Persisting risk factors for preeclampsia among high-risk pregnancies already using prophylactic aspirin: a multi-country retrospective investigation.

BACKGROUND: Low-dose aspirin is recommended for pregnant individuals at high-risk of developing preeclampsia, but less is known about those that develop preeclampsia even while using prophylactic aspirin for preeclampsia prevention as the best course of treatment. OBJECTIVES: The objective of this study is to investigate the risk factors with the highest risk of developing preeclampsia among pregnant individuals already using aspirin from high-risk obstetrical centers across five countries. DESIGN: This is a secondary analysis of pregnant individuals from the Folic Acid Clinical Trial (FACT) who were using prophylactic aspirin before 16 weeks gestation. The FACT randomized control trial took place in 70 high risk obstetrical centers in Canada, United Kingdom, Australia, Jamaica, and Argentina between 2011-2015. Participants were included if they had any of the risk factors for preeclampsia: diabetes, chronic hypertension, twin pregnancy, history of preeclampsia, and/or obesity (Body Mass Index ≥35). The outcomes of interest were preeclampsia and preterm preeclampsia (<37 weeks). Log binomial regressions assessed factors significantly associated with any preeclampsia or preterm-preeclampsia (<37 weeks) using adjusted risk ratios (ARR) and 95% confidence intervals (CI). RESULTS: There were 2296 pregnant individuals with complete information on aspirin included in this study. At baseline, all patients were at high risk of preeclampsia and were eligible for aspirin prophylaxis, however, only 660 (28.7%) were taking aspirin. Among the 660 pregnant individuals taking aspirin, 132 (20%) developed preeclampsia and 60 (9.09%) preterm preeclampsia. Among pregnant individuals using aspirin, the risks of preeclampsia were highest for twins (ARR:2.62, 95% CI: 1.68-4.11), history of preeclampsia (ARR: 2.42, 95% CI: 1.74-3.38), and hypertension (ARR:1.92, 95% CI: 1.37-2.69). Similar trends were found for preterm-preeclampsia for twins (ARR:4.10, 95% CI:2.15-7.82), history of preeclampsia (ARR:2.75, 95% CI:1.62-4.67), and hypertension (ARR:2.18, 95% CI:1.28-3.72). No significant differences were found for obesity or diabetes. CONCLUSION: These findings suggest that individuals with twin pregnancies, a history of preeclampsia, or hypertension may not benefit from aspirin to the same extent as those with other complications such as obesity or diabetes. Careful clinical monitoring for these risks factors is recommended and future research into the effectiveness in these populations would increase our understanding of the current best practice of prophylactic aspirin use to prevent preeclampsia. TRIAL REGISTRATION: Current Controlled Trials ISRCTN23781770 and ClinicalTrials.gov NCT01355159.

Folic Acid Supplementation in Early Pregnancy, Homocysteine Concentration, and Risk of Gestational Diabetes Mellitus.

We used a prospective cohort of pregnant women at 12 to 20 weeks gestation between 2002 and 2008 in Ottawa and Kingston to evaluate the impact of early pregnancy folic acid supplementation on the risk of gestational diabetes mellitus. Among 7552 eligible women, 84 (1.11%) were diagnosed of gestational diabetes mellitus. Non-significant associations were observed between gestational diabetes mellitus and folate supplementation, homocysteine levels, and methylenetetrahydrofolate reductase 677 TT genotype. Although we found no significant associations between folic acid supplementation and the risk of gestational diabetes mellitus, genetic associations were not confounded by lifestyle or socioeconomic factors, which may have biased previous studies.

Effect of high-dose folic acid supplementation on the prevention of preeclampsia in twin pregnancy.

