Abstract
Objective
To assess whether folic acid intake during the first trimester of pregnancy is related to asthma in the offspring by the age of 6 years.
Study design
Prospective cohort study of 1,499 women who were followed from first trimester of pregnancy. Their children were followed until they were 6 years old.
Results
51% of the women used folic acid in the month before conception and 88% in the third month of pregnancy. The adjusted OR per 100 microgram increase in average daily intake of folic acid was 0.98 (95% CI:0.93-1.04). For categories of daily folate intake, there was no evidence of associations with childhood asthma nor evidence of any dose response relation for any time period (all ptrend>0.05)
Conclusion
Our results do not support any association of folic acid supplementation in pregnancy and asthma risk in offspring by age 6 years.
Keywords: childhood asthma, folic acid, pregnancy
Introduction
In 1991, an influential report published by the British Medical Council concluded that folic acid supplementation starting before pregnancy had a protective effect on the recurrence of neural tube defects (NTD) in the newborn infant.1 The following year, a randomised controlled trial further demonstrated the protective effect of folic acid on first occurrence of NTDs.2 To benefit from these studies, women of childbearing age were advised to use folic acid supplementation.3 In the late 1990s several countries introduced mandatory folic acid supplementation of wheat flour, following which folate status in women of reproductive age has improved substantially.4-6 The subsequent 50% decrease in neural tube defects has clearly demonstrated the positive effect of folic acid supplementation.7-11
It has been questioned whether in utero folic acid supplementation might also enhance development of adverse health outcomes. Folate, a source of methyl donors, regulates a complex network of biological pathways that are vital to growth.12 A change in DNA methylation influences the degree of DNA accessibility for gene transcription and genomic stability.13, 14 Increased methylation is usually associated with gene silencing or reduced gene expression which can bind the transient exposure of folic acid in early life to changes in gene expression. Immune development and differentiation are under epigenetic regulation,15 and folate may have the capacity to promote an allergic phenotype by altering gene expression during early development. Animal studies have shown that the heritable risk of allergic airway disease was modified by in utero exposure to a diet rich in methyl donors16 resulting in an increased risk of allergic airway disease in offspring.
In humans, results are conflicting whether folic acid intake before and/or during pregnancy is associated with increased risk of allergic disease in the offspring. Håberg et al. found that exposure to folic acid supplementation, particularly during the first trimester, was associated with a moderate increase in the risk of lower respiratory tract infections and wheezing up to 18 months of age.17 Whitrow et al. reported that folic acid supplementation in late pregnancy was associated with an increased risk of asthma at 3.5 years of age.18 Due to the uncertainty about any potential and unintended side effects of folic acid exposure in utero, these reported associations merit further study. Since prevention of neural tube defects through folate supplementation is one of the most important neonatal health advances to have been reported in recent years, it is important that supplementation does not gain distrust on unsubstantiated scientific grounds. In this cohort of nearly 1,500 US women with prospective information about folic acid intake, we assess the association of first trimester folic acid supplementation with asthma in the offspring at 6 years of age.
Materials and Methods
Between April 1997 and June 2000 a total of 3,413 women were invited from 56 private obstetric practices and 15 community-based clinics in Massachusetts and Connecticut to participate in the prospective Asthma in Pregnancy (AIP) study.19 These women were interviewed in the first trimester, their hospital records from delivery were reviewed and the women were interviewed after delivery. Later, from September 2003 through January 2007 a subgroup of these subjects took part in a follow up study, Perinatal Risk of Asthma in Infants of Asthmatic Mothers (PRAM). In that study, women with a history of asthma diagnosis (n=872) or women who had symptoms or took asthma medications during pregnancy (n=449), and a simple random sample of pregnant women without asthma or asthma symptoms (n=550) were included. Details of study enrolment have been published elsewhere.20 Non English speaking participants were excluded, as were three infant deaths which left 1,807 subjects eligible for interview. Of these, 302 mothers were excluded because of refusal, inability to locate, and missed interviews. Thus, 1505 women (83.3% of the 1807 eligible ones) were interviewed when the child was 6 years (+/− 3 months) old and included in our primary analyses. We excluded six individuals where information on confounding factors (marital status, family income and maternal asthma) was missing, leaving 1,499 participants in the final analyses.
