 g elemental calcium/d) or calcium supplementation (1.5­2 g elemental calcium/d) may reduce the burden of both early­ and late­onset PE.

Prepregnancy and early pregnancy calcium supplementation among women at high risk of pre-eclampsia: a multicentre, double-blind, randomised, placebo-controlled trial.

BACKGROUND: Reducing deaths from hypertensive disorders of pregnancy is a global priority. Low dietary calcium might account for the high prevalence of pre-eclampsia and eclampsia in low-income countries. Calcium supplementation in the second half of pregnancy is known to reduce the serious consequences of pre-eclampsia; however, the effect of calcium supplementation during placentation is not known. We aimed to test the hypothesis that calcium supplementation before and in early pregnancy (up to 20 weeks' gestation) prevents the development of pre-eclampsia METHODS: We did a multicountry, parallel arm, double-blind, randomised, placebo-controlled trial in South Africa, Zimbabwe, and Argentina. Participants with previous pre-eclampsia and eclampsia received 500 mg calcium or placebo daily from enrolment prepregnancy until 20 weeks' gestation. Participants were parous women whose most recent pregnancy had been complicated by pre-eclampsia or eclampsia and who were intending to become pregnant. All participants received unblinded calcium 1·5 g daily after 20 weeks' gestation. The allocation sequence (1:1 ratio) used computer-generated random numbers in balanced blocks of variable size. The primary outcome was pre-eclampsia, defined as gestational hypertension and proteinuria. The trial is registered with the Pan-African Clinical Trials Registry, number PACTR201105000267371. The trial closed on Oct 31, 2017. FINDINGS: Between July 12, 2011, and Sept 8, 2016, we randomly allocated 1355 women to receive calcium or placebo; 331 of 678 participants in the calcium group versus 320 of 677 in the placebo group became pregnant, and 298 of 678 versus 283 of 677 had pregnancies beyond 20 weeks' gestation. Pre-eclampsia occurred in 69 (23%) of 296 participants in the calcium group versus 82 (29%) of 283 participants in the placebo group with pregnancies beyond 20 weeks' gestation (risk ratio [RR] 0·80, 95% CI 0·61-1·06; p=0·121). For participants with compliance of more than 80% from the last visit before pregnancy to 20 weeks' gestation, the pre-eclampsia risk was 30 (21%) of 144 versus 47 (32%) of 149 (RR 0·66, CI 0·44-0·98; p=0·037). There were no serious adverse effects of calcium reported. INTERPRETATION: Calcium supplementation that commenced before pregnancy until 20 weeks' gestation, compared with placebo, did not show a significant reduction in recurrent pre-eclampsia. As the trial was powered to detect a large effect size, we cannot rule out a small to moderate effect of this intervention. FUNDING: The University of British Columbia, a grantee of the Bill & Melinda Gates Foundation; UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, Development and Research Training in Human Reproduction, WHO; the Argentina Fund for Horizontal Cooperation of the Argentinean Ministry of Foreign Affairs; and the Centre for Intervention Science in Maternal and Child Health.

Health care provider knowledge and routine management of pre-eclampsia in Pakistan.

BACKGROUND: Maternal mortality ratio is 276 per 100,000 live births in Pakistan. Eclampsia is responsible for one in every ten maternal deaths despite the fact that management of this disease is inexpensive and has been available for decades. Many studies have shown that health care providers in low and middle-income countries have limited training to manage patients with eclampsia. Hence, we aimed to explore the knowledge of different cadres of health care providers regarding aetiology, diagnosis and treatment of pre-eclampsia and eclampsia and current management practices. METHODS: We conducted a mixed method study in the districts of Hyderabad and Matiari in Sindh province, Pakistan. Focus group discussions and interviews were conducted with community health care providers, which included Lady Health Workers and their supervisors; traditional birth attendants and facility care providers. In total seven focus groups and 26 interviews were conducted. NVivo 10 was used for analysis and emerging themes and sub-themes were drawn. RESULTS: All participants were providing care for pregnant women for more than a decade except one traditional birth attendant and two doctors. The most common cause of pre-eclampsia mentioned by community health care providers was stress of daily life: the burden of care giving, physical workload, short birth spacing and financial constraints. All health care provider groups except traditional birth attendants correctly identified the signs, symptoms, and complications of pre-eclampsia and eclampsia and were referring such women to tertiary health facilities. Only doctors were aware that magnesium sulphate is recommended for eclampsia management and prevention; however, they expressed fears regarding its use at first and secondary level health facilities. CONCLUSION: This study found several gaps in knowledge regarding aetiology, diagnosis and treatment of pre-eclampsia among health care providers in Sindh. Findings suggest that lesser knowledge regarding management of pre-eclampsia is due to lack of refresher trainings and written guidelines for management of pre-eclampsia and presentation of fewer pre-eclamptic patients at first and secondary level health care facilities. We suggest to include management of pre-eclampsia in regular trainings of health care providers and to provide management protocols at all health facilities. TRIAL REGISTRATION: NCT01911494.