OBJECTIVE: To determine the efficacy of high-dose folic acid for the prevention of preeclampsia in twin pregnancies. METHODS: Secondary analysis of a randomized controlled trial in 70 obstetrical sites in Argentina, Australia, Canada, Jamaica, and the UK between 2011 and 2015. Eligible women pregnant with twins who were aged 18 y or older and between 8 and 16 completed weeks' gestation were randomized between to receive daily high-dose folic acid (4.0-5.1 mg) or placebo. The primary outcome was preeclampsia, presenting as hypertension after 20 weeks' gestation with significant proteinuria. Secondary outcomes included severe preeclampsia, preterm birth, and adverse fetal and neonatal outcomes. RESULTS: Of 2464 participants randomized between 18 April 2011 and 14 December 2015, 462 (18.8%) had a confirmed twin pregnancy. Thirty-four of these participants withdrew consent or did not have primary outcome data available, and 428 women were analyzed. The rate of preeclampsia was significantly higher in the folic acid group compared to the placebo group in crude analyses (17.2 versus 9.9%; relative risk 1.75 [95% CI 1.06-2.88], p = .029). Multivariable analyses attenuated this effect, rendering it not statistically significant (RR 1.58 [95% CI 0.95-2.63], p = .079). CONCLUSION: High-dose folic acid supplementation was not significantly associated with preeclampsia in a subgroup of twin pregnancies. Although a suggested elevated risk cannot be confirmed, these results may help to gain novel insights in the etiology of preeclampsia, which continues to be poorly understood. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01355159.

Maternal folic acid supplementation and infant birthweight in low- and middle-income countries: A systematic review.

The relationship between maternal folic acid supplementation in pregnancy and infant birthweight has not been well described in low- and middle-income countries. We conducted a systematic review and meta-analysis of the current evidence of the association between folic acid supplementation in pregnancy on three primary outcomes: the incidence of low birthweight, small for gestational age, and mean birthweight. Seventeen studies were identified, which satisfied the inclusion criteria, covering a total of 275,421 women from 13 cohort studies and four randomized controlled trials. For the primary outcome of mean birthweight (n = 9), the pooled mean difference between folic acid and control groups was 0.37 kg (95% confidence interval [CI]: 0.24 to 0.50), and this effect was larger in the randomized controlled trials (0.56, 95% CI: 0.15 to 0.97, n = 3). The pooled odds ratio was 0.59 for low birthweight (95% CI: 0.47 to 0.74, n = 10) among folic acid supplementation versus control. The pooled odds ratio for the association with small for gestational age was 0.63 (95% CI: 0.39 to 1.01, n = 5). Maternal folic acid supplementation in low- and middle-income countries was associated with an increased mean birthweight of infants and decreases in the incidence of low birthweight and small for gestational age.

Assessing associational strength of 23 correlates of child anthropometric failure: An econometric analysis of the 2015-2016 National Family Health Survey, India.

Despite the broad consensus that investments in nutrition-sensitive programmes are required to reduce child undernutrition, in practice empirical studies and interventions tend to focus on few nutrition-specific risk factors in isolation. The 2015-16 National Family Health Survey provides the first opportunity in more than a decade to conduct an up-to-date comprehensive evaluation of the relative importance of various maternal and child health and nutrition (MCHN) factors in respect to child anthropometric failures in India. The primary analysis included 140,444 children aged 6-59 months with complete data on 20 MCHN factors, and the secondary analysis included a subset of 25,603 children with additional paternal data. Outcome variables were stunting, underweight and wasting. We conducted logistic regression models to first evaluate each correlate separately in age- and sex-adjusted models, and then jointly in a mutually adjusted model. For all anthropometric failures, indicators of past and present socioeconomic conditions showed the most robust associations. The strongest correlates for stunting were short maternal stature (OR: 4.39; 95%CI: 4.00, 4.81), lack of maternal education (OR: 1.74; 95%CI: 1.60, 1.89), low maternal BMI (OR: 1.64; 95%CI: 1.54, 1.75), poor household wealth (OR: 1.25; 95%CI: 1.15, 1.35) and poor household air quality (OR: 1.22; 95%CI: 1.16, 1.29). Weaker associations were found for other correlates, including dietary diversity, vitamin A supplementation and breastfeeding initiation. Paternal factors were also important predictors of anthropometric failures, but to a lesser degree than maternal factors. The results remained consistent when stratified by children's age (6-23 vs 24-59 months) and sex (girls vs boys), and when low birth weight was additionally considered. Our findings indicate the limitation of nutrition-specific interventions. Breaking multi-generational poverty and improving environmental factors are promising investments to prevent anthropometric failures in early childhood.

