Pregnancy

Botto, Olney, Erickson
15 Feb 2004 Vitamin supplements and the risk for congenital anomalies other than neural tube defects.
Am J Med Genet. Pages: 12-21; Volume(Issue): 125C (1)

Randomized trials, supported by many observational studies, have shown that periconceptional use of folic acid, alone or in multivitamin supplements, is effective for the primary prevention of neural tube defects (NTDs). Whether this is true also for other congenital anomalies is a complex issue and the focus of this review. It is useful to consider the evidence not only for specific birth defects separately but, importantly, also for all birth defects combined. For the latter, the Hungarian randomized clinical trial indicated, for periconceptional multivitamin use, a reduction in the risk for all birth defects (odds ratio (OR) = 0.53, 95% confidence interval (CI) = 0.35-0.70), even after excluding NTDs (OR = 0.53, 95% CI = 0.38-0.75). The Atlanta population-based case-control study, the only large observational study to date on all major birth defects, also found a significant risk reduction for all birth defects (OR = 0.80, 95% CI = 0.69-0.93) even after excluding NTDs (OR = 0.84, 95% CI = 0.72-0.97). These and other studies also evaluated specific anomalies, including those of the heart, limb, and urinary tract, as well as orofacial clefts, omphalocele, and imperforate anus. For cardiovascular anomalies, two studies were negative, whereas three, including the randomized clinical trial, suggest a possible 25-50% overall risk reduction, more marked for some conotruncal and septal defects. For orofacial clefts, six of seven case-control studies suggest an apparent reduced risk, which could vary by cleft type and perhaps, according to some investigators, by pill dosage. For limb deficiencies, three case-control studies and the randomized trial estimated approximately a 50% reduced risk. For urinary tract defects, three case-control studies and the randomized trial reported reduced risks, as did one study of nonsyndromic omphalocele. All these studies examined multivitamin supplement use. With respect to folic acid alone, a reduced rate of imperforate anus was observed among folic acid users in China. We discuss key gaps in knowledge, possible avenues for future research, and counseling issues for families concerned about occurrence or recurrence of these birth defects.

Byrne
Folic acid knowledge and use among relatives in Irish families with neural tube defects: an intervention study.
Ir J Med Sci. Pages: 118-22; Volume(Issue): 172 (3)

BACKGROUND: Relatives in families where a child has a neural tube defect (NTD) may be at higher risk of having an affected child. Little is known of their level of knowledge and use of folic acid. AIM: To carry out an intervention study intended to increase knowledge and use of folic acid among relatives.

METHODS: One hundred aunts and female first cousins (relatives of the proband) were interviewed by telephone before and after receiving an information pack.

RESULTS: At baseline, although knowledge of the benefits of folic acid was high (73%), use of folic acid was low (8.8%). After the intervention, knowledge increased and use went up to 19% (p < 0.05).

CONCLUSIONS: This study suggests that relatives in Irish NTD families have a high level of information about folic acid benefits. This awareness may not translate into action since the intervention produced only a modest increase in folic acid use overall. Future studies focussing on women who are planning a pregnancy may show larger benefits from intervention.

Martínez-Frías, Rodríguez-Pinilla, Bermejo
6 Dec 2003 [Analysis of the Spanish situation regarding folic acid/calcic folinate consumption for birth defects prevention]
Med Clin (Barc). Pages: 772-5; Volume(Issue): 121 (20)

BACKGROUND AND OBJECTIVE: Since 1992, the recommendation on the ingestion of folic acid (FA) to prevent congenital defects has become general in developed countries. In this paper, we analyze such a situation in Spain in most recent years.

PATIENTS AND METHOD: We used the information concerning mothers of infants selected as controls in the ECEMC database. These mothers make up a sample of pregnant women of the general population. We analyzed the evolution of the consumption of FA/calcic folinate (CF) by pregnant women over the last 22 years, considering the period of pregnancy during which this vitamin was taken and the dosage.

RESULTS: The proportion of women who take FA/CF during the first trimester of pregnancy increased dramatically in the last 9 years, up to 80% in 2002. However, only about 9% took the vitamin before becoming pregnant. Moreover, many daily doses are much higher than those internationally recommended for the general population of women planning pregnancy.

