Interaction of Maternal Asthma History and Plasma Folate Levels on Child Asthma Risk in the Boston Birth Cohort

Abstract

Background

Previous studies on maternal folate status during pregnancy and child asthma risk yielded mixed results, and few considered maternal asthma history, a known risk factor of childhood asthma. This study examined whether the role of maternal folate in childhood asthma differs by maternal asthma history and whether there is an interaction between the two factors.

Methods

This study included 1,948 mother-child dyads from the Boston Birth Cohort (BBC). Childhood asthma was defined based on physician diagnosis documented in electronic medical records; and maternal asthma was based on standard questionnaire interview. Maternal plasma folate level within a few days of delivery was measured by chemiluminescent immunoassay. Logistic regression models were applied to examine individual and joint associations of maternal asthma history and plasma folate level with childhood asthma, adjusting for other covariables.

Results

When stratified by maternal asthma history, an L-shaped relationship between maternal folate level and child asthma was observed in children born to mothers with asthma history (P_interaction=0.03). The highest risk was found in children having maternal asthma history and low maternal folate level (OR=5.93; 95%CI: 2.86–12.3) compared to children without maternal asthma history and with sufficient maternal folate levels. Sensitivity analyses using different definitions of asthma and stratified by major covariables yielded similar findings.

Conclusion

In this US prospective high-risk birth cohort, maternal asthma history and low folate level interactively increased the risk of child asthma. If further confirmed, optimizing maternal folate levels during pregnancy may mitigate child asthma risk in the setting of maternal asthma history.

INTRODUCTION

Childhood asthma is one of the most common chronic childhood disorders and affects nearly 8.3% children under age 18 years in the U.S. ¹. The prevalence rate is disproportionately high among socioeconomically disadvantaged minorities, particularly African Americans ^{1, 2}. The causes of asthma are not completely understood yet, but several biological, environmental and genetic risk factors have been documented previously ³. Maternal asthma is a known predictor of child asthma⁴. Nutritional condition in pregnancy is another important factor with long-term effect on childhood development and later health outcomes ⁵.

Folate, one of the eight B vitamins, is important for fetal growth and development. It is critical in the synthesis of S-adenosylmethionine (SAM), an important methyl source in biochemical reactions ⁶. Folate is widely recognized to have a protective effect against neural tube defects (NTDs) ⁷. The World Health Organization (WHO) recommends a daily folate intake of 400ug for all women from planning pregnancy to 12 gestational weeks. Previous studies also reported periconceptional intake of folic acid supplements reduced risk of adverse birth outcomes including congenital heart defects and small for gestational age ^{8, 9}.

The relationship between maternal folate level and childhood asthma has been inconsistent across studies ^{10, 11}. Some found that higher level of folate intake or folic acid supplement is protective against asthma ¹², while others found positive association ^13–15, or no association ¹⁰. The reasons for the inconsistent findings are multiple. The differences in the use of duration and dosage of folic acid supplement, as well as measurement of folate level at different time-point could contribute to such inconsistent results. Of note, most previous study was small in sample size; folate status was determined based on self-reported intake or supplement; asthma data was collected based on self-report; and was cross-sectional or retrospective in design. None of those studies considered maternal asthma history-folate interaction, although a number of studies has shown that children with family history of atopic diseases have an increased risk of asthma ¹⁶.

Using a prospective birth cohort design, the objectives of this study were to investigate the association between maternal plasma folate levels and the risk of childhood asthma as documented in the electronic medical records (EMRs) and whether the association was modified by maternal history of asthma in a large sample of mother-child pairs from the Boston Birth Cohort (BBC) who were recruited within a few days after birth and followed prospectively through childhood. A unique aspect of the BBC is that it is a US, urban, predominantly low-income, minority population; and is known to be disproportionally affected by asthma. This is also a population traditionally understudied and underrepresented in pediatric and clinical research. As such, findings from this study are directly relevant to understand and reduce asthma disparity in minority children.

