Abstract
Objective
To investigate the relationship between spina bifida and two established risk factors, pregestational diabetes and obesity, in both the presence and absence of the recommended daily folic acid intake in the periconceptional period.
Study Design
Cases of spina bifida (n=1154) and controls (n=9439) from the Slone Epidemiology Center Birth Defects Study (1976–2011) were included. Information on preexisting diabetes (collected 1976+) and obesity (collected 1993+), defined as BMI ≥30 kg/m2, were collected through interviews conducted within six months of delivery. Periconceptional folic acid intake was calculated using both dietary and supplement information. Mothers were classified as consuming more or less than 400µg/day of folic acid, with food folate included at a 30% discount for its lower bioavailability. Logistic regression models, adjusted for maternal race, education, and study site, were used to calculate adjusted odds ratios (aOR) and 95% confidence intervals (CI) for the joint effects of low folic acid intake coupled with diabetes or obesity.
Results
Mothers of cases were more likely to have diabetes or be obese (0.7% and 19.0%, respectively) than control mothers (0.4% and 10.8%, respectively). The joint effect of diabetes and lower folic acid intake on spina bifida was larger (aOR:3.95; CI: 1.56, 10.00) than that of diabetes and higher folic acid intake (aOR:1.31; CI: 0.17, 10.30). Folic acid intake made little difference on the association between obesity and spina bifida.
Conclusion
Our findings suggest that folic acid further attenuates, though does not eliminate, the risk of spina bifida associated with diabetes, than that with obesity.
Keywords: folic acid, obesity, preexisting diabetes, pregnancy, spina bifida
Introduction
Folic acid intake in the periconceptional period reduces the risk of spina bifida in offspring1–4. Spina bifida, a neural tube defect, develops in the earliest part of pregnancy, frequently prior to recognition of pregnancy. Due to this early developmental timing and the fact that approximately half of all pregnancies in the United States are unplanned5, the United States Public Health Service, the Institute of Medicine6, and the United States Preventive Services Task Force7 recommend that women of child-bearing age consume at least 400µg of folic acid daily through supplements and fortified food products8. Despite these recommendations and mandatory fortification of enriched cereal grain products beginning in the U.S. in 1998, a recent study estimated that only one in four women of child-bearing age consumes the recommended amount of folic acid9. Given the established role of folic acid in reducing the occurrence of spina bifida, it is possible that risk factors for spina bifida may operate differently in the presence and absence of folic acid.
Preexisting diabetes and obesity have both been identified as independent risk factors for spina bifida10–13, yet few studies have addressed the impact of folic acid intake on these associations. In animal studies, folic acid supplementation has been shown to decrease the incidence of neural tube defects among diabetic pregnancies14,15. The only epidemiologic study conducted to date observed that diabetic women using folic acid-containing supplements had a lower risk of spina bifida than non-supplementing diabetic women16. Similarities in the physiology of diabetes and obesity, including abnormalities in glucose metabolism, might suggest that folic acid may also affect the association between obesity and spina bifida. A studyof prepregnancy weight and neural tube defects observed that folic acid offered some protection among lighter women (<70 kg), but no such protection among heavier women17.
With recent studies suggesting that, in the era of folic acid fortification, achieving higher levels of folic acid intake through supplement use18,19 and dietary folate19 may not reduce the risk of neural tube defects, it is important to understand if higher levels of folic acid intake alter the effect of other risk factors for spina bifida. Using data from the Slone Epidemiology Center Birth Defects Study, we sought to describe the effect of obesity and diabetes on the risk of spina bifida in both the presence and absence of the recommended amount of daily folic acid intake.
Materials and Methods
Study Population
The Slone Epidemiology Center Birth Defects Study is an on-going case-control study in the United States and Canada that began in 1976. Cases of birth defects are ascertained from birth hospitals, tertiary care centers, or birth defects registries in Massachusetts(1976+); Philadelphia, PA(1976+); San Diego, CA(2001+); Toronto, Canada(1976–2005); selected counties in Iowa(1983–1985); and parts of New York State(2004+). Cases include livebirths, fetal deaths(1990+), and elective terminations(1990+). Controls are liveborn infants selected from study hospitals and birth certificates of the catchment area from which cases were collected. Prior to 1993, controls consisted of infants with minor malformations, such as heart murmurs and skin tags. Beginning in 1993, non-malformed infants were used. The study has been approved by the Boston University Institutional Review Board and is in compliance with the Health Insurance Portability and Accountability Act.