CONCLUSIONS: In our country, the use of FA/CF to prevent congenital defects is correct in a small part of the population of pregnant women. Therefore, it is necessary to continue disseminating appropriate guidelines not only among gynecologists but also among family and general practitioners and health professionals working at family planning centers. Thus, they can transmit to women the need of using FA/CF and the right way to do it.

Bakker, Cornel, de Walle
6 Dec 2003 [Awareness and periconceptional use of folic acid among non-western and western women in the Netherlands following the 1995 publicity campaign]
Ned Tijdschr Geneeskd. Pages: 2426-30; Volume(Issue): 147 (49)

OBJECTIVE: To investigate the influence of ethnicity on the awareness and use of folic acid by pregnant women. DESIGN: Secondary data analysis. METHOD: Using the data on 1555 women, collected during a cross-sectional study conducted among pregnant women with good knowledge of the Dutch language in 1996, the authors determined what was known about the recommendation to use folic acid around the time of conception and what the actual use was. Women were defined as either 'western' or 'non-western' on the basis of the place of birth of the woman and her parents. RESULTS: Of the 1555 pregnant women, 74 (5%) were non-western or of non-western descent. Non-western women more often had a lower educational level than western women (51% versus 34%; p = 0.002) and more often had an unintended pregnancy (24% versus 8%; p < 0.0001). 41% of the non-western women had heard of the recommendation to use folic acid before pregnancy, compared to 79% of the western women (p < 0.0001). However, the use of folic acid was not significantly different between non-western and western women (56% versus 69%) if they had been aware of the recommendation to use folic acid before pregnancy. Awareness of the recommendation to use folic acid was higher in older women (OR: 1.46; 95% CI: 1.13-1.89), women of western descent (0.27; 0.16-0.47), women with a higher level of education (0.35; 0.27-0.45) and in case of planned pregnancy (0.45; 0.31-0.67). The use of folic acid, restricted to women who were aware of the recommendation to use folic acid before their pregnancy, was higher in older women (1.37; 1.05-1.80) and lower in those with more previous pregnancies (0.57; 0.43-0.75) and in case of an unplanned pregnancy (0.55; 0.34-0.88). CONCLUSION: Although non-western women had less knowledge of the recommendation to use folic acid than western women, the use of folic acid was not significantly different from that by western women if they had been aware of the recommendation to use folic acid before pregnancy. Continued education on folic acid targeting non-western and western women is important.

Alozie Arole, Puder, Reznar, Eby, Zhu
Nov 2003 Folic acid awareness in Michigan, 1996-1999.
Obstet Gynecol. Pages: 1046-50; Volume(Issue): 102 (5 Pt 1)

OBJECTIVE: To evaluate the prevalence and trend of folic acid awareness among Michigan mothers during 1996-1999 and to identify maternal characteristics predictive of folic acid awareness. METHODS: We analyzed data from the Michigan Pregnancy Risk Assessment Monitoring System, a population-based survey of women with recent live births. A positive response to the question, "Before you became pregnant, did you know that folic acid could help prevent some birth defects?" was used as an indicator of folic acid awareness. Logistic regression was used to evaluate trends in folic acid awareness prevalence and the association between folic acid awareness and certain maternal characteristics. RESULTS: Of the women invited to participate, 7252 responded (67.3%). Overall, folic acid awareness increased from 1996 to 1999 (60.3-71.4%; P < .001). However, folic acid awareness decreased for women with no high school education from 1997 to 1999 (59.3-13.8%, P = .05). In addition, folic acid awareness was lower among black women (adjusted odds ratio [OR] 0.43; 95% confidence interval [CI] 0.4, 0.5, versus other races), women with unplanned pregnancies (adjusted OR 0.6; 95% CI 0.5, 0.8, versus those with planned pregnancies), and those with no high school education (adjusted OR 0.08; 95% CI 0.03, 0.2, versus women with college education). CONCLUSION: Although folic acid awareness has increased among Michigan mothers overall during 1996-1999, it has decreased among women with less than a high school education, and substantial gaps exist among socioeconomic subgroups. Continued efforts are needed to improve folic acid awareness and consumption of folic acid among women of reproductive age, with special attention focused on populations experiencing gaps or declines in folic acid awareness.

