Folic Acid In Early Pregnancy Research Articles

Diabetic Nephropathy in Women With Preexisting Diabetes: From Pregnancy Planning to Breastfeeding

In women with preexisting diabetes and nephropathy or microalbuminuria, it is important to deliver careful preconception counselling to assess the risk for the mother and the foetus, for optimizing glycaemic status and to adjust medical treatment. If serum creatinine is normal in early pregnancy, kidney function is often preserved during pregnancy, but complications such as severe preeclampsia and preterm delivery are still common. Perinatal mortality is now comparable with that in women with diabetes and normal kidney function. Besides strict glycaemic control before and during pregnancy, early and intensive antihypertensive treatment is important to optimize pregnancy outcomes. Methyldopa, labetalol, nifedipine and diltiazem are considered safe, whereas angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers should be stopped before or at confirmation of pregnancy. Supplementation with folic acid in early pregnancy and low-dose aspirin from 10 to 12 weeks reduces the risk of adverse pregnancy outcomes. During breastfeeding, several ACE inhibitors are considered safe.

Risk and protective factors in the origin of atrial septal defect secundum--national population-based case-control study.

The aim of this study was to assess the risk factors in the origin of lethal or surgically corrected isolated atrial septal defect secundum. The population-based Hungarian Case-Control Surveillance of Congenital Abnormalities (conducted between 1980 and 1996) comprised 472 atrial septal defect secundum cases, 678 matched controls and 38,151 available controls without any defects; in addition, 21,022 malformed controls with other isolated defects. Medically recorded chronic disorders in the prenatal maternity logbook were evaluated, while acute maternal diseases, drug treatments and pregnancy supplements were analyzed on the basis of both prospective medically recorded data and retrospective maternal information. Acute pelvic inflammatory disease, paroxysmal supraventricular tachycardia and phenolphthalein treatment due to severe constipation of mothers were shown to contribute to the development of atrial septal defect secundum of their children. High doses of folic acid in early pregnancy had positively influenced a minor part of isolated atrial septal defect secundum in foetuses. In conclusion, the obvious genetic predisposition for atrial septal defect secundum is connected with maternal paroxysmal supraventricular tachycardia and triggered by acute pelvic inflammatory diseases and phenolphthalein treatment, while the manifestation of atrial septal defect secundum can be reduced by high doses of folic acid supplementation in early pregnancy.

One‐carbon metabolite levels in mid‐pregnancy and risks of conotruncal heart defects

Evidence exists for an association between use of vitamin supplements with folic acid in early pregnancy and reduced risk for offspring with conotruncal heart defects. A few observations have been made about nutrients related to one-carbon metabolism other than folate. Our prospective study attempted to extend information on nutrition and conotruncal heart defects by measuring analytes in mid-pregnancy sera. This study included data from a repository of women's mid-pregnancy serum specimens based on screened pregnancies in California from 2002-2007. Each woman's specimen was linked with delivery information to determine whether her fetus had a conotruncal heart defect or another structural malformation, or was nonmalformed. We identified 140 conotruncal cases and randomly selected 280 specimens as nonmalformed controls. Specimens were tested for a variety of analytes, including homocysteine, methylmalonic acid, folate, vitamin B12 , pyridoxal phosphate, pyridoxal, pyridoxic acid, riboflavin, total choline, betaine, methionine, cysteine, cystathionine, arginine, asymmetric and symmetric dimethylarginine. We did not observe statistical evidence for substantial differences between cases and controls for any of the measured analytes. Analyses specifically targeting B-vitamins also did not reveal differences between cases and controls.

Maternal hypertension with nifedipine treatment associated with a higher risk for right-sided obstructive defects of the heart: a population-based case–control study

ObjectiveTo establish possible aetiological factors contributing to congenital heart defects (CHD) overall and separately for different types of CHD, as causes are unknown for the vast majority of patients.DesignTo estimate...