Community health worker knowledge and management of pre-eclampsia in rural Karnataka State, India.

BACKGROUND: In India, the hypertensive disorders of pregnancy and postpartum haemorrhage are responsible for nearly 40 % of all maternal deaths. Most of these deaths occur in primary health settings which frequently lack essential equipment and medication, are understaffed, and have limited or no access to specialist care. Community health care workers are regarded as essential providers of basic maternity care; and the quality of care they provide is dependent on the level of knowledge and skills they possess. However, there is limited research regarding their ability to manage pregnancy complications. This study aims to describe the current state of knowledge regarding pre-eclampsia and eclampsia among community health care workers (auxiliary nurse midwives, accredited social health activists, staff nurses) in northern Karnataka, India. Furthermore, this study describes the treatment approaches used by various cadres of community health workers for these conditions. The findings of this study can help plan focussed training sessions to build upon their strengths and to address the identified gaps. METHODS: Data were collected as part of a larger study aimed at assessing the feasibility of community-based treatment for pre-eclampsia. Eight focus group discussions were conducted in 2012-2013 in northern Karnataka State: four with staff nurses and auxiliary nurse midwives and four with accredited social health activists. In addition, twelve auxiliary nurse midwives and staff nurses completed questionnaires to explore their competence and self-efficacy in managing pre-eclampsia. Qualitative data were audio-recorded, transcribed verbatim and translated for thematic analysis using NVivo 10. RESULTS: Community health workers described their understanding of the origins of hypertension and seizures in pregnancy. Psychological explanations of hypertension were most commonly reported: stress, tension, and fear. The most common explanation for eclampsia was not receiving a tetanus vaccination. Despite some common misperceptions regarding aetiology, these community health workers demonstrated a good grasp of the potential consequences of hypertension in pregnancy. According to auxiliary nurse midwives and staff nurses, if hypertension was detected they encouraged rest, decreased salt intake, iron supplementation and tetanus vaccination. In addition, some staff nurses administered antihypertensives, MgSO4, or other anticonvulsants. All auxiliary nurse midwives had some awareness of MgSO4, but none had administered it themselves. CONCLUSIONS: This study showed that knowledge regarding the aetiology of pre-eclampsia was limited. Nevertheless, their basic knowledge and skills could be strengthened to more effectively manage the hypertensive disorders of pregnancy in their communities. TRIAL REGISTRATION: NCT01911494.

Potential for task-sharing to Lady Health Workers for identification and emergency management of pre-eclampsia at community level in Pakistan.

