Maternal Folate Levels Research Articles

Histone modification mapping in human brain reveals aberrant expression of histone H3 lysine 79 dimethylation in neural tube defects

Neural tube defects (NTDs) are severe, common birth defects that result from failure of neural tube closure, but their pathological mechanisms are not yet fully understood. Histone modifications have an important role in gene regulation during fetal development. We therefore hypothesized that the human NTDs may be partly caused by an imbalance in metabolism, perhaps caused by nutritional deficiencies, that leads to aberrant histone modifications. Here, we report a screen of fetal brain histone modifications using 2D nano-LC strong cation exchange reverse phase (SCX/RP) MS/MS and the identification of 61 unique post-translational modification sites on histones H1, H2a, H2b, H3, and H4. Of these, 38 sites are novel (not already found in the Uniprot database). Furthermore, we compared the histone modification patterns between normal brains and NTD brains special of which maternal folate levels were lower than of normal control. The results showed that histone H3 lysine 79 dimethylation (H3K79me2) and a novel identified site, H2bK5 monomethylation (H2bK5me1), were completely absent in individuals with NTDs. Follow-up Western blotting validated the decreased H3K79me2 expression in brains with NTDs, but the amplified samples experiments displayed that decreased H3K79me2 expression was not suitable for all samples with NTDs. Furthermore, folate-free treated mouse embryonic stem cells induced the decreased H3K79me2 level. Subsequently, our ChIP results in normal fetal brain tissues showed that H3K79me2 binds to SUFU, RARA and ITGA3 which induce NTDs phenotype after knockout in mice, and in NTDs brain tissues the bindings of H3K79me2 to these three genes were significantly altered. Taken together, our study indicated that low folate treatment might attenuate H3K79 dimethylation, further affect its regulate activation on target genes, some of which are NTDs-resulting associated, lastly interrupt early embryo developing. Our study increases the understanding of normal fetal brain histone modifications and provides a platform for investigating histone modifications in neural disease and also has an insight into a potential role of aberrant histone modification in etiology of NTDs.

Recent Increase in Autism and ADHD: True or Inflated?