A maternal interview is conducted by a trained nurse within six months of delivery among subjects providing informed consent. The interview includes questions on reproductive history, medication use and illnesses during pregnancy. Beginning in 1988, data on diet were collected using a food frequency questionnaire (FFQ).
The present study includes cases of spina bifida and controls ascertained between 1976 through 2011. Spina bifida cases were excluded in the presence of chromosomal anomalies, Mendelian inherited disorders, recognized syndromes, amniotic bands, body wall defects, or conjoined twins. Cases were reviewed by a clinical geneticist and classified into isolated and multiple defect categories. Cases were considered multiple if another major defect, unrelated to spina bifida, was present.
Diabetes and Obesity
Information on diabetes, both preexisting and gestational, was collected throughout all years of the study. Preexisting diabetes was defined as the onset of type 1 or type 2 diabetes prior to pregnancy. Gestational diabetes was defined as the onset of diabetes after the first lunar month of the index pregnancy. Body mass index (BMI) was calculated based on the mother’s self-reported height and prepregnancy weight. Data on BMI were available from 1993 onwards when information on maternal height was incorporated into the interview. BMI was categorized into four groups; underweight (<18.5 kg/m2), normal-weight (18.5–24.9 kg/m2), overweight (25– 29.9 kg/m2), and obese (≥30 kg/m2)20.
Folic Acid Intake Assessment
Folic acid intake in the periconceptional period, defined as the month prior to the last menstrual period through the first lunar month of pregnancy, was calculated by summing average daily folic acid intake from supplements and fortified foods. Natural folate from diet was also included, but discounted by 30% due to its lower bioavailability6. Data on dietary intake was collected from an adapted Willett FFQ. The FFQ asked about diet in the six months prior to pregnancy to best capture nutritional intake in the periconceptional period. Dietary values of folic acid and folate were adjusted for total energy intake using the residual method21. Subjects were categorized into two groups, those achieving the recommended intake of ≥400µg /day of folic acid (high intake) and those with an intake of <400 µg/day (low intake). Subjects with extreme caloric intake (<500 or >4,000 kcal/day) and incomplete (≥3 missing items) FFQs were excluded from analyses involving folic acid intake; however, two exceptions were made. Women reporting ≥400µg of daily folic acid from vitamin supplementation remained in the analysis, because regardless of dietary intake they would be included in the ≥400µg/day category. Secondly, women reporting no supplementation remained in the analysis because regardless of dietary intake it is unlikely they would reach ≥400µg/day of folic acid9. Women with missing information on diet and an intake of <400µg/day from supplementation were excluded.
Statistical Analyses
Logistic regression models were used to calculate odds ratios and 95% confidence intervals (95%CI). We calculated crude and adjusted odds ratios (cOR and aOR, respectively) for the associations between spina bifida and preexisting diabetes and gestational diabetes, separately. To assess the joint effect of low folic acid intake on the association between preexisting diabetes and spina bifida, subjects were categorized into four unique groups; (1) no diabetes and ≥400µg/day folic acid (referent), (2) diabetes and ≥400µg/day of folic acid, (3) no diabetes and <400µg/day of folic acid, and (4) diabetes and <400µg/day of folic acid. The relative excess risk due to interaction (RERI) and 95% CI between diabetes and low folic acid intake was calculated. Women with gestational diabetes were excluded from the analysis of joint effect.
Analyses in which BMI was assessed were restricted to 1993–2011 birth years and excluded women with preexisting diabetes. We calculated odds ratios for underweight, overweight, and obese groups. To assess the joint effect of low folic acid intake and obesity, subjects were categorized into four unique groups; (1) normal-weight and ≥400µg/day of folic acid (referent), (2) obese and ≥400µg/day of folic acid, (3) normal-weight and <400µg/day of folic acid, and (4) obese and <400µg/day of folic acid. The RERI and 95% CI was calculated. BMI data were missing for 2.5% percent of participants and missing BMI did not appear to be independent of other analytic variables. Therefore, we conducted a sensitivity analysis in which multiple imputation methods were used to impute BMI; the impact of using these imputed values to estimate the association between BMI and spina bifida was assessed. Due to changes in case and control ascertainment over the study period, a sensitivity analysis to address the possibility of selection bias was performed by restricting cases and controls to those from the same birth hospitals. Maternal age, education, race, study site, and folic acid intake (<400µg/day, ≥400µg/day) were included in regression models to adjust for potential confounding. Joint effect models did not include folic acid intake as a covariate. Analyses were performed using SAS software 9.3.
