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Growing evidence suggests that maternal folic acid supplementation during pregnancy may be associated with the risk of childhood asthma, but these findings remain controversial. Therefore, the purpose of this systematic review and meta-analysis was to assess the association between maternal folic acid supplementation during pregnancy and the risk of childhood asthma, and to determine the safe dose of folic acid supplementation during pregnancy based on a dose-response analysis to lower the risk of childhood asthma. The PubMed, Embase, Cochrane Library, and Web of Science databases were searched for relevant studies published before April 2022. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of eligible studies, and a fixed-effect model was employed to calculate the odds ratio (OR) of asthma with 95% confidence intervals (CI). In addition, the generalized least-squares trend (GLST) was used to explore a nonlinear dose-response relationship. Stata 15.0 was used for the statistical analysis mentioned above. This systematic review included 18 studies (13 cohort studies, 5 case-control studies) with a total of 252,770 participants, 50,248 of whom were children with asthma. The meta-analysis showed that maternal folic acid supplementation during pregnancy was significantly associated with the risk of childhood asthma (OR = 1.07; 95% CI = 1.04–1.11). The subgroup analysis revealed a significant correlation between the risk of childhood asthma and the folic acid supplementation in the first Trimester (OR = 1.09; 95% CI = 1.05–1.12), the third Trimester (OR = 1.15; 95% CI = 1.04–1.26) and the whole pregnancy (OR = 1.13; 95% CI = 1.10–1.16). At the same time, the dose-response analysis showed a nonlinear relationship between maternal folic acid intake during pregnancy and the risk of childhood asthma. The risk of asthma in children significantly increased when maternal folic acid intake reached 581 μg/day. This meta-analysis showed that maternal folic acid supplementation during pregnancy increased the risk of asthma in children. Based on the results of the dose-response analysis, less than 580 μg folic acid per day is advised in order to effectively prevent birth defects without increasing the risk of childhood asthma.
Asthma is the most prevalent chronic respiratory disease in children and adults, affecting approximately 334 million people worldwide. It is characterized by variable expiratory airflow restriction and recurrent symptoms, such as wheezing, shortness of breath, chest tightness, and cough (
Asthma is caused by a complex gene-environment interaction. The occurrence of asthma is closely correlated with nutritional supplementation (
In recent years, researchers have increasingly focused on the association between folic acid supplementation during pregnancy and the risk of childhood asthma, but their findings are inconsistent. Therefore, we conducted a comprehensive systematic review and meta-analysis based on available evidence to investigate (1) whether maternal folic acid supplementation during pregnancy is associated with the risk of childhood asthma; (2) whether there is a relationship between the occurrence of asthma in children and the daily intake of folic acid in mothers; (3) the relationship between folic acid supplementation and childhood asthma development at different stages (before conception, first trimester, second trimester, third trimester, whole trimester, and others); and (4) whether the association between maternal folic acid supplementation and the risk of childhood asthma varies with economic development levels of different countries.
This meta-analysis was reported according to the PRISMA 2020 (The Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020) guideline and MOOSE (Meta-analysis of Observational Studies in Epidemiology) recommendations (
The PubMed, Embase, Cochrane Library, and Web of Science databases were retrieved for relevant studies published before April 12th, 2022. Both subject words (MeSH) and free words were searched. The search terms included “Folic Acid” [Mesh] and “Asthma” [Mesh]; the keywords were: “Folic Acid” OR “Vitamin M” OR “Vitamin B9” OR “B9, Vitamin” OR “Pteroylglutamic Acid” OR “Folvite” OR “Folacin” OR “Folate” in combination with “Asthma” OR “Asthmas”. The search strategy is shown in
This systematic review complied with the following inclusion and exclusion criteria to select eligible studies.
Inclusion criteria: original studies on the association between folic acid supplementation during pregnancy and the risk of childhood asthma; (2) cohort studies or case-control studies; (3) studies that provided risk evaluation of the association between childhood asthma and maternal daily folic acid intake or serum folate concentrations in women during their pregnancy; (4) studies published in English.