The prevalence of autism spectrum disorder (ASD) has increased markedly over the past 40 yr (1). It was reported to be 4-10/10,000 by the early 1990s, but increased to 20-116/10,000 after the year 2000, and was even up to 1/88 in recent studies (1, 2). The prevalence of ASD in Korea was reported to be as strikingly high as 2.64% (3). The change in the prevalence of attention deficit hyperactivity disorder (ADHD) is not as dramatic as that of ASD, but the overall trend has been similar over the past 10 yr. A survey from the United States reported that ADHD increased from 7.8% to 9.5% between 2003 and 2007 (4). There are several different interpretations as to how this change occurred within only decades. The first possible influential factors are diagnostic substitution and changes in the definitions of the diseases. In particular, some studies have suggested that diagnostic substitution (diagnosing as one condition at one time and subsequently as another condition at another time) has played an important role in the increasing prevalence of autism over time. Diagnostic substitution is closely related to changes in the diagnostic system, particularly of the broadened concept of ASD. Autism was first narrowly defined by Leo Kanner in 1943, but after the 1980s, the diagnostic system started to acknowledge milder phenotypes. The most dramatic change was listing Asperger's disorder (social impairment without language delay) and pervasive developmental disorder not otherwise specified (PDD NOS; individual who fails to meet age criteria or does not display all the key elements of autism or other subtypes of PDDs) in the DSM-IV (1994). Regarding ADHD, diagnostic substitution has not played as large a role as in ASD because the diagnostic criteria have largely remained unchanged since 1980. However, possible confounders may contribute to the variable prevalence of ADHD. The most problematic notions of the DSM-IV criteria for ADHD are functional impairment and dysfunction evident in at least 2 different settings. As the degree and range are poorly defined and are dependent on the raters, the criteria may allow room for a subjective judgment of diagnosis. The second potentially influential factors are the methods of case identification and source of data; these factors raise one of the most essential questions about whether the increased prevalence reflects a true upsurge in incidence or an increased discovery rate. In particular, when the cases are identified from a pre-registered database, such as national registers, the prevalence can be significantly biased by accessibility to healthcare and education services, the attitude of parents toward mental health problems, and the clinician's experience and level of expertise. As both ASD and ADHD are diagnosed based on behavioral profiles reported from multiple data sources and direct observation, factors affecting prevalence may be present even in population-based epidemiological studies. Typically, first-line screening depends on the checklists completed by parents, teachers, or both. Therefore, the positive screening rate might be influenced by the sensitivity of the screening instruments, the level of the raters' understanding of the questionnaire, and their pre-existing concerns regarding the disease screened. Also, the participation rate for the screening and confirmation process can be a major issue (nonresponse bias). Diagnoses are also influenced by the instruments used for the diagnostic confirmation. Thus, epidemiological studies should be cautiously interpreted as to whether these potential confounders have been carefully controlled, particularly when the reported prevalence is extremely high. The third and most controversial element in the increased prevalence is the environmental contribution to the incidence of ASD and ADHD. Environmental influences can be accounted for by gene-environmental interactions or epigenetic modification of risk gene expression. Suggested factors for ASD are mainly biological, such as intrauterine infection, advancing maternal age, air pollution, organophosphates, and heavy metals (5, 6). The relationship between the rapid increase in autism and MMR vaccinations was once debated very intensely; however, large-scale epidemiological studies have clearly disproven the possible relationship between those factors (7). The environmental risk factors for ADHD include prenatal substance exposure, heavy metals, maternal folate levels, obesity, food additives, early traumatic events, and maternal stress (8). Compared to ASD, there might be a higher possibility that recent environmental changes have contributed to the increase in ADHD. However, it has yet to be confirmed whether there is a direct, quantitative correlation between these factors and increased prevalence. Although the increase in ASD and ADHD is verging on a social issue as well as a public health concern, the underlying etiology is likely a multi-factorial one, much more complicated than the phenomenon itself. Prospective studies with identical protocols are needed for measuring genuine incidence. In the long run, the establishment of biological markers of ASD and ADHD could provide clearer answers by clarifying debates over the stability of the diagnostic system and its reliability.

763 Vitamin B12 and Folate Deficiency in Healthy Neonates and their Mothers

Background and AimWe aimed to determine the incidence of vitamin B12 and folate deficiency in healthy neonates and their mothers; to show the correlation between maternal and neonatal B12 and...

Antiepileptic drugs and the fetal epigenome

Antiepileptic drugs (AEDs) can lower maternal folate and increase maternal homocysteine levels, which are known to affect the methyl cycle and hence DNA methylation levels. The influence of in utero exposure to AEDs on fetal DNA methylation was investigated. Genome-wide fetal epigenomic profiles were determined using the Infinium 27K BeadArray from Illumina (San Diego, CA, U.S.A.). The Infinium array measures approximately 27,000 CpG loci associated with 14,496 genes at single-nucleotide resolution. Eighteen cord blood samples (nine samples from babies exposed to AEDs and nine controls) from otherwise uncomplicated pregnancies were compared. Unsupervised hierarchic clustering was used to compare the calculated methylation profiles. A clear distinction between the methylation profiles of samples from babies exposed to AEDs in utero compared with controls was detected. These data provide evidence of an epigenetic effect associated with antenatal AED and high-dose folate supplementation during pregnancy. The differences in fetal DNA methylation of those exposed to AEDs shows that a genome-wide effect of methylation is evident. In addition, the epigenetic changes observed appear to be, in this limited sample, independent of extremes of birth weight centiles. These preliminary data highlight possible mechanisms by which AEDs might influence fetal outcomes and the potential of optimizing AED-specific folate supplementation regimens to offset these effects.

