Abstract
Objectives. To examine maternal folic acid supplementation and plasma folate concentrations in the Boston Birth Cohort, a predominantly urban, low-income, minority population in Boston, Massachusetts.
Methods. This report includes 7612 mothers with singleton live births (3829 Black, 2023 Hispanic, 865 White, and 895 others) enrolled in the Boston Birth Cohort at the Boston Medical Center, during 1999 to 2014. Folic acid supplementation during preconception and each trimester was obtained via interview questionnaire. In a subset (n = 2598), maternal plasma folate concentrations were measured in blood samples drawn within a few days of delivery.
Results. The percentage of mothers taking folic acid supplementation almost daily during preconception and the first, second, and third trimesters were 4.3%, 55.9%, 59.4%, and 58.0%, respectively. Most striking, we observed a wide range of maternal plasma folate concentrations, with approximately 11% insufficient (< 13.4 nmol/L) and 23% elevated (> 45.3 nmol/L).
Conclusions. Findings indicate that fewer than 5% of mothers in the Boston Birth Cohort started folic acid supplements before pregnancy, and approximately one third of mothers had either too low or too high plasma folate levels, which may have important health consequences on both the mother and the child.
Studies, including clinical trials around the world, have shown that periconceptual folic acid supplementation can prevent 50% to 70% of neural tube defects (NTDs).1–3 These findings led to the universal folic acid fortification program implemented in the United States since 1998 and the recommendation on folic acid supplementation for all women of reproductive age.4 Recently, the US Preventive Services Task Force (USPSTF) reaffirmed its grade A rating on this recommendation.5 Because these birth defects happen very early in pregnancy and often before a woman knows that she is pregnant, and because half of all US pregnancies are unintended, it is important for all women of childbearing age to use folic acid supplementation.6 Currently, the USPSTF, Centers for Disease Control and Prevention, and American Academy of Pediatrics recommend daily folate intake of 400 to 800 micrograms before and during pregnancy for all women of childbearing age,5–7 either by food intake or folic acid supplementation.
Despite the recommendations and interventions to increase folate intake, limited data exist on maternal folic acid supplementation before conception and during each trimester and plasma folate concentrations (an objective biomarker of maternal folate status), especially among high-risk US populations. Previous studies were primarily conducted in nonpregnant women, and most did not measure blood folate concentrations.8 From a public health perspective, there are several concerns. First, reported preconception folic acid supplementation is low. Healthy People 2020 goals include increasing the proportion of women of childbearing age with intake of at least 400 micrograms of folate daily from fortified foods or dietary supplements from a baseline of 23.8%, and increasing the proportion of women delivering a live birth who took folic acid before pregnancy from a daily intake baseline of 30.3%.9 It is uncertain how much progress has been made to date.
Second, in the United States, the mandatory folic acid fortification of grains has led to a substantial increase in blood folate concentrations in the general population. According to data from the National Health and Nutrition Examination Survey (NHANES 1999–2000), compared with the levels of prefortification (1988–1994), the average serum levels increased from 12.1 to 30.2 nanomoles per liter.10 A growing number of reports and reviews have raised concern about potential diverse health effects of excessive folic acid intake, including cancer, asthma, developmental delay, and autism.4,11–14
Finally, racial/ethnic disparities exist in folic acid supplementation and the rate of NTDs. Babies born to Hispanic mothers are at an increased risk for NTDs for reasons that are poorly understood.15 After mandatory fortification, NTD prevalence has declined; however, Hispanic women continue to be at significantly greater risk for having a child with an NTD.16 Other studies have found that, compared with non-Hispanic White women, Black and Hispanic women have lower rates of prepregnancy folate intake17–20 as well as lower serum and red blood cell folate concentrations.18,21 However, most previous studies included women of reproductive age, not specifically pregnant mothers, and most did not measure folate concentration.
The main objective of this study was to examine maternal folic acid supplementation and plasma folate concentrations in the Boston Birth Cohort (BBC), a predominantly urban, low-income, multiethnic population in Boston, Massachusetts. We were particularly interested in the percentage of mothers in compliance with the recommendation during preconception and each trimester, the percentage of mothers with optimal plasma folate concentrations, and whether there were racial/ethnic differences in folic acid intake before and during pregnancy and in plasma folate concentrations.
METHODS
This was a secondary data analysis of the BBC. Detailed information on the study population and data collection methods can be found elsewhere.22 Briefly, the BBC was initiated in 1998 at the Boston Medical Center (BMC), a large urban hospital serving a multiethnic inner-city population. As of June 2014, 8494 mother–infant pairs had been recruited. Inclusion criteria were mothers who delivered singleton live births at the BMC. The exclusion criteria included multiple-gestation pregnancies (e.g., twins, triplets) and newborns with major birth defects. The BBC consisted of predominately urban, low-income, minority population, which reflected the patient population of the BMC.