Risk and protective factors in the origin of conotruncal defects of heart—a population‐based case–control study

Congenital heart defect (CHD) cases have been evaluated together as a group in some previous epidemiological studies. However, different CHD entities have different etiologies, and the underlying causes are unclear in the vast majority of patients. Thus the aim of this study was to analyze the possible association of different maternal diseases with the risk of four types of conotruncal defects (CTD), that is, truncus arteriosus, d-transposition of the great arteries, tetralogy of Fallot, and double-outlet right ventricle based on autopsy or surgical report diagnosis. Acute and chronic diseases with related drug treatments and peri-conceptual folic acid or multivitamin supplementations were compared in mothers of 598 CTD cases, of 902 matched controls, and 38,151 population controls without any defects, and with 20,896 malformed controls with other isolated non-cardiac defects in the population-based large dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities. Mothers who had medically recorded influenza and the common cold with secondary complications in the prenatal maternity logbook during the second and/or third gestational months were associated with a higher risk of CTD (OR with 95% CI: 2.22, 1.19-3.88). The common denominator of these maternal diseases may be high fever, which could be prevented by antifever therapies. On the other hand, high doses of medically recorded folic acid in early pregnancy were able to reduce the birth prevalence of CTD (OR with 95% CI: 0.54, 0.39-0.73), and this reduction was significant in transposition of the great arteries (0.46, 0.29-0.71) as well. In conclusion, high fever related maternal diseases may have a role in the origin of CTD, while high doses of folic acid in early pregnancy were able to reduce of CTD, particularly transposition of great vessels.

Isolated atrioventricular canal defects: Birth outcomes and risk factors: A population‐based hungarian case–control study, 1980–1996

The role of possible environmental factors in the origin of congenital heart defects is unclear in the vast majority of patients. The objective of this study was to describe the birth outcomes and risk factors in isolated atrioventricular canal defect (AVCD) cases. Medically recorded birth outcomes, maternal age, parity, acute and chronic maternal diseases with related drug treatments and folic acid/multivitamin supplementation were evaluated in isolated AVCD cases. The diagnosis of AVCD was based on the autopsy report or surgical description in the population-based Hungarian Case-Control Surveillance of Congenital Abnormalities, between 1980 and 1996. The birth outcomes and exposures of 77 isolated AVCD cases were compared with 38,151 controls without defect. Mean gestational age at delivery (38.6 week) and birth weight (2992 g), rate of preterm birth (20.8%) and low birthweight (23.4%) of cases with a female excess (59.7%) differed significantly from the controls. Mothers of cases had higher parity, higher prevalence of conduction disorders/cardiac dysrhythmias and chronic hypertension. The high doses of folic acid in early pregnancy associated with a reduced rate of AVCD. Conduction disorders/cardiac dysrhythmias and chronic hypertension of mothers may have a role in the origin of AVCD, while high doses of folic acid in early pregnancy may reduce the risk of the development of AVCD. Birth Defects Research (Part A) 97:217-224, 2013. © 2013 Wiley Periodicals, Inc.

Association of maternal diseases during pregnancy with the risk of single ventricular septal defects in the offspring – a population-based case-control study

Objective: In general, the analytical epidemiological studies evaluated cases with congenital heart defects (CHDs) together. However, different CHD entities have different etiology, and in the vast majority of patients the underlying causes are unclear. Thus the objective of the study was to evaluate the possible etiological factors in the origin of single ventricular septal defect (VSD) after surgical intervention or lethal outcome, i.e. as homogeneous as possible.Method: In the population-based large dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities acute and chronic maternal diseases with related drug treatments and pregnancy supplements in early pregnancy were evaluated in the mothers of 1661 cases with isolated/single VSD and their 2534 matched and 38 151 all controls without defect, and 19 833 malformed controls with other isolated non-cardiac defect.Results: There was a higher risk of VSD in the children of mothers with high fever related influenza during the critical period of VSD and this risk was limited by antifever therapy. In addition paroxysmal supraventricular tachycardia and epilepsy treated with anticonvulsant drugs associated with higher risk of VSD. Finally, the high doses of folic acid alone in early pregnancy.Conclusions: High-fever-related maternal diseases may have a role in the origin of VSD which is preventable with antifever drug therapy, and the high doses of folic acid in early pregnancy reduced the risk of VSD.