Glucocorticoids in hair as biomarkers of traumatization in healthy individuals and PTSD patients

Rationale/statement of the problemSubstantial evidence suggests conditions in intrauterine life may play a critical role in subsequent health and disease susceptibility related outcomes (i.e., the concept of fetal or developmental programming of health and disease). The elucidation of biological mechanisms underlying these effects is an area of active investigation. We suggest that telomere biology may represent a novel mechanism underlying the effects of a disparate set of suboptimal intrauterine exposures on various health and disease risk phenotypes. From an evolutionary-developmental perspective, energy substrate availability (i.e., nutrition) and challenges that have the potential to impact the structural or functional integrity and survival of the organism (i.e., stress) likely represent the most important environmental considerations underlying natural selection and developmental plasticity. Maternal stress and nutrition in pregnancy therefore represent attractive candidate processes in the context of fetal programming of telomere biology. Our previous work has established an important role for prenatal stress and stress-related processes in adult telomere biologyMethodsIn two longitudinal birth cohorts, stress- and nutrition-related processes were assessed during pregnancy and telomere length (TL) was subsequently measured in newborns (cord blood) and infants (buccal cells).Results(1) Among the nutrition-related factors, maternal lower folate levels (an essential methyl donor) and higher triglyceride concentrations in early pregnancy were significantly and independently associated with shorter newborn TL. (2) Among psychosocial stress-related measures, higher maternal pregnancy-specific stress was associated with shorter newborn TL. (3) Maternal estrogen (E3) levels during early pregnancy were associated with longer infant TL.ConclusionTaken together, our findings provide the first evidence in humans that maternal nutrition and stress-related processes during pregnancy may exert a programming effect on the newborn and infant telomere biology system. In utero telomere biology represents a potential molecular mechanism whereby different exposures in this critical developmental period before birth could impact subsequent health and disease susceptibility related outcomes over the life span, including aging and longevity

Prenatal programming of newborn and infant telomere length

Rationale / statement of the problem: Substantial evidence suggests conditions in intrauterine life may play a critical role in subsequent health and disease susceptibility related outcomes (i.e., the concept of fetal or developmental programming of health and disease). The elucidation of biological mechanisms underlying these effects is an area of active investigation. We suggest that telomere biology may represent a novel mechanism underlying the effects of a disparate set of suboptimal intrauterine exposures on various health and disease risk phenotypes. From an evolutionary-developmental perspective, energy substrate availability (i.e., nutrition) and challenges that have the potential to impact the structural or functional integrity and survival of the organism (i.e., stress) likely represent the most important environmental considerations underlying natural selection and developmental plasticity. Maternal stress and nutrition in pregnancy therefore represent attractive candidate processes in the context of fetal programming of telomere biology. Our previous work has established an important role for prenatal stress and stress-related processes in adult telomere biologyMethods: In two longitudinal birth cohorts, stress- and nutrition-related processes were assessed during pregnancy and telomere length (TL) was subsequently measured in newborns (cord blood) and infants (buccal cells).Results: (1) Among the nutrition-related factors, maternal lower folate levels (an essential methyl donor) and higher triglyceride concentrations in early pregnancy were significantly and independently associated with shorter newborn TL. (2) Among psychosocial stress-related measures, higher maternal pregnancy-specific stress was associated with shorter newborn TL. (3) Maternal estrogen (E3) levels during early pregnancy were associated with longer infant TL.Conclusion: Taken together, our findings provide the first evidence in humans that maternal nutrition and stress-related processes during pregnancy may exert a programming effect on the newborn and infant telomere biology system. In utero telomere biology represents a potential molecular mechanism whereby different exposures in this critical developmental period before birth could impact subsequent health and disease susceptibility related outcomes over the life span, including aging and longevity

Folic acid supplementation is not the sole factor in determining neural tube defects: The possible role of autoantibodies

Neural tube defects (NTDs) are severe but common congenital malformations. Neonates who suffer from NTDs may experience long-term complications throughout their lives. These NTD complications which have been reduced worldwide are primarily due to environmental and genetic factors. Multicenter NTD studies conducted in Malaysia report a prevalence ranging from 0.79 to 1.29 per 1000 live births based on NTD etiologies, such as anti-epileptic drug consumption and maternal folate levels. In addition, intervention studies concluded that daily consumption of 400 μg of folic acid effectively reduced NTD risk; however, this data has not been robustly tested on the entire population due to the inefficiency of the three interrelated folate transport mechanisms and autoantibody generation. In this review, we evaluated the studies indicating that folic acid supplementation may not be the sole factor in reducing NTD incidence and that autoantibodies may have an important role in the NTD etiological pathway. Key words : Neural tube defect, folic acid, methylenetetrahydrofolate reductase (MTHFR), Malaysia, anti-epileptic, folate transport mechanisms, autoantibodies