MATERIALS AND METHODS

Study Population

This study included 1,948 mother-child pairs from the Boston Birth Cohort (BBC) which consists of predominantly urban, low income, and minority population, specifically, African Americans ¹⁷. The mothers were recruited within 24–72 hours after delivery during the period of 1998–2010 at the Boston Medical Center (BMC) at Boston, MA, USA. Their newborns have been followed prospectively since 2004 at BMC. Prenatal and postnatal epidemiological information was collected using a structured questionnaire interview at enrollment and during follow-ups. The clinical information of mothers and children was extracted from the electronic medical records (EMRs) at BMC starting in 2003. The inclusion criteria and data collection were described in details previously ^{17, 18}. The selection of the study sample is illustrated in the flow chart (Figure 1), and the baseline characteristics between included and excluded participants are provided in E-Table 2. Children’s age, maternal ethnicity, maternal gestational age, preterm birth rate, maternal asthma diagnosis, breastfeeding status, and maternal smoking are significantly different between the two groups. The BBC study has been approved by the institutional review boards of Boston University Medical Center and Johns Hopkins Bloomberg School of Public Health. Informed consent has been obtained from the participated mothers.

Figure 1.

Flow chart illustrating sample selection of the study.

Covariates

Child’s characteristics (e.g., age at the last visit, sex, gestational age, delivery type, and preterm birth status) were abstracted from EMRs ¹⁸. Delivery type was classified as vaginal and Cesarean-section. Breastfeeding status, self-reported by mothers, was classified into breast fed only, mixed, and bottle fed only. Maternal characteristics (e.g., race/ethnicity, maternal age at delivery, parity status, disease history of asthma, educational level, prepregnant body mass index (BMI) and smoking status during pregnancy) were obtained and adjusted in the subsequent analyses. Maternal race/ethnicity was classified as African American, and others. Maternal pre-pregnancy BMI was classified into three groups: normal weight (≤24.9 kg/m²), overweight (25.0–29.9 kg/m²), and obesity (≥30.0 kg/m²). Missing data for the above categorical variables were coded into a separate category. Smoking status during pregnancy was categorized into three groups: never smoking, ever smoking but quitted, and continuous smoking. Maternal educational level was classified into high school or below, and college or above.

Measurements of Plasma Folate Level

Maternal blood samples were collected within 48–72 hours after delivery to measure plasma folate level using chemiluminescent immunoassay (Shenzhen New Industries Biomedical Engineering Co., Ltd. China). Maternal plasma folate level was classified into low (<13.5 nmol/L) and high (≥13.5 nmol/L) based on the World Health Organization (WHO) suggested threshold for folate deficiency ¹⁹. Children’s total plasma folate level was measured in stored children’s plasma collected mostly during early childhood via chemiluminescent immunoassay using a MAGLUMI 2000 Analyzer (Snibe Co LTD) ²⁰.

Definitions of Childhood Asthma

We defined childhood asthma based on ever physician-diagnosed asthma identified from EMRs, specifically, ICD-9-CM codes: 493.0–493.9; and ICD-10-CM codes: J45.2-J45.5, J45.9. For sensitivity analyses, we further defined childhood asthma as follows: 1) asthmatic cases as those with ever physician-diagnosed asthma at 6 years or older; and 2) recurrent asthmatic cases as those with physician-diagnosed asthma at two or more visits with at least one-week apart, as recorded in EMRs.

Statistical Analysis

We compared population characteristics between subgroups defined by maternal folate levels using t-test for continuous variables and chi-squared tests for categorical variables, respectively. The association between maternal plasma folate level and the risk of childhood asthma was examined using the Locally Weighted Scatterplot Smoothing (LOWESS) analyses in total population, and stratified by maternal history of asthma. Children with maternal folate level beyond 2 standard deviations (SDs) were excluded in LOWESS analyses. The individual effects of maternal history of asthma and maternal plasma folate level were investigated using logistic regression models, with and without adjustments for the covariates listed above.

