Prevention of NTDs with periconceptional multivitamin supplementation containing folic acid in China

BACKGROUND: Maternal nutritional factors seem to contribute substantially to the complex etiologies of NTDs. Foremost among these factors is the periconceptional use of supplementation containing folic acid, which is associated with a reduction in the risk of women having NTD‐affected pregnancies. This study was designed to observe the effectiveness of multivitamin supplementation containing folic acid in preventing NTDs in a Chinese population and to detect factors that would impact the effectiveness. METHODS: Through family planning networks, a population‐based community intervention study was carried out in 18 counties of China. Participants were divided into an intervention (taking multivitamin) group and a control group, and were followed up according to periconceptional multivitamin supplementation (in general 6 mg) for 2 years. Women who had a pregnancy were followed up from 28 weeks gestation at least to pregnancy termination, and the outcome was recorded. The incidence rate of the two groups and the relative risks were calculated to evaluate the efficacy of the multivitamin supplement in preventing NTDs. RESULTS: During 2000 and 2002, all of the women having pregnancies with birth defects and women whose pregnancies were without any birth defects were interviewed. Nine NTDs were recorded from 25,444 pregnancies (NTD birth prevalence = 0.35/1,000 pregnancies) in the intervention group and 48 NTDs among 26,599 pregnancies (NTD birth prevalence = 1.80/1,000 pregnancies) in the control group. The protective rate was 80.4%. CONCLUSIONS: Periconceptional multivitamin supplementation containing folic acid can prevent the occurrence of NTDs with the beneficial effect dependent on the frequency and timing of the supplementation. Our study suggests that multivitamin supplement containing folic acid taken from a time point of 2 months before conception and continuing until completion of the second month after conception and taken more than five times per week can significantly reduce the risks of NTDs. Birth Defects Research (Part A), 2008. © 2008 Wiley‐Liss, Inc.     

What proportion of congenital abnormalities can be prevented?

OBJECTIVE--To estimate the proportion of preventable congenital abnormalities in Hungary. DESIGN--Analysis of available Hungarian data-bases and of the effectiveness of primary, secondary, and tertiary preventive methods. SETTING--Databases of ad hoc epidemiological studies and of the Hungarian congenital abnormality registry. MAIN OUTCOME MEASURES--Prevalence at birth and prevalence after prevention in 73 congenital abnormality types or groups. RESULTS--Preventive methods are available for 51 (70%) of the 73 congenital abnormality types or groups evaluated. The birth prevalence of all congenital abnormalities could be reduced from 65 to 26 per 1000; thus 39 per 1000 (60%) are preventable. Without congenital dislocation of the hip, which is unusually common in Hungary, the preventable proportion of congenital abnormalities is 52%. CONCLUSION--Many congenital abnormalities can be prevented, but as they do not represent a single pathological category there is no single strategy for their prevention.     

Prevention of congenital abnormalities by periconceptional multivitamin supplementation.

OBJECTIVE--To study the effect of periconceptional multivitamin supplementation on neural tube defects and other congenital abnormality entities. DESIGN--Randomised controlled trial of supplementation with multivitamins and trace elements. SETTING--Hungarian family planning programme. SUBJECTS--4156 pregnancies with known outcome and 3713 infants evaluated in the eighth month of life. INTERVENTIONS--A single tablet of a multivitamin including 0.8 mg of folic acid or trace elements supplement daily for at least one month before conception and at least two months after conception. MAIN OUTCOME MEASURES--Number of major and mild congenital abnormalities. RESULTS--The rate of all major congenital abnormalities was significantly lower in the group given vitamins than in the group given trace elements and this difference cannot be explained totally by the significant reduction of neural tube defects. The rate of major congenital abnormalities other than neural tube defects and genetic syndromes was 9.0/1000 in pregnancies with known outcome in the vitamin group and 16.6/1000 in the trace element group; relative risk 1.85 (95% confidence interval 1.02 to 3.38); difference, 7.6/1000. The rate of all major congenital abnormalities other than neural tube defects and genetic syndromes diagnosed up to the eighth month of life was 14.7/1000 informative pregnancies in the vitamin group and 28.3/1000 in the trace element group; relative risk 1.95 (1.23 to 3.09); difference, 13.6/1000. The rate of some congenital abnormalities was lower in the vitamin group than in the trace element group but the differences for each group of abnormalities were not significant. CONCLUSIONS--Periconceptional multivitamin supplementation can reduce not only the rate of neural tube defects but also the rate of other major non-genetic syndromatic congenital abnormalities. Further studies are needed to differentiate the chance effect and vitamin dependent effect.     

