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Folic acid supplementation in pregnancy: are there

devils in the detail?

Burdge GC, Lillycrop KA.

Academic Unit of Human Development and Health, Faculty of Medicine, Institute of Developmental Sciences Building (MP887), Southampton General Hospital, University of Southampton, Tremona Road, Southampton SO16 6YD, UK.

Maternal folic acid (FA) supplementation is well recognised to protect against neural tube defects. Folate is a critical cofactor in one-carbon metabolism involved in the epigenetic regulation of transcription that underpins development. Thus, it is possible that maternal FA supplementation may have additional, unforeseen persistent effects in the offspring. This is supported by the modification by maternal supplementation with one-carbon donors and FA of the epigenetic regulation of offspring phenotype in mutant mice. The present article reviews studies in human subjects and experimental animals of the effect of maternal FA intake and phenotypic outcomes in the offspring. Maternal FA intake was associated with a short-term increased incidence of allergy-related respiratory impairment in children and multigenerational respiratory impairment in rats. Higher maternal folate status during pregnancy was associated positively with insulin resistance in 6-year-olds. In rats, maternal FA supplementation modified hepatic metabolism and vascular function through altered transcription, in some cases underpinned by epigenetic changes. FA supplementation in pregnant rats increased mammary tumorigenesis, but decreased colorectal cancer in the offspring. Maternal FA supplementation decreased a range of congenital cardiac defects in children. These findings support the view that maternal FA supplementation induces persistent changes in a number of phenotypic outcomes in the offspring. However, the number of studies is limited and insufficient to indicate a need to change current recommendations for FA intake in pregnancy. Nevertheless, such effects should be investigated thoroughly in order to support firm conclusions about the risk of unanticipated long-term negative effects of maternal FA supplementation in humans
PMID:23046900[PubMed - as supplied by publisher]


Awareness of periconceptional folic acid supplementation among Nepalese women of childbearing age: a cross-sectional study.
Paudel P, Wing K, Silpakar SK.


Department of General Surgery, Kathmandu Model Hospital, GPO Box: 6064, Pradarshani Marg, Kathmandu, Nepal. Electronic address:

OBJECTIVE: Maternal folate deficiency is associated with neural tube defects (NTDs), the most common congenital birth defect at Maternity Hospital, Kathmandu, Nepal. NTDs can be prevented with periconceptional folic acid supplementation (FAS). This study was performed to assess the awareness of FAS among women of reproductive age in Kathmandu. METHODS: A semi-structured questionnaire was administered to 400 randomly selected patients aged 15 to 45years visiting Kathmandu Model Hospital from May to July 2011, seeking any awareness of FAS, knowledge of its impact on fetal development and knowledge of the appropriate time of supplementation. RESULTS: Forty percent (95% CI 35.1-45.0) of women had heard about FAS, 16.3% (95% CI 12.8-20.2) knew that folate affects fetal health and 5.0% (95% CI 3.1-7.6) knew that it should be taken pre-pregnancy. Level of education was strongly associated with awareness (multivariate Odds Ratio for lowest vs. highest level of education: 0.29, 95% CI 0.15-0.56). CONCLUSIONS: Knowledge of FAS is very low among women of childbearing age in Kathmandu. Inclusion of FAS information in health awareness programs is recommended. Copyright 2012 Elsevier Inc. All rights reserved.
PMID:22975411[PubMed - as supplied by publisher

Effect of folate intake on health outcomes in pregnancy: a systematic review and meta-analysis on birth weight, placental weight and length of gestation.
Fekete K, Berti C, Trovato M, Lohner S, Dullemeijer C, Souverein OW , Cetin I, Decsi T.

ABSTRACT: The beneficial effect of folic acid supplementation before and shortly after conception is well recognized, whereas the effect ofsupplementation during the second and third trimesters is controversial and poorly documented. Our aims were to systematically review randomized controlled trials (RCTs) investigating the effect of folate supplementation on birth weight, placental weight and length of gestation and to assess the dose--response relationship between folate intake (folic acid plus dietary folate) and health outcomes. The MEDLINE, EMBASE and Cochrane Library CENTRAL databases were searched from inception to February 2010 for RCTs in which folate intake and health outcomes in pregnancy were investigated. We calculated the overall intake-health regression coefficient (beta^) by using random-

effects meta-analysis on a loge-loge scale. Data of 10 studies from 8 RCTs were analyzed. We found significant dose--response relationship between folate intake and birth weight (P=0.001), the overall beta^ was 0.03 (95% confidence interval (CI): 0.01, 0.05). This relationship indicated 2% increase in birth weight for every two-fold increase in folate intake. In contrast, we did not find any beneficial effect of folate supplementation on placental weight or on length of gestation. There is a paucity of well-conducted RCTs investigating the effect of folate supplementation on health outcomes in pregnancy. The dose-response methodology outlined in the present systematic review may be useful for designing clinical studies on folate supplementation and for developing recommendations for pregnant women.
PMID:22992251[PubMed - as supplied by publisher]

