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

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          Abstract

          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.

          Related collections

          Most cited references25

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          Pre-eclampsia: pathophysiology, diagnosis, and management

          The incidence of pre-eclampsia ranges from 3% to 7% for nulliparas and 1% to 3% for multiparas. Pre-eclampsia is a major cause of maternal mortality and morbidity, preterm birth, perinatal death, and intrauterine growth restriction. Unfortunately, the pathophysiology of this multisystem disorder, characterized by abnormal vascular response to placentation, is still unclear. Despite great polymorphism of the disease, the criteria for pre-eclampsia have not changed over the past decade (systolic blood pressure >140 mmHg or diastolic blood pressure ≥90 mmHg and 24-hour proteinuria ≥0.3 g). Clinical features and laboratory abnormalities define and determine the severity of pre-eclampsia. Delivery is the only curative treatment for pre-eclampsia. Multidisciplinary management, involving an obstetrician, anesthetist, and pediatrician, is carried out with consideration of the maternal risks due to continued pregnancy and the fetal risks associated with induced preterm delivery. Screening women at high risk and preventing recurrences are key issues in the management of pre-eclampsia.
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            Maternal mortality associated with hypertensive disorders of pregnancy in Africa, Asia, Latin America and the Caribbean.

            L Duley (1992)
            To present estimates of maternal mortality associated with hypertensive disorders of pregnancy in Africa, Asia, Latin America and the Caribbean, and to discuss strategies to prevent these deaths. Retrospective review of all available data. Database of the World Health Organization's Maternal Health and Safe Motherhood Programme. Estimates of the total maternal mortality and the proportions of deaths associated with hypertensive disorders of pregnancy. Estimates of mortality associated with hypertensive disorders of pregnancy were similar in Africa, Latin America and the Caribbean, despite considerably higher total mortality in Africa. Variations in both overall mortality and that associated with hypertensive disorders of pregnancy were greatest in Asia. Despite their limitations, these data suggest that between 10-15% of maternal deaths are associated with hypertensive disorders of pregnancy, and that 10% are associated with eclampsia. Where maternal mortality is relatively high, the excess is likely to be due to a high mortality associated with haemorrhage and infection and reductions are most likely to come from reductions in these deaths. Evidence from both developed and developing countries suggests that deaths associated with hypertensive disorders of pregnancy are the most difficult to prevent. More rigorous assessment of interventions designed to prevent these deaths is urgently required.
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              Folic acid supplementation during pregnancy for maternal health and pregnancy outcomes.

              During pregnancy, fetal growth causes an increase in the total number of rapidly dividing cells, which leads to increased requirements for folate. Inadequate folate intake leads to a decrease in serum folate concentration, resulting in a decrease in erythrocyte folate concentration, a rise in homocysteine concentration, and megaloblastic changes in the bone marrow and other tissues with rapidly dividing cells To assess the effectiveness of oral folic acid supplementation alone or with other micronutrients versus no folic acid (placebo or same micronutrients but no folic acid) during pregnancy on haematological and biochemical parameters during pregnancy and on pregnancy outcomes. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 December 2012) and we contacted major organisations working in micronutrient supplementation, including UNICEF Nutrition Section, World Health Organization (WHO) Maternal and Reproductive Health, WHO Nutrition Division, and National Center on Birth defects and Developmnetal Disabilities, US Centers for Disease Control and Prevention (CDC). All randomised, cluster-randomised and cross-over controlled trials evaluating supplementation of folic acid alone or with other micronutrients versus no folic acid (placebo or same micronutrients but no folic acid) in pregnancy. Two review authors independently assessed trials for inclusion, assessed risk of bias and extracted data. Data were checked for accuracy. Thirty-one trials involving 17,771 women are included in this review. This review found that folic acid supplementation has no impact on pregnancy outcomes such as preterm birth (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.73 to 1.38; three studies, 2959 participants), and stillbirths/neonatal deaths (RR 1.33, 95% CI 0.96 to 1.85; three studies, 3110 participants). However, improvements were seen in the mean birthweight (mean difference (MD) 135.75, 95% CI 47.85 to 223.68). On the other hand, the review found no impact on improving pre-delivery anaemia (average RR 0.62, 95% CI 0.35 to 1.10; eight studies, 4149 participants; random-effects), mean pre-delivery haemoglobin level (MD -0.03, 95% CI -0.25 to 0.19; 12 studies, 1806 participants), mean pre-delivery serum folate levels (standardised mean difference (SMD) 2.03, 95% CI 0.80 to 3.27; eight studies, 1250 participants; random-effects), and mean pre-delivery red cell folate levels (SMD 1.59, 95% CI -0.07 to 3.26; four studies, 427 participants; random-effects). However, a significant reduction was seen in the incidence of megaloblastic anaemia (RR 0.21, 95% CI 0.11 to 0.38, four studies, 3839 participants). We found no conclusive evidence of benefit of folic acid supplementation during pregnancy on pregnancy outcomes.
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                Author and article information