To investigate the interactive effect of maternal history of asthma and maternal folate level, a four-category variable (0=no maternal history & high maternal folate level; 1= no maternal history & low maternal folate level, 2= maternal history & high maternal folate level, and 3=maternal history of asthma and low maternal folate level) was coded and tested for its relationship with risk of childhood asthma. The product term of maternal history and maternal folate level was then added into regression models to explore the interactive effect. Stratified analyses by preterm birth status (term vs. preterm), ethnicity (African American vs. others), and sex were performed to evaluate their effect modification. Interaction effects with those stratification variables were tested. We also performed sensitivity analyses to examine the robustness of the findings based on different asthma diagnostic definitions. We further adjusted for child’s plasma folate concentration and preterm birth as sensitivity analyses. Data analysis was performed using R version 3.4.1 software.

RESULTS

Population Characteristics

A total of 1,948 mother-child pairs were included in this study. The mean age and the SD of the children at the last visit was 9.2±4.3 years and the prevalence of childhood asthma was 25.2%. About 10.3% of mothers had low folate (<13.5nmol/L) and 14.5% had maternal history of asthma. Significant difference of maternal ethnicity, smoking, education, children’s age, delivery type, and breastfeeding were observed between mothers with sufficient and deficient folate. (Table 1; all P<0.05). No significant difference was found for other variables (Table 1). We also presented population characteristics grouped by childhood asthma status (E-Table 1), and compared the included and excluded population from the subsequent analyses (E-Table 2).

Table 1.

Maternal and child characteristics by maternal plasma folate levels

Maternal and child variables a	Folate ≥ 13.5nmol/L	Folate<13.5nmol/L	P b
N	1,748	200
Maternal ethnicity, n (%)
African American/Black	1,052 (60.2)	150 (75.0)	<0.001
White	85 (4.9)	3 (1.5)
Hispanic	435 (24.9)	37 (18.5)
Others	176 (10.1)	10 (5.0)
Mean maternal age at delivery, yr, mean ± SD	28.5±6.5	28.2±6.5	0.45
Parity ≥ 1, n (%)	1,007 (57.6)	127 (63.5)	0.13
Maternal asthma diagnosis, n (%)	248 (14.2)	35 (17.5)	0.25
Cesarean-section delivery, n (%)	610 (34.9)	92 (46.0)	0.01
Missing	5 (0.3)	0 (0.0)
Gestational age (weeks), mean ± SD	37.9±3.4	3.4±37.7	0.37
Pre-pregnancy BMI, n (%)
Normal (<25kg/m2)	804 (46.0)	90 (45.0)	0.99
Overweight(25–30kg/m2)	470 (26.9)	56 (28.0)
Obesity(>30kg/m2)	385 (22.0)	44 (22.0)
Missing	89 (5.1)	10 (5.0)
Maternal smoking during pregnancy, n (%)
Never	1,448 (82.8)	153 (76.5)	0.03
Quitter	121 (6.9)	22 (11.0)
Continuous	162 (9.3)	25 (12.5)
Missing	17 (1.0)	0 (0.0)
Maternal education level, n (%)
College & above	618 (35.4)	51 (25.5)	0.02
High school & below	1,119 (64.0)	147 (73.5)
Missing	11 (0.6)	2 (1.0)
Child’s sex, male, n (%)	890 (50.9)	104 (52.0)	0.83
Mean children age at last visit, yr, mean ± SD	9.2±4.3	10.5±4.7	<0.001
Preterm, n (%)	437 (25.0)	55 (27.5)	0.50
Breastfeeding, n (%)
Bottle fed only	421 (24.1)	75 (37.5)	<0.001
Mixed	1,186 (67.8)	115 (57.5)
Breastfed only	129 (7.4)	10 (5.0)
Missing	12 (0.7)	0 (0.0)

NOTE:

Abbreviation: BMI: body mass index; SD: standard deviation.

^aThe Student’s t test was performed for the continuous covariates (child age at last visit, gestational age, and maternal age at delivery). The Chi-squared test was performed for categorical covariates (sex, ethnicity, parity, delivery type, breast feeding, maternal asthma, preterm birth, maternal pre-pregnancy BMI category, maternal smoking, and maternal education).