Studies with the following characteristics were excluded: (1) the sample size was too small (sample size <50); (2) there was no direct or indirect access to the odds ratio (OR) or relative risk (RR); (3) there were serious defects in the research data, and the literature was published in gray journals.
The retrieved studies were imported into EndNote X9. After removing duplicates, irrelevant studies were also deleted based on the titles and abstracts. Then the full texts of the remaining articles were downloaded and read to determine whether they could be finally included. The following data were extracted from all included studies: first author, date of publication, country and region, study design, source of participants, time of sampling, sample size, age, the period of folic acid supplementation, folic acid intake, statistical analysis, covariate adjustment, outcome measures, and other relevant characteristics. If several included studies reported ORs adjusted for different covariates, the ORs with the most adjusted covariates were extracted.
Literature screening and data extraction were independently carried out by two researchers (Y. F. S. and W. Z. T.) and cross-checked after completion. If there were any dissent, a third researcher (S. L. P.) was consulted to assist in the determination. If there was a lack of data, the researchers tried to contact the author to obtain it. If the information was inadequate, the researchers contacted the corresponding authors for more detailed data or other relevant information.
The Newcastle-Ottawa Scale (NOS) (
The meta-analysis was performed using Stata 15.0 (StataCorp, College Station, TX, United States), and the effect size was evaluated by OR with 95% confidence intervals (CI). The heterogeneity among the included studies was calculated by the
Initially, 999 studies were retrieved from PubMed (
Flow diagram of literature selection.
Basic information for the included studies.
The first author (y) | Country | Study design | Sources of participants | Sampling time | No. of participants/cases | Age (years) | Folic acid intake | Statistical analysis | Adjustment for covariates | Outcome measure | Study quality |
---|---|---|---|---|---|---|---|---|---|---|---|
Chu S, 2022 | China | Case-control study | Shanghai, China | 2015.06–2016.01 | 1364/548 | 4–12 | 400–800 µg/D | Unconditional logistic regression models. | Maternal education levels, paternal education levels, family history of allergic diseases in any of his family members, child age, gender, birthweight, gestational age, delivered by caesarean section, newborn resuscitation, and feeding in the first 6 months. | Period of folic acid exposure supplementation | 7 |
Miyashita C, 2021 | Japan | Cohort study | Hokkaido, Japan | 2008–2015.09 | 6651/732 (1 years of age); 6651/1087 (2 years of age); 6651/838 (4 years of age); 6651/466 (7 years of age) | 1, 2, 4, and 7 | — | Logistic regression analysis. | Maternal age, parity, delivery year, alcohol consumption during pregnancy, log10-transformed maternal cotinine level, maternal allergic history, paternal allergic history, annual household income, and sex of the child. | Folic acid exposure | 8 |
Liu J, 2020 | China | Case-control study | China | 2000.12–2001.09 | 9090/109 | 4–6 | 400 µg/D | Logistic regression analysis. | Maternal age at child birth, education, occupation, and parity. | Folic acid exposure | 6 |
Alfonso VH, 2018 | United States | Case-control study | Los Angeles, United States | 2006–2007 | 1176/465 | 3 | — | Poisson regression models with robust error variance and a log link function. | Mother's race/ethnicity and nativity, mother's age at pregnancy, mother's education at the time of pregnancy, use of preconception vitamins, initiation of prenatal care, alcohol use during pregnancy, home environmental tobacco smoke during pregnancy, pre-pregnancy BMI, marital status, primary source of payment for prenatal care, parity, and birth outcome. Maternal history of atopy, duration of exclusive breastfeeding, child attendance to daycare or preschool, infection during pregnancy, and housing characteristics. | Folic acid exposure | 6 |