Results
Diabetes
A total of 1,154 cases of spina bifida and 9,439 controls ascertained between 1976 through 2011 were included in the diabetes analysis. Cases and controls differed byrace/ethnicity, maternal age, education, and folic acid intake (Table 1). Among case mothers, the prevalence of preexisting diabetes was 0.69% compared to 0.44% among control mothers. The aOR for preexisting diabetes and spina bifida was 1.84 (95% CI:0.80, 4.22); that for gestational diabetes was 1.19 (95% CI:0.84, 1.71)(Table 2). Spina bifida in the presence of other defects had an aOR of 2.56 (95% CI:0.59, 11.13) for preexisting diabetes, while that for isolated spina bifida was 1.70 (95% CI:0.68, 4.29)(data not shown).
Table 1.
Maternal Characteristics of Spina Bifida Cases and Controls, Slone Birth Defects Study
| 1976–2011a | 1993–2011b | |||||||
|---|---|---|---|---|---|---|---|---|
| Spina Bifida Cases |
Controlsc | Spina Bifida Cases |
Controls | |||||
| No. | % | No. | % | No. | % | No. | % | |
| Total | 1154 | 9439 | 389 | 8062 | ||||
| Maternal race/ethnicity | ||||||||
| White, non-Hispanic | 991 | 85.9% | 7112 | 75.3% | 279 | 71.7% | 5816 | 72.1% |
| Black, non-Hispanic | 58 | 5.0% | 628 | 6.7% | 30 | 7.7% | 580 | 7.2% |
| Other races | 105 | 9.1% | 1693 | 17.9% | 80 | 20.6% | 1660 | 20.6% |
| Hispanicd | 73 | 6.3% | 1095 | 11.6% | 57 | 14.7% | 1079 | 13.4% |
| Missing data | 0 | 0.0% | 6 | 0.1% | 0 | 0.0% | 6 | 0.1% |
| Maternal age at conception | ||||||||
| <20 years | 92 | 8.0% | 594 | 6.3% | 24 | 6.2% | 535 | 6.6% |
| 20–24 years | 263 | 22.8% | 1441 | 15.3% | 57 | 14.7% | 1122 | 13.9% |
| 25–29 years | 390 | 33.8% | 2687 | 28.5% | 136 | 35.0% | 2143 | 26.6% |
| 30–34 years | 296 | 25.6% | 3125 | 33.1% | 109 | 28.0% | 2767 | 34.3% |
| 35–39 years | 94 | 8.1% | 1371 | 14.5% | 53 | 13.6% | 1287 | 16.0% |
| ≥40 years | 19 | 1.6% | 200 | 2.1% | 10 | 2.6% | 188 | 2.3% |
| Missing data | 0 | 0.0% | 21 | 0.2% | 0 | 0.0% | 20 | 0.2% |
| Maternal education | ||||||||
| <12years | 178 | 15.4% | 854 | 9.0% | 63 | 16.2% | 701 | 8.7% |
| 12 years | 418 | 36.2% | 1964 | 20.8% | 104 | 26.7% | 1479 | 18.3% |
| >12 years | 557 | 48.3% | 6614 | 70.1% | 222 | 57.1% | 5877 | 72.9% |
| Missing data | 1 | 0.1% | 7 | 0.1% | 0 | 0.0% | 5 | 0.1% |
| Study center (years in study) | ||||||||
| Boston (1976+) | 300 | 26.0% | 4491 | 47.6% | 84 | 21.6% | 4121 | 51.1% |
| Philadelphia (1976+) | 417 | 36.1% | 2173 | 23.0% | 137 | 35.2% | 1581 | 19.6% |
| Toronto (1979–2005) | 359 | 31.1% | 1236 | 13.1% | 106 | 27.2% | 960 | 11.9% |
| Iowa (1983–1985) | 15 | 1.3% | 132 | 1.4% | -- | -- | -- | -- |
| San Diego (2001+) | 33 | 2.9% | 1007 | 10.7% | 32 | 8.2% | 1002 | 12.4% |
| New York (2004+) | 30 | 2.6% | 400 | 4.2% | 30 | 7.7% | 398 | 4.9% |
| Daily folic acid intake | ||||||||
| <400 µg | 832 | 72.1% | 5023 | 53.2% | 225 | 57.8% | 4005 | 49.7% |
| ≥400 µg | 259 | 22.4% | 3991 | 42.3% | 139 | 35.7% | 3797 | 47.1% |
| Missing data | 63 | 5.5% | 425 | 4.5% | 25 | 6.4% | 260 | 3.2% |
Diabetes analysis
Obesity analysis
From 1976–1993 cases with minor malformations were used as controls
Hispanic ethnicity was ascertained from 1983 onwards
Table 2.