Maternal multivitamin use and orofacial clefts in offspring

BACKGROUND: Cleft lip with or without cleft palate (CLP) and cleft palate alone (CP) affect approximately 1 in 1000 infants and 1 in 2,500 infants, respectively. Studies of the relation between orofacial clefts and multivitamins or folic acid have been inconsistent. METHODS: We used data from a population-based case-control study involving 309 nonsyndromic cleft-affected births (222 with CLP, 87 with CP) and 3,029 control births from 1968 to 1980 to evaluate the relation between regular multivitamin use and the birth prevalence of orofacial clefts. RESULTS: We found a 48% risk reduction for CLP (odds ratio = 0.52, 95% confidence interval = 0.34-0.80) among mothers who used multivitamins during the periconceptional period or who started multivitamin use during the first postconceptional month, after controlling for several covariates. The risk reduction for CP was less than those for CLP (odds ratio = 0.81, 95% confidence interval = 0.44-1.52); however, a small number of CP cases limited interpretation. No risk reductions for CLP or CP were found for women who began multivitamin use in the second or third month after conception. CONCLUSIONS: The magnitude of the risk reduction in our study is comparable to those of other recent studies; our study does not support the contention that only large dosages of folic acid are needed to prevent orofacial clefts. More studies are needed to test the effects of multivitamins and varying dosages of folic acid on the recurrence and/or occurrence of orofacial clefts to provide information needed to determine possible prevention strategies. Published 2001 Wiley-Liss, Inc.     

The Effects of Periconceptional Risk Factor Exposure and Micronutrient Supplementation on Birth Defects in Shaanxi Province in Western China

Objectives

1) To understand the current prevalence and main types of birth defects, 2) assess the periconceptional exposure of factors associated with birth defects in Shaanxi Province, and 3) provide scientific evidence for local governments to formulate services for the primary prevention of birth defects.

Methods

We sampled 16,541 households from 128 townships in 16 counties/districts in Shaanxi province using a multi-stage random sampling method. Among them, 10,544 women who had live born or stillborn infants with gestational age ≥28 weeks between 2008 and 2009 were interviewed using a structured questionnaire designed to collect information about periconceptional risk factor exposure, health care service utilization, and micronutrient supplements. Logistic regression was performed to assess the risk factors associated with birth defects and adjustments were made for imbalanced social-demographic characteristics between case and control groups.

Results

The prevalence of congenital birth defect in Shaanxi province was 14.3/1000 births. The environment risk factors associated with birth defects include unhealthy lifestyle (Alcohol, odds ratio (OR): 3.60, 95% confidence interval (CI) 1.64−7.91; Smoking, OR: 1.32, 95% CI: 0.99−1.75; Drink strong tea, OR: 1.81, 95% CI: 1.27−2.59), exposure to heavy pollution (OR: 1.53, 95% CI: 1.01−2.30), maternal diseases (OR: 1.77, 95% CI: 1.35−2.33), drug use (OR: 2.11, 95% CI: 1.51−2.95), maternal chemical pesticide exposure (OR: 2.30, 95% CI: 1.16−4.57), and adverse pregnancy history (OR: 10.10, 95% CI: 7.55−13.53). Periconceptional folic acid or multiple micronutrients including folic acid supplementation, was associated with a reduced rate of birth defects (OR: 0.54, 95% CI: 0.29−0.998).

Conclusions

Health care service utilization, unhealthy lifestyle factors, and environment risk factors seem to be associated with birth defects in Shaanxi province. Governmental agencies should focus on effective primary preventative methods, such as the delivery of periconceptional health education for minimizing potential risk factor exposures, periconceptional folic acid or micronutrient supplementation, environment monitoring, and assessment of factories with high levels of pollution.     