Roy A, 2018 | United States | Cohort study | Memphis, Tennessee, United States | 2006–2011 | 849/174 | 3 | 10 ng/ml (Maternal plasma folate level) | Logistic regression analysis. | Maternal age at enrollment, self-reported race, education, prenatal smoking, asthma, pre-pregnancy body mass index, 2nd trimester vitamin D levels, parity, delivery route, and child sex and birth weight, breastfeeding. | Supplementary period | 8 |
Parr CL, 2017 | Norway | Cohort study | Norwegian birth registry and Norwegian Prescription Database | 2014.04.01 | 39,846/1901 | 7 | 400 µg/D | Log binomial regression or multinomial logistic regressio. | Maternal age at delivery, parity, maternal education, prepregnancy body mass index, maternal smoking in pregnancy, and use of cod liver oil, other dietary supplements, and maternal energy intake in pregnancy. | Folic acid exposure supplement dosage | 8 |
Veeranki SP, 2015 | United States | Cohort study | Tennessee, United States | 1996–2005 | 104,428/15,776 | 4.5–6 | 1000 µg/D | Multivariable logistic regression analysis. | Maternal characteristics included race, age at delivery, education, smoking during pregnancy, marital status, year of pregnancy, history of asthma, region of residence, and adequacy of prenatal care. Child characteristics included gender, birth weight, estimated gestational age and number of siblings. | Supplementary period | 7 |
Zetstra-van der Woude PA, 2014 | Netherlands | Case-control study | The pregnancy database IADB.nl, Netherlands | 1994–2011 | 35,604/11,780 | — | 5000 µg/D | Logistic regression analysis. | Age of the mother, single or multiple pregnancy, maternal asthma medication, and paternal asthma medication. Dispension of iron supplements, antifolate medication, antidepressants, antihypertensives, antidiabetics, and benzodiazepines during pregnancy. | Folic acid exposure | 6 |
Martinussen MP, 2012 | United States | Cohort study | Massachusetts and Connecticut, United States | 2003.09–2007.01 | 1499/223 | 6 | Q1, 0 µg/D; Q2, <400 µg/D; Q3, 400–800 µg/D; Q4, >800 µg/D. | Logistic regression analysis. Variance (ANOVA) with Bonferroni and Scheffes Post Hoc tests. | 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. | Supplementary period | 8 |
Dunstan JA, 2012 | Australia | Cohort study | Western Australia | — | 628/59 | 1 | Q1, <200 µg/D; Q2, 200–499 µg/D; Q3, >500 µg/D. | Associations between normally and lognormally distributed variables were evaluated in linear models. Logistic regression analysis. | Maternal age, maternal allergic disease, previous pregnancies, socioeconomic status, and education level. Infants' daycare attendance, infection history, postnatal dietary intervention, pet keeping, breast-feeding, and infant dietary patterns. | Folic acid exposure supplement dosage | 8 |
Bekkers MB, 2012 | Netherlands | Cohort study | Netherlands | 2004–2005 | 3604/822, 3 years of age; 3484/653, 4 years of age; 3418/605, 5 years of age; 3389/496, 6 years of age; 3299/406, 7 years of age; 3237/419, 8 years of age. | 1–8 | — | Log binomial regression analyses. | Sex, birth weight, gestational age, number of older siblings, maternal education, maternal allergy, maternal body mass index before pregnancy, maternal smoking during pregnancy, maternal use of other vitamin supplements (A, C, D or E) than folic acid-only, prenatal and multivitamin or vitamin B complex supplements, maternal age at child birth, breast feeding duration, smoking in the home by anyone at 1 yr of age, type of day care at 1 yr of age and region. | Folic acid exposure | 8 |