Of all eligible mothers approached by the BBC field team, more than 90% enrolled. Of the 8494 participating mothers, 882 were excluded from this analysis because of missing prenatal vitamin intake data leaving a sample of 7612 mothers. Of these mothers, 2598 had plasma folate data. Mothers with plasma folate concentrations were those continuing pediatric care at BMC. Those included in the final sample and those who had plasma folate level data were very similar with regard to baseline characteristics, except for a higher proportion of African American and multiparous mothers in the plasma folate sample (Table A, available as a supplement to the online version of this article at http://www.ajph.org).
Measures
Self-reported folic acid intake.
Folic acid intake was obtained during a face-to-face maternal interview with a standardized questionnaire 24 to 72 hours postpartum. It was based on the following questions: “Did you take prenatal vitamins prescribed by your doctor?” and “Did you take any over-the-counter multivitamins?” during prepregnancy (6 months before conception), first trimester (day 1 to day 90 of pregnancy), second trimester (day 91 to day 180 of pregnancy), third trimester (day 181 of pregnancy to birth)? Response categories were none, 1 time per week, 2 times per week, 3 to 5 times per week, and almost daily. Responses to the 2 questions were combined to none, 1 to 2 times per week, 3 to 5 times per week, and almost daily.
Plasma folate concentrations.
Maternal venous blood was drawn at 24 to 72 hours postpartum and the plasma sample was stored in −80 °C freezers until laboratory assay. Plasma folate concentrations were measured via chemiluminescent immunoassay with diagnostic kits (Shenzhen New Industries Biomedical Engineering Co Ltd, Shenzhen, China) using a Beckman Coulter ACCESS Immunoassay System (Beckman-Coulter Canada, Mississauga, Canada). Eight quality-control samples in the low, median, and high range of the assay were included in each batch, and the interassay coefficient of variation was less than 4% as reported in previous publications.22,23
Race/ethnicity.
Maternal race/ethnicity, the primary independent variable, was based on response to fixed categories (non-Hispanic Black, Hispanic, non-Hispanic White, and other) obtained through the maternal questionnaire interview.
Covariates.
We also obtained information on additional sociodemographic and clinical factors including maternal age, marital status, parity, educational level, native language, country of origin, and length of time residing in the United States from the maternal interview. We collapsed age into 3 categories: younger than 20 years, 20 to 29 years, and 30 years or older. We dichotomized educational attainment into 2 categories: (1) high school or less education and (2) college or more education.
We based native language on response to fixed categories: English, Spanish, Haitian Creole, French, Portuguese, and other and then grouped them into English versus others. Country of origin consisted of 2 response categories, either born in the United States or born in a foreign country. Information on length of time living in the United States was available as a continuous variable and we dichotomized it as 10 years or less versus more than 10 years.
We obtained maternal smoking and alcohol consumption from the maternal interview. We classified maternal smoking during pregnancy into 3 groups: never smoker (did not smoke cigarettes throughout index pregnancy), quitter (only smoked in the 3 months before pregnancy or during the first trimester), or continuous smoker (smoked continuously from prepregnancy to delivery). We dichotomized alcohol consumption during pregnancy as never drank versus any alcohol.
We classified planned pregnancy as “no” versus “yes” according to the response to the following question: “Just before you became pregnant, did you want to become pregnant at that time?” We calculated prepregnancy body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) on the basis of self-reported prepregnancy height and weight. We further grouped BMI into 4 categories: normal weight (18.5–24.9 kg/m2), underweight (< 18.5 kg/m2), overweight (25–29.9 kg/m2), and obesity (≥ 30 kg/m2).
Finally, we assessed 2 clinical variables by maternal medical records: hypertensive disorders defined as 1 or more of the following during pregnancy: preeclampsia, eclampsia, chronic hypertension, hemolysis, elevated liver enzymes, and low platelets syndrome; and maternal diabetes defined as having either gestational or pregestational diabetes. Gestational age was determined by the first day of the last menstrual period and early prenatal ultrasonographic results,24 and categorized into term (≥ 37 weeks) and preterm (< 37 weeks).
Data Analysis
We conducted all analyses with SAS version 9.4 (SAS Institute, Cary, NC). We calculated frequencies of sociodemographic factors by race/ethnicity as folic acid intake during preconception and trimesters 1 to 3. Because the distribution of plasma folate concentration was positively skewed, it was presented as geometric means and medians (interquartile range [IQR]), and we used logarithmic transformation to normalize the data for subsequent statistical analyses. We classified folate levels as sufficient (13.5–45.3 nmol/L), insufficient (6.8–13.4 nmol/L), deficient (< 6.8 nmol/L), and elevated (> 45.3 nmol/L) according to previously published cutoffs.25
We used χ2 test to estimate differences in categorical variables between races/ethnicities. We applied analysis of variance to test the mean difference among groups. We performed Wilcoxon–Mann–Whitney test to test median differences between races/ethnicities. We used generalized linear models to test the difference of plasma folate concentrations between folic acid intake groups in the third trimester. We applied univariate and multivariate linear regression models to estimate the crude and adjusted associations between log-transformed folate concentrations and prenatal variables. Multivariate regression variables were year of delivery, maternal age, education level, race/ethnicity, marital status, parity, smoking status, alcohol use, planned pregnancy, pregravid BMI, maternal hypertension and diabetes, gestational age, and folic acid supplementation. To make the results easy to interpret, we exponentiated all of the regression coefficients, and represented the point estimate of the fold change of plasma folate concentrations on the original scale. We calculated the variance and SD and the 95% confidence interval (CI) of the fold change of plasma folate concentrations according to methods previously reported.22 We regarded a 2-sided P value less than .05 as statistically significant.