Crude and Adjusted Odds Ratios and 95% Confidence Intervals for the Association between Diabetes and Spina Bifida, Slone Birth Defects Study, 1976–2011
| Cases (n=1154) |
Controls (n=9439) |
cOR (95% CI) | aORa (95% CI) | |||
|---|---|---|---|---|---|---|
| Diabetes | n | % | n | % | ||
| Pre-existing | 8 | 0.69% | 42 | 0.44% | 1.56 (0.73, 3.32) | 1.84 (0.80, 4.22) |
| Gestational | 39 | 3.38% | 371 | 3.93% | 0.86 (0.61, 1.20) | 1.19 (0.84, 1.71) |
| None | 1107 | 95.93% | 9026 | 95.62% | 1.0 (ref) | 1.0 (ref) |
aOR: adjusted odds ratio; CI: confidence interval; cOR: crude odds ratio
Adjusted for maternal age, education, race/ethnicity, folic acid intake, and study center
The joint effect of low folic acid intake and preexisting diabetes resulted in 4-fold increased risk for spina bifida (aOR:3.95, 95%CI:1.56,10.00) relative to mothers without diabetes and with higher daily folic acid intake, which was greater than expected given the individual additive effects of low folic acid intake and preexisting diabetes (RERI:1.65, 95% CI:2.87,6.18). In the presence of ≥400µg/day of folic acid, this association was attenuated (aOR:1.31, 95% CI: 0.17, 10.30), although this estimate was based on one exposed case (Table 3).
Table 3.
The Joint Effect of Folic Acid Intake and Diabetes and the Risk of Spina Bifida, Slone Birth Defects Study, 1976–2011
| Preexisting Diabetes |
<400 µg Folic Acid |
Ca/Co | aORa (95% CI) |
|---|---|---|---|
| No | No | 242/3827 | 1.0 (ref) |
| No | Yes | 803/4798 | 1.99 (1.69, 2.34) |
| Yes | No | 1/15 | 1.31 (0.17, 10.30) |
| Yes | Yes | 7/24 | 3.95 (1.56, 10.00) |
| RERI (95% CI): 1.65 (−2.87, 6.18) | |||
aOR: adjusted odds ratio; CI: confidence interval; RERI: relative excess risk due to interaction
Adjusted for maternal age, education, race/ethnicity, and study center
Sensitivity analyses restricted to cases and controls from the same birth hospitals changed diabetes results modestly, but the RERI still indicated synergy between diabetes and low folic acid intake (data not shown).
Obesity
Restrictions to the years in which data on BMI were available and exclusion of women with preexisting diabetes yielded a total of 389 cases and 8062 controls in the BMI analysis. During this time period, cases and controls differed by maternal age, education and folic acid intake (Table 1). Among case mothers, 19.0% were obese compared to 10.8% of control mothers. The aOR for spina bifida among overweight women was 1.24 (95% CI:0.93, 1.63); that for obese women was 1.97 (95% CI:1.46, 2.65) (Table 4). Overall, 4.37% of cases and 2.44% of controls were missing data on BMI, with Hispanic mothers more likely to have missing BMI data (15.8% of cases and 9.4% of controls) (data not shown). Multiple imputation of BMI did not materially change the results (Table 4).
Table 4.