Effect of high doses of folic acid supplementation in early pregnancy on child neurodevelopment at 18 months of age: the mother–child cohort ‘Rhea’ study in Crete, Greece

To investigate whether high doses of folic acid supplementation in early pregnancy are associated with child neurodevelopment at 18 months of age. The study uses data from the prospective mother-child cohort 'Rhea' study. Pregnant women completed an interviewer-administered questionnaire on folic acid supplementation at 14-18 weeks of gestation. Neurodevelopment at 18 months was assessed with the use of the Bayley Scales of Infant and Toddler Development (3rd edition). Red-blood-cell folate concentrations in cord blood were measured in a sub-sample of the study population (n 58). Heraklion, Crete, Greece, 2007-2010. Five hundred and fifty-three mother-child pairs participating in the 'Rhea' cohort. Sixty-eight per cent of the study participants reported high doses of supplemental folic acid use (5 mg/d), while 24 % reported excessive doses of folic acid (>5 mg/d) in early pregnancy. Compared with non-users, daily intake of 5 mg supplemental folic acid was associated with a 5-unit increase on the scale of receptive communication and a 3·5-unit increase on the scale of expressive communication. Doses of folic acid supplementation higher than 5 mg/d were not associated with additional increase in the neurodevelopmental scales. This is the first prospective study showing that high doses of supplementary folic acid in early pregnancy may be associated with enhanced vocabulary development, communicational skills and verbal comprehension at 18 months of age. Additional longitudinal studies and trials are needed to confirm these results.

Folic acid in early pregnancy: a public health success story

Folate is a water-soluble B vitamin that must be obtained in the diet or through supplementation. For >50 yr, it has been known that folate plays an integral role in embryonic development. In mice, inactivation of genes in the folate pathway results in malformations of the neural tube, heart, and craniofacial structures. It has been shown that diets and blood levels of women who had a fetus with a neural tube defect are low for several micronutrients, particularly folate. Periconceptional use of folic acid containing supplements decreased recurrent neural tube defects in the offspring of women with a previously affected child and the occurrence of a neural tube defect and possibly other birth defects in the offspring of women with no prior history. Based on these findings, the U.S. Public Health Service recommended that all women at risk take folic acid supplements, but many did not. Mandatory food fortification programs were introduced in numerous countries, including the United States, to improve folate nutritional status and have resulted in a major decrease in neural tube defect prevalence. The success story of folate represents the cooperation of embryologists, experimentalists, epidemiologists, public health scientists, and policymakers.

Nested Case-Control Study of One-Carbon Metabolites in Mid-Pregnancy and Risks of Cleft Lip With and Without Cleft Palate

Evidence exists for an association between use of vitamin supplements with folic acid in early pregnancy and reduced risk for offspring with cleft lip with/without cleft palate (CLP). A few observations have been made about nutrients related to one-carbon metabolism other than folate. Our prospective study attempted to extend information on nutrition and CLP by measuring nutrient analytes in mid-pregnancy sera. This study included data from a repository of women's mid-pregnancy serum specimens collected in California from 2003-04. Each woman's specimen was linked with delivery information to determine whether her fetus had CLP or another structural malformation, or was nonmalformed. We identified 89 CLP cases. We randomly selected 409 specimens as controls. Specimens were tested for homocysteine, methylmalonic acid, folate, vitamin B12, pyridoxal phosphate, pyridoxal, pyridoxic acid, riboflavin, choline, betaine, methionine, methionine sulfoxide, cysteine, cystathionine, arginine, and asymmetric and symmetric dimethylarginine. We observed three analytes with odds ratios unlikely to be explained by random variation, i.e., elevated CLP risks were observed for low levels and for high levels of pyridoxal phosphate (vitamin B6), higher levels of choline, and low levels of symmetric dimethylarginine. These data did not show meaningful differences between cases and controls for any other analytes.