Potential biological therapies for severe preeclampsia: a systematic review and meta-analysis.

BACKGROUND: Preeclampsia remains a significant danger to both mother and child and current prevention and treatment management strategies are limited. The objective of this systematic review was to investigate the current literature on evidence for the use of the regenerative capacity of mesenchymal stem cell (MSC) therapy, the anticoagulant activity of antithrombin (AT), or the free radical scavenging activity of alpha-1-microglobulin (A1M) as potential novel treatments for severe preeclampsia and Hemolysis, Elevated Liver enzymes, Low Platelet count (HELLP). METHOD: We conducted a systematic review of potential biological therapies for preeclampsia. We screened MEDLINE and Embase from inception through May 2017 for studies using AT, A1M or MSCs as potential treatments for preeclampsia and/or HELLP. A meta-analysis was performed to pool data from randomized control trials (RCTs) with homogenous outcomes using the inverse variance method. The Newcastle-Ottawa Scale, the Cochrane risk of bias tool for RCTs, and SYRCLE's risk of bias tool for animal studies were used to investigate potential bias of studies. RESULTS: The literature search retrieved a total of 1015 articles, however, only 17 studies met the selection criteria: AT (n = 9, 8 human and 1 animal); A1M (n = 4, 3 animal and 1 ex-vivo); and, MSCs (n = 4, 3 animal and 1 ex-vivo). A meta-analysis of AT therapy versus placebo and a meta-analysis for AT therapy with heparin versus heparin alone did not show significant differences between study groups. Animal and ex-vivo studies demonstrated significant benefits in relevant outcomes for A1M and MSCs versus control treatments. Most RCT studies were rated as having a low risk of bias across categories with some studies showing an unclear risk of bias in some categories. The two cohort studies both received a total of four out of nine stars (a rating of "poor" quality). Most animal studies had an unclear risk of bias across most categories, with some studies having a low risk of bias in some categories. CONCLUSIONS: The findings of this review are strengthened by rigorous systematic search and review of the literature. Results of our meta-analyses do not currently warrant further exploration of AT as a treatment of preeclampsia in human trials. Results of animal and ex-vivo studies of A1M and MSCs were encouraging and supportive of initiating human investigations.

Intergenerational influences on childhood anaemia.

Prior research on assessing intergenerational influences on child anaemia has largely approached it from purely maternal perspective. Although there is much merit to focus on that, it is an extremely limited/reductionist view of understanding intergenerational influences. We expanded the intergenerational influences to include the fathers and overall of intergenerational household transfers. We analysed a sample of 19,619 mother-father-offspring trios from the 2015-2016 Indian National Fertility and Health Survey with available data on haemoglobin (Hb). Multinomial logistic regression models were used to establish associations between parent anaemia, household characteristics, and categories of offspring anaemia. Maternal and paternal Hb was measured as in children using a finger prick blood sample. The primary outcome was child's Hb level (in g/dl) and grades of anaemia defined as mild (10-10.9 g/dl), moderate (7-9.9 g/dl), and severe (<7 g/dl). Mean Hb was 10.1 g/dl for children, 14.2 g/dl among fathers, and 11.4 g/dl among mothers. Hb correlation was 0.1 between fathers and offspring and 0.2 between mothers and offspring (P < 0.001 for all correlations). Maternal-paternal Hb correlations were consistent across quintiles of wealth index. Maternal anaemia was associated with odds ratio of 1.3 (95% CI [1.1, 1.4]) and 1.6 (95% CI [1.4, 1.7]) for childhood mild and moderate/severe anaemia, respectively. Paternal mild anaemia was associated with an odds ratio of 1.1 (95% CI [0.9, 1.4]) and 1.4 (95% CI [1.2, 1.7]) for child moderate/severe anaemia. The clustering of poor circumstances suggests that public health strategies target social deprivation at the household level. A comprehensive perspective will provide holistic interventions to control childhood anaemia.