Benefits of docosahexaenoic acid, folic acid, vitamin D and iodine on foetal and infant brain development and function following maternal supplementation during pregnancy and lactation.
Morse NL.

Efamol Ltd., 14 Mole Business Park, Leatherhead KT22 7BA, UK.

Scientific literature is increasingly reporting on dietary deficiencies in many populations of some nutrients critical for foetal and infant brain development and function. PURPOSE: To highlight the potential benefits of maternal supplementation with docosahexaenoic acid (DHA) and other important complimentary nutrients, including vitamin D, folic acid and iodine during pregnancy and/or breast feeding for foetal and/or infant brain development and/or function. METHODS: English language systematic reviews, meta-analyses, randomised controlled trials, cohort studies, crosssectional and case-control studies were obtained through searches on MEDLINE and the Cochrane Register of Controlled Trials from January 2000 through to February 2012 and reference lists of retrieved articles. Reports were selected if they included benefits and harms of maternal supplementation of DHA, vitamin D, folic acid or iodine supplementation during pregnancy and/or lactation. RESULTS: Maternal DHA intake during pregnancy and/or lactation can prolong high risk pregnancies, increase birth weight, head circumference and birth length, and can enhance visual acuity, hand and eye co-ordination, attention, problem solving and information processing. Vitamin D helps maintain pregnancy and promotes normal skeletal and brain development. Folic acid is necessary for normal foetal spine, brain and skull development. Iodine is essential for thyroid hormone production necessary for normal brain and nervous system development during gestation that impacts childhood function.

CONCLUSION: Maternal supplementation within recommended safe intakes in populations with dietary deficiencies may prevent many brain and central nervous system malfunctions and even enhance brain development and function in their offspring.
PMID:22852064[PubMed - in process] PMCID:PMC3407995

Effects of prenatal and/or postnatal (maternal and/or child) folic acid supplementation on the mental performance of children.
Skrka A, Gieruszczak-Biaek D, Piecik M, Szajewska H.

Department of Pediatrics, The Medical University of Warsaw, Warsaw, Poland.

It has been suggested that a deficiency in folic acid during early, critical central nervous system development may result in persistent cognitive and behavioral effects. The purpose of this systematic review was to evaluate evidence regarding whether folic acid supplementation during pregnancy and early life influences mental performance outcomes in children. The following electronic databases were searched through December 2009 for studies relevant to mental performance and folic acid: MEDLINE, EMBASE and The Cochrane Library; additional references were obtained from reviewed articles. Only randomized controlled trials (RCTs) were included. Of 8 RCTs identified, only 2 met the inclusion criteria. Both studies involved periconceptional, multivitamin-containing, folic acid supplementation. Evidence from these 2 RCTs suggests that such supplementation does not affect the postnatal mental development of infants at a mean age of 11 mo, the developmental quotient (DQ) at 2 y of age, or the intelligence quotient (IQ) and Goodenough man drawing test quotient (DrQ) at 6 y of age. We conclude that the use of multivitamin-containing folic acid supplementationduring pregnancy is associated with no benefit to the mental performance of children. These findings should be interpreted with caution due to the very limited number of studies included in this systemic review.
PMID:22823344[PubMed - in process

Extremely high prevalence of neural tube defects in a 4-county area in Shanxi Province, China.

Li Z, Ren A, Zhang L, Ye R, Li S, Zheng J, Hong S, Wang T, Li Z.

Institute of Reproductive and Child Health, Peking University Health Science Center, People's Republic of China.