The relationship between maternal folate status in pregnancy, cord blood folate levels, and allergic outcomes in early childhood

Dietary changes may epigenetically modify fetal gene expression during critical periods of development to potentially influence disease susceptibility. This study examined whether maternal and/or fetal folate status in pregnancy is associated with infant allergic outcomes. Pregnant women (n=628) were recruited in the last trimester of pregnancy. Folate status determined by both food frequency questionnaires and folate levels in maternal and cord blood serum was examined in relation to infant allergic outcomes at 1 year of age (n=484). Infants who developed allergic disease (namely eczema) did not show any differences in cord blood or maternal folate levels compared with children without disease. Although maternal folate intake from foods was also not different, folate derived from supplements was higher (P=0.017) in children with subsequent eczema. Furthermore, infants exposed to >500 μg folic acid/day as a supplement in utero were more likely to develop eczema than those taking <200 μg/day (OR [odds ratio] =1.85; 95% CI 1.14-3.02; P=0.013), remaining significant after adjustment for maternal allergy and other confounders. There was a nonlinear relationship between cord blood folate and sensitization, with folate levels <50 nmol/l (OR=3.02; 95% CI 1.16-7.87; P=0.024) and >75 nmol/l (OR=3.59; 95% CI 1.40-9.20; P=0.008) associated with greater sensitization risk than levels between 50 and 75 nmol/l. Fetal levels between 50 and 75 nmol/l appeared optimal for minimizing sensitization. While folate taken as a supplement in higher doses during the third trimester was associated with eczema, there was no effect on other allergic outcomes including sensitization. Further studies are needed to determine the significance of this.

Maternal one‐carbon metabolism, MTHFR and TCN2 genotypes and neural tube defects in India

Neural tube defects (NTDs) are among the most common severe congenital malformations, representing a long-term public health burden in India. A deranged one-carbon metabolism and genes regulating this metabolism have been linked to NTDs. Vitamin B(12) deficiency is reported to be more prevalent than folate deficiency in the Indian population. We investigated the role of maternal nutritional and genetic markers related to one-carbon metabolism in the etiology of NTDs. We conducted a multicenter case-control study to compare plasma folate, vitamin B(12) , homocysteine and holo-transcobalamin levels, and polymorphisms in methylenetetrahydrofolate reductase (MTHFR, 677C>T, 1298A>C, 1781G>A and 236+724A>G) and transcobalamin (TCN2, 776C>G) genes, in 318 women with NTD-affected offspring (cases) and 702 women with apparently healthy offspring (controls). The samples were collected at diagnosis in cases and at delivery in controls. We observed a significant association of high maternal plasma homocysteine concentrations with NTDs in the offspring (p = 0.026). There was no association of maternal folate or B(12) levels with NTDs (p > 0.05) but low maternal holo-transcobalamin predicted strong risk of NTDs in the offspring (p = 0.003). The commonly associated maternal polymorphism 677C>T in the MTHFR gene did not predict risk of NTDs in the offspring (p > 0.05) and 1298A>C and 1781G>A polymorphisms in MTHFR were protective (p = 0.024 and 0.0004 respectively). Maternal 776C>G polymorphism in TCN2 was strongly predictive of NTD in the offspring (p = 0.006). Our study has demonstrated a possible role for maternal B(12) deficiency in the etiology of NTDs in India over and above the well-established role of folate deficiency.

Maternal folate, vitamin B12 and homocysteine levels in pregnancies affected by congenital malformations other than neural tube defects

Background Periconceptional use of folic acid prevents most neural tube defects (NTDs). Whether folic acid and/or multivitamins can prevent other congenital anomalies is not clear. This study tested whether maternal blood levels of folate and vitamin B12 in pregnancies affected by congenital malformations excluding NTDs are lower when compared to non-affected pregnancies.

