Homocysteine and Folate Concentrations in Early Pregnancy and the Risk of Adverse Pregnancy Outcomes

The Generation R Study Group, Department of Obstetrics and Gynaecology/Division of Obstetrics and Prenatal Medicine, Erasmus University Medical Centre, Rotterdam, the Netherlands.
BJOG An International Journal of Obstetrics & Gynaecology (Impact Factor: 3.45). 05/2012; 119(6):739-51. DOI: 10.1111/j.1471-0528.2012.03321.x
Source: PubMed


To investigate associations between early pregnancy homocysteine, folate and vitamin B12 concentrations and placental weight, birthweight and adverse pregnancy outcomes.
Population-based birth cohort study.
Rotterdam, the Netherlands.
Cohort of 5805 pregnant women.
To analyse homocysteine, folate and vitamin B12 concentrations, blood was drawn in early pregnancy. These concentrations were divided into quintiles. Information on birth outcomes was retrieved from medical records. Multivariate regression analyses were used.
Placental weight, birthweight, small for gestational age at birth (SGA) (<5th centile), prematurity and pre-eclampsia.
High homocysteine concentrations (highest quintile) were associated with lower placental weight (difference 30 g; P < 0.001) and birthweight (difference 110 g; P < 0.001), and increased risk of SGA [odds ratio (OR) 1.7; P = 0.006] compared with lowest quintile (reference). Low folate concentrations (lowest quintile) were associated with lower placental weight (difference 26 g; P = 0.001) and birthweight (difference 125 g; P < 0.001), and increased risks of SGA (OR 1.9; P = 0.002), prematurity (OR 2.2; P = 0.002) and pre-eclampsia (OR 2.1; P = 0.04) compared with highest quintile (reference). The risk of developing SGA and pre-eclampsia was substantially higher in women who had higher homocysteine and lower folate concentrations. No associations were found with vitamin B12.
Higher homocysteine and lower folate concentrations in early pregnancy are associated with lower placental weight and birthweight, and higher risk of adverse pregnancy outcomes. These findings suggest that high homocysteine and low folate concentrations in early pregnancy may adversely influence placentation and subsequently affect the success of pregnancy and birth outcomes.