Effects of inositol supplementation in a cohort of mothers at risk of producing an NTD pregnancy

Neural tube defects (NTDs), most commonly spina bifida and anencephaly, can be prevented with periconceptional intake of folic acid in about 70% of cases. Recurrence of NTDs despite supplementation of high dose of folic acid further suggests that a proportion of NTD cases might be resistant to folic acid. Moreover, heterogeneity of NTDs has been suggested in animal studies, indicating that only some sub-type of NTDs should be considered sensitive to folate intake. Inositol isomers (particularly myo- and chiro-inositol) can prevent folate-resistant NTDs in the curly-tail mutant mouse, suggesting that some cases of human NTDs might benefit from inositol supplementation. In humans, lower inositol blood concentration was found in pregnant women carrying NTD fetuses, whereas a periconceptional combination therapy with folic acid associated with inositol has been linked to normal live births, despite high NTD recurrence risk. Fifteen pregnancies from 12 Caucasian women from different parts of Italy with at least one previous NTD-affected pregnancy underwent periconceptional combined myo-inositol and folic acid supplementation. Maternal serum α-feto-protein levels were found in the normal range, and normal results on ultrasound examination were found in all the pregnancies that followed. No collateral effects or intense uterine contractions were demonstrated in this pilot study in any of the pregnancies after inositol supplementation, and seventeen babies were born without any type of NTD.     

Folic acid and primary prevention of birth defects

Birth defects (BDs) are an important public health problem, due to their overall incidence, occurring in 2-3% of live births in European Union. Neural tube defects (NTDs) are among major NTDs, due to their severity and relatively high incidence; in the meanwhile NTDs are also the most effectively preventable BDs to date. In particular, an adequate folic acid (FA) intake reduces both the occurrence and the recurrence of NTDs; FA is the synthetic form of folates, naturally occurring vitamins in a number of foods, especially vegetables. The daily intake of 0.4 mg of FA should be recommended to all women of childbearing age who plan to become pregnant. The Italian Network for Primary Prevention of BDs through FA Promotion has achieved a significant improvement in FA awareness and use in the periconceptional period. Nevertheless, primary prevention of BDs needs to make further progress; the Italian National Centre for Rare Diseases participates in european sureveillance of congenital anomalies (EUROCAT) Joint Action as coordinator of activities on the effectiveness of BDs prevention. Mandatory food fortification with FA has not been introduced in any European country. The health benefits of FA in reducing the risk of NTDs are undisputed; however mechanistic and animal studies suggest a relationship between high FA intakes and increased cancer promotion, while human studies are still inconsistent and inconclusive. A Working Group organized by the European Food Safety Authority pointed out significant uncertainties about fortification safety and the need for more studies; currently, FA intake from fortified foods and supplements should not exceed 1 mg/day in adults. In conclusion, based on up-to-date scientific evidence, the Italian Network strategy pivots on periconceptional supplementation integrated with promotion of healthy eating habits, support to health education, enhancing the role of women in managing life choices about their health and pregnancy and increasing the scientific knowledge about BDs primary prevention.     

Periconceptional health and lifestyle factors of both parents affect the risk of live-born children with orofacial clefts

BACKGROUND: Nonsyndromic cleft lip with or without cleft palate (CL/P) or cleft palate only (CPO) are orofacial clefts and have a multifactorial etiology. The identification of amendable parental risk factors may contribute to a reduced occurrence of these malformations in the future. METHODS: Standardized demographic and periconceptional exposure data from 284 parents of a child with CL/P, 66 parents of a child with a CPO and 222 parents of a child without congenital malformations were collected at approximately 24 months after the periconceptional period of the index child. Univariate and multivariate logistic regression analyses were used to estimate relative risks by odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: Univariate results suggest that low parental education, periconceptional maternal medication use and illnesses, paternal smoking, and first-trimester maternal common cold increased CL/P risk. Pregnancy planning and periconceptional folic acid supplementation, however, reduced CL/P risk by approximately 50% (OR, 0.5; 95% CI, 0.3-0.8) and 40% (OR, 0.6; 95% CI, 0.4-0.9), respectively. Mostly comparable results were obtained for CPO. Being a boy (OR, 2.0; 95% CI, 1.4-3.0), folic acid supplementation (OR, 0.6; 95% CI, 0.4-0.9), and low paternal education (OR, 1.6; 95% CI, 1.0-2.3) mainly determined CL/P in the multivariate analyses, compared to low paternal (OR, 4.5; 95% CI, 2.1-9.4) and maternal medication use (OR, 2.0; 95% CI, 1.0-4.0) for CPO. CONCLUSIONS: Preconceptional counseling for orofacial cleft risk assessment should pay attention to maternal medication use, periconceptional folic acid supplementation, and exposures of the father. These determinants can be amended, thereby modifying orofacial cleft risk.     