BACKGROUND: An estimated 276 Pakistani women die for every 100,000 live births; with eclampsia accounting for about 10 % of these deaths. Community health workers contribute to the existing health system in Pakistan under the banner of the Lady Health Worker (LHW) Programme and are responsible to provide a comprehensive package of antenatal services. However, there is a need to increase focus on early identification and prompt diagnosis of pre-eclampsia in community settings, since women with mild pre-eclampsia often present without symptoms. This study aims to explore the potential for task-sharing to LHWs for the community-level management of pre-eclampsia and eclampsia in Pakistan. METHODS: A qualitative exploratory study was undertaken February-July 2012 in two districts, Hyderabad and Matiari, in the southern province of Sindh, Pakistan. Altogether 33 focus group discussions (FGDs) were conducted and the LHW curriculum and training materials were also reviewed. The data was audio-recorded, then transcribed verbatim for thematic analysis using QSR NVivo-version10. RESULTS: Findings from the review of the LHW curriculum and training program describe that in the existing community delivery system, LHWs are responsible for identification of pregnant women, screening women for danger signs and referrals for antenatal care. They are the first point of contact for women in pregnancy and provide nutritional counselling along with distribution of iron and folic acid supplements. Findings from FGDs suggest that LHWs do not carry a blood pressure device or antihypertensive medications; they refer to the nearest public facility in the event of a pregnancy complication. Currently, they provide tetanus toxoid in pregnancy. The health advice provided by lady health workers is highly valued and accepted by pregnant women and their families. Many Supervisors of LHWs recognized the need for increased training regarding pre-eclampsia and eclampsia, with a focus on identifying women at high risk. The entire budget of the existing lady health worker Programme is provided by the Government of Pakistan, indicating a strong support by policy makers and the government for the tasks undertaken by these providers. CONCLUSION: There is a potential for training and task-sharing to LHWs for providing comprehensive antenatal care; specifically for the identification and management of pre-eclampsia in Pakistan. However, the implementation needs to be combined with appropriate training, equipment availability and supervision. TRIAL REGISTRATION: ClinicalTrial.gov, NCT01911494.

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.

Community's perceptions of pre-eclampsia and eclampsia in Sindh Pakistan: a qualitative study.

BACKGROUND: Maternal mortality is of global public health concern and >99 % of maternal deaths occur in less developed countries. The common causes of direct maternal death are hemorrhage, sepsis and pre-eclampsia/eclampsia. In Pakistan, pre-eclampsia/eclampsia deaths represents one-third of maternal deaths reported at the tertiary care hospital settings. This study explored community perceptions, and traditional management practices about pre-eclampsia/eclampsia. METHODS: A qualitative study was conducted in Sindh Province of Pakistan from February to July 2012. Twenty-six focus groups were conducted, 19 with women of reproductive age/mothers-in-law (N = 173); and 7 with husbands/fathers-in-law (N = 65). The data were transcribed verbatim in Sindhi and Urdu, then analyzed for emerging themes and sub-themes using NVivo version 10 software. RESULTS: Pre-eclampsia in pregnancy was not recognized as a disease and there was no name in the local languages to describe this. Women however, knew about high blood pressure and were aware they can develop it during pregnancy. It was widely believed that stress and weakness caused high blood pressure in pregnancy and it caused symptoms of headache. The perception of high blood pressure was not based on measurement but on symptoms. Self-medication was often used for headaches associated with high blood pressure. They were also awareness that severely high blood pressure could result in death. CONCLUSIONS: Community-based participatory health education strategies are recommended to dispel myths and misperceptions regarding pre-eclampsia and eclampsia. The educational initiatives should include information on the presentation, progression of illness, danger signs associated with pregnancy, and appropriate treatment.

Community perceptions of pre-eclampsia in rural Karnataka State, India: a qualitative study.

BACKGROUND: Maternal deaths have been attributed in large part to delays in recognition of illness, timely transport to facility, and timely treatment once there. As community perceptions of pregnancy and their complications are critical to averting maternal morbidity and mortality, this study sought to contribute to the literature and explore community-based understandings of pre-eclampsia and eclampsia. METHODS: The study was conducted in rural Karnataka State, India, in 2012-2013. Fourteen focus groups were held with the following community stakeholders: three with community leaders (n = 27), two with male decision-makers (n = 19), three with female decision-makers (n = 41), and six with reproductive age women (n = 132). Focus groups were facilitated by local researchers with clinical and research expertise. Discussions were audio-recorded, transcribed verbatim and translated to English for thematic analysis using NVivo 10. RESULTS: Terminology exists in the local language (Kannada) to describe convulsions and hypertension, but there were no terms that are specific to pregnancy. Community participants perceived stress, tension and poor diet to be precipitants of hypertension in pregnancy. Seizures in pregnancy were thought to be brought on by anaemia, poor medical adherence, lack of tetanus toxoid immunization, and exposure in pregnancy to fire or water. Sweating, fatigue, dizziness-unsteadiness, swelling, and irritability were perceived to be signs of hypertension, which was recognized to have the potential to lead to eclampsia or death. Home remedies, such as providing the smell of onion, placing an iron object in the hands, or squeezing the fingers and toes, were all used regularly to treat seizures prior to accessing facility-based care although transport is not delayed. CONCLUSIONS: It is evident that 'pre-eclampsia' and 'eclampsia' are not well-known; instead hypertension and seizures are perceived as conditions that may occur during or outside pregnancy. Improving community knowledge about, and modifying attitudes towards, hypertension in pregnancy and its complications (including eclampsia) has the potential to address community-based delays in disease recognition and delays in treatment that contribute to maternal and perinatal morbidity and mortality. Advocacy and educational initiatives should be designed to target knowledge gaps and potentially harmful practices, and respond to cultural understandings of disease. TRIAL REGISTRATION: NCT01911494.