RESULTS
Characteristics of the study population by race/ethnicity are presented in Table 1. Mothers were predominantly African American (50.3%) or Hispanic (26.6%), had a high-school education or below (64.4%), were unmarried (64.9%), and were multiparous (55.7%). White mothers were more likely to smoke and less likely to be multiparous or overweight.
TABLE 1—
The Characteristics of Study Mothers Stratified by Race/Ethnicity in the Boston Birth Cohort, Enrolled in 1999–2014: Boston, MA
| Race/Ethnicity |
||||||
| Variable | Total Sample (n = 7612), No. (%) | Black (n = 3829), No. (%) | White (n = 865), No. (%) | Hispanic (n = 2023), No. (%) | Other (n = 895), No. (%) | Pa |
| Age, y | < .001 | |||||
| < 20 | 814 (10.7) | 418 (10.9) | 59 (6.8) | 242 (12.0) | 95 (10.6) | |
| 20–29 | 3814 (50.1) | 1784 (46.6) | 457 (52.8) | 1133 (56.0) | 440 (49.2) | |
| ≥ 30 | 2984 (39.2) | 1627 (42.5) | 349 (40.4) | 648 (32.0) | 360 (40.2) | |
| Education | < .001 | |||||
| High school and lower | 4904 (64.4) | 2282 (59.6) | 463 (53.5) | 1650 (81.6) | 509 (56.9) | |
| College and higher | 2692 (35.4) | 1540 (40.2) | 401 (46.4) | 366 (18.1) | 385 (43.0) | |
| Missing | 16 (0.2) | 7 (0.2) | 1 (0.1) | 7 (0.4) | 1 (0.1) | |
| Marital status | < .001 | |||||
| Single | 4941 (64.9) | 2479 (64.7) | 541 (62.5) | 1404 (69.4) | 517 (57.8) | |
| Married | 2633 (34.6) | 1332 (34.8) | 319 (36.9) | 609 (30.1) | 373 (46.7) | |
| Missing | 38 (0.5) | 18 (0.5) | 5 (0.6) | 10 (0.5) | 5 (0.5) | |
| Smoking status | < .001 | |||||
| Never | 6208 (81.6) | 3202 (83.6) | 408 (47.2) | 1814 (89.7) | 784 (87.6) | |
| Quitter | 531 (7.0) | 292 (7.6) | 85 (9.8) | 103 (5.1) | 51 (5.7) | |
| Continuous | 870 (11.4) | 333 (8.7) | 372 (43.0) | 105 (5.2) | 60 (6.7) | |
| Missing | 3 (0.04) | 2 (0.05) | 0 (0.0) | 1 (0.05) | 0 (0.0) | |
| Alcohol consumption | .101 | |||||
| No | 6732 (88.4) | 3398 (88.7) | 703 (81.3) | 1847 (91.3) | 784 (87.6) | |
| Yes | 643 (8.5) | 309 (8.1) | 137 (15.8) | 129 (6.4) | 68 (7.6) | |
| Missing | 237 (3.1) | 122 (3.2) | 25 (2.9) | 47 (2.3) | 43 (4.8) | |
| Parity | .001 | |||||
| Nulliparous | 3354 (44.1) | 1654 (43.2) | 454 (52.5) | 818 (40.4) | 428 (47.8) | |
| Multiparous | 4243 (55.7) | 2169 (56.7) | 406 (46.9) | 1203 (59.5) | 465 (52.0) | |
| Missing | 15 (0.2) | 6 (0.1) | 5 (0.6) | 2 (0.1) | 2 (0.2) | |
| Planned pregnant | < .001 | |||||
| No | 3685 (48.4) | 2038 (53.2) | 424 (49.0) | 846 (41.8) | 377 (42.1) | |
| Yes | 3845 (50.5) | 1747 (45.6) | 430 (49.7) | 1166 (57.7) | 502 (56.1) | |
| Missing | 82 (1.1) | 44 (1.2) | 11 (1.3) | 11 (0.5) | 16 (1.8) | |
| Prepregnancy BMI, kg/m2 | < .001 | |||||
| < 18.5 | 306 (4.0) | 109 (2.9) | 37 (4.3) | 78 (3.9) | 82 (9.2) | |
| 18.5–24.9 | 3285 (43.2) | 1387 (36.2) | 431 (49.8) | 974 (48.1) | 493 (55.1) | |
| 25–29.9 | 1897 (24.9) | 972 (25.4) | 185 (21.4) | 544 (26.9) | 196 (21.9) | |
| ≥ 30 | 1376 (18.1) | 813 (21.2) | 116 (13.4) | 339 (16.8) | 108 (12.0) | |
| Missing | 748 (9.8) | 548 (14.3) | 96 (11.1) | 88 (4.3) | 16 (1.8) | |
| Hypertensive disorder | < .001 | |||||
| No | 6630 (87.1) | 3235 (84.5) | 790 (91.3) | 1813 (89.6) | 792 (88.5) | |
| Yes | 982 (12.9) | 594 (15.5) | 75 (8.7) | 210 (10.4) | 103 (11.5) | |
| Diabetes | .38 | |||||
| No | 6871 (90.3) | 3437 (89.8) | 784 (90.6) | 1845 (91.2) | 805 (89.9) | |