^bP-value less than 0.05 is in bold

Association of Maternal Plasma Folate Level with Childhood Asthma

The LOWESS plots indicated no association between maternal folate level and the risk of childhood asthma in the total sample (Figure 2a). When we divided the samples into two groups, children with positive maternal history of asthma had higher risk of asthma; within this high-risk group, we observed a non-linear relationship between maternal folate level and the risk of asthma: The highest risk of asthma was seen among children with the lowest maternal folate levels; however, the beneficial effect of folate appears to be plateaued at the higher end of folate levels (Figure 2b). When we limit the samples to term births, there appears to be a “U” shaped relationship (Figure 2c).

Figure 2.

Smoothing plot for the probability of having childhood asthma with maternal plasma folate levels at delivery in the total sample (a), stratified by maternal asthma history in the total sample (b) and in the term birth subset (c).

The individual and combined effects of maternal history of asthma and maternal folate level, respectively, on childhood asthma were presented in Table 2. Continuous maternal folate level was not associated with childhood asthma, either in the unadjusted or adjusted model. Children with maternal history of asthma had significant higher risk of asthma without (crude odds ratio (COR)=3.31; 95%CI: 2.55–4.29) and with adjustment of covariates (adjusted odds ratio (AOR)=3.24; 95%CI: 2.45–4.29), while maternal plasma folate level showed no association with risk of childhood asthma in the total population. When stratified by maternal history of asthma, we observed a marginal association between low maternal folate level and an increased risk of childhood asthma among children with maternal asthma history in the crude model (P=0.05) but not the adjusted model (P=0.16); No associations were observed in children without maternal history of asthma (Table 2). Maternal history of asthma and low maternal folate level may be jointly associated with an elevated risk of childhood asthma (Table 2), for which, the highest OR was observed in the group of children with maternal asthma history and low maternal folate concentration (AOR=5.93; 95%CI: 2.86–12.29), compared to those with high maternal folate level (≥13.5nmol/L) and having no history of asthma. This result remained unchanged after adjustment of covariates and there was a significant interaction between maternal history of asthma and low maternal folate level on childhood asthma (Table 2; P_interaction=0.03).

Table 2.

Individual and joint effects of maternal asthma status and plasma folate levels on childhood asthma risk

Variables			Child’s asthma, unadjusted				Child’s asthma, adjusteda
Maternal asthma history	Maternal folate level, nmol/L	n	%	OR	95% CI	p	OR	95% CI	P
		Individual effects b
No	-	1,665	21.4	Ref			Ref
Yes	-	283	47.3	3.31	(2.55,4.29)	<0.001	3.24	(2.45,4.29)	<0.001
-	≥13.5	1,748	24.7	Ref			Ref
-	<13.5	200	29.5	1.28	(0.93,1.77)	0.14	0.98	(0.69,1.38)	0.98
-	Continuous	1,948	25.2	1.00	(1.00,1.00)	0.85	1.00	(1.00,1.01)	0.17
No	Continuous	1,665	21.4	1.00	(1.00,1.01)	0.31	1.00	(0.99,1.01)	0.53
Yes	Continuous	283	47.3	1.00	(1.00,1.01)	0.11	1.00	(0.99,1.01)	0.83
Joint effects
No	≥13.5	1,500	21.3	Ref			Ref
	<13.5	165	22.4	1.07	(0.73,1.57)	0.73	0.79	(0.53,1.19)	0.26
Yes	≥13.5	248	45.2	3.05	(2.31,4.03)	<0.001	2.90	(2.15,3.90)	<0.001
	<13.5	35	62.9	6.27	(3.12,12.6)	<0.001	5.93	(2.86,12.3)	<0.001
Individual effects, stratified by maternal asthma history
No	≥13.5	1,500	21.3	Ref			Ref
	<13.5	165	22.4	1.07	(0.73,1.57)	0.73	0.8	(0.53,1.20)	0.28
Yes	≥13.5	248	45.2	Ref			Ref
	<13.5	35	62.9	2.05	(0.99,4.26)	0.05	1.78	(0.80,3.96)	0.16
P for maternal history*folate interaction			0.12				0.03

Abbreviation: OR: odds ratio; CI: confidence interval; Ref: Reference.

^aAdjusted for maternal age at delivery, parity, delivery type, breastfeeding, education, ethnicity, pre-pregnancy BMI, smoking, child’s last visit age and child’s sex.