BACKGROUND: In the past, northern China's Shanxi Province has reported the highest incidence of neural tube defects (NTDs) in the world. However, little is known about the epidemiology of NTDs in this area in recent years. METHODS: Data were collected from a population-based birth defects surveillance system in 4 counties that captures information on all live births, stillbirths of at least 20 weeks' gestation, and pregnancy terminations at any gestational age resulting from prenatal diagnosis of a birth defect. We also surveyed mothers of NTD case patients to determine their use of folic acid before and during early pregnancy. RESULTS: During 2003, 160 NTD cases were identified among 11,534 births (NTD birth prevalence = 138.7/10,000 births). The rates of anencephaly, spina bifida and encephalocele were 65.9, 58.1, and 14.7 per 10,000, respectively, and a female predominance was observed among anencephaly cases (male-to-female relative risk [RR], 0.49; 95% confidence interval [CI], 0.30-0.79), but not among spina bifida (RR, 0.90; 95% CI, 0.55-1.45) and encephalocele (RR, 1.03; 95% CI, 0.40-2.69) cases. The percentages of pregnancy termination following prenatal diagnosis of anencephaly, spina bifida, and encephalocele were 50%, 41.8%, and 35.3%, respectively. NTD birth prevalence tended to be higher among mothers aged <20 or > or =30 years (P = .06) and was markedly associated with lower levels of maternal education (P < .001). Among 143 NTD mothers, only 6 (4.2%) used folicacid supplements during the periconceptional period. CONCLUSIONS: The NTD birth prevalence rate in the study area is among the highest worldwide. Folic acid deficiency may be one important risk factor. Copyright 2006 Wiley-Liss, Inc.
PMID:16575897[PubMed - indexed for MEDLINE

Epidemiologic and genetic aspects of spina bifida and other neural tube defects.
Au KS, Ashley-Koch A, Northrup H.

Division of Medical Genetics, Department of Pediatrics, The University of Texas, Medical School at Houston, Houston, Texas 77030, USA.


The worldwide incidence of neural tube defects (NTDs) ranges from 1.0 to 10.0 per 1,000 births with almost equal frequencies between two major categories: anencephaly and spina bifida (SB). Epidemiological studies have provided valuable insight for (a) researchers to identify nongenetic and genetic factors contributing to etiology, (b) public health officials to design and implement policies to prevent NTD pregnancies, and (c) individuals to take precautions to reduce the chance of having an NTDaffected pregnancy. Despite extensive research, our knowledge of the genetic etiology of human NTDs is limited. Although more than 200 small animal models with NTDs exist, most of these models do not replicate the human disease phenotype. Over a hundred candidate genes have been examined for risk association to human SB. The candidate genes studied include those important in folic acid metabolism, glucose metabolism, retinoid metabolism, and apoptosis. Many genes that regulate transcription in early embryogenesis and maintain planar cell polarity have also been tested as candidates. Additionally, genes identified through mouse models of NTDs have been explored as candidates. We do not know how many genes in the human genome may confer risk for NTDs in human. Less than 20% of the studied candidate genes have been determined to confer even a minor effect on risk association. Many studies have provided conflicting conclusions due to limitations in study design that potentially affect the power of statistical analysis. Future directions such as genomewide association studies (GWAS) and whole exome or even whole genome sequencing are discussed as possible avenues to identify genes that affect risk for human NTDs.
PMID:20419766[PubMed - indexed for MEDLINE] PMCID:PMC3053142

[The effect of folic acid fortification on the reduction of neural tube defects].
[Article in Portuguese]
Santos LM, Pereira MZ.

Departamento de Nutrio, Faculdade de Cincias da Sade, Universidade de Braslia, Braslia, Brasil.

Neural tube defects are congenital malformations that occur during initial fetal development, leading to anencephaly and spina bifida; folic acid deficiency is the most important risk factor identified to date. Brazil has one of the world's highest neural tube defect rates. Food consumption surveys among pregnant Brazilian women showed a high rate of inadequate folic acid intake (< 0.6 mg/day). In 2004, the National Health Surveillance Agency (ANVISA) mandated the fortification of corn meal and wheat flour with folic acid (0.15 mg/100g). The National Family Budget Survey estimated the average amount of bread/flour products available in households as 106.1g/day (contributing with 0.16 mg folic acid/day). However, while in the South of the country the supply was 144 g/day, in the North and Central West it barely reached 70 g/day. Folic acid food fortification is mandatory in some 40 countries, but only four have assessed this strategy. The existing studies have all shown a significant impact, ranging from 19 to 78%. Folic acid fortification is an undeniably important intervention for primary prevention, and neural tube defects can now be considered a preventable epidemic.

PMID:17187100[PubMed - indexed for MEDLINE]