| Yes | 718 (9.4) | 383 (10.0) | 77 (8.9) | 170 (8.4) | 88 (9.9) | |
| Missing | 23 (0.3) | 9 (0.2) | 4 (0.5) | 8 (0.4) | 2 (0.2) | |
| Preterm birth | < .001 | |||||
| No | 5564 (73.1) | 2732 (71.4) | 612 (70.8) | 1548 (76.5) | 672 (75.1) | |
| Yes | 2048 (26.9) | 1097 (28.7) | 253 (29.2) | 475 (23.5) | 223 (24.9) | |
Note. BMI = body mass index.
P value was for the difference among races/ethnicities.
Folic Acid Intake Across Race/Ethnicity
More than half of mothers took folic acid almost daily in the 3 trimesters of pregnancy, whereas only 4.3% of mothers reported daily prescribed prenatal vitamin intake in the preconception period, which did not differ by race/ethnicity (Table 2). After pregnancy, most women took prenatal vitamins, though a substantial proportion did not take the recommended daily intake of these vitamins. White mothers were more likely to take almost daily folic acid supplementation than Black or Hispanic mothers, especially during pregnancy. If we combined the vitamin intakes of prescribed prenatal vitamins and over-the-counter multivitamins, the proportion distribution is similar (Table B, available as a supplement to the online version of this article at http://www.ajph.org).
TABLE 2—
Frequency of Prescribed Prenatal Vitamin Intake Stratified by Race/Ethnicity in the Boston Birth Cohort, Enrolled in 1999–2014: Boston, MA
| Race/Ethnicity |
||||||
| Frequency | Total Sample (n = 7612), No. (%) | Black (n = 3829), No. (%) | White (n = 865), No. (%) | Hispanic (n = 2023), No. (%) | Other (n = 895), No. (%) | Pa |
| Preconception | < .001 | |||||
| None | 6592 (86.6) | 3309 (86.4) | 764 (88.3) | 1742 (86.1) | 777 (86.8) | |
| 1–2 times/week | 16 (0.2) | 8 (0.2) | 5 (0.6) | 3 (0.1) | 0 (0.0) | |
| 3–5 times/week | 34 (0.4) | 15 (0.4) | 10 (1.2) | 7 (0.4) | 2 (0.2) | |
| Almost daily | 325 (4.3) | 183 (4.8) | 40 (4.6) | 68 (3.4) | 34 (3.8) | |
| Missing | 645 (8.5) | 314 (8.2) | 46 (5.3) | 203 (10.0) | 82 (9.2) | |
| 1st trimester | < .001 | |||||
| None | 752 (9.9) | 409 (10.7) | 83 (9.6) | 163 (8.1) | 97 (10.8) | |
| 1–2 times/week | 326 (4.3) | 200 (5.2) | 21 (2.4) | 67 (3.3) | 38 (4.3) | |
| 3–5 times/week | 2203 (28.9) | 984 (25.7) | 224 (25.9) | 718 (35.5) | 272 (31.0) | |
| Almost daily | 4257 (55.9) | 2196 (57.4) | 532 (61.5) | 1057 (52.2) | 472 (52.7) | |
| Missing | 74 (1.0) | 40 (1.0) | 5 (0.6) | 18 (0.9) | 11 (1.2) | |
| 2nd trimester | < .001 | |||||
| None | 370 (4.9) | 193 (5.0) | 44 (5.1) | 90 (4.4) | 43 (4.8) | |
| 1–2 times/week | 359 (4.7) | 219 (5.7) | 23 (2.7) | 70 (3.5) | 47 (5.2) | |
| 3–5 times/week | 2314 (30.4) | 1056 (27.6) | 233 (26.9) | 737 (36.4) | 288 (32.2) | |
| Almost daily | 4520 (59.4) | 2332 (60.9) | 563 (65.1) | 1116 (55.2) | 509 (56.9) | |
| Missing | 49 (0.6) | 29 (0.8) | 2 (0.2) | 10 (0.5) | 8 (0.9) | |
| 3rd trimester | < .001 | |||||
| None | 443 (5.8) | 234 (6.1) | 49 (5.6) | 108 (5.3) | 52 (5.8) | |
| 1–2 times/week | 382 (5.0) | 228 (5.9) | 37 (4.3) | 71 (3.5) | 46 (5.2) | |
| 3–5 times/week | 2268 (29.8) | 1030 (26.9) | 223 (25.8) | 732 (36.2) | 283 (31.6) | |
| Almost daily | 4416 (58.0) | 2277 (59.5) | 551 (63.7) | 1092 (54.0) | 496 (55.4) | |
| Missing | 103 (1.4) | 60 (1.6) | 5 (0.6) | 20 (1.0) | 18 (2.0) | |
P value was for the difference among races/ethnicities.