Periconceptional Maternal Folic Acid Use of 400 μg per Day Is Related to Increased Methylation of the IGF2 Gene in the Very Young Child

Background

Countries worldwide recommend women planning pregnancy to use daily 400 µg of synthetic folic acid in the periconceptional period to prevent birth defects in children. The underlying mechanisms of this preventive effect are not clear, however, epigenetic modulation of growth processes by folic acid is hypothesized. Here, we investigated whether periconceptional maternal folic acid use and markers of global DNA methylation potential (S-adenosylmethionine and S-adenosylhomocysteine blood levels) in mothers and children affect methylation of the insulin-like growth factor 2 gene differentially methylation region (IGF2 DMR) in the child. Moreover, we tested whether the methylation of the IGF2 DMR was independently associated with birth weight.

Methodology/Principal Findings

IGF2 DMR methylation in 120 children aged 17 months (SD 0.3) of whom 86 mothers had used and 34 had not used folic acid periconceptionally were studied. Methylation was measured of 5 CpG dinucleotides covering the DMR using a mass spectrometry-based method. Children of mother who used folic acid had a 4.5% higher methylation of the IGF2 DMR than children who were not exposed to folic acid (49.5% vs. 47.4%; p = 0.014). IGF2 DMR methylation of the children also was associated with the S-adenosylmethionine blood level of the mother but not of the child (+1.7% methylation per SD S-adenosylmethionine; p = 0.037). Finally, we observed an inverse independent association between IGF2 DMR methylation and birth weight (−1.7% methylation per SD birthweight; p = 0.034).

Conclusions

Periconceptional folic acid use is associated with epigenetic changes in IGF2 in the child that may affect intrauterine programming of growth and development with consequences for health and disease throughout life. These results indicate plasticity of IGF2 methylation by periconceptional folic acid use.     

Prevalence of periconceptional folic acid use and perceived barriers to the postgestation continuance of supplemental folic acid: survey results from a Teratogen Information Service

BACKGROUND: Fewer than 40% of U.S. women are taking folic acid supplements periconceptionally at a time when the risk of neural tube defects (NTDs) can be reduced by supplementation. A better understanding of the vitamin-taking habits of childbearing-age women and effective methods for improving periconceptional supplement use are needed. METHODS: A telephone survey conducted through the California Teratogen Information Service (TIS) between August 2003 and January 2004 assessed the prevalence and characteristics of pregnant callers who did not use folic acid supplements in the periconceptional period, and explored attitudes toward advice to continue vitamin use following pregnancy in order to be protected in a future pregnancy. RESULTS: A total of 327 pregnant women who called the TIS for information agreed to participate in the survey. More than half (53.2%) were not taking folic acid-containing supplements in the periconceptional period. Predictors of lack of use included a higher prepregnancy body mass index, younger maternal age, non-white race/ethnicity, lower education level, and unplanned pregnancy. One-quarter of the women said they would be willing to continue taking vitamins after the pregnancy if advised to do so by a physician. The remainder identified obstacles to following that advice--notably, not planning to become pregnant again and the belief that enough folate is derived from diet alone. CONCLUSIONS: More than half of the callers to the TIS were not compliant with recommendations regarding periconceptional folic acid supplementation. This represents an opportunity for TIS specialists and physicians to intervene in a current pregnancy to encourage maintenance of supplement use in the subsequent interpregnancy interval.     

Folate concentrations and folic acid supplementation among women in their first trimester of pregnancy in a rural area with a high prevalence of neural tube defects in Shanxi, China