Hypospadias and Intake of Nutrients Related to One-Carbon Metabolism

We examined whether hypospadias is associated with maternal intake of folic acid containing vitamin/mineral supplements or dietary intake of nutrients related to one-carbon metabolism (folate, choline, vitamins B12 and B6, thiamine, riboflavin, methionine and zinc). The study included births from October 1997 to December 2003 that were part of the National Birth Defects Prevention Study. Diet was assessed by food frequency questionnaire during maternal telephone interviews. Analyses included 915 cases with second or third degree hypospadias (urethra opened at the penile shaft, scrotum or perineum) and 2,266 male, liveborn, nonmalformed controls. All ORs and 95% CIs were estimated from logistic regression models that included several potential confounders. Nutrient based analyses also included energy intake. Hypospadias risk was not associated with supplement use (adjusted ORs were 1.2, 95% CI 0.9-1.6 for intake beginning in the month before or the first month of pregnancy and 1.1, 95% CI 0.8-1.4 for intake beginning in the second or third month, relative to no intake). Among women who took supplements reduced hypospadias risk was associated with higher dietary intakes of choline, methionine and vitamin B12. The respective ORs (CIs) for the highest vs lowest quartiles were 0.7 (0.5-1.1), 0.6 (0.4-0.9) and 0.7 (0.5-1.0). Among women who did not take supplements increased risk of hypospadias was associated with higher vitamin B12 intake. The OR (CI) for the highest vs lowest quartile was 3.1 (1.1-9.0). This study suggests an association of hypospadias with intake of certain nutrients related to one-carbon metabolism.

Congenital malformations in infants whose mothers reported the use of folic acid in early pregnancy in Sweden. A prospective population study

The use of folic acid prior to conception is generally recommended for the prevention of birth defects, notably neural tube defects. In a previous study from Sweden, based on interviews of women in early pregnancy, no such effect was found on the general malformation rate, but data for neural tube defects were scarce. Using data from the Swedish Medical Birth Register for the years 1995-2004, 20 891 women were identified who reported the use of folic acid in early pregnancy, but not of anticonvulsants. These women were compared to all other women who gave birth during the study period. Malformations in the infants born were identified from multiple sources. No reduction in the general malformation rate was seen among infants born to women who reported the use of folic acid (OR = 1.09, 95% CI 1.02-1.17) and no effect of neural tube defect rate was seen (RR = 1.35, 95% CI 0.82-2.22), based on 16 infants with neural tube defect whose mother reported the use of folic acid. No effect was seen on the rates of other malformations except for cardiac defects, where a statistically significant increased risk (notably for severe defects) was found (OR = 1.19, 95% CI 1.05-1.35). The effect of various deficiencies in data collection is discussed, but is unlikely to explain the lack of protective effect noticed. So far, it has not been possible to demonstrate a beneficial effect of folic acid supplementation on malformation risk in Sweden. A more complete ascertainment and detailed timing and dosage of folic acid use in a prospective study is recommended.

Polymorphisms in genes MTHFR, MTR and MTRR are not risk factors for cleft lip/palate in South Brazil

Non-syndromic cleft lip and palate (CL/P) occurs due to interaction between genetic and environmental factors. Abnormalities in homocysteine metabolism may play a role in its etiology due to polymorphisms in genes involved in this pathway. Because of the involvement of MTHFR, MTR and MTRR genes with folate metabolism and the evidence that maternal use of folic acid in early pregnancy reduces the risk for CL/P, we evaluated the influence of their polymorphisms on the etiology of CL/P through a case-control study. The analyses involved 114 non-syndromic phenotypically white children with clefts (case) and 110 mothers, and 100 non-affected (control) children and their mothers. The polymorphisms 677C>T of MTHFR, 2756A>G of MTR, and 66A>G of MTRR genes were analyzed by PCR-RFLP. Allelic frequencies did not differ from other studies conducted on white populations for MTHFR 677T allele (0.35) and for MTR 2756G allele (0.17), but MTRR 66G allele frequency (0.35) was lower than observed elsewhere. The genotypic distribution of the 677C>T polymorphisms under study did not show significant differences between CL/P patients, their mothers and controls. These results suggest that the alterations of folate metabolism related to these polymorphisms are not involved in clefting in the population under study.