Plasma Folate Concentration Across Race/Ethnicity
There was large variability in plasma folate concentrations in our study population (Table 3). The geometric mean and median of plasma folate concentration were 29.2 nanomoles per liter (95% CI = 28.5, 29.8) and 30.0 nanomoles per liter (IQR = 19.8–43.8), respectively. Black and Hispanic mothers had lower plasma folate concentrations than White mothers (geometric mean = 28.2 nmol/L [95% CI = 27.4, 29.0] and 30.4 nmol/L [95% CI = 28.9, 31.9] vs 34.2 nmol/L [95% CI = 30.7, 38.1], respectively). Consistently, Black and Hispanic mothers had higher rates of folate deficiency and insufficiency, but lower rates of elevated folate. Only 16 mothers had a folate level less than 6.8 nanomoles per liter, of which 14 self-identified as Black and 2 as Hispanic. The rates of folate insufficiency among Blacks and Hispanics were 12.2% and 8.1%, respectively. Elevated folate levels at greater than 45.3 nanomoles per liter were found in 22.9% of the sample and were highest among White mothers (30.6%).
TABLE 3—
Geometric Mean of Maternal Plasma Folate at Delivery Stratified by Race/Ethnicity in the Boston Birth Cohort, Enrolled in 1999–2014: Boston, MA
| Race/Ethnicity |
||||||
| Maternal Plasma Folate, nmol/L | Total Sample (n = 2598) | Black (n = 1786) | White (n = 98) | Hispanic (n = 507) | Other (n = 207) | Pa |
| Geometric mean (95% CI) | 29.2 (28.5, 29.8) | 28.2 (27.4, 29.0) | 34.2 (30.7, 38.1) | 30.4 (28.9, 31.9) | 33.2 (30.6, 36.0) | < .001 |
| Median (IQR) | 30.0 (19.8–43.8) | 29.0 (18.7–43.2) | 35.7 (25.6–48.8) | 30.6 (21.8–43.3) | 34.7 (22.7–46.8) | .004 |
| Deficiency,b No. (%) | 16 (0.6) | 14 (0.8) | 0 (0.0) | 2 (0.4) | 0 (0.0) | .37 |
| Insufficiency,c No. (%) | 278 (10.7) | 217 (12.2) | 5 (5.1) | 41 (8.1) | 15 (7.3) | .004 |
| Elevated,d No. (%) | 595 (22.9) | 396 (22.2) | 30 (30.6) | 112 (22.1) | 57 (27.5) | .09 |
Note. CI = confidence interval; IQR = interquartile range.
P value was for the difference among races/ethnicities.
Plasma folate < 6.8 nmol/L.
Plasma folate < 13.4 nmol/L.
Plasma folate > 45.3 nmol/L.
Linear regression models adjusting for confounders further confirmed that Black race was a significant factor associated with low folate concentration. In addition, continuous smoking during pregnancy, obesity, preterm delivery, and hypertensive disorder during pregnancy were also associated with decreased plasma folate concentrations while high folic acid intake in 2 or more periods (preconception, first trimester, second trimester, and third trimester) was associated with higher folate concentration (Table 4). Hispanic mothers were also more likely to have low folate levels compared with Whites, though this finding was not statistically significant (P = .07). Furthermore, mothers with folic acid intake 3 or more times per week in the third trimester had higher plasma folate concentrations (Figure A, available as a supplement to the online version of this article at http://www.ajph.org). In each self-reported folate intake group, there was a wide variability in plasma concentrations (Figure A).