^bFolate level or maternal asthma history was included as a covariate if not the exposure in the model.

To further explore the “U” shaped relationship observed in LOWESS plot (Figure 2b), we divided maternal folate levels into three groups based on WHO cutoffs: <13.5 nmol/L, 13.5–45.3 nmol/L, and >45.3 nmol/L. We tested their association with childhood asthma in the total sample and in groups stratified by maternal asthma. Folate excess (>45.3 nmol/L) was not associated with childhood asthma risk in the adjusted and unadjusted models (E-Table 6) in the total sample and stratified analysis.

Sensitivity Analyses

Table 3 shows the results from analyses stratified on preterm birth status, ethnicities, and child’s sex. Significant associations were observed in the group of children with maternal history of asthma and low maternal plasma folate level, across all subgroups, compared to the group of children without maternal history of asthma and high maternal plasma folate level (Table 3). Table 3 shows that the joint effects seem more significant in term children or in female children. After changing the definitions of asthma to children with ever asthma, and diagnosed with asthma at age≥ 6 years and recurrent asthma, our findings remained consistent. In the interaction effect analysis, preterm birth showed significant interaction in the unadjusted (P=0.04) and adjusted model (P=0.04). We then adjusted for preterm birth as a sensitivity analysis (E-Table 4). Increased risk of asthma was observed for children with maternal history of asthma, and those with low maternal folate level had the highest risk (AOR=5.55; 95% CI: 2.64–11.7). The interaction effect between folate level and maternal asthma history remains significant in those analyses (P=0.04). Among the 998 mother-child pairs with available child’s plasma folate data, we found no significant correlation between maternal and child’s plasma folate levels (Pearson’s correlation=−0.01, P=0.72). Moreover, we evaluated individual and joint effects of maternal history of asthma and maternal plasma folate level on childhood asthma by further adjusting child’s plasma folate level in the models. Our findings remained largely unchanged as those in Table 2 when child’s plasma folate level was treated as a covariate in the model (E-Table 3). We also examined the association with children’s plasma folate level and childhood asthma. The children’s plasma folate level as continuous variable was not associated with childhood asthma in the crude (OR= 1.00; 95%CI: 0.99–1.01; p-value=0.58) and adjusted models (OR= 1.00; 95%CI: 0.99–1.01; p-value=0.51). However, folate deficiency (<13.5 nmol/L) was significantly associated with childhood asthma, but only in the adjusted model (OR= 3.00; 95%CI: 1.05–8.58; p-value=0.04) (E-Table 7).

Table 3.

Subgroup analyses on joint effect of maternal history of asthma and maternal plasma folate level on risk of childhood asthma. The subgroups are defined by term vs. preterm birth; African vs. non-African; male vs female; ever asthma vs. recurrent asthma, asthma diagnosed before age 6 vs. ≥6 years

