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      Periconceptional multiple-micronutrient supplementation and placental function in rural Gambian women: a double-blind, randomized, placebo-controlled trial 1

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          Abstract

          Background: Maternal micronutrient deficiencies are commonly associated with clinical indicators of placental dysfunction.

          Objective: We tested the hypothesis that periconceptional multiple-micronutrient supplementation (MMS) affects placental function.

          Design: We conducted a double-blind, randomized, placebo-controlled trial of MMS in 17- to 45-y-old Gambian women who were menstruating regularly and within the previous 3 mo. Eligible subjects were pre–randomly assigned to supplementation with the UNICEF/WHO/United Nations University multiple micronutrient preparation (UNIMMAP) or placebo on recruitment and until they reached their first antenatal check-up or for 1 y if they failed to conceive. Primary outcome measures were midgestational indexes of utero-placental vascular-endothelial function [ratio of plasminogen-activator inhibitor (PAI) 1 to PAI-2 and mean uterine-artery resistance index (UtARI)] and placental active transport capacity at delivery [fetal to maternal measles antibody (MMA) ratio].

          Results: We recruited 1156 women who yielded 415 pregnancies, of which 376 met all of the inclusion criteria. With adjustment for gestational age at sampling, there were no differences in PAI-1 to PAI-2 or MMA ratios between trial arms, but there was a 0.02-unit reduction in UtARI between 18 and 32 wk of gestation (95% CI: −0.03, −0.00; P = 0.040) in women taking UNIMMAP.

          Conclusions: Placental vascular function was modifiable by periconceptional micronutrient supplementation. However, the effect was small and supplementation did not further affect other variables of placental function. This trial was registered at www.controlled-trials.com as ISRCTN 13687662.

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          Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial.

          Oxidative stress has been implicated in the pathophysiology of pre-eclampsia. This randomised controlled trial investigated the effect of supplementation with vitamins C and E in women at increased risk of the disorder on plasma markers of vascular endothelial activation and placental insufficiency and the occurrence of pre-eclampsia. 283 women were identified as being at increased risk of pre-eclampsia by abnormal two-stage uterine-artery doppler analysis or a previous history of the disorder and were randomly assigned vitamin C (1000 mg/day) and vitamin E (400 IU/day) or placebo at 16-22 weeks' gestation. Plasma markers of endothelial activation (plasminogen-activator inhibitor 1 [PAI-1]) and placental dysfunction (PAI-2) were measured every month until delivery. Pre-eclampsia was assessed by the development of proteinuric hypertension. Analyses were done by intention to treat, and in the cohort who completed the study. Supplementation with vitamins C and E was associated with a 21% decrease in the PAI-1/PAI-2 ratio during gestation (95% CI 4-35, p=0.015). In the intention-to-treat cohort, pre-eclampsia occurred in 24 (17%) of 142 women in the placebo group and 11 (8%) of 141 in the vitamin group (adjusted odds ratio 0.39 [0.17-0.90], p=0.02). In the cohort who completed the study (81 placebo group, 79 vitamin group), the odds ratio for pre-eclampsia was 0.24 (0.08-0.70, p=0.002). Supplementation with vitamins C and E may be beneficial in the prevention of pre-eclampsia in women at increased risk of the disease. Multicentre trials are needed to show whether vitamin supplementation affects the occurrence of pre-eclampsia in low-risk women and to confirm our results in larger groups of high-risk women from different populations.
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            Biological mechanisms for nutritional regulation of maternal health and fetal development.