TABLE 4—
The Determinants of Maternal Plasma Folate Concentrations at Delivery in the Boston Birth Cohort, Enrolled in 1999–2014 (n = 2598): Boston, MA
| Determinant | No. | Geometric Mean (95% CI) | Univariate Model, Fold Changea (95% CI) | Multivariate Model, Fold Changea (95% CI) |
| Age at delivery, y | ||||
| 20–30 | 1291 | 28.6 (27.7, 29.6) | 1 (Ref) | 1 (Ref) |
| < 20 | 254 | 31.2 (29.0, 33.6) | 1.09 (1.01, 1.18) | 1.09 (1.01, 1.18) |
| > 30 | 1053 | 29.3 (28.3, 30.4) | 1.02 (0.98, 1.06) | 1.04 (0.98, 1.10) |
| Race/ethnicity | ||||
| White | 98 | 34.2 (30.7, 38.1) | 1 (Ref) | 1 (Ref) |
| Black | 1786 | 28.2 (27.4, 29.0) | 0.83 (0.73, 0.92) | 0.84 (0.74, 0.93) |
| Hispanic | 507 | 30.4 (28.9, 31.9) | 0.89 (0.77, 1.01) | 0.89 (0.77, 1.01) |
| Other | 207 | 33.2 (30.6, 36.0) | 0.97 (0.84, 1.10) | 0.95 (0.82, 1.08) |
| Education attainment | ||||
| High school and lower | 1680 | 28.4 (27.6, 29.3) | 1 (Ref) | 1 (Ref) |
| College and higher | 915 | 30.5 (28.4, 31.7) | 1.07 (1.03, 1.11) | 1.05 (0.99, 1.11) |
| Marital status | ||||
| Married | 856 | 29.8 (28.6, 31.0) | 1 (Ref) | 1 (Ref) |
| Single | 1732 | 28.8 (28.0, 29.7) | 0.97 (0.93, 1.01) | 0.99 (0.93, 1.05) |
| Planned pregnant | ||||
| No | 1275 | 28.8 (27.9, 29.8) | 1 (Ref) | 1 (Ref) |
| Yes | 1304 | 29.5 (28.6, 30.5) | 1.02 (0.98, 1.06) | 1.00 (0.96, 1.04) |
| Smoking status | ||||
| Never | 2126 | 29.6 (28.9, 30.4) | 1 (Ref) | 1 (Ref) |
| Quitter | 206 | 28.7 (26.3, 31.3) | 0.97 (0.89, 1.05) | 0.99 (0.91, 1.07) |
| Continuous | 266 | 25.9 (24.1, 27.8) | 0.87 (0.80, 0.94) | 0.89 (0.82, 0.96) |
| Alcohol consumption | ||||
| No | 2323 | 29.1 (28.4, 29.8) | 1 (Ref) | 1 (Ref) |
| Yes | 199 | 30.0 (27.6, 32.6) | 1.03 (0.95, 1.11) | 1.06 (0.98, 1.15) |
| Parity | ||||
| Nulliparous | 1072 | 30.5 (29.5, 31.6) | 1 (Ref) | 1 (Ref) |
| Multiparous | 1526 | 28.2 (27.4, 29.1) | 0.92 (0.89, 0.96) | 0.95 (0.90, 1.01) |
| Pregravid BMI, kg/m2 | ||||
| 18.5–24.9 | 1148 | 30.3 (29.2, 31.4) | 1 (Ref) | 1 (Ref) |
| < 18.5 | 97 | 29.0 (25.2, 33.3) | 0.96 (0.85, 1.07) | 0.94 (0.83, 1.05) |
| 25–29.9 | 754 | 29.1 (27.8, 30.3) | 0.96 (0.90, 1.02) | 0.98 (0.92, 1.04) |
| ≥ 30 | 589 | 27.4 (26.2, 28.6) | 0.90 (0.85, 0.96) | 0.93 (0.88, 0.99) |
| Hypertensive disorder | ||||
| No | 2217 | 29.7 (29.0, 30.5) | 1 (Ref) | 1 (Ref) |
| Yes | 381 | 26.2 (24.8, 27.8) | 0.89 (0.83, 0.94) | 0.91 (0.86, 0.97) |
| Diabetes | ||||
| No | 2311 | 29.2 (28.5, 29.9) | 1 (Ref) | 1 (Ref) |
| Yes | 284 | 29.1 (27.3, 31.1) | 1.00 (0.92, 1.08) | 1.01 (0.93, 1.09) |
| Preterm delivery | ||||
| No | 1798 | 30.1 (29.2, 30.9) | 1 (Ref) | 1 (Ref) |
| Yes | 800 | 27.2 (26.2, 28.3) | 0.90 (0.85, 0.96) | 0.94 (0.89, 1.00) |
| Folate intake preconception and during pregnancyb | ||||
| ≤ 2 times/week | 344 | 23.9 (22.3, 25.6) | 1 (Ref) | 1 (Ref) |
| Only 1 period high intake | 112 | 25.5 (22.7, 28.7) | 1.07 (0.95, 1.20) | 1.04 (0.92, 1.16) |
| 2 periods high intake | 438 | 28.2 (26.6, 29.8) | 1.17 (1.08, 1.27) | 1.15 (1.06, 1.24) |
| 3 or more periods high intake | 1704 | 30.9 (30.1, 31.8) | 1.30 (1.22, 1.37) | 1.22 (1.13, 1.32) |
| Year at delivery | ||||
| 1998–2003 | 625 | 25.7 (24.4, 27.1) | 1 (Ref) | 1 (Ref) |
| 2004–2008 | 1307 | 29.6 (28.6, 30.6) | 1.15 (1.08, 1.22) | 1.12 (1.05, 1.18) |
| 2009–2014 | 666 | 31.9 (30.8, 33.0) | 1.23 (1.16, 1.31) | 1.21 (1.14, 1.28) |
Note. BMI = body mass index; CI = confidence interval.