Maternal folate levels in pregnancy and asthma in children at age 3 years

This is the first study to examine measured folate levels in pregnancy in relation to respiratory outcomes in the children. Higher pregnancy levels of folate were associated with increased risk of asthma at age 3.

Serological Differences in Folate/Vitamin B12 in Pregnancies Affected by Neural Tube Defects

Laboratory evidence is presented of significant associations between reduced maternal serum folate and vitamin B12 levels and neural tube birth defects (NTD) compared to referents. This was an incident case-control study. Cases of neural tube defects (including anencephaly and open spina bifida) diagnosed in residents within 100 miles of the US-Mexico border from January 1993 to October 2000 were eligible. Most cases were diagnosed in utero upon visits to clinics, obstetrical or genetic expert offices. Cases identified upon hospital admission or at delivery were also eligible. Cases identified after discharge were not. Controls were matched on geographic region, maternal age, race/ethnicity, gestational age, and type of health insurance (including none). Three hundred eighty-two border area residents (107 cases and 275 individually matched controls) provided biological specimens. Median folate concentrations for case mothers were 36% lower than controls (9.8 ng/mL vs. 15 ng/mL). Maternal serum folate concentrations in quartiles above 9.5 ng/mL indicated significantly reduced risk (OR = 0.4, OR = 0.3, and OR = 0.2). Likewise, the risk for NTD decreased (OR = 0.4, OR = 0.3, and OR = 0.2) in quartiles of sera B12 concentrations above 246 pg/mL. Physician attention is invited to significantly lower concentrations of serum folate and vitamin B12 in women with NTD-affected pregnancies. This study assayed sera samples from women while still pregnant or immediately after delivery. The confounding effect of reduced folate and B12 levels with other biological and chemical exposures will be addressed in subsequent communications.

Folate status, serum C‐reactive protein level and gestational age: Mothers and Children′s Environmental Health (MOCEH)

Folate deficiency and elevated serum C‐reactive protein (CRP) levels in pregnant women are independently known to be associated with adverse pregnancy outcomes, however, limited studies have been reported. This study was to investigate the relation between folate nutrition and elevated CRP level during pregnancy and their associations with birth outcome in 883 pregnant women of 12–28 weeks of gestation. Serum folate and CRP levels were analyzed by the radioimmunoassay and latex agglutination test, respectively. Maternal serum folate levels at mid‐pregnancy were positively correlated with dietary folate intake at mid‐pregnancy (p&lt;0.05). Maternal serum CRP levels at mid‐ (p&lt;0.05) and late‐pregnancy (p&lt;0.01) were negatively correlated with serum folate levels at each time of pregnancy, respectively. Multiple regression analysis with covariates revealed that the maternal CRP levels at mid‐ and late‐pregnancy were negatively associated with the gestational age. Further studies are warranted to explore the mechanisms underlying the associations between folate nutrition and CRP levels during pregnancy, and adverse pregnancy outcome.Supported by the Ministry of Environment and the 2nd stage of Brain Korea 21 project in 2009.

Folic acid fortification: a double-edged sword

To examine the impact of folic acid fortification, including its use as a functional food component, on human health. There is a consensus view that folic acid supplementation has numerous health benefits, many of which are significant in their impact. However, emerging evidence suggests that increased population exposure to folic acid may also have a negative impact with respect to certain developmental and degenerative disorders. As examples, presently much attention is focused on the role of folic acid fortification augmenting colon cancer risk, whereas earlier in the life cycle, the vitamin may additionally influence insulin resistance. Without question, conditions that are influenced by folic acid are both diverse and many - from concerns relating to cognitive decline, breast cancer and vascular disease through to preconceptional issues where maternal folate levels might conceivably alter the phenotype of offspring via epimutations. The highly complex and critical biological importance of folic acid-related molecular nutrition makes it a difficult micronutrient to deploy as a simple intervention at a population level - it has far too many biochemical spheres of influence to predict effects in a generalized way. Additionally, several gene variants and other nutrients are interactive factors. It is, therefore, hardly surprising that the scientific community does not have a true consensus view on whether mandatory fortification is appropriate as a population measure. This latter point not withstanding, any ultimate decisions on fortification should be well rooted in scientific fact rather than political expediency.