Kiefte-de Jong JC, 2012 | Netherlands | Cohort study | Netherlands | 2002.04–2006.1 | 8742/3409, 1 years of age; 8742/1923, 2 years of age; 8742/1311, 3, 4 years of age. | 0–4 | 400–500 µg/D | Logistic GEE analyses. | Maternal age at pregnancy; maternal BMI at inclusion; maternal educational level; maternal ethnicity; infant's sex; infant's birth weight and gestational age at birth; any maternal smoking during pregnancy; any maternal alcohol consumption during pregnancy; duration of breastfeeding; any attendance of day care of the child in the first 24 mo of the infant's life; parental atopic constitution. | Period of folic acid exposure supplementation | 6 |
Miyake Y, 2011 | Japan | Cohort study | Neyagawa City, Japan | 2001.11–2003.03 | 763/169 | 16–24 months | Q1, 206.8 µg/D; Q2, 255.1 µg/D; Q3, 291.2 µg/D; Q4, 370.6 µg/D. | Logistic regression analysis; Multiple logistic regression analysis. | Adjustment for maternal age, gestation at baseline, residential municipality at baseline, family income, maternal and paternal education, maternal and paternal history of asthma, atopic eczema, and allergic rhinitis, changes in maternal diet in the previous 1 month, season when data at baseline were collected, maternal smoking during pregnancy, baby's older siblings, baby's sex, baby's birth weight, household smoking in same room as infant, breastfeeding duration, age at which solid foods were introduced, age of infant at the third survey, and maternal intake of docosahexaenoic acid, n-6 polyunsaturated fatty acids, vitamin D, calcium, vitamin E, and |
Folic acid exposure supplement dosage | 7 |
Magdelijns FJ, 2011 | Netherlands | Cohort study | the KOALA study, Netherlands | 2002.01 | 2640/130 | 6–7 | — | Univariable and multivariable logisticregression analysis. | Recruitment group, maternal antibiotic, smoking and alcohol use during pregnancy, mode and place of delivery, birth weight, gender, treatment with antibiotics during the first 6 months of life, exposure to environmental tobacco smoke and domestic animals, breastfeeding, maternal education level, family history of atopy, siblings, day care attendance, and multivitamin or other supplement use during pregnancy. | Period of folic acid exposure supplementation | 8 |
Håberg SE, 2011 | Norway | Case-control study | the MoBa study, Norway | 2002.07–2004.06 | 1962/507 | 3 | Q1, <5.54 nmol/l; Q2, 5.54–7.68 nmol/l; Q3, 7.68–10.6 nmol/l; Q4, 10.6–17.84 nmol/l; Q5, >17.84 nmol/l. (Maternal plasma folate level) | Univariate and multivariate logistic regression analysis. | Maternal atopy, maternal educational level, parity, maternal prepregnancy body mass index (BMI) calculated from height and prepregnancy weight, maternal smoking in pregnancy, maternal smoking when the child was three years, and the child's use of vitamin supplements or cod liver oil at three years of age. | Folic acid exposure | 8 |
Whitrow MJ, 2009 | Australia | Cohort study | Adelaide, Australia | 1998–2005 | 557/57, 3.5 years of age; 557/50, 5.5 years of age. | 3.5, 5.5 | 400 µg/D | Poisson regression model. | — | Supplementary period | 5 |
Håberg SE, 2009 | Norway | Cohort study | the MoBa study, Norway | 2000.01–2005.06 | 32,077/12,656 | 6–18 months | 400 µg/D | Generalized linear model. | Other supplements in pregnancy, sex, birth weight, month of birth, and maternal atopy, maternal educational level, parity, maternal smoking in pregnancy, type of day care, parental smoking in first 3 months after birth, breast feeding at 6 months, and exposure to vitamin supplements or cod liver oil at 6 months of age. | Supplementary period | 6 |
Litonjua AA, 2006 | United States | Cohort study | Boston, United States | 1999.04–2002.07 | 1290/376 | 2 | 400 µg/D | Bivariate logistic regression models. | Birth weight, neonate sex, maternal age, maternal prepregnancy body mass index, breastfeeding duration, the number of children <12 y old in the home, postnatal passive smoke exposure, family income, and maternal and paternal asthma. | Folic acid exposure | 8 |
Of the 18 included studies, 13 studies (
Eight studies (
Subgroup analysis based on folic acid supplementation in different periods of pregnancy.