Crude, Adjusted, and Imputed Odds Ratios and 95% Confidence Intervals for the Association between Body Mass Index and Spina Bifida, Slone Birth Defects Study, 1993–2011
| Cases (n=389) |
Controls (n=8062) |
Observed Data cOR (95% CI) |
Observed Data aORa (95% CI) |
Imputed Data aORa (95% CI) |
|||
|---|---|---|---|---|---|---|---|
| n | % | n | % | ||||
| Body Mass Index (kg/m2) | |||||||
| Underweight (<18.5) | 20 | 5.14% | 476 | 5.90% | 1.07 (0.67, 1.70) | 1.00 (0.62, 1.62) | 0.99 (0.60,1.61) |
| Normal (18.5 – 24.9) | 197 | 50.64% | 4992 | 61.92% | 1.0 (ref) | 1.0 (ref) | 1.0 (ref) |
| Overweight (25 – 29.9) | 81 | 20.82% | 1529 | 18.97% | 1.34 (1.03, 1.75) | 1.24 (0.93, 1.63) | 1.22 (0.93, 1.62) |
| Obese (≥ 30) | 74 | 19.02% | 868 | 10.77% | 2.16 (1.64, 2.85) | 1.97 (1.46, 2.65) | 1.97 (1.47, 2.65) |
| Missing | 17 | 4.37% | 197 | 2.44% | --- | --- | --- |
aOR: adjusted odds ratio; CI: confidence interval; cOR: crude odds ratio
Adjusted for maternal age, education, race/ethnicity, folic acid intake, and study center
There did not appear to be a joint effect between obesity and folic acid intake (RERI: 0.14, 95% CI: 1.08, 1.35). With normal-weight and higher folic acid intake as the referent, the aOR for obesity and low folic acid intake was 2.43 (95%CI: 1.63, 3.63), which is expected under the assumption of independent additive associations of obesity and low folic acid intake (Table 5).
Table 5.
The Joint Effect of Folic Acid Intake and Obesity and the Risk of Spina Bifida, Slone Birth Defects Study, 1993–2011
| Obese | < 400 µg Folic Acid |
Ca/Co | aORa (95% CI) |
|---|---|---|---|
| No | No | 80/2494 | 1.0 (ref) |
| No | Yes | 102/2333 | 1.22 (0.89, 1.68) |
| Yes | No | 23/340 | 2.08 (1.27, 3.39) |
| Yes | Yes | 48/506 | 2.43 (1.63, 3.63) |
| RERI (95% CI): 0.14 (−1.08, 1.35) | |||
aOR: adjusted odds ratio; CI: confidence interval; RERI: relative excess risk due to interaction
Adjusted for maternal age, education, race/ethnicity, and study center
Obesity results remained unchanged when restricted to cases and controls from the same birth hospitals (data not shown).
Comment
Failure to achieve the recommended intake of folic acid during the periconceptional period is suggestive of a further increase in the risk for spina bifida among mothers with preexisting diabetes, while the increased risk among obese mothers was not more than expected.
We observed a two-fold increased risk of spina bifida among women with preexisting diabetes, but the estimate was unstable due to a small number of diabetic cases. Although other studies to date have considered the relationship between preexisting diabetes and the combined group of all neural tube defects, including spina bifida and anencephaly, few have quantified the association between diabetes and spina bifida, specifically. Our odds ratio, based on eight exposed cases, was well above the estimates observed in two previous studies, which reported odds ratios of 0.4 (0–4.4) and 0.75 (0.17–3.24)22,23, but was smaller in magnitude than that reported from a cohort study in Nova Scotia (RR: 17.2, 2.3–128.8)24. Findings were similar to those from a study with an odds ratio of 1.81 (0.53–6.20) for non-Hispanic whites25. Of note, the previous findings were each based on less than four exposed cases.
Our observation regarding the joint effect of folic acid intake and diabetes are consistent with that previously reported16. In the study by Correa et al., the odds ratio for spina bifida among mothers who used folic acid-containing supplements and had preexisting diabetes was 1.66(0.62–4.42), compatible with the 1.31(0.17–10.30) we observed. Our risk estimate for diabetic mothers who did not consume the recommended intake of folic acid was somewhat larger than the odds ratio reported for the equivalent group in that study (i.e., diabetics not using supplements), 3.95 and 2.37, respectively16. It should be noted that the previous study did not include dietary intake of folic acid and defined the window of folic acid intake as the month prior to conception through the first three months of pregnancy; in contrast, the present study included dietary intake of both synthetic folic acid and natural food folate and estimated daily folic acid intake during the month before and after the last menstrual period. The neural tube closes during the second month of pregnancy and the proportion of women taking supplements vastly increases during the second and third month, which would contribute to misclassification of folic acid intake.