Data collection in pregnancy (AIP study)
The pregnant women were interviewed, usually at home, before 24 weeks of gestational age. A standardized questionnaire included information on demographic and household characteristics including marital status, family income, health risk factors, medical conditions, and obstetric history. Pregnancy outcome data, which included prenatal, labour and delivery information including information of the newborn, was abstracted from medical records. A post partum interview was conducted in the hospital or by telephone within one month after delivery.
Information on folic acid, iron and vitamin use was obtained before 24 weeks of gestation from the following questions in the prenatal exposure questionnaire. “Have you used any of the following vitamin or mineral supplements: prenatal supplement vitamins, Multivitamin, Vitamin A, Vitamin C, Vitamin E, Iron/Ferrous Sulphate, Folic Acid/Folate, Calcium, or Other; specify.” If a respondent answered yes, she was specifically asked how often each item had been used (not at all, once a month, 2-3 times a month, twice a week, 3-4 times a week, 5-6 times a week, once a day or two or more times a day). This information was collected for the month before conception through the third month of pregnancy.
Folic Acid Exposure
We collected information on folic acid content (micrograms (mcg)) in each of the self-reported vitamin supplements. Using the detailed frequency information from the pregnancy questionnaire, we could calculate mean daily folic acid intake. Prenatal vitamins were estimated to contain 800 micrograms (mcg) folic acid per tablet, whereas vitamin supplements were estimated to contain 400 mcg folic acid20 per tablet.
A dichotomous variable was created to characterize users from non-users. Mean daily intake was calculated for each month from the month before pregnancy through the third month and mean folic acid intake in the first trimester was defined as the average daily intake over these four months. For each month and for the total first trimester, daily folic acid intake was also divided into four categories (0, <400 mcg, 400-800 mcg, >800mcg). The majority of women (n=1,457) were enrolled in the study after starting of their third month of pregnancy and reported all three months of folic acid intake directly. Since 85% of the women with complete information reported the same intake in month two and three, women who were enrolled in the study and interviewed in their second month of pregnancy (n=42) were assumed to have the same folic acid intake in the third month as in the second.
Follow up of the children at 6 years of age (PRAM study)
Asthma in the 6 year old children was assessed by asking the mother the following questions “Has the child ever been diagnosed by a doctor or health professional as having asthma?” and “Has your child had wheezing or whistling in the chest in the last 12 months?” A positive answer to both these questions was considered a positive definition of current asthma.
Study ethics
The Human Investigation Committee of Yale University Medical School (New Haven, Connecticut) approved the study and all respondents provided written informed consent prior to participation.
Statistical analysis
Logistic regression was used to assess the association between folic acid supplementation in pregnancy and asthma in the children and expressed the effect estimates as odds ratios (ORs) with 95% confidence intervals (CIs). Information on potential confounding variables was obtained from the interviews conducted during early pregnancy and at 6 years (+/− 3 months) of age. They included maternal parity, ethnicity and marital status, household income, maternal asthma, smoking during pregnancy, use of other vitamins (C, D and E), iron use, and calcium use in first trimester.
Group differences in folic acid supplementation were initially identified using of unpaired t-tests if the variables were dichotomized and by analysis of variance (ANOVA) with Bonferroni and Scheffes Post Hoc tests when they were categorized in more than two groups. Covariables were identified as potential confounders and included in the analyses if they were associated with both the exposure of daily folic acid supplementation and outcome of asthma at six years of age, at a level of p<0.10 Adjusted models used a backward elimination procedure which retained only covariates that resulted in 10% or greater change in the effect estimate. The final model included maternal marital status, family income and maternal asthma.
The effect of folic acid supplementation was first assessed for the continuous variable per 100 mcg increase in daily intake, and successively for the four categories of intake (no use, <400mcg, 400-800 mcg and >800 mcg daily use). All analyses were done separately for four different time periods (the month before pregnancy and during 1st, 2nd and 3rd month). In these categorical analyses, no use of folic acid was used as the reference and two-sided P-values from linear trend tests were calculated by treating the folic acid dose categories as ordinal variables in the regression model.
P-values <0.05 and CIs that excluded the null value of 1 were considered statistically significant. Statistical analyses were performed with STATA/SE10 (College Station, TX, USA)
Results
Table 1 describes characteristics of the study population by daily intake of folic acid (mcg) in the month before conception and during the first trimester. Pregnant women who were above 25 years of age, of white ethnicity, had higher education, higher income, and were married, used higher doses of folic acid, as did women who did not smoke or had quit smoking before pregnancy. By study design, there was an over-sampling of women who had been diagnosed with asthma. These women had higher intake of folic acid compared to women without asthma in the month before and in the first trimester overall, with mean values (SD) of 323 (369) mcg vs. 279 (363) mcg (p<0.01) and 510 (299) vs. 481 (302) mcg (p<0.05) respectively (Table 1). Women who were giving birth for the first and second time used higher daily doses of folic acid than those who had given birth twice or more, but we found no association between parity and asthma in the children (P=0.30). Women who took other vitamins, iron and/or calcium used higher doses of folic acid supplementation than women who did not take these supplements. However, such supplementation was not associated with asthma development, (P=0.5).