Wilson, Davies, Désilets, Reid, Summers, Wyatt, Young
Nov 2003 The use of folic acid for the prevention of neural tube defects and other congenital anomalies.
J Obstet Gynaecol Can. Pages: 959-73; Volume(Issue): 25 (11)

RECOMMENDATIONS: 1. Women in the reproductive age group should be advised about the benefits of folic acid supplementation during wellness visits (birth control renewal, Pap testing, yearly examination), especially if pregnancy is contemplated. (III-A) 2. Women should be advised to maintain a healthy nutritional diet, as recommended in Canada's Food Guide to Healthy Eating (good or excellent sources of folic acid: broccoli, spinach, peas, Brussels sprouts, corn, beans, lentils, oranges). (III-A)

Medical Research Council Study Research Group
Prevention of neural tube defects
Lancet. 1991; 338:131-7.

A randomised double-blind prevention trial with a factorial design was conducted at 33 centres in seven countries to determine whether supplementation with folic acid (one of the vitamins in the B group) or a mixture of seven other vitamins (A,D,B1,B2,B6,C and nicotinamide) around the time of conception can prevent neural tube defects (anencephaly, spina bifida, encephalocele). A total of 1817 women at high risk of having a pregnancy with a neural tube defect, because of a previous affected pregnancy, were allocated at random to one of four groups--namely, folic acid, other vitamins, both, or neither. 1195 had a completed pregnancy in which the fetus or infant was known to have or not have a neural tube defect; 27 of these had a known neural tube defect, 6 in the folic acid groups and 21 in the two other groups, a 72% protective effect (relative risk 0.28, 95% confidence interval 0.12-0.71). The other vitamins showed no significant protective effect (relative risk 0.80, 95% Cl 0.32-1.72). There was no demonstrable harm from the folic acid supplementation, though the ability of the study to detect rare or slight adverse effects was limited. Folic acid supplementation starting before pregnancy can now be firmly recommended for all women who have had an affected pregnancy, and public health measures should be taken to ensure that the diet of all women who may bear children contains an adequate amount of folic acid.

Daly, Kirke, Molloy
Folate levels and neural tube defects. Implications for prevention.
JAMA 1995 Dec 6;274(21):1698-702

Using data from a recent case-control study, a woman's risk of having a child with a neural tube defect (NTD) was found to be associated with early pregnancy red cell folate levels in a continuous dose-response relationship. These findings were used to calculate the reduction in NTD cases that would be expected under two different strategies to raise folate levels. Targeting high-risk individuals has a small effect on the population prevalence but can substantially change an individual's risk. Targeting the population produces a small change in individual risk but has a large effect on the population prevalence. Supplementation of high-risk women would be the most efficient method to implement the high-risk strategy, while food fortification would be preferable for the population approach. The current guidelines for the prevention of NTD are for an increased folic acid intake of 0.4 mg per day. This would result in a 48% reduction in NTDs, which may be near optimal. The two intervention strategies should be considered complementary in prevention of NTDs.

Van Allen, Fraser, Dallaire
Recommendations on the use of folic acid supplementation to prevent the recurrence of neural tube defects.
CMAJ 1993 Nov 1;149(9):1239-43.