Determinants of health care seeking behaviour during pregnancy in Ogun State, Nigeria.

BACKGROUND: In Nigeria, women too often suffer the consequences of serious obstetric complications that may lead to death. Delay in seeking care (phase I delay) is a recognized contributor to adverse pregnancy outcomes. This qualitative study aimed to describe the health care seeking practices in pregnancy, as well as the socio-cultural factors that influence these actions. METHODS: The study was conducted in Ogun State, in south-western Nigeria. Data were collected through focus group discussions with pregnant women, recently pregnant mothers, male decision-makers, opinion leaders, traditional birth attendants, health workers, and health administrators. A thematic analysis approach was used with QSR NVivo version 10. RESULTS: Findings show that women utilized multiple care givers during pregnancy, with a preference for traditional providers. There was a strong sense of trust in traditional medicine, particularly that provided by traditional birth attendants who are long-term residents in the community. The patriarchal c influenced health-seeking behaviour in pregnancy. Economic factors contributed to the delay in access to appropriate services. There was a consistent concern regarding the cost barrier in accessing health services. The challenges of accessing services were well recognised and these were greater when referral was to a higher level of care which in most cases attracted unaffordable costs. CONCLUSION: While the high cost of care is a deterrent to health seeking behaviour, the cost of death of a woman or a child to the family and community is immeasurable. The use of innovative mechanisms for health care financing may be beneficial for women in these communities to reduce the barrier of high cost services. To reduce maternal deaths all stakeholders must be engaged in the process including policy makers, opinion leaders, health care consumers and providers. Underlying socio-cultural factors, such as structure of patriarchy, must also be addressed to sustainably improve maternal health. TRIAL REGISTRATION: NCT01911494.

Barriers and facilitators to health care seeking behaviours in pregnancy in rural communities of southern Mozambique.

BACKGROUND: In countries, such as Mozambique, where maternal mortality remains high, the greatest contribution of mortality comes from the poor and vulnerable communities, who frequently reside in remote and rural areas with limited access to health care services. This study aimed to understand women's health care seeking practices during pregnancy, taking into account the underlying social, cultural and structural barriers to accessing timely appropriate care in Maputo and Gaza Provinces, southern Mozambique. METHODS: This ethnographic study collected data through in-depth interviews and focus group discussions with women of reproductive age, including pregnant women, as well as household-level decision makers (partners, mothers and mothers-in-law), traditional healers, matrons, and primary health care providers. Data was analysed thematically using NVivo 10. RESULTS: Antenatal care was sought at the heath facility for the purpose of opening the antenatal record. Women without antenatal cards feared mistreatment during labour. Antenatal care was also sought to resolve discomforts, such as headaches, flu-like symptoms, body pain and backache. However, partners and husbands considered lower abdominal pain as the only symptom requiring care and discouraged women from revealing their pregnancy early in gestation. Health care providers for pregnant women often included those at the health facility, matrons, elders, traditional birth attendants, and community health workers. Although seeking care from traditional healers was discouraged during the antenatal period, they did provide services during pregnancy and after delivery. Besides household-level decision-makers, matrons, community health workers, and neighbours were key actors in the referral of pregnant women. The decision-making process may be delayed and particularly complex if an emergency occurs in their absence. Limited access to transport and money makes the decision-making process to seek care at the health facility even more complex. CONCLUSIONS: Women do seek antenatal care at health facilities, despite the presence of other health care providers in the community. There are important factors that prevent timely care-seeking for obstetric emergencies and delivery. Unfamiliarity with warning signs, especially among partners, discouragement from revealing pregnancy early in gestation, complex and untimely decision-making processes, fear of mistreatment by health-care providers, lack of transport and financial constraints were the most commonly cited barriers. Women of reproductive age would benefit from community saving schemes for transport and medication, which in turn would improve their birth preparedness and emergency readiness; in addition, pregnancy follow-up should include key family members, and community-based health care providers should encourage prompt referrals to health facilities, when appropriate. TRIAL REGISTRATION: NCT01911494.