            This review paper highlights mechanisms for nutritional regulation of maternal health and fetal development. Malnutrition (nutrient deficiencies or obesity) in pregnant women adversely affects their health by causing or exacerbating a plethora of problems, such as anaemia, maternal haemorrhage, insulin resistance, and hypertensive disorders (e.g. pre-eclampsia/eclampsia). Maternal malnutrition during gestation also impairs embryonic and fetal growth and development, resulting in deleterious outcomes, including intrauterine growth restriction (IUGR), low birthweight, preterm birth, and birth defects (e.g. neural tube defects and iodine deficiency disorders). IUGR and preterm birth contribute to high rates of neonatal morbidity and mortality. Major common mechanisms responsible for malnutrition-induced IUGR and preterm birth include: (i) abnormal growth and development of the placenta; (ii) impaired placental transfer of nutrients from mother to fetus; (iii) endocrine disorders; and (iv) disturbances in normal metabolic processes. Activation of a series of physiological responses leading to premature and sustained contraction of the uterine myometrium also results in preterm birth. Recent epidemiologic studies have suggested a link between IUGR and chronic metabolic disease in children and adults, and the effects of IUGR may be carried forward to subsequent generations through epigenetics. While advanced medical therapies, which are generally unavailable in low-income countries, are required to support preterm and IUGR infants, optimal nutrition during pregnancy may help ameliorate many of these problems. Future studies are necessary to develop effective nutritional interventions to enhance fetal growth and development and alleviate the burden of maternal morbidity and mortality in low- and middle-income countries. © 2012 Blackwell Publishing Ltd.
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              Developmental biology of the placenta and the origins of placental insufficiency.

              Defects in all the trophoblast-differentiating pathways--endovascular, interstitial and chorionic villous--play a role in the pathogenesis of early-onset intra-uterine growth restriction (IUGR). There are two types of extravillous trophoblast: endovascular trophoblast, that forms the definitive placenta by occlusion of the spiral arteriole at the implantation site, and interstitial extravillous trophoblast, responsible for the anatomical erosion of the distal spiral arteriole and the secretion of angiogenic and vasodilator signals to improve uterine blood flow. Defective endovascular erosion may render the basal plate inadequate to meet the demands of the fetus. Failed interstitial invasion of spiral arterioles could lead to failure of local angiogenic and systemic cardiovascular adaptation signals that could be the underlying basis for early-onset IUGR and pre-eclampsia. As debate persists regarding the relative importance of cord, stem and terminal villous pathology, the study of factors controlling trophoblast turnover from immature intermediate villi to conductance stem villi and gas-exchanging terminal villi, translation of our knowledge from mouse placental genetics into human placental development, and defining causes of thrombo-occlusive damage to the placenta would help our understanding of the pathophysiology of early-onset IUGR.
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                Author and article information

                Journal
                Am J Clin Nutr
                Am. J. Clin. Nutr
                ajcn
                The American Journal of Clinical Nutrition
                American Society for Nutrition
                0002-9165
                1938-3207
                December 2015
                11 November 2015
                11 November 2015
                : 102
                : 6
                : 1450-1459
                Affiliations
                [2 ]Children's Unit, Northumbria Healthcare NHS Foundation Trust, North Shields, United Kingdom;
                [3 ]Medical Research Council (MRC) International Nutrition Group, London School of Hygiene and Tropical Medicine, London, United Kingdom, and MRC Keneba, Fajara, The Gambia;
                [4 ]MRC Centre for Reproductive Health, The Queen’s Medical Research Institute, Edinburgh, United Kingdom; and
                [5 ]Child and Reproductive Health Group, Liverpool School of Tropical Medicine, Liverpool, United Kingdom
                Author notes
                [* ]To whom correspondence should be addressed. E-mail: stephen.owens@ 123456ncl.ac.uk .
                [1]

                Supported by the UK Medical Research Council (MC-A760-5QX00) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement. This is an open access article distributed under the CC-BY license ( http://creativecommons.org/licenses/by/3.0/).

                Article
                072413
                10.3945/ajcn.113.072413
                4658455
                26561613
                6370026a-1494-4798-a827-b7ae10c1229b

                This is an open access article distributed under the CC-BY license ( http://creativecommons.org/licenses/by/3.0/).

                History
                : 27 July 2013
                : 10 September 2015
                Page count
                Pages: 10
                Categories
                Pregnancy and Lactation

                Nutrition & Dietetics
                periconceptional,micronutrients,pregnancy,placenta,africa,birth weight,fetal growth
                Nutrition & Dietetics
                periconceptional, micronutrients, pregnancy, placenta, africa, birth weight, fetal growth

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