OBJECTIVE: To prevent the recurrence of neural tube defects (NTDs) in families at increased risk of having offspring with NTDs with the use of periconceptional folic acid supplementation. OPTIONS: Genetic counselling and prenatal diagnosis of NTDs. OUTCOMES: NTDs cause stillbirth, neonatal death and severe disabilities. The cost for medical care and rehabilitation in the first 10 years of life of a child with spina bifida cystica was estimated to be $42,507 in 1987. EVIDENCE: The authors reviewed the medical literature, communicated with investigators from key studies, reviewed policy recommendations from other organizations and drew on their own expertise. A recent multicentre randomized controlled trial showed that among women at high risk of having a child with an NTD those who received 4 mg/d of folic acid had 72% fewer cases of NTD-affected offspring than nonsupplemented women. Two previous intervention studies also demonstrated that folic acid supplementation was effective in reducing the rate of NTD recurrence. Several retrospective studies support this conclusion. VALUES: Recommendations are the consensus of the Clinical Teratology Committee of the Canadian College of Medical Geneticists (CCMG) and have been approved by the CCMG Board. The committee believes that primary prevention of NTDs is preferable to treatment or to prenatal detection and abortion. BENEFITS, HARMS AND COSTS: Folic acid supplementation should result in fewer NTDs among infants in Canada and ancillary savings in medical costs. The recommended dosage of folic acid is not known to be associated with adverse effects. Higher dosages of folic acid may make vitamin B12 deficiency difficult to diagnose and may alter seizure frequency in patients with epilepsy due to drug interactions with anticonvulsants. RECOMMENDATIONS: A minimum dosage of folic acid of 0.8 mg/d, not to exceed 5.0 mg/d, is recommended along with a well-balanced, nutritious diet for all women who are at increased risk of having offspring with NTDs and who are planning a pregnancy or may become pregnant. Supplementation should begin before conception and continue for at least 10 to 12 weeks of pregnancy. VALIDATION: These guidelines are similar to those of the Society of Obstetricians and Gynaecologists of Canada, the US Centers for Disease Control and Prevention and the Department of Health in Britain. SPONSORS: These guidelines were developed by the CCMG Clinical Teratology Committee and endorsed by the Board of the CCMG. No funding for the development of these guidelines was obtained from any other sources.

Wallock, Tamura, Mayr
Low seminal plasma folate concentrations are associated with low sperm density and count in male smokers and nonsmokers.
Fertility and Sterility 2001:75:252-259

OBJECTIVE: To measure folate levels in seminal plasma from smokers and nonsmokers and to evaluate relationships between seminal plasma folate levels and both folate nutriture and semen quality measures. DESIGN: Observational study. SETTING: United States Department of Agriculture, Western Human Nutrition Research Center, Presidio of San Francisco, San Francisco, California. PATIENT(S): Healthy male smokers (n=24) and nonsmokers (n=24). MAIN OUTCOME MEASURE(S): Blood levels of plasma folate and homocysteine, seminal plasma total, non-methyl- and 5-methyltetrahydrofolate concentrations, and total sperm count and density. RESULTS: Total seminal plasma folate concentrations were on average 1.5 times higher than blood plasma folate concentrations in all men. Seminal plasma folates contained 5-methyltetrahyrdofolate (74% of total) and non-methyltetrahydrofolates (26% of total); all samples had less than four glutamyl residues. Total and 5-methyltetrahydrofolate concentrations correlated significantly with blood plasma folate and homocysteine concentrations. Seminal plasma non-methyltetrahydrofolate levels correlated significantly with sperm density and total sperm count. Seminal plasma of smokers contained a proportionally lower concentration of non-methyltetrahydrofolates compared with nonsmokers. CONCLUSION(S): Seminal plasma total folate and 5-methyltetrahydrofolate concentrations reflect folate nutriture. The non-methyltetrahydrofolate fraction of seminal plasma may be important for male reproductive function.

Shaw, Lammer, Wasserman
Risk of orofacial clefts in children born to women using multivitamins containing folic acid periconceptionally. Lancet 1995- 345: 39396.

Women are advised to take folic acid before they conceive as a precaution against neural-tube defects. However, the use of folic acid in preventing orofacial clefts is unknown. We investigated whether a woman's periconceptional use of multivitamins containing folic acid was associated with a reduced risk of orofacial clefts. We derived data from a population-based case-control study of fetuses and liveborn infants with orofacial anomalies among a 1987-89 cohort of births in California. We interviewed 731 (84.7%) of eligible mothers with orofacial cleft case infants and 734 (78.2%) mothers with non-malformed control infants. We found a reduced risk of orofacial clefts if the mother had used multivitamins containing folic acid during the period from one month before through two months after conception. The odds ratios ranged from 0.50-0.73 depending on cleft phenotype. Controlling for the potential influence of other variables did not substantially alter the results. Maternal daily consumption of cereal containing folic acid was also associated with a reduced risk of orofacial clefts. Women who used multivitamins containing folic acid periconceptionally had a 25-50% reduction in risk for offspring with orofacial clefts compared to women who did not use such vitamins. However, this association may not be attributable to folic acid specifically, but may be a consequence of other multivitamin supplement components, or behaviours, that are highly correlated with the use of multivitamins containing folic acid.