                Contributors
                Role: professor
                Role: senior project manager
                Role: project manager
                Role: obstetrician gynecologist, maternal fetal medicine
                Role: obstetrician gynecologist, maternal fetal medicine
                Role: professor internal medicine
                Role: obstetrician gynecologist
                Role: professor
                Role: obstetrician gynecologist, maternal fetal medicine
                Role: obstetrician gynecologist, maternal fetal medicine
                Role: professor
                Role: professor
                Role: obstetrician gynecologist, maternal fetal medicine
                Role: professor
                Role: professor
                Role: epidemiologist
                Role: project coordinator
                Role: statistician
                Role: professor
                Role: professor obstetrics and gynecology
                Role: obstetrician gynecologist, maternal fetal medicine
                Role: obstetrician gynecologist, maternal fetal medicine
                Journal
                BMJ
                BMJ
                BMJ-UK
                bmj
                The BMJ
                BMJ Publishing Group Ltd.
                0959-8138
                1756-1833
                2018
                13 September 2018
                : 362
                : k3478
                Affiliations
                [1 ]OMNI Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
                [2 ]School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, Ontario, Canada
                [3 ]Department of Obstetrics, Gynecology & Newborn Care, University of Ottawa, Ottawa, Ontario, Canada
                [4 ]Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, UK
                [5 ]Obstetric Medicine, Robinson Research Institute, University of Adelaide, South Australia, Australia
                [6 ]Women's and Children’s Hospital, Adelaide, South Australia, Australia
                [7 ]Department of Obstetrics and Gynaecology, Faculty of Medical Sciences, The University of the West Indies, Mona, Kingston, Jamaica
                [8 ]Centro Rosarino de Estudios Perinatales (CREP), Rosario, Santa Fé, Argentina
                [9 ]Queen’s Perinatal Research Unit, Kingston General Hospital, Department of Obstetrics and Gynecology, Queens University, Kingston, Ontario, Canada
                [10 ]Mother & Child Axis, Centre de recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada
                [11 ]Centre de Recherche, Universite de Sherbrooke, Sherbrooke, Quebec, Canada
                [12 ]Department of Obstetrics and Gynecology, Faculty of Medicine and Health Sciences, Centre de recherche du CHUS, University of Sherbrooke, Sherbrooke, Quebec, Canada;
                [13 ]Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
                [14 ]Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
                [15 ]Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
                [16 ]Women and Children’s Health Research Institute, University of Alberta, Edmonton, Alberta, Canada
                [17 ]Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada
                [18 ]Department of Physiology, University of Alberta, Edmonton, Alberta, Canada
                [19 ]Maternal-Fetal Medicine Division, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
                [20 ]Departments of Medicine, School of Epidemiology, Public Health and Preventive Medicine, University of Ottawa, Ottawa, Ontario, Canada
                [21 ]Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia
                [22 ]Department of Obstetrics, University Medical Center, Utrecht, Utrecht, Netherlands
                [23 ]Department of Obstetrics, Academic Medical Center, Amsterdam, Netherlands
                Author notes
                Correspondence to: MC Walker, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada mwalker@ 123456ohri.ca
                Article
                wens044406
                10.1136/bmj.k3478
                6133042
                30209050
                446ff8aa-50cc-4d06-9f2a-41e2f55fd1a2
                Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions

                This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

                History
                : 11 July 2018
                Categories
                Research

                Medicine
                Medicine

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