Fold change of folate concentration was calculated by taking exponentiation of regression coefficients (exp[B]).
If prenatal vitamins or over-the-counter multivitamin intake ≥ 3 times/week, it was defined as high intake for each trimester of pregnancy; ≥ 1 times/week in preconception was defined as high intake.
Plasma Folate Concentrations and Acculturation Factors
Table C (available as a supplement to the online version of this article at http://www.ajph.org) shows the geometric mean plasma folate concentrations by acculturation factors including native language, country of origin, and time in the United States. In the pooled analysis, less than 10 years spent living in the United States was associated with higher folate concentrations (geometric mean = 30.3 nmol/L [95% CI = 29.1, 31.5] vs 27.8 nmol/L [95% CI = 26.1, 29.5]) and higher rate of elevated folate levels (24.6% vs 18.1%), compared with mothers living in the United States for more than 10 years. This relationship was also statistically significant for Blacks. For Hispanic mothers, foreign country of origin was associated with higher folate concentrations (geometric mean = 31.3 nmol/L [95% CI = 29.7, 33.1] vs 26.9 nmol/L [95% CI = 24.1, 30.1]), and there was a higher rate of elevated folate: 23.7% versus 14.0%, compared with US-born mothers. Similarly, non–English speakers had higher rates of elevated folate than English speakers (23.1% vs 10.7%).
DISCUSSION
In our sample of low-income, urban, minority mothers, we identified 2 findings of public health concern. First, we found extremely low use of preconception folic acid supplementation with only 4.3% of mothers reporting daily prenatal vitamin intake with most (86.6%) taking no vitamins in the 6 months before their pregnancy. This is lower than what has been reported for other US studies of women of childbearing age17 and women in the National Pregnancy Risk Assessment Monitoring System (PRAMS).17,26 Our sample disproportionately included minority women with low income and education and high rates of obesity, all of which are known to be risk factors for low vitamin intake and low folate concentrations.17,19,27 In addition, we found lower daily folic acid supplementation among Black and Hispanic groups compared with Whites, which is consistent with findings from PRAMS.17,26
Second, we observed that approximately one third of mothers did not have optimal plasma folate levels. That is, about 11% of mothers had insufficient (< 13.4 nmol/L) folate and 23% had elevated (> 45.3 nmol/L) folate concentrations. Notably, maternal blood was drawn within a few days of delivery. We speculate that during preconception, the rate of folate insufficiency may have been even higher because around 87% women did not take folate supplements. In the United States, the mandatory fortification of grains has been associated with increased folate concentrations and decreased NTDs. There is emerging evidence that adequate maternal folate nutrition may be protective against intergenerational transmission of obesity23 and elevated blood pressure.28 Although approximately 80 countries have now adopted folate fortification, much of Europe and many other countries have not and, thus, have not experienced the same decline in NTDs.4,29 As shown in our study, some subpopulations in the United States have not benefitted from efforts to increase folic acid intake and may require targeted interventions. Efforts to encourage folic acid supplementation and consumption of fortified grains are necessary to close the gap in folate concentrations by race/ethnicity. As interventions encourage increased intake, optimal intake and concentrations must be ascertained.
Few studies have examined elevated folate concentrations in mothers and their determinants. We found that about a quarter of our sample had levels greater than 45.3 nanomoles per liter, suggesting that some women may be at risk for ingesting too much folic acid. Some have expressed concern about the potential dangers of excessive folate levels in mothers and their children, including cancer, asthma, developmental delay, and autism,4,11–13 though, to date, these associations have not been well established. A recent review further echoed concerns of maternal high folic acid intake on offsprings’ autism.14
We also explored factors associated with low versus high folic acid intake. Previous studies have demonstrated an association between folic acid supplementation and higher plasma folate concentrations.30 In addition, a comparison of the time periods from before to after fortification of enriched grains found increased rates of serum and RBC folate in women and men and in all racial/ethnic groups.21,31 Few previous studies examined blood folate concentrations of reproductive-age women and even fewer in pregnant women. We found that folic acid supplementation in pregnant women was associated with increased folate concentration. However, given the frequency of maternal folic acid intake, there was a wide range of maternal plasma folate concentrations, indicating that folic acid supplementation is only 1 of the factors affecting plasma folate. Indeed, we found that low plasma folate concentrations were associated with mothers who were Black, smokers, obese, or hypertensive, or who delivered preterm.