Use of Folic Acid Supplementation and Risk for Dizygotic Twinning

Women planning pregnancy often are urged to take extra folic acid or fortified food to lower the risk of a neural tube defect and other malformations. Some studies have found evidence of an increased rate of dizygotic twinning in women taking folic acid supplements, but others have failed to confirm such an effect. This study explored the putative association between folic acid supplementation and twinning in 6953 women in the Swedish Medical Birth Registry who had a total of 7181 infants and who had taken folic acid in early pregnancy. Of 8676 women who had different-sexed dizygotic twins, 232 reported having used folic acid. In Sweden, folic acid is available in doses of 400 μg over the counter and 5 mg by prescription. After adjusting for year of birth, maternal age, parity, smoking, and years of unplanned childlessness, the odds ratio (OR) for folic acid use by women with a body mass index (BMI) less than 19.8 was 0.96, and for those with a BMI greater than 26, 0.89. Those with a BMI less than 19.8 had a lowered risk of dizygotic twinning (OR, 0.75), whereas the others had an increased risk (OR, 1.13). The use of gestagens or ovulation-stimulating drugs was associated with both folic acid use and having dizygotic twins. When nonSwedish women and those born outside Sweden were excluded along with those who were involuntarily childless or had used ovarian stimulants or gestagens, the OR for dizygotic twinning was 1.71 after adjusting for year of birth, maternal age, parity, and smoking. An increased risk of dizygotic twinning associated with folic acid supplementation must be weighed against the lowered risk of congenital malformations, especially neural tube defects.

Use of folic acid and delivery outcome: a prospective registry study

Periconceptional use of folic acid is thought to reduce the risk for both neural tube defects and other congenital malformations. Most published data were obtained retrospectively. We used the Swedish Medical Birth Registry to study congenital malformations in infants born of women who reported the use of folic acid in early pregnancy (of which 70% probably used it also preconceptionally) and compared them with population rates. We divided the material according to two major confounders: subfertility problems and use of antiepileptic drugs. We found no protective effect of folic acid tablet use on the rate of congenital malformations but data on neural tube defects were scarce. Our results support the scepticism recently expressed in the literature on the beneficial effect of folic acid in preventing congenital malformations, especially of a non-neural tube defect type.

Folic Acid Supplementation and Risk for Imperforate Anus in China

Maternal use of folic acid in early pregnancy has lowered the risk of some birth defects, notably neural tube defects. It is not clear whether it also lowers the risk of imperforate anus, a defect resulting from incomplete hindgut formation. The anus is either absent or abnormally located at about 8 weeks' development, with the rectum either ending in a blind pouch or opening into the urethra, bladder, or vagina. In the course of a public health campaign carried out in China from 1993 through 1995, pregnancy outcomes at 20 weeks' and more gestation were assessed in women asked to take one 400-pg pill, without other vitamins, each day from the preconception exam until the end of the first trimester. The study group of singleton pregnancies, totalling 222,314, came from one northern province and two southern provinces of China. Fifty women had a fetus or infant with imperforate anus; males predominated in a ratio of 1.66 to 1. Multiple anomalies were present in 16% of the group, and 22% had additional caudal anomalies such as persistent cloaca. None of the mothers had a history of diabetes. Imperforate anus was less frequent in offspring of women taking folic acid, with a risk ratio of 0.5 (95% CI, 0.29-0.88). The risk could not be related to geographic area, education, or occupational category. Higher parity and maternal age were associated with a greater risk of imperforate anus; controlling for either factor had only a small effect on the relative risk estimate. When adjusting for maternal age, the risk reduction among pill-takers was 41% (relative risk, 0.59). The United States and other nations have recommended that all women who might become pregnant take 400 μg of folic acid daily to lower the risk of neural tube defects. This measure may also help to reduce the risk of other defects such as imperforate anus.

Maternal periconceptional vitamin use, genetic variation of infant reduced folate carrier (A80G), and risk of spina bifida.