Table 1.
Folic acid supplementation use during first trimester of pregnancy in the PRAM study, Connecticut, USA by characteristics of study population (n=1499).
| Characteristics | n | Proportion (%) |
Folic acid Intake per day, month before pregnancy Mean (mcg) (SD) |
Folic acid Intake per day in first trimester Mean(mcg) (SD) |
|---|---|---|---|---|
| All Participants | 1499 | 100 | 304 (367) | 497 (301) |
| Maternal age (years) | ||||
| <25 | 341 | 22.75 | 66 (200) | 280 (257) |
| 25-35 | 884 | 58.97 | 364 (365)a | 548 (272)a |
| >35 | 274 | 18.28 | 405 (407)a | 603 (311)a, b |
| Maternal ethnicity | ||||
| White | 1086 | 72.45 | 375 (373)a | 565 (277)a |
| African American | 144 | 9.61 | 105 (286) | 318 (299) |
| Hispanic | 209 | 13.94 | 90 (222) | 294 (260) |
| Asian/other | 60 | 4.00 | 222 (363) | 394 (333) |
| Maternal education | ||||
| Less than or equal 12 years | 418 | 27.89 | 111 (246) | 317 (267) |
| At least some College | 735 | 49.03 | 338 (368)a | 542 (283)a |
| At least some graduate school | 346 | 23.08 | 463 (388)a, b | 619 (279)a, b |
| Household income ($) | ||||
| > 40 000 | 1061 | 70.78 | 368 (365)a | 558 (273)a |
| <= 40 000 | 390 | 26.02 | 107 (281) | 317 (229) |
| Do not know | 48 | 3.20 | 467 (440)a | 604 (344)a |
| Maternal marital status | ||||
| Married | 1093 | 72.92 | 388 (375)a | 572 (279)a |
| Single/divorced | 406 | 28.08 | 76 (220) | 294 (262) |
| Smoking | ||||
| Never | 917 | 61.17 | 345 (375)a | 523 (297)a |
| Quit before becoming pregnant | 315 | 21.01 | 351 (386)a | 543 (322)a |
| 1st trimester | 173 | 11.54 | 104 (227) | 353 (241) |
| Throughout pregnancy | 94 | 6.27 | 107 (223) | 346 (236) |
| Mothers diagnosed with asthma | ||||
| Yes | 828 | 55.24 | 323 (369)a | 510 (299)a |
| No | 671 | 44.76 | 279 (363) | 481 (302) |
| Parity | ||||
| 0 | 670 | 44.70 | 324 (376)a | 518 (299)a |
| 1 | 516 | 34.42 | 317 (367)a | 500 (295)a |
| ≥2 | 313 | 20.88 | 238 (341) | 445 (308) |
| Also vitamins C, D, E | ||||
| No | 1316 | 87.79 | 286 (363) | 480 (299) |
| Yes | 183 | 12.21 | 431 (371)a | 618 (284)a |
| Iron use | ||||
| No | 1374 | 91.66 | 299 (357) | 491 (290) |
| Yes | 125 | 8.34 | 348 (459) | 559 (399) |
| Calcium use | ||||
| No | 1334 | 88.99 | 278 (352) | 475 (294) |
| Yes | 165 | 11.01 | 509 (417)a | 674 (298)a |
P<0.05 vs. the lower number within each category,
P<0.05 vs. the second lowest number within each category
A number of maternal characteristics were associated with asthma in the six year old child. In unadjusted analyses, asthma was significantly more often diagnosed in children whose mothers were younger, children of African-American or Hispanic mothers, mothers who had low education, low income, were single, who smoked, and who had themselves been diagnosed with asthma21.