BACKGROUND: Although an information campaign concerning periconceptional folic acid supplementation was launched in 1998 in Shanxi Province, China, the prevalence of neural tube defects in rural areas was reported as high as 140 per 10,000 births in 2002. The blood folate concentrations and the practice of folic acid supplementation among pregnant women in rural areas of the province are described. METHODS: A total of 483 pregnant women (mean gestation, 8.1 weeks) in a rural area of Shanxi were interviewed. Nonfasting blood samples and information on folic acid supplementation were collected. Folate concentrations in plasma and erythrocytes were determined by a microbiological assay. RESULTS: The mean concentrations of plasma and erythrocyte folate for pregnant women was 10.4 nmol/liter and 375.8 nmol/liter, respectively. Deficiencies of plasma and erythrocyte folate were observed in 20.9% and 47.6% of women, respectively. Seasonal variations were noted in the prevalence of folate deficiency, with significantly lower plasma folate concentrations in spring and summer and lower erythrocyte folate concentrations in seasons other than summer. Among pregnant women, <10% reported having taken or currently taking folic acid, and virtually no women (0.6%) took folic acid as recommended. CONCLUSIONS: Women in rural areas had low plasma and erythrocyte folate levels, and folate deficiency was highly prevalent in the area. Few women followed the recommendations regarding folic acid supplementation, and the information campaign in Shanxi was unsuccessful. These findings suggest the urgent need for combined strategies in rural areas to fortify grain with folic acid and promote folic acid supplements for childbearing-age women.     

Maternal influenza during pregnancy and risk of congenital abnormalities in offspring

BACKGROUND: The teratogenic effect of influenza viruses is currently being debated, and we examined the large population-based data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA) to study the possible association between maternal influenza and various congenital abnormalities (CAs). METHODS: The 1980-1996 HCCSCA includes 22,843 newborns or fetuses with CAs, and 38,151 matched controls (newborn infants without any abnormalities). RESULTS: In the case group, 1328 (5.8%) mothers had influenza at some time during their pregnancies compared to 1838 (4.8%) mothers in the control group (adjusted prevalence odds ratios [PORs], 1.3; 95% confidence interval [CI], 1.2-1.4). In the calculation of the adjusted PORs, the use of antifever drugs and maternal employment status were considered. When cases and their matched controls were compared, there was a higher prevalence of maternal influenza during the second and/or third month of pregnancy for the group of newborns with cleft lip +/- palate (adjusted POR, 3.2; 95% CI, 2.0-5.3), neural-tube defects (adjusted POR, 1.9; 95% CI, 1.1-3.3), and cardiovascular malformations (adjusted POR, 1.7; 95% CI, 1.3-2.3). However, a direct teratogenic effect from influenza viruses appears to be unlikely, and we suggest that the higher prevalence of the CAs indicated above can be explained mainly by fever, because this risk was reduced by the use of antifever drugs. Periconceptional folic acid supplementation also showed some preventive effect for these CAs. CONCLUSIONS: The indirect teratogenic effect of maternal influenza during pregnancy may be restricted by appropriate medical treatment (e.g., antifever drugs) and periconceptional folic acid supplementation.     

Does prenatal screening for 5,10-methylenetetrahydrofolate reductase (MTHFR) mutations in high-risk neural tube defect pregnancies make sense?

Despite the fact that neural tube defects (NTDs) are the most common congenital malformations of the central nervous system, investigators have yet to identify responsible gene(s). Research efforts have been productive in the identification of environmental factors, such as periconceptional folic acid supplementation, that modulate risk for the development of NTDs. Studies of the folic acid biosynthetic pathway led to the discovery of an association between elevated levels of homocysteine and NTD risk. Researchers subsequently identified single nucleotide polymorphisms in the gene coding for the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR). Association studies suggested it was a potential risk factor for NTDs, because the thermolabile form of the enzyme led to elevated homocysteine concentrations when folic acid intake is low. Numerous studies analyzing MTHFR variants have resulted in positive associations with increased NTD risk only in certain populations, suggesting that these variants are not large contributors to the etiology of NTDs. With our limited understanding of the genes involved in regulating NTD susceptibility, the paucity of data on how folic acid protects the developing embryo, as well as the observed decrease in birth prevalence of NTDs following folic acid supplementation and food fortification, it makes little sense for prospective parents to be tested for MTHFR variants, or for variants of other known folate pathway genes.     