Reduced folate carrier 80A→G polymorphism, plasma folate, and risk of placental abruption

Folate deficiency and maternal smoking are strong risk factors for placental abruption. We assessed whether the reduced folate carrier [NM_194255.1: c.80A-->G (i.e., p.His27Arg)] (RFC-1) polymorphism was associated with placental abruption, and evaluated if maternal smoking modified the association between plasma folate and abruption. Data were derived from the New Jersey-Placental Abruption Study--a multicenter, case-control study of placental abruption (2002-2007). Maternal DNA was assayed for the RFC-1 c.80A-->G polymorphism using a PCR-dependent diagnostic test. Maternal folate (nmol/l) was assessed from maternal plasma, collected immediately following delivery. Due to assay limitations, folate levels at > or =60 nmol/l were truncated at 60 nmol/l. Therefore, case-control differences in folate were assessed from censored log-normal regression models following adjustment for potential confounders. Distribution of the mutant allele (G) of the RFC-1 c.80A-->G polymorphism was similar between cases (52.3%; n = 196) and controls (50.5%; n = 191), as was the homozygous mutant (G/G) genotype (OR 1.1, 95% CI 0.6-2.2). In a sub-sample of 136 cases and 140 controls, maternal plasma folate levels (mean +/- standard error) corrected for assay detection limits were similar between placental abruption cases (63.6 +/- 5.1 nmol/l) and controls (58.3 +/- 4.7 nmol/l; P = 0.270), and maternal smoking did not modify this relationship (interaction P = 0.169). We did not detect any association between the RFC-1 c.80A-->G polymorphism and placental abruption, nor was an association between plasma folate and abruption risk evident. These findings may be the consequence of high prevalence of prenatal multivitamin and folate supplementation in this population (over 80%). It is therefore not surprising that folate deficiency may be rare and that the RFC-1 c.80A-->G polymorphism is less biologically significant for placental abruption.

Associations of maternal folate intake with antepartum and postpartum serum folate levels

This study was carried out to evaluate the effect of maternal folate intake on the maternal serum folate level. Pregnant women of 18–20 weeks of gestation were recruited from prenatal clinic in Seoul, Cheonan and Ulsan. In 429 pregnant women, dietary intake during pregnancy was assessed by a 24‐hour recall method. Serum folate level was analyzed by the radioimmunoassay(RIA). The daily mean energy and protein intakes were 1804.9 kcal (90.9% of EER), 68.1g (125.8% of EAR, 97.0% of RI), respectively. The average daily folate intake was 238.2 μg DFE (45.95% of EAR, 39.82% of RI) for the pregnant women. The maternal antepartum(18–20 wk) and postpartum(at delivery) serum folate concentration were 10.4 ± 7.9 ng/ml, 13.5 ± 9.3 ng/ml. The maternal antepartum serum folate level was significantly lower than that of the postpartum serum(p&lt;0.001). Pregnant women whose intake of folate was above the median value showed a greater increase in postpartum serum folate level than those with intakes below the median(p&lt;0.05). Maternal intake of folate was positively correlated with postpartum serum folate level (p&lt;0.05). These results suggest that the maternal folate intake may affect the postpartum folate level.This work was supported by the Ministry of Environment and the Brain Korea 21 project in 2007

Endothelial Function in Newborn Infants Is Related to Folate Levels and Birth Weight