The mechanism by which folic acid may reduce the risk of spina bifida due to diabetic embryopathy is not well understood. It has been proposed that folic acid has antioxidant properties that mitigate the effect of reactive oxygen species and abnormal apoptosis resulting from diabetes15,26,27. A potential explanation of our findings involves the ability of folic acid to reduce oxidative stress in the embryo caused by increased levels of glucose. Oxidative stress leads to reduced expression of the Pax3 gene which may result in malformation of the neural tube27. In addition to folic acid, other antioxidants have been shown to reduce the occurrence of malformations in diabetic animal models28,29.
Few studies have addressed the association between diabetes and spina bifida specifically, and those displayed inconsistent results; on the other hand, research on obesity and spina bifida is more abundant and results more consistent. Data from the present investigation are consistent with previously published studies reporting odds ratios ranging from 1.5 to 3.510,12 contributing to the growing body of evidence supporting a two-fold increase in the risk of spina bifida among obese women.
The risk of spina bifida among obese women achieving the recommended intake of folic acid was comparable with the risk among obese women who did not consume the recommended amount. This finding is consistent with a previous study, based on the same data source in a different time period as the present study, that observed that 400µg/day of folic acid was not protective against neural tube defects among heavier women, defined as >70 kg17. In a study comparing risks of neural tube defects by maternal weight categories in pre-fortification and post-fortification time periods, the reduction in risk was lowest among women in the highest weight quartile30. Serum folate levels have been shown to be lower among obese women, even after controlling for folic acid intake31. It has been estimated that obese women need to consume an additional 350µg/day of folic acid to achieve the same serum levels of folate as women in the lowest BMI category31.
Strengths of this study are the large sample size and the amount of diabetic cases, more than in previous studies. Another strength of this study is the short interval between delivery and interview. The short time period between delivery and interview likely improved the mothers’ reporting accuracy. Lastly, we were able to include both diet and supplements in the calculation of folic acid intake. The FFQ asked about diet in the six months prior to the last menstrual period, which is likely reflective of diet in early pregnancy and neural tube development. Furthermore, dietary data were available from a validated FFQ and the Slone Birth Defect Study has a comprehensive database of supplement information which improved classification of folic acid in specific supplement products over time.
Despite these strengths, some limitations should be considered when interpreting the results. Data on preexisting diabetes and obesity were collected by maternal report, which may have resulted in misclassification. The prevalence of previously diagnosed diabetes among women aged 20–39, from 1988–1994, was 1.1%32. The reported prevalence of preexisting diabetes among control mothers in our study was 0.44%. The estimated prevalence of prepregnancy obesity in the U.S. from 1993 to 2003 ranges from 13–22%33. In the present study, the prevalence among controls was 11%. In addition to underreporting, time trends and demographic differences may explain some of the discrepancy between published prevalences of diabetes and obesity and those reported in our study. Observed associations would have been attenuated if misclassification of preexisting diabetes and obesity was similar for cases and controls.
A limitation that may have affected our findings regarding diabetes, folic acid, and spina bifida is lack of information of glycemic control. Enhanced glycemic control during pregnancy reduces the rate of birth defects to levels similar to the general population34–36. Additionally, diabetic women who achieve glycemic control are more likely to have preconception care and subsequently more likely to take folic acid supplements37. We could not determine if the observed reduction in risk was due to higher folic acid intake or to glycemic control. Another limitation of the diabetes analysis was lack of data on BMI prior to 1993, making it infeasible to include BMI in the multivariate analyses for all study years. However, pre-pregnancy weight was available for all years of the study, and a sub-analysis adjusting for pre-pregnancy weight yielded comparable results (data not shown). Additionally, we lacked dietary data prior to 1988. However, it is expected that the contribution of diet to overall folic acid intake would be low prior to fortification.
In summary, achieving the daily recommended intake of ≥400µg of folic acid reduced the risk of spina bifida, yet this level of intake had a greater effect on reducing the risk of spina bifida due to diabetes than that due to obesity. An understanding of the mechanism by which diabetes appears to increase the risk for spina bifida and how folic acid may reduce its teratogenicity would provide more insight into whether or not higher levels of folic acid intake has the potential to further attenuate the risk of spina bifida due to obesity.