Lack of maternal folic acid supplementation is associated with heart defects in Down syndrome: a report from the National Down Syndrome Project

BACKGROUND: Maternal folic acid supplementation has been associated with a reduced risk for neural tube defects and may be associated with a reduced risk for congenital heart defects and other birth defects. Individuals with Down syndrome are at high risk for congenital heart defects and have been shown to have abnormal folate metabolism. METHODS: As part of the population‐based case‐control National Down Syndrome Project, 1011 mothers of infants with Down syndrome reported their use of supplements containing folic acid. These data were used to determine whether a lack of periconceptional maternal folic acid supplementation is associated with congenital heart defects in Down syndrome. We used logistic regression to test the relationship between maternal folic acid supplementation and the frequency of specific heart defects correcting for maternal race or ethnicity, proband sex, maternal use of alcohol and cigarettes, and maternal age at conception. RESULTS: Lack of maternal folic acid supplementation was more frequent among infants with Down syndrome and atrioventricular septal defects (odds ratio [OR], 1.69; 95% confidence interval [CI], 1.08–2.63; p = 0.011) or atrial septal defects (OR, 1.69; 95% CI, 1.11–2.58; p = 0.007) than among infants with Down syndrome and no heart defect. Preliminary evidence suggests that the patterns of association differ by race or ethnicity and sex of the proband. There was no statistically significant association with ventricular septal defects (OR, 1.26; 95% CI, 0.85–1.87; p = 0.124). CONCLUSIONS: Our results suggest that lack of maternal folic acid supplementation is associated with septal defects in infants with Down syndrome. Birth Defects Research (Part A), 2011. © 2011 Wiley‐Liss, Inc.     

Awareness of folic acid for prevention of neural tube defects in a community with high prevalence of consanguineous marriages

Neural tube defects (NTDs) are severe congenital malformations and can be fatal. Intake of 0.4 mg folic in the periconceptional period reduces the risk of NTD by 50-70%. Consanguinity in the Arab population in Israel is a prevalent custom. The aim of this study was to assess the level of awareness regarding folic acid and its effect in the prevention of NTD among Arab Israeli women of childbearing age. We conducted a cross-sectional study. Of the 653 women (18-45 years) who were randomly selected for interview while visiting their family physician or well-baby clinic, 624 women completed the questionnaire. Fifty-three percent (n = 333) of the respondents had heard of folic acid; 14% (n = 89) were familiar with the protective effect of NTD and 3% (n = 18) had taken folic acid in the first months of pregnancy whereas none of them had used it in the preconception period. Highly educated women, women with one or two children, paramedics, and women of high socioeconomic status were more knowledgeable about the protective effects of folic acid (P < 0.001). Age and religion had no significant effect. An urgent need exists to improve the awareness of this population to the protective effect of folic acid. Daily supplementation and fertification of food with folic acid should be considered as the best way to improve the balance of folic acid in women of childbearing age of this special population (high prevalence of consanguinity).     

Birth defects in India: Hidden truth,need for urgent attention

Birth defects (structural, functional and metabolic disorder present from birth, may be diagnosed later) rising up as an important cause of infant mortality even in developing countries where infant mortality has been reduced to much extent. Seventy percent of birth defects are preventable through the application of various cost effective community genetic services.Indian people are living in the midst of risk factors for birth defects, e.g., universality of marriage, high fertility, large number of unplanned pregnancies, poor coverage of antenatal care, poor maternal nutritional status, high consanguineous marriages rate, and high carrier rate for hemoglobinopathies. India being the second most populous country with a large number infant born annually with birth defects should focus its attention on strategies for control of birth defects. Many population based strategies such as iodization, double fortification of salt, flour fortification with multivitamins, folic acid supplementation, periconceptional care, carrier screening and prenatal screening are some of proven strategies for control of birth defects. Strategies such as iodization of salt in spite of being initiated for a long time in the past do have a very little impact on its consumption (only 50% were using iodized salt). Community genetic services for control of birth defects can be easily flourished and integrated with primary health care in India because of its well established infrastructure and personnel in the field of maternal and child health care. As there is wide variation for infant mortality rate (IMR) in different states in India, so there is a need of deferential approach to implement community genetic services in states those had already achieved national goal of IMR. On the other hand, states those have not achieved the national goal on IMR priority should be given to management of other causes of infant mortality.     

Multivitamin and Iron Supplementation to Prevent Periconceptional Anemia in Rural Tanzanian Women: A Randomized,Controlled Trial

Objective

Women’s nutritional status during conception and early pregnancy can influence maternal and infant outcomes. This study examined the efficacy of pre-pregnancy supplementation with iron and multivitamins to reduce the prevalence of anemia during the periconceptional period among rural Tanzanian women and adolescent girls.

Design

A double-blind, randomized controlled trial was conducted in which participants were individually randomized to receive daily oral supplements of folic acid alone, folic acid and iron, or folic acid, iron, and vitamins A, B-complex, C, and E at approximately single recommended dietary allowance (RDA) doses for six months.