Women who consume folic acid in early pregnancy reduced their risks for delivering offspring with neural tube defects (NTDs). The underlying process by which folic acid facilitated this risk reduction is unknown. Investigating genetic variation that influences cellular absorption, transport, and metabolism of folate will help fill this data gap. We focused our studies on a candidate gene that is involved in folate transport, the reduced folate carrier 1 (RFC1). Using data from a California population-based case control interview study (1989-1991 birth cohorts), we investigated whether spina bifida risk was influenced by an interaction between a polymorphism of infant RFC1 at nucleotide 80 (A80G) and maternal periconceptional use of vitamins containing folic acid. Allelic variants of RFC1 were determined by genotyping 133 live-born spina bifida case infants and 188 control infants. The percentages of case infants with the A80/A80, G80/G80, and G80/A80 genotypes were 27.2%, 28.0%, and 44.7%, respectively. The percentages of control infants were similar: 26.1%, 29.3%, and 44.7%. Odds ratios of 1.0 (95% confidence interval 0.5-2.0) for the G80/G80 genotype and 1.1 (0.6-2.0) for the G80/A80 genotype were observed relative to the A80/A80 genotype. Among mothers who did not use vitamins, spina bifida risk was 2.4 (0.8-6.9) for infants with genotype G80/G80 compared to those with A80/A80 genotype. Among mothers who did use vitamins, the risk was 0.5 (0.1-3.1) for infants with the G80/G80 genotype. Although this study did not find an increased spina bifida risk for infants who were heterozygous or homozygous for RFC1 A80G, it did reveal modest evidence for a gene-nutrient interaction between infant homozygosity for the RFC1 G80/G80 genotype and maternal periconceptional intake of vitamins containing folic acid on the risk of spina bifida.

Use of Multivitamins and Folic Acid in Early Pregnancy and Multiple Births in Sweden

Use of Multivitamins and Folic Acid in Early Pregnancy and Multiple Births in Sweden

Use of Multivitamins and Folic Acid in Early Pregnancy and Multiple Births in Sweden

Folic acid is recommended to reduce the risk of neural tube defects and other congenital malformations. Data from the Swedish Medical Birth Registry were used to study frequency of twinning in women who in early pregnancy reported the use of folic acid. Women (n = 2,569) who in early pregnancy reported the use of folic acid had an increased rate of twin deliveries after consideration of maternal age and of length of involuntary childlessness, both variables being significant confounders. The effect of folic acid was seen also in women who did not report involuntary childlessness. A similar but not statistically significant trend was seen after use of multivitamins without simultaneous use of folic acid tablets (n = 1,979). The increased risk seems to be limited to dizygotic twinning (relative risk = 2.13, 95% CI 1.64-2.74). If this association is causal, wide-spread supplementation with folic acid may represent a hazard larger than the postulated beneficial effect on neural tube defects, at least in low-risk areas.

Infant C677T mutation in MTHFR, maternal periconceptional vitamin use, and cleft lip.

Studies have reported an association between homozygosity for a variant form of the methylenetetrahydrofolate reductase (MTHFR) gene and risk for neural tube defects. Because of MTHFR's involvement with folate metabolism and evidence that maternal use of a multivitamin with folic acid in early pregnancy reduces risk for cleft lip with or without cleft palate (CLP), we hypothesized that infants homozygous for the C677T genotype would be at increased risk for CLP because of lower MTHFR enzymatic activity. Data were derived from a large population-based, case-control study of fetuses and liveborn infants among a cohort of 1987 to 1989 California births. The analyses involved 310 infants with isolated CLP whose mothers completed a telephone interview and whose DNA was available from newborn screening blood specimens and involved 383 control infants without a congenital anomaly whose mothers completed a telephone interview and whose DNA was available. Cases and controls were genotyped TT if homozygous for the C677T allele, CT if heterozygous for the C677T allele, and CC if homozygous for the C677 (wild-type) allele. Odds ratios for CLP were 0.89 (0.55 to 1.4) and 0.78 (0.56 to 1.1) for infants with TT versus CC and infants with CT versus CC genotypes, respectively. Compared with the CC genotype, the odds ratios for CLP among infants with the TT genotype were 0.74 (0.39 to 1.4) for those infants whose mothers were users and 1.4 (0.54 to 3.6) for those infants whose mothers were not users of multivitamins containing folic acid periconceptionally. The two estimates were not statistically heterogeneous (P = 0.30). Our results did not indicate increased risks for CLP among infants homozygous for the C677T genotype, nor do they indicate an interaction between infant C677T genotype and maternal multivitamin use on the occurrence of CLP.