Table 2 presents mean daily folic acid dose in micrograms (mcg), and categories for daily folic acid intake for each of the four time periods under study. Mean intake of folic acid increased from 303 mcg the month before pregnancy, to 404 mcg in the first, 605 mcg in the second and 676 mcg in the third month of pregnancy. Mean supplementation in the first trimester as a whole was 497 mcg. Furthermore, the proportion of women who used folic acid supplementation increased from 51% before pregnancy to 61%, 81%, and 88% in the first, second and third months, respectively. Overall, 92 % of the pregnant women had used folic acid at some point during the first trimester.
Table 2.
Daily Supplementation of Folic acid in the PRAM study (Connecticut, USA): month before conception through 3rd month of pregnancy.
|
Folic acid Mean (SD) |
N |
% of total group |
Asthma at 6 years | ||
|---|---|---|---|---|---|
| (n=223) | (14.9%) | ||||
|
Month before
conception |
|||||
| Folic acid (mcg) | 303 (367) | 768 | 51.2 | 92 | 6.1 |
| No use | 731 | 48.8 | 131 | 8.7 | |
| <400 | 89 | 5.9 | 15 | 1 | |
| 400-800 | 625 | 41.7 | 70 | 4.7 | |
| >800 | 54 | 3.6 | 7 | 0.5 | |
|
First month of
pregnancy |
|||||
| Folic acid (mcg) | 402 (402) | 913 | 60.9 | 112 | 7.5 |
| No use | 586 | 39.1 | 111 | 7.4 | |
| <400 | 87 | 5.8 | 16 | 1.1 | |
| 400-800 | 746 | 49.8 | 86 | 5.7 | |
| >800 | 80 | 5.3 | 10 | 0.7 | |
|
Second month of
pregnancy |
|||||
| Folic acid (mcg) | 605 (390) | 1218 | 81.3 | 174 | 11.6 |
| No use | 281 | 18.8 | 49 | 3.3 | |
| <400 | 92 | 6.1 | 11 | 0.7 | |
| 400-800 | 1009 | 67.3 | 152 | 10.1 | |
| >800 | 117 | 7.8 | 11 | 0.7 | |
|
Third month of
pregnancy |
|||||
| Folic acid (mcg) | 676 (349) | 1288 | 88.4 | 187 | 12.5 |
| No use | 191 | 12.7 | 36 | 2.4 | |
| <400 | 69 | 4.6 | 11 | 0.7 | |
| 400-800 | 1144 | 76.3 | 165 | 11 | |
| >800 | 95 | 6.3 | 11 | 0.7 | |
| First trimester | |||||
| Folic acid (mcg) | 497 (301) | 1381 | 92.1 | 202 | 13.5 |
| No | 118 | 7.9 | 21 | 1.4 | |
| <400 | 342 | 22.8 | 65 | 4.3 | |
| 400-800 | 953 | 63.6 | 130 | 8.7 | |
| >800 | 86 | 5.7 | 7 | 0.1 | |
Table 3 presents the crude and adjusted risk estimates for childhood asthma with folic acid use versus none. In unadjusted analyses, women who had taken folic acid in the month before and in the first month of pregnancy were less likely to have children with asthma. In adjusted analyses, there were no differences between users and non users.
Table 3.
Association between Folic Acid supplementation one to three months before conception, during first trimester of pregnancy and asthma in offspring at six years of age (n = 1499).
| Folic Acid Supplementation |
Unadjusted | Adjusteda | ||
|---|---|---|---|---|
| (OR associated with use versus non-use) |
OR | 95% CI | OR | 95% CI |
| Month before conception | 0.62 | 0.47-0.83 | 0.95 | 0.68-1.32 |
| First Month | 0.60 | 0.45-0.80 | 0.89 | 0.69-1.23 |
| Second month | 0.79 | 0.56-1.11 | 1.31 | 0.89-1.93 |
| Third month | 0.72 | 0.48-1.07 | 0.94 | 0.62-1.43 |
| First trimester | 0.79 | 0.48-1.30 | 1.23 | 0.73-2.07 |
Adjusted for household annual income (40 000 USD <vs.>40 000 USD), maternal marital status (married vs not married) and physician diagnosed maternal asthma (yes/no).
Table 4 shows the crude and adjusted estimates of the logistic modeling of folic acid use per 100 mcg increase and daily intake with childhood asthma. Exposed women were compared with non exposed ones by time period. In the unadjusted analyses, we found a significant decreased risk of asthma from folic acid supplementation before conception, in the first month of pregnancy, and in the first trimester as a whole. In a final model that adjusted for potential confounders we found no significant increased risk of asthma from folic acid supplementation for any of the time periods studied (First trimester OR 0.98 CI (0.93-1.04).