Our study revealed racial/ethnic differences. Compared with White mothers, Hispanic mothers had lower folate concentrations, although this was not statistically significant. Other population studies that used NHANES data have found similar associations including racial/ethnic disparities for both Blacks and Hispanics and lower concentrations in smokers and overweight and obese women.18,20,21 Because of a higher rate of NTDs among babies born to Hispanic mothers, Marchetta and Hamner examined differences in serum and red blood cell folate concentrations between Whites and Mexican American women and the impact of supplement use on folate concentrations.18 Mexican American women with fewer acculturation factors were less likely to take folic acid and had lower folate levels.18
In our sample, concentrations among Hispanic mothers were lower than those for White mothers, though this difference was not statistically significant (P = .07) and acculturation patterns were different. Our population of Hispanic mothers were heterogeneous (Central American: 56.3%, Caribbean: 10.5%, South American: 10.4%, Puerto Rican: 7.8%, and Mexican American: 3.3%) with Puerto Rican mothers reporting less folic acid intake compared with other ethnicities. The foreign-born Hispanic mothers in our study had higher plasma concentrations and higher rates of elevated folate than those born in the United States (P = .016; P = .035). Future studies should explore maternal MTHFR C677T genotypes in which the Hispanic population has a higher rate of homozygous mutation (TT).32 A combination of high TT genotype and low folic acid intake (lower intake of supplementation or fortified grains, but higher nonfortified corn products16) could make Hispanic mothers more susceptible to NTDs.
Limitations and Strengths
Our study was subject to some limitations. First, although our findings are directly relevant to US urban low-income minorities, caution is needed to generalize our findings to other populations in different settings. Second, the survey was completed and blood collected within a few days after delivery at 1 point in time, which is at best a proxy of third-trimester folate status. We did not assess folate concentrations in preconception and early periods of pregnancy. Reported folic acid intake was retrospective, and thus likely subject to recall bias. Third, statistically significant differences in intake or plasma concentrations may not equate to biologically or clinically significant differences; additional studies are needed to link differences with health outcomes. Fourth, we recognize that Hispanic ethnicity reflects multiple subpopulations and that their risks for NTDs may differ.15 Finally, we only measured plasma total folate by using immunoassay. Both serum and red blood cell folate concentrations have been shown to increase in response to supplementation with serum folate showing a greater response with less influence by analytic variables.33 It should be noted that available cut-offs of plasma folate concentrations were established for nonpregnant populations, which may not be appropriate for pregnant women.
This study also had several important strengths. The study sample size was large with oversampling of minority racial/ethnic groups and mothers of low socioeconomic status. We assessed both self-reported supplementation and biomarkers of folate status, which revealed a remarkable range of folate concentrations, from insufficiency to excess. The BBC is unique in that it is specifically designed to include vulnerable populations. This makes it particularly well suited to study exposures that are highly prevalent among these groups, such as low folate levels in pregnant women.
Public Health and Policy Implications
Our study findings, if further confirmed by additional research, may have important clinical and public health implications. Our study showed that fewer than 5% of the BBC mothers followed the recommendation of starting folic acid supplementation before pregnancy, and probably did not receive the protective effect against NTDs that is the primary reason for taking it. This serves as an example of how public health interventions do not always reach vulnerable populations. This observation is important for public health agencies both in the United States and in other countries.
Furthermore, as there was both insufficiency and excess in our study population, further studies are urgently needed on (1) the relationship between intake (through supplementation and fortification sources) and blood concentrations and (2) potential adverse effects of both insufficient and excess folate concentrations, including the fraction of unmetabolized folic acid, on a range of health outcomes in the mother, fetus, and child, both short-term and long-term. It may be prudent for health care clinicians to carefully evaluate folic acid intake and potentially screen for blood folate concentrations in preconception and prenatal care. A personalized approach, rather than 1 size fits all, may be required to maximize health benefits and minimize potential adverse effects of folic acid supplementation.
ACKNOWLEDGMENTS
The Boston Birth Cohort (the parent study) was supported in part by grants from the March of Dimes (PERI 20-FY02-56, #21-FY07-605), the National Institutes of Health (R21ES011666, 2R01HD041702, R21HD066471, U01AI090727, R21AI079872, R01HD086013), and the Maternal and Child Health Bureau (R40MC27443 and UJ2MC31074). T. L. Cheng was supported by the Rockefeller Foundation Bellagio Center Writing Residency.
Note. The funders had no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the article; or the decision to submit the article for publication. The views expressed in this article are those of the authors, and no official endorsement by the Agency for Healthcare Research and Quality or the Department of Health and Human Services is intended or should be inferred.
HUMAN PARTICIPANT PROTECTION
The study was approved by the institutional review boards at Boston Medical Center and the Johns Hopkins Bloomberg School of Public Health. Written informed consent was obtained from all study participants.
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