The feasibility of community level interventions for pre-eclampsia in South Asia and Sub-Saharan Africa: a mixed-methods design.

BACKGROUND: Globally, pre-eclampsia and eclampsia are major contributors to maternal and perinatal mortality; of which the vast majority of deaths occur in less developed countries. In addition, a disproportionate number of morbidities and mortalities occur due to delayed access to health services. The Community Level Interventions for Pre-eclampsia (CLIP) Trial aims to task-shift to community health workers the identification and emergency management of pre-eclampsia and eclampsia to improve access and timely care. Literature revealed paucity of published feasibility assessments prior to initiating large-scale community-based interventions. Arguably, well-conducted feasibility studies can provide valuable information about the potential success of clinical trials prior to implementation. Failure to fully understand the study context risks the effective implementation of the intervention and limits the likelihood of post-trial scale-up. Therefore, it was imperative to conduct community-level feasibility assessments for a trial of this magnitude. METHODS: A mixed methods design guided by normalization process theory was used for this study in Nigeria, Mozambique, Pakistan, and India to explore enabling and impeding factors for the CLIP Trial implementation. Qualitative data were collected through participant observation, document review, focus group discussion and in-depth interviews with diverse groups of community members, key informants at community level, healthcare providers, and policy makers. Quantitative data were collected through health facility assessments, self-administered community health worker surveys, and household demographic and health surveillance. RESULTS: Refer to CLIP Trial feasibility publications in the current and/or forthcoming supplement. CONCLUSIONS: Feasibility assessments for community level interventions, particularly those involving task-shifting across diverse regions, require an appropriate theoretical framework and careful selection of research methods. The use of qualitative and quantitative methods increased the data richness to better understand the community contexts. TRIAL REGISTRATION: NCT01911494.

Community perceptions of pre-eclampsia and eclampsia in Ogun State, Nigeria: a qualitative study.

BACKGROUND: Pre-eclampsia is a complication of pregnancy responsible for high rates of morbidity and mortality, particularly in sub-Saharan Africa. When undetected or poorly managed, it may progress to eclampsia which further worsens the prognosis. While most studies examining pre-eclampsia have used a bio-medical model, this study recognizes the role of the socio-cultural environment, in order to understand perceptions of pre-eclampsia within the community. METHODS: The study was conducted in Ogun State, Nigeria in 2011-2012. Data were obtained through twenty-eight focus group discussions; seven with pregnant women (N = 80), eight with new mothers (N = 95), three with male decision-makers (N = 35), six with community leaders (N = 68), and three with traditional birth attendants (N = 36). Interviews were also conducted with the heads of the local traditional birth attendants (N = 4) and with community leaders (N = 5). Data were transcribed verbatim and analysed in NVivo 10 software. RESULTS: There was no terminology reportedly used for pre-eclampsia in the native language - Yoruba; however, hypertension has several terms independent of pregnancy status. Generally, 'gìrì âlábôyún' describes seizures specific to pregnancy. The cause of hypertension in pregnancy was thought to be due to depressive thoughts as a result of marital conflict and financial worries, while seizures in pregnancy were perceived to result from prolonged exposure to cold. There seemed to be no traditional treatment for hypertension. However for seizures the use of herbs, concoctions, incisions, and topical application of black soap were widespread. CONCLUSION: This study illustrates that knowledge of pre-eclampsia and eclampsia are limited amongst communities of Ogun State, Nigeria. Findings reveal that pre-eclampsia was perceived as a stress-induced condition, while eclampsia was perceived as a product of prolonged exposure to cold. Thus, heat-related local medicines and herbal concoctions were the treatment options. Perceptions anchored on cultural values and lack of adequate and focused public health awareness is a major constraint to knowledge of the aetiology and treatment of the conditions. A holistic approach is recommended for sensitization at the community level and the need to change the community perceptions of pre-eclampsia remains a challenge. TRIAL REGISTRATION: NCT01911494 .