Effect of high dose folic acid supplementation in pregnancy on pre-eclampsia (FACT): double blind, phase III, randomised controlled, international, multicentre trial.

OBJECTIVE: To determine the efficacy of high dose folic acid supplementation for prevention of pre-eclampsia in women with at least one risk factor: pre-existing hypertension, prepregnancy diabetes (type 1 or 2), twin pregnancy, pre-eclampsia in a previous pregnancy, or body mass index ≥35. DESIGN: Randomised, phase III, double blinded international, multicentre clinical trial. SETTING: 70 obstetrical centres in five countries (Argentina, Australia, Canada, Jamaica, and UK). PARTICIPANTS: 2464 pregnant women with at least one high risk factor for pre-eclampsia were randomised between 2011 and 2015 (1144 to the folic acid group and 1157 to the placebo group); 2301 were included in the intention to treat analyses. INTERVENTION: Eligible women were randomised to receive either daily high dose folic acid (four 1.0 mg oral tablets) or placebo from eight weeks of gestation to the end of week 16 of gestation until delivery. Clinicians, participants, adjudicators, and study staff were masked to study treatment allocation. MAIN OUTCOME MEASURE: The primary outcome was pre-eclampsia, defined as hypertension presenting after 20 weeks' gestation with major proteinuria or HELLP syndrome (haemolysis, elevated liver enzymes, low platelets). RESULTS: Pre-eclampsia occurred in 169/1144 (14.8%) women in the folic acid group and 156/1157 (13.5%) in the placebo group (relative risk 1.10, 95% confidence interval 0.90 to 1.34; P=0.37). There was no evidence of differences between the groups for any other adverse maternal or neonatal outcomes. CONCLUSION: Supplementation with 4.0 mg/day folic acid beyond the first trimester does not prevent pre-eclampsia in women at high risk for this condition. TRIAL REGISTRATION: Current Controlled Trials ISRCTN23781770 and ClinicalTrials.gov NCT01355159.

Risk factors for chronic undernutrition among children in India: Estimating relative importance, population attributable risk and fractions.

Nearly 40% of the world's stunted children live in India and the prevalence of undernutrition has been persistently high in recent decades. Given numerous available interventions for reducing undernutrition in children, it is not clear of the relative importance of each within a multifactorial framework. We assess the simultaneous contribution of 15 known risk factors for child chronic undernutrition in India. Data are from the 3rd Indian National Family Health Survey (NFHS-3), a nationally representative cross-sectional survey undertaken in 2005-2006. The study population consisted of children aged 6-59 months [n = 26,842 (stunting/low height-for-age), n = 27,483 (underweight/low weight-for-age)]. Risk factors examined for their association with undernutrition were: vitamin A supplementation, vaccination, use of iodized salt, household air quality, improved sanitary facilities, safe disposal of stools, improved drinking water, prevalence of infectious disease, initiation of breastfeeding, dietary diversity, age at marriage, maternal BMI, height, education, and household wealth. Age/sex-adjusted and multivariable adjusted effect sizes (odds ratios) were calculated for risk factors along with Population Attributable Risks (PAR) and Fractions (PAF) using logistic regression. In the mutually adjusted models, the five most important predictors of childhood stunting/underweight were short maternal stature, mother having no education, households in lowest wealth quintile, poor dietary diversity, and maternal underweight. These five factors had a combined PAR of 67.2% (95% CI: 63.3-70.7) and 69.7% (95% CI: 66.3-72.8) for stunting and underweight, respectively. The remaining factors were associated with a combined PAR of 11.7% (95% CI: 6.0-17.4) and 15.1% (95% CI: 8.9-21.3) for stunting and underweight, respectively. Implementing strategies focused on broader progress on social circumstances and infrastructural domains as well as investments in nutrition specific programs to promote dietary adequacy and diversity are required to ensure a long term trajectory of optimal child growth and development in India.