Low maternal folate levels during pregnancy correlate with low birth weight, a perinatal risk factor for later cardiovascular disease. We studied relationships between red blood cell folate levels, birth weight, and vascular endothelial function (a key factor in the early pathophysiologic processes of heart disease) in newborn infants. We included 82 infants (30 low birth weight) and their mothers. A laser Doppler technique was used to measure skin perfusion during transdermal iontophoresis of acetylcholine (an endothelium-dependent vasodilator). Red blood cell folate, vitamin B12, and homocysteine levels were determined. The perfusion response to acetylcholine was lower in low birth weight infants than in normal birth weight control subjects (mean: 35 vs 76 perfusion units). The neonatal acetylcholine response correlated with red blood cell folate levels in both infants and their mothers. The folate levels of low birth weight and control infants did not differ significantly (mean: 1603 vs 1795 nmol/L), but mothers of low birth weight infants had lower folate levels than did mothers of control infants (mean: 805 vs 1109 nmol/L). In multivariate analysis, low birth weight and red blood cell folate levels contributed independently to endothelial function in newborn infants. The levels of vitamin B12 and homocysteine were similar in the 2 groups and did not correlate with endothelial function. The data presented here provide the first evidence for a relationship between folate levels and vascular endothelial function in newborn infants.

Maternal plasma and erythrocyte folate levels and risk of oral clefts in Utah

Maternal plasma and erythrocyte folate levels and risk of oral clefts in Utah

Folate, vitamin B12, and homocysteine levels in South Asian women with growth‐retarded fetuses

To investigate whether intrauterine growth retardation (IUGR) and preterm delivery in a poor population of South Asia was associated with altered maternal and fetal levels of folate, vitamin B12, and homocysteine. Hundred and twenty-eight pregnant women from a low socio-economic strata in the city of Lahore, Pakistan were followed with ultrasound of fetal growth from the 12th week of pregnancy. Blood samples were drawn from the woman and the cord at delivery. Serum was analyzed by a chemiluminescent immunoassay for folate and vitamin B12 and by fluorescence polarization immunoassay for total homocysteine (tHcy). Fourty-six infants showed IUGR. In term, but not preterm, deliveries with IUGR, maternal and cord blood folate levels were half of those in deliveries of normal birth weight infants (P=0.004 and P=0.005). The risk of IUGR was reduced among women with folate levels in the highest quartile (OR 0.31, 95% CI 0.10--0.84). There was no association between vitamin B12 and IUGR. Total homocysteine levels were higher in women delivering IUGR infants (P=0.02). There was an inverse correlation between cord blood folate and tHcy levels (r=-0.26, P=0.006). We also found increased risks for hypertensive illness (OR 3.5, 95% CI 1.4--8.6) and premature delivery (OR 2.5, 95% CI 1.1--6.2) in women in the highest quartile of tHcy. The occurrence of IUGR increased with low maternal and cord concentrations of folate and high maternal levels of tHcy. Further studies on the effects of vitamin B supplementation through pregnancy are warranted.

The impact of plasma folate levels of mothers and newborns on intrauterine growth retardation and birth weight

Folate plays an important role in the genomic stability of human cells. In our studies of the impact of environmental pollution on human health, we have found that air pollution can affect pregnancy outcome. As it may be also affected by nutrition, we examined the effect of plasma folate levels of mothers and newborns on intrauterine growth retardation (IUGR) and birth weight (BW) in cohorts from Prague ( N = 319) and Teplice ( N = 444). The lower plasma levels (<6.1 nmol/L) were observed in 7.1% of mothers in Prague, and in 9.6% of mothers in Teplice. The higher plasma levels (>36.5 nmol/L) were observed in 28.4% of mothers in Prague, and in 15.7% of mothers in Teplice. The higher plasma levels were observed in 75.4% of newborns in Prague, and 73.2% of newborns in Teplice. When comparing maternal high versus low folate plasma levels and IUGR by logistic regression, the risk of IUGR was significantly decreased for European cohort (according to ethnicity) with gestation age >36 weeks [ N = 536, OR = 0.44, P = 0.026], and even more pronounced in the group of European smokers [ N = 157, OR = 0.14, P = 0.015]. Using multiple regression analysis, plasma folate levels of mothers and newborns significantly affected the birth weight of newborns of smoking mothers ( P < 0.05). The obtained results seem to indicate a positive effect of folate on pregnancy outcome, especially its potential to decrease the risk of IUGR in European population and lower birth weight in smoking European mothers. It would be warranted to study the effect of folate levels on pregnancy outcomes in the relationship to different environmental pollution and life styles of mothers.