Variables		n	%	OR	95% CI	P	n	%	OR	95% CI	P
Maternal asthma history	Maternal folate level, nmol/L
		Term birth *					Preterm birth *
No	≥13.5	1,140	17.1	Ref			360	34.4	Ref
No	<13.5	124	21.8	0.98	(0.61, 1.57)	0.92	41	24.4	0.46	(0.21, 1.04)	0.06
Yes	≥13.5	170	37.6	2.71	(1.87, 3.91)	<0.001	77	61.0	3.25	(1.86, 5.70)	<0.001
Yes	<13.5	21	66.7	9.33	(3.52, 24.7)	<0.001	14	57.1	2.55	(0.79, 8.22)	0.12
		African American					Non-African American
No	≥13.5	902	23.5	Ref			598	17.9	Ref
No	<13.5	122	28.7	1.01	(0.65, 1.56)	0.98	43	4.7	0.19	(0.04, 0.80)	0.02
Yes	≥13.5	150	51.3	3.47	(2.37, 5.08)	<0.001	98	35.7	2.55	(1.53, 4.24)	<0.001
Yes	<13.5	28	60.7	5.55	(2.45, 12.5)	<0.001	7	71.4	9.42	(1.68, 52.7)	0.01
		Male					Female
No	≥13.5	761	24.7	Ref			739	17.7	Ref
No	<13.5	91	26.4	0.85	(0.5, 1.43)	0.53	74	17.6	0.72	(0.37, 1.40)	0.34
Yes	≥13.5	129	48.8	2.81	(1.87, 4.22)	<0.001	119	41.2	3.54	(2.26, 5.56)	<0.001
Yes	<13.5	13	53.8	3.15	(0.99, 10.0)	0.05	22	68.2	9.39	(3.54, 24.9)	<0.001
		Ever asthma					Recurrent asthma
No	≥13.5	1,500	21.3	Ref			1436	17.8	Ref
No	<13.5	165	22.4	1.07	(0.73, 1.57)	0.73	234	20.5	0.88	(0.57, 1.34)	0.54
Yes	≥13.5	248	45.2	3.05	(2.31, 4.03)	<0.001	161	41.9	3.20	(2.34, 4.39)	<0.001
Yes	<13.5	35	62.9	6.27	(3.12, 12.6)	<0.001	33	60.6	6.91	(3.26, 14.7)	<0.001
		Asthma ≥ 6 years					Asthma < 6 years
No	≥13.5	1,137	15.4	Ref			363	9.6	Ref
No	<13.5	134	20.1	0.97	(0.6, 1.56)	0.91	31	6.5	0.49	(0.11, 2.3)	0.37
Yes	≥13.5	198	31.8	2.45	(1.7, 3.54)	<0.001	50	20.0	2.23	(0.93, 5.35)	0.07
Yes	<13.5	24	54.2	6.34	(2.68, 15.0)	<0.001	12	63.6	15.5	(3.67, 65.1)	<0.001

NOTE:

Abbreviation: OR: odds ratio; CI: confidence interval; Ref: Reference.

The models were adjusted for maternal age at delivery, delivery type, breastfeeding status, parity, education, ethnicity, pre-pregnancy BMI, smoking, child’s last visit age and child’s sex.

^*Test for interaction between folate and preterm status was significant: P=0.04

DISCUSSION

This study has addressed the knowledge gap by investigating the association of not only individual effect of maternal plasma folate level, but also its interaction with maternal asthma history on childhood asthma in BBC, one of the largest urban, low income, African American-dominant birth cohorts in U.S. Most previous studies on maternal folate level and childhood asthma were conducted in European countries ^{12–14, 21, 22}. To our knowledge, this is the first study simultaneously investigating individual and joint associations of maternal plasma folate level and maternal asthma history on childhood asthma in an African American-dominant birth cohort.

Our results suggested an increased risk of childhood asthma associated with folate deficiency only in those born by mothers with maternal history of asthma, but not in their counterpart. In children with maternal history of asthma, the risk for asthma was about 1.8 times higher among those born to women with plasma folate concentration below 13.5nmol/L than those with higher maternal folate concentration. In addition, we found significant interaction of maternal plasma folate level and maternal history of asthma on the risk for childhood asthma (P for interaction=0.03). Those observations remained when further performing sensitivity analyses using different definitions of asthma, subgroups defined by preterm birth, race/ethnicity, and sex, and the inclusion of child folate and preterm status in the models, respectively.

Our findings are in line with some of previous studies. It is well observed that asthmatic mothers play a more important role than asthmatic fathers on the development of asthma in their offspring ²³. While some previous studies on maternal folate and childhood asthma controlled maternal history or family history of atopy or asthma in analytical models ^{14, 15, 21, 24}, few has specifically tested for their interaction on childhood asthma. A nested case-control study in the U.S. reported that late initiation of folate supplement in the 2^nd or 3^rd trimester was associated with higher risk of wheeze in the first 3 years of life only in children born by mothers with atopic history ²⁵. Of note, this study was not specific to maternal asthma history and asthma diagnosis. In an Australian prospective cohort study, an increase of folic acid supplement in late pregnancy was associated with the reduced risk of asthma in children if mothers had asthma ¹³. However, this study was based on self-reported supplement, not plasma folate level.