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Available from: Hein Raat, Jan 15, 2015
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    • "Birth weight shows a positive association with FA intake or folate status [33] [34] [35] which is explained by extension of the gestational age or prevention of preterm birth. Newborns of Dutch women with serum folate > 25.8 nmol/L were on average 167 g heavier than those of women with serum folate < 9.3 nmol/L [36]. Considering FA supplementation, birth outcomes were studied in newborns of Hungarian women. "
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    ABSTRACT: Each year approximately 2400 pregnancies develop folic acid-preventable spina bifida and anencephaly in Europe. Currently, 70% of all affected pregnancies are terminated after prenatal diagnosis. The prevalence of neural tube defects (NTDs) has been significantly lowered in more than 70 countries worldwide by applying fortification with folic acid. Periconceptional supplementation of folic acid also reduces the risk of congenital heart diseases, preterm birth, low birth weight, and health problems associated with child mortality and morbidity. All European governments failed to issue folic acid fortification of centrally processed and widely eaten foods in order to prevent NTDs and other unwanted birth outcomes. The estimated average dietary intake of folate in Germany is 200 μg dietary folate equivalents (DFE)/day. More than half of German women of reproductive age do not consume sufficient dietary folate to achieve optimal serum or red blood cell folate concentrations (>18 or 1000 nmol/L, respectively) necessary to prevent spina bifida and anencephaly. To date, targeted supplementation is recommended in Europe, but this approach failed to reduce the rate of NTDs during the last 10 years. Public health centers for prenatal care and fortification with folic acid in Europe are urgently needed. Only such an action will sufficiently improve folate status, prevent at least 50% of the NTD cases, reduce child mortality and morbidity, and alleviate other health problems associated with low folate such as anemia.
    Journal of Perinatal Medicine 03/2015; DOI:10.1515/jpm-2014-0346 · 1.36 Impact Factor
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    • "The first consequence of even light folate insufficiency is an increase of plasmatic homocysteine. Such a condition is clinically silent, but is now recognized as a metabolic risk factor for many multifactorial diseases [27,28]. "
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    ABSTRACT: BackgroundIn 2010 a Cochrane review confirmed that folic acid (FA) supplementation prevents the first- and second-time occurrence of neural tube defects (NTDs). At present some evidence from observational studies supports the hypothesis that FA supplementation can reduce the risk of all congenital malformations (CMs) or the risk of a specific and selected group of them, namely cardiac defects and oral clefts. Furthermore, the effects on the prevention of prematurity, foetal growth retardation and pre-eclampsia are unclear.Although the most common recommendation is to take 0.4 mg/day, the problem of the most appropriate dose of FA is still open.The aim of this project is to assess the effect a higher dose of peri-conceptional FA supplementation on reducing the occurrence of all CMs. Other aims include the promotion of pre-conceptional counselling, comparing rates of selected CMs, miscarriage, pre-eclampsia, preterm birth, small for gestational age, abruptio placentae.Methods/DesignThis project is a joint effort by research groups in Italy and the Netherlands. Women of childbearing age, who intend to become pregnant within 12 months are eligible for the studies. Women are randomly assigned to receive 4 mg of FA (treatment in study) or 0.4 mg of FA (referent treatment) daily. Information on pregnancy outcomes are derived from women-and-physician information.We foresee to analyze the data considering all the adverse outcomes of pregnancy taken together in a global end point (e.g.: CMs, miscarriage, pre-eclampsia, preterm birth, small for gestational age). A total of about 1,000 pregnancies need to be evaluated to detect an absolute reduction of the frequency of 8%. Since the sample size needed for studying outcomes separately is large, this project also promotes an international prospective meta-analysis.DiscussionThe rationale of these randomized clinical trials (RCTs) is the hypothesis that a higher intake of FA is related to a higher risk reduction of NTDs, other CMs and other adverse pregnancy outcomes. Our hope is that these trials will act as catalysers, and lead to other large RCTs studying the effects of this supplementation on CMs and other infant and maternal outcomes.Trial registrationItalian trial: ClinicalTrials.gov Identifier: NCT01244347.Dutch trial: Dutch Trial Register ID: NTR3161.
    BMC Pregnancy and Childbirth 05/2014; 14(1):166. DOI:10.1186/1471-2393-14-166 · 2.19 Impact Factor
    • "Some randomized trials have also been shown that prenatal use of vitamins, including folic acid, is associated with infant birth size.[3637] The improvement in the birth size due to high content of folic acid in the multivitamin-mineral supplement group may be resulted from its effect in the increase of placental size, cell number[38] and rescue the gene expressions negatively induced by IUGR.[39] Despite the non-significant effect of received supplements by pregnant women in this study, we found a significant predictor of between the two groups in terms of their effects on infants’ weight and length. "
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    ABSTRACT: Increased requirement and decreased dietary intakes of micronutrients during pregnancy might affect maternal health and pregnancy outcomes. This study was aimed to examine the effects of two types of multiple micronutrient supplementations on pregnancy outcomes in Kashan, Iran. In a randomized single-blind controlled clinical trial, 104 primigravid singleton pregnant women aged 18-30 years were randomly assigned to receive either a multivitamin (n = 51) or a multivitamin-mineral (n = 53) supplements for 20 weeks. Participants consumed supplements once a day at week 16 of gestation. Maternal anthropometric data as well as newborn's weight, height, head circumference and 5-min Apgar score were also determined. Independent samples t-test was used for comparing between-group means. Multivariate linear regression analysis was used to identify determinants of newborn's weight, height and head circumference. Women taking multivitamin-mineral supplements gained marginally less weight until week 28 than those taking multivitamin supplements (weight at week 28 of gestation: 67.5 ± 11.4 vs. 71.6 ± 10.3 kg, P = 0.06). Mean body mass index at week 28 (25.8 ± 4.0 vs. 28.4 ± 3.7 kg/m(2), P = 0.001) as well as at delivery (28.0 ± 3.9 vs. 30.1 ± 3.8 kg/m(2), P = 0.006) was lower among women taking multivitamin-mineral supplements than those taking multivitamin supplements. Although no significant difference was seen in newborns' height and Apgar score between the two groups, mean birth weight (3.3 ± 0.4 vs. 3.1 ± 0.4 kg, P = 0.04) and head circumference (35 ± 1.4 vs. 34 ± 1.3 cm, P < 0.0001) of the infants whose mothers receiving multivitamin-mineral supplements were higher than those whose mothers received multivitamins. Multivitamin-mineral use by pregnant women was a significant predictor of infants' weight (β =0.191, P = 0.03) and head circumference (β =0.907, P = 0.005). In conclusion, we found that birth weight and head circumference was increased in infants whose mothers received multivitamin-mineral supplements for 5 months during pregnancy compared with infants whose mothers received multivitamin supplements.
    International journal of preventive medicine 04/2014; 5(4):439-46.
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