Jezewski, Vieira
Complete sequencing shows a role for MSX1 in non-syndromic cleft lip and palate
Journal of Medical Genetics Jun 2003; 40: 399 - 407.
MSX1 has been proposed as a gene in which mutations may contribute to non-syndromic forms of cleft lip and/or cleft palate. Support for this comes from human linkage and linkage disequilibrium studies, chromosomal deletions resulting in haploinsufficiency, a large family with a stop codon mutation that includes clefting as a phenotype, and the Msx1 phenotype in a knockout mouse. This report describes a population based scan for mutations encompassing the sense and antisense transcribed sequence of MSX1 (two exons, one intron). We compare the completed genomic sequence of MSX1 to the mouse Msx1 sequence to identify non-coding homology regions, and sequence highly conserved elements. The samples studied were drawn from a panethnic collection including people of European, Asian, and native South American ancestry. The gene was sequenced in 917 people and potentially aetiological mutations were identified in 16. These included missense mutations in conserved amino acids and point mutations in conserved regions not identified in any of 500 controls sequenced. Five different missense mutations in seven unrelated subjects with clefting are described. Evolutionary sequence comparisons of all known Msx1 orthologues placed the amino acid substitutions in context. Four rare mutations were found in non-coding regions that are highly conserved and disrupt probable regulatory regions. In addition, a panel of 18 population specific polymorphic variants were identified that will be useful in future haplotype analyses of MSX1. MSX1 mutations are found in 2% of cases of clefting and should be considered for genetic counselling implications, particularly in those families in which autosomal dominant inheritance patterns or dental anomalies appear to be cosegregating with the clefting phenotype.

van Rooij, Vermeij-Keers
Does the interaction between maternal folate intake and the methylenetetrahydrofolate reductase polymorphisms affect the risk of cleft lip with or without cleft palate?
American Journal Epidemiology 2003 Apr 1;157(7):583-91.

Periconceptional folic acid supplementation may reduce the risk of cleft lip with or without cleft palate (CL(P)). Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene reduce availability of 5-methyltetrahydrofolate, the predominant circulating form of folate. To determine the effect of MTHFR C677T and MTHFR A1298C genotypes and haplotypes on CL(P) risk and the interaction with maternal periconceptional dietary folate and folic acid supplement intake, the authors conducted a case-control triad study in the Netherlands (1998-2000) among 179 CL(P) and 204 control families. Infant and parental MTHFR C677T and MTHFR A1298C genotypes and haplotypes were not associated with CL(P) risk in the case-control and transmission disequilibrium test analyses. Mothers carrying the MTHFR 677TT genotype and who either did not use folic acid supplements periconceptionally or had a low dietary folate intake, or both, had an increased risk of delivering a CL(P) child (odds ratio (OR) = 5.9, 95% confidence interval (CI): 1.1, 30.9; OR = 2.8, 95% CI: 0.7, 10.5; OR = 10.0, 95% CI: 1.3, 79.1, respectively). No supplement use, low dietary folate intake, and maternal MTHFR 1298CC genotype increased the risk of CL(P) offspring almost sevenfold (OR = 6.5, 95% CI: 1.4, 30.2). Thus, the detrimental effect of low periconceptional folate intake on the risk of giving birth to a CL(P) child was more pronounced in mothers with the MTHFR 677TT or MTHFR 1298CC genotype.

Relton, Br J Nutrition 2005; 93:
593-599

Low levels of folic acid during early pregnancy have been linked to low infant birth weight, a Newcastle study has found.

Although the benefit of taking folic acid before and during early pregnancy to guard against neural tube defects has been well documented, the researchers say this is the first time folic acid status at that time has been linked with birth weight.

The research team analysed the blood folic acid levels in blood samples supplied by nearly 1,000 expectant mothers during their first trimester of pregnancy. In addition, the birth weight of each participant’s baby was recorded.

Increasing RBC folate status was significantly associated with increasing infant birth weight. Lead author Caroline Relton said the study emphasised the need for folic acid supplementation during the first few weeks of gestation.