Acknowledgements
We thank Dawn Jacobs, RN, MPH, Fiona Rice, MPH, Rita Krolak, RN, Kathleen Sheehan, RN, Moira Quinn, RN, Clare Coughlin, RN, Laurie Cincotta, RN, Nancy Rodriquez-Sheridan, Ileana Gatica, Laine Catlin Fletcher, Joan Shander, Mark Abcede, Judy Jean, RN and Julia Venanzi for their assistance in data collection; Nastia Dynkin for computer programming; the staff of the Massachusetts Department of Public Health Center for Birth Defects Research and Prevention and the Massachusetts Registry of Vital Records, Dr. Charlotte Druschel and the New York State Health Department, and Drs. Christina Chambers and Kenneth Jones of the University of California, San Diego, as well as the medical and nursing staff at all participating hospitals for assistance with case ascertainment: Baystate Medical Center, Beth Israel Deaconess Medical Center, Boston Medical Center, Brigham & Women's Hospital, Brockton Hospital, Cambridge Hospital, Caritas Good Samaritan Medical Center, Charlton Memorial Hospital, Children's Hospital, Emerson Hospital, Falmouth Hospital, Haverhill-Hale Hospital, Jordan Hospital, Kent Hospital, Lawrence General Hospital, Lowell General Hospital, Melrose-Wakefield Hospital, Metro West Medical Center-Framingham, Mt. Auburn Hospital, New England Medical Center, Newton-Wellesley Hospital, North Shore Medical Center, Rhode Island Hospital, Saints Memorial Medical Center, South Shore Hospital, Southern New Hampshire Medical Center, St. Elizabeth's Medical Center, St. Luke's Hospital, St. Vincent Hospital, UMASS Memorial Health Care, Women & Infants' Hospital, Abington Memorial Hospital, Albert Einstein Medical Center, Alfred I. duPont Hospital for Children, Bryn Mawr Hospital, Chester County Hospital, Children's Hospital of Philadelphia, Christiana Care Health Services, Community Hospital, Crozer-Chester Medical Center, Doylestown Hospital, Frankford Hospital, Hahnemann University Hospital, The Hospital of the University of Pennsylvania, Lankenau Hospital, Lancaster General Hospital, Lehigh Valley Hospital, Nanticoke Memorial Hospital, Pennsylvania Hospital, Sacred Heart Hospital, St. Christopher’s Hospital for Children, St. Mary Medical Center, Temple University Health Sciences Center, Reading Hospital & Medical Center, Thomas Jefferson University Hospital, Grand River Hospital, Guelph General Hospital, Hamilton Health Sciences Corporation, The Hospital for Sick Children, Humber River Regional Hospital-Church Site, Humber River Regional Hospital-Finch Site, Joseph Brant Memorial Hospital, Lakeridge Health Corporation, London Health Sciences Center, Mt. Sinai Hospital, North York General Hospital, Oakville Trafalgar Memorial Hospital, Scarborough Hospital– General Division, Scarborough Hospital–Grace Division, St. Joseph's Health Centre-London, St. Joseph's Health Centre-Toronto, St. Joseph's Healthcare-Hamilton, St. Michael's Hospital, Sunnybrook & Women's College Health Sciences Center, Toronto East General Hospital, Toronto General Hospital, Trillium Health Center, William Osler Heath Centre, York Central Hospital, York County Hospital, Alvarado Hospital, Balboa Naval Medical Center, Camp Pendleton Naval Hospital, Children’s Hospital and Health Center, Kaiser Zion Medical Center, Palomar Medical Center, Pomerado Hospital, Scripps Mercy Hospital, Scripps Memorial Hospital-Chula Vista, Scripps Memorial Hospital-Encinitas, Scripps Memorial Hospital-La Jolla, Sharp Chula Vista Hospital, Sharp Coronado Hospital, Sharp Grossmont Hospital, Sharp Mary Birch Hospital, Tri-City Medical Center, and UCSD Medical Center; we particularly thank all the mothers who participated in the study.
This work was supported by the Centers for Disease Control and Prevention (DD000697). Samantha Parker was a pre-doctoral trainee supported by NIH T32 HD052458 (Boston University Reproductive, Perinatal and Pediatric Epidemiology training program).
Footnotes
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The authors report no conflict of interest.
Presented as a poster at the 25th Annual Meeting of the Society for Pediatric and Perinatal in Minneapolis, MN, June 25–27, 2012.
Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
Contributor Information
Samantha E Parker, Boston, MA, Slone Epidemiology Center, Boston University.
Mahsa M Yazdy, Boston, MA, Slone Epidemiology Center, Boston University.
Sarah C Tinker, Atlanta, GA; National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention.
Allen A Mitchell, Boston, MA; Slone Epidemiology Center, Boston University.
Martha M Werler, Boston, MA; Slone Epidemiology Center, Boston University.
References
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