Table 4.
Association between Folic Acid supplementation (per 100 mcg increase in average daily intake) one month before conception, during first trimester of pregnancy and asthma in the offspring at six years of age (n = 1499).
| Folic Acid Supplementation |
Unadjusted | Adjusteda | ||
|---|---|---|---|---|
| ( per 100mcg increase in daily intake ) |
OR | 95% CI | OR | 95% CI |
| Month before conception | 0.93 | 0.89-.097 | 0.98 | 0.94-1.03 |
| First Month | 0.94 | 0.90-0.97 | 0.98 | 0.94-1.02 |
| Second month | 0.96 | 0.92-1.00 | 0.99 | 0.95-1.03 |
| Third month | 0.96 | 0.92-1.00 | 0.99 | 0.95-1.03 |
| First trimester | 0.92 | 0.87-0.97 | 0.98 | 0.93-1.04 |
Adjusted for household annual income (40 000 USD <vs.>40 000 USD), maternal marital status (married vs not married) and physician diagnosed maternal asthma (yes/no).
Table 5 presents the crude and adjusted estimates of categories of folic acid supplementation for each time period with asthma among six year old children. In unadjusted analyses, daily doses from 400 to 800 mcg of folic acid in the month before and in the first month of pregnancy was significantly associated with a decreased risk of asthma. In the second month only doses >800 mcg was associated with a decreased risk, whereas in the third month as well as the whole first trimester, there was no association between folic acid supplementation and asthma. After adjustment for confounders, there was neither evidence of any associations between categories of folic acid intake and childhood asthma nor evidence of a dose response relationship for any time period (all ptrend >0.05).
Table 5.
Association between Amount of Folic Acid Supplementation One Month Before Conception and During First Trimester of Pregnancy, and Asthma in the Offspring at Six Years of Age. Results are presented as Odds Ratio (OR) with 95% Confidence Intervals (95% CI) and p for trend
| Unadjusted | Adjusteda | ||||||
|---|---|---|---|---|---|---|---|
| Folic Acid Use | n | OR | 95% CI | P trend | OR | 95% CI | P trend |
| Month before Conception | |||||||
| No use | 731 | Ref | Ref | ||||
| <400 mcg | 89 | 0.93 | 0.52-1.67 | 1.29 | 0.70-2.40 | ||
| 400-800 mcg | 625 | 0.58 | 0.42-0.79 | 0.89 | 0.62-1.27 | ||
| >800 mcg | 54 | 0.68 | 0.30-1.54 | 0.001 | 1.02 | 0.44-2.40 | 0.70 |
| Month 1 of pregnancy | |||||||
| No use | 586 | Ref | Ref | ||||
| <400 mcg | 87 | 0.96 | 0.54-1.72 | 1.31 | 0.71-2.41 | ||
| 400-800 mcg | 746 | 0.56 | 0.41-0.76 | 0.82 | 0.58-1.17 | ||
| >800 mcg | 80 | 0.61 | 0.31-1.22 | <0.001 | 0.94 | 0.46-1.97 | 0.33 |
| Month 2 of pregnancy | |||||||
| No use | 281 | Ref | Ref | ||||
| <400 mcg | 92 | 0.64 | 0.32-1.30 | 1.03 | 0.49-2.14 | ||
| 400-800 mcg | 1009 | 0.84 | 0.59-1.20 | 1.45 | 0.97-2.16 | ||
| >800 mcg | 117 | 0.49 | 0.25-0.98 | 0.13 | 0.88 | 0.42-1.82 | 0.30 |
| Month 3 of pregnancy | |||||||
| No use | 191 | Ref | Ref | ||||
| <400 mcg | 69 | 0.82 | 0.39-1.71 | 0.80 | 0.37-1.72 | ||
| 400-800 mcg | 1144 | 0.73 | 0.49-1.08 | 0.96 | 0.63-1.47 | ||
| >800 mcg | 95 | 0.56 | 0.27-1.16 | 0.07 | 0.79 | 0.37-1.68 | 0.77 |
| First trimester overall | |||||||
| No use | 118 | Ref | Ref | ||||
| <400 | 342 | 1.08 | 0.63-1.87 | 1.34 | 0.76-2.35 | ||
| 400-800 | 953 | 0.73 | 0.44-1.21 | 1.18 | 0.68-2.04 | ||
| >800 | 86 | 0.41 | 0.17-1.01 | 0.006 | 0.73 | 0.28-1.87 | 0.70 |
Adjusted for household annual income (40 000 USD <vs.>=40 000 USD), maternal marital status (married vs not married) and physician diagnosed maternal asthma (yes/no).