Setting

Rural Rufiji District, Tanzania.

Subjects

Non-pregnant women and adolescent girls aged 15–29 years (n = 802).

Results

The study arms were comparable in demographic and socioeconomic characteristics, food security, nutritional status, pregnancy history, and compliance with the regimen (p>0.05). In total, 561 participants (70%) completed the study and were included in the intention-to-treat analysis. Hemoglobin levels were not different across treatments (median: 11.1 g/dL, Q1-Q3: 10.0–12.4 g/dL, p = 0.65). However, compared with the folic acid arm (28%), there was a significant reduction in the risk of hypochromic microcytic anemia in the folic acid and iron arm (17%, RR: 0.61, 95% CI: 0.42–0.90, p = 0.01) and the folic acid, iron, and multivitamin arm (19%, RR: 0.66, 95% CI: 0.45–0.96, p = 0.03). Inverse probability of treatment weighting (IPTW) to adjust for potential selection bias due to loss to follow-up did not materially change these results. The effect of the regimens was not modified by frequency of household meat consumption, baseline underweight status, parity, breastfeeding status, or level of compliance (in all cases, p for interaction>0.2).

Conclusions

Daily oral supplementation with iron and folic acid among women and adolescents prior to pregnancy reduces risk of anemia. The potential benefits of supplementation on the risk of periconceptional anemia and adverse pregnancy outcomes warrant investigation in larger studies.

Trial Registration

ClinicalTrials.gov NCT01183572     

Trends of selected malformations in relation to folic acid recommendations and fortification: an international assessment

BACKGROUND: Two crucial issues relative to the benefits and impact of folic acid in the prevention of birth defects are whether supplementation recommendations alone, without fortification, are effective in reducing the population-wide rates of neural tube defects (NTDs), and whether such policies can reduce the occurrence of other birth defects. Using data from 15 registries, we assessed rates and trends of 14 major defects, including NTDs, in areas with official recommendations or fortification to assess the effectiveness of recommendations and fortification on a wide range of major birth defects. METHODS: We evaluated surveillance data through 2003 on major birth defects from population-based registries from Europe, North America, and Australia. All included ascertainment of pregnancy terminations (where legal). Trends before and after policies or fortification were assessed via Poisson regression and were compared via rate ratios. RESULTS: Significant changes in trends were seen for NTDs in areas with fortification but not in areas with supplementation recommendations alone. For other major birth defects, there was an overall lack of major trend changes after recommendations or fortification. However, some significant declines were observed for select birth defects in individual areas. CONCLUSIONS: Recommendations alone remain an ineffective approach in translating the known protective effect of folic acid in population-wide decline in NTD rates. Fortification appears to be effective in reducing NTDs. The effect on other birth defects remains unclear.     

Plasma vitamin values and antiepileptic therapy: case reports of pregnancy outcomes affected by a neural tube defect

BACKGROUND: Folic acid supplementation reduces the occurrence of neural tube defects (NTDs); however, it is not clear whether it protects against teratogenic effects of antiepileptic drugs. METHODS: We report the cases of four pregnant women receiving valproic acid therapy, who all had NTD-affected offspring, despite periconceptional 5 mg/day of folic acid supplementation (cases), and investigated homocysteine metabolism, linked with folate metabolism. Their plasma homocysteine, folates, and vitamin B6 and B12 results were compared with values of two other women, who were also receiving valproic acid and folic acid complement, but who had normal pregnancies (valproic acid controls), and values of 40 pregnant women who had normal pregnancies and were not receiving any therapy (controls without therapy). Because of the possible existence of a genetic susceptibility, polymorphisms in homocysteine metabolism were sought. RESULTS: Two cases showed a decreased phosphopyridoxal level, compared with levels in the controls not receiving therapy. The genotype TT (C677T) is an NTD genetic susceptibility, but it was observed in only one valproic acid control. Various polymorphisms were observed in the cases, but were also common in the controls. Several studies have reported that valproic acid therapy lowers vitamin B6 levels. Our case with the greatest decrease in plasma phosphopyridoxal, who was taking periconceptional folic acid plus pyridoxine therapy, had a normal second pregnancy outcome. CONCLUSIONS: In addition to folates, other vitamins, such as vitamin B6, may have played a role in NTDs in our patients taking an antiepileptic drug.