Another subgroup analysis was conducted according to the economic development level of different countries. Eleven studies (
Studies with relevant data were selected for a dose-response analysis (
Dose-response analysis of daily maternal folic acid intake and risk of childhood asthma.
A funnel plot was plotted to test the publication bias. The results showed that the left and right distributions were symmetrical, as shown in
Funnel diagram.
Egger's test.
The results of the meta-analysis suggested that maternal folic acid supplementation during pregnancy was associated with the risk of childhood asthma. According to subgroup analyses, the effects of folic acid supplementation were found to be significant in the first trimester, the third trimester, and the whole pregnancy. In addition, folic acid supplementation during pregnancy increased the risk of childhood asthma regardless of the economic development levels of different countries. The dose-response analysis showed a nonlinear relationship between maternal folic acid intake during pregnancy and the risk of childhood asthma. The maternal folic acid intake of less than 581 µg per day is not correlated with the risk of childhood asthma. However, the risk of childhood asthma significantly increases when the intake reaches 581 µg or more per day.
Litonjua AA. et al. (
The relationship between folic acid supplementation during pregnancy and childhood asthma is under exploration. Current evidence suggests that DNA methylation plays a key role in this process (
WHO and most countries recommend that pregnant women should maintain a healthy diet and take folic acid supplementation of 400 micrograms/day to prevent birth defects (
There are several advantages to our study. First, our analysis included 18 relevant studies, including those published in 2022. It is more statistically convincing than previous studies due to newer and larger sample sizes. Second, a subgroup analysis was conducted according to the different folic acid supplementation periods to explore the effect of folic acid supplementation at different periods on the risk of childhood asthma. Third, we made full use of the dose data of the included studies to conduct a dose-response analysis, which quantitatively revealed the relationship between folic acid intake during pregnancy and the risk of childhood asthma based on a qualitative summary. A dose-response curve was drawn, which may help develop strategies for safe folic acid supplementation during pregnancy. Finally, there is no publication bias in our analysis. However, some limitations of the present study should also be taken into account. First, all included studies adjusted for multiple confounding factors, but these factors were inconsistent and the effects of other confounding factors could not be excluded. Second, it is difficult to accurately calculate the dose of folic acid that pregnant women consume from both natural food and synthetics (vitamin supplements or prenatal fortification supplements). Third, the age of study participants varied widely from less than one year old to twelve years old, which might lead to a bias in the study results. Finally, only three studies were included in the dose-response analysis; therefore further dose-response studies are required for further validation.
Maternal folic acid supplementation during pregnancy increases the risk of childhood asthma. At the same time, dose-response analysis testified a nonlinear relationship between folic acid intake during pregnancy and the risk of childhood asthma. When the maternal folate intake is ≥581 μg/day, the risk of asthma in children significantly increases. Although folic acid supplementation during pregnancy can prevent birth defects, its adverse effects on the health of offspring cannot be ignored. Therefore, we recommend that the daily dose of folic acid supplementation for pregnant women should be less than 580 μg, which can effectively prevent birth defects without increasing the risk of asthma in children.
The original contributions presented in the study are included in the article/
Concept and design: FSY, JPZ, ZTW, LW, THT, LPS. Acquisition of data: FSY, JPZ, LPS. Statistical analysis: FSY, ZTW, LPS. Interpretation of data: FSY, LW, THT, LPS. Writing original draft: FSY, LPS. Writing review and editing: all authors. All authors contributed to the article and approved the submitted version.
This work was supported by the National Natural Science Foundation of China (grant no. 81974579); Jilin Science and Technology Innovation Platform, Jilin Traditional Chinese Medicine Pediatrics Clinical Medical Center, Changchun, China.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
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