Comment
In this prospective cohort study, supplementary folic acid in the month before and/or the first trimester of pregnancy was not associated with asthma in the offspring at 6 years of age.
A previous paper reported a slightly increased risk of wheezing and respiratory tract infections in children up to 18 months when mothers had used folic acid supplementation in early pregnancy.17 However, no supplementation doses were recorded and the authors could not establish an adverse dose-response effect. In contrast to their findings, Whitrow et al. reported no association between folate intake or folic acid supplementation and asthma at 3.5 and 5.5 years of age.18.
The major strength of our study is its prospective design that enabled assessment of the association between prenatal exposures and childhood asthma. The study also included prospectively collected information on numerous potentially important confounding variables. Further, we were able to classify the quantity of folic acid supplementation and the time span of exposure. It is unlikely that misclassification of exposure was related to the outcome because folic acid supplementation was reported before birth. The sample size is robust (n=1499) and, given the hereditary risk of asthma, the sample was enriched with mothers who themselves had asthma. This allowed for examination of modifying effects by maternal asthma status.
The folic acid and asthma hypothesis was most likely unknown to mothers, interviewers or physicians, making information bias unlikely. One strength of the study is that only cases with a physician verified diagnosis of asthma and with current symptoms at 6 years of age were included in the analyses. It is, however, a limitation that the doctor diagnosed asthma was ascertained through a renewed contact with the mother when the child was 6 years of age, at which time they were also asked about persistent symptoms. We are aware that some of the children might not have wheezing or whistling in the chest due to the effect of the prescribed asthma medications. In this category we found 38 infants. Re-analysis using this modification of our outcome did not materially affect the results.
The definition of asthma we used is common in epidemiologic research, and these same limitations affected the studies that previously reported increased risk of respiratory problems with folic acid supplementation.17, 18
It is a limitation that we had no information about folate intake from nutrients. Daily intake of folate from nutrients has been estimated to around 200 mcg without fortification22 and around 400 mcg with fortification in flour.6 If we assume that the nutrient intake of folic acid was evenly distributed among cases and controls, one should expect fortification had no influence on our results. Furthermore, the group of women that had intake above 800 mcg was small and too underpowered to demonstrate differences.
It is proposed that an increased risk of asthma may develop in the offspring due to an effect of folate on epigenic regulation of immune responses,16 that silences the pathways for T1 helper cells. These cells normally inhibit T2 helper cells, which are allergy promoting. Mice have been tested to see whether in utero exposure to a diet rich in methyl donors enhances the allergy-promoting immunity. By reducing expression of key genes that regulate immunity, the severity of airway disease was enhanced.16
Whether the same allergy-promoting mechanism develops after folic acid supplementation in the human fetus is unknown. Given the extreme importance of folic acid supplementation in preventing congenital birth defects, it is paramount to establish whether exposures during the intrauterine period are truly causally related to development of asthma in later life. Given the clear relationship of maternal intake of folic acid and concentrations of folate in maternal serum and red blood cell folate, it is reasonable to think that maternal intake in pregnancy is a proxy for fetal exposure.6 Studies in human embryos and fetuses are difficult to conduct. However, to support a causal relationship it may be required to study the association between maternal folic acid concentrations and immunologic and epigenetic characteristics of cord blood.24 Methylation of DNA is an epigenetic regulator of gene-expression and is essential for normal embryonic development.13
Folic acid supplementation to women of childbearing age and fortification of nutrients has been greatly advantageous with rapidly decreasing NTD rates in several countries. 7-10 A dose-response of folic acid supplementation has been shown with a reduction in NTD of 23% from 200 mcg to 85% reduction with 5000 mcg daily intake.25
Large scale public health interventions, such as mandatory fortification of food, need to be carefully assessed for risks of harm. We were unable to find any effect of the recommended folic acid supplementation in early pregnancy on development of asthma in the offspring by the age of 6 years. However, further studies are needed to assess both the risk at doses higher than 800 mcg in early pregnancy as well as the risk, at all doses, of folic acid supplementation in the second and third trimesters.
Acknowledgments
Sources of Financial Support: This work was supported by grants AI41040 and DA05484 from the National Institutes of Health.
Footnotes
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The studies were conducted in New Haven, Connecticut, USA.
None of the authors have a conflict of interest, financial or otherwise.
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