When it comes to the role of folate in childhood asthma, previous studies yielded inconsistent findings. Possible explanations for such inconsistency include differences in study designs, sample size, selection criteria, definition of asthma, exposure measurements based on self-report (few based on biomarkers), timing of the exposure (e.g., preconception, early pregnancy, or late pregnancy), and adjustment of covariates. For example, Magdelijns et al. reported no association between maternal intake of folic acid supplement during pregnancy and childhood atopic diseases ¹². On the other hand, in a case-control study among a Norwegian cohort, Håberg et al. concluded that only modest positive associations of folate levels in the second trimester with early childhood respiratory outcomes were observed ¹⁴. Our study offered another possible explanation. Previous studies have not considered maternal asthma history and folate interaction on childhood asthma. Our study indicated that the associations between maternal folate level and child risk of asthma may vary in those with and without maternal asthma history. In the presence of such interaction as we demonstrated in the BBC, ignoring such interaction may obscure the true association.

The biological mechanisms underlying maternal asthma history-folate interaction remain to be elucidated. Folate is a methyl donor and one potential mechanism might be through in-utero folate exposure and epigenetic alterations. An epigenome-wide meta-analysis of newborns found various methylated loci associated with maternal folate ²⁶. Additional studies are needed to trace the epigenetic pathways from in-utero folate exposure to childhood asthma risk among children born to mothers with asthma history vs. mothers without asthma history, using a prospective birth cohort study design.

This study has several strengths, including its prospective birth cohort design, large sample size, use of biomarker to evaluate maternal folate status, and asthma outcome based on physician diagnosis documented in EMRs rather than self-report.

However, the following limitations are acknowledged. First, maternal plasma folate was measured at 1–3 days after delivery and thus could be considered as a proxy for the folate status during the third trimester of pregnancy. The timing effect of folate exposure at different stages of pregnancy on childhood asthma remains to be explored. Second, maternal asthma history was determined based on self-reports and thus might be subject to reporting bias, but this report was shortly after birth, when the mothers did not know their children’s future asthma risk. In addition, this study only analyzed a subset of the BBC who had information on maternal history of asthma and plasma folate levels. While we identified several demographic characteristics that differed between the included and the excluded participants, there could still be other unaccounted factors leading to exclusion and bias our sample selection. Third, due to the limited sample size in the low maternal folate level group (n~200), we had insufficient power to perform effective statistical analysis in certain stratums (e.g., preterm birth and asthma diagnosed at age <6 years). We observed wide confidence intervals in these stratums. Thus, the estimated risk should be interpreted with caution. Fourth, we defined asthma based on EMR records in this study, diagnostic uncertainty remains a concern. However, robust results have been observed when we further performed sensitivity analyses using more stringent definitions of asthma. Fifth, the study sample are urban, low income, African American-dominant birth cohort. Our results may or may not be generalizable to other populations. Sixth, the potential selection bias should be noted even no substantial difference was found in population characteristics between included and excluded participants. Lastly, we cannot exclude possible residual confounding due to the fact we did not control for all known or suggested factors that could affect the risk of childhood asthma.

CONCLUSION

Our study demonstrates increased risk of childhood asthma among children born to mothers with asthma history and with folate deficiency (< 13.5 nmol/L). Our results provide evidence that maternal asthma history and low maternal folate could interactively increase the risk of childhood asthma. Our findings warrant additional investigation. If further confirmed, optimizing maternal folate levels during pregnancy may represent a simple and inexpensive strategy to mitigate child asthma risk in the setting of maternal asthma history.

List of Abbreviations

BBC

the Boston Birth Cohort

PTB

preterm birth

NTDs

neural tube defects

BMC

the Boston Medical Center

WHO

the World Health Organization

EMR

electronic medical record

ICD-9-CM

International Classification of Diseases, Ninth Revision, Clinical Modification

ICD-10-CM

International Classification of Diseases, Tenth Revision, Clinical Modification

SAM

S-adenosylmethionine

BMI

body mass index

LOWESS

Locally Weighted Scatterplot Smoothing

SD

standard deviation

OR

odds ratio

CI

confidence interval

MTHFR

methylene tetrahydrofolate reductase