a March of Dimes Birth Defects Foundation, California Birth Defects Monitoring Program, Emeryville, CA, USA.
b Division of Research, Kaiser Permanente Medical Care Program, Oakland, CA, USA.
c Divisions of Epidemiology and Biostatistics, University of California, Berkeley, CA, USA.
Reprint requests to: Dr Shaw, California Birth Defects Monitoring Program, 1900 Powell St. Suite 1050, Emeryville, CA 94608, USA.
Abstract
Background Maternal nutritional factors have been implicated in the complex aetiology of neural tube defects (NTD). We investigated whether the amount of weight a woman gained during pregnancy was associated with her risk of delivering an infant with an NTD.
Methods We conducted a population-based case-control study within the cohort of 708 129 live births and fetal deaths occurring in selected California counties in 19891991. Face-to-face interviews were conducted with mothers of 538 (88% of eligible) NTD cases (including those electively terminated, stillborn, or liveborn) and with mothers of 539 (88%) non-malformed liveborn controls within an average of 5 months from the term delivery date. Respondent-reported weight gain during pregnancy (kg) was analysed. Risks of infants having NTD were estimated among women who gained <10kg compared to those who gained 10kg during
38 week gestations.
Results Compared to women who gained 10kg, an increased risk for NTD offspring was observed among women who gained <10kg (odds ratio [OR] = 3.2, 95% CI : 2.34.6). The OR was 5.0 (95% CI : 2.69.7) among those women who gained <5 kg during pregnancy. The increased risk was not attributable to maternal non-use of a multivitamin containing folic acid, diabetes, NTD-pregnancy history, age, race/ethnicity, education, gravidity, alcohol use, cigarette use, prepregnant obesity, low socioeconomic status, dieting, nausea, nor to lower dietary intakes of folate, zinc, energy, protein, fat, carbohydrates, and methionine. An increased risk was observed even after simultaneous adjustment for most of these factors (OR = 2.2, 95% CI : 1.23.8). The risk associated with gaining <10kg was greater for anencephaly, but still elevated for spina bifida.
Conclusions We did not have information on weight gain during early pregnancy. Because weight gain during the relevant embryological period for NTD (first month post-conception) is relatively small and often variable, it seems less likely that elevated NTD risks indicate a causal association between lowered weight gain throughout pregnancy and abnormal development of the neural tube. It seems more likely that lowered weight gain is a consequence of carrying an NTD-affected fetus. However, what this consequence is and why risk was substantially larger for anencephaly is unknown.
Keywords Congenital anomalies, anencephaly, birth defects, pregnancy, teratogens, aetiology, spina bifida, body mass index
Accepted 8 February 2000
In the last decade, epidemiological research has made some intriguing observations about the complex aetiologies of neural tube defects (NTD). Foremost, maternal nutritional factors have been identified as important contributors.1 Best known of these factors is the preventive role of supplemental folic acid.2,3 In addition, several investigators have observed the risk for NTD-affected pregnancies to be substantially elevated among women who were obese before pregnancy.48 No additional studied maternal factor, including supplemental folic acid use, appeared to substantially influence this observed association. Although compromised nutrient intakes and possibly innate metabolic disorders could hypothetically be contributors to this NTD-obesity association, the underlying mechanisms for the association are unknown. Further, at least one report has suggested that weight reduction in early pregnancy may be associated with increased NTD risk.9 Elevated risks of delivering offspring with NTD following intrauterine famine exposure have also been observed.10,11 Evidence from animal models supports the observation that maternal fasting may be teratogenic.12
Thus, the literature suggests that compromised maternal nutrient intake, prepregnancy obesity, and possibly alteration in pregnancy weight gain contribute substantially to the risk of delivering infants with NTD. Numerous studies have investigated potentially compromised nutrient intakes and prepregnancy obesity as NTD risk factors. Limited information, however, is available about lower pregnancy weight gain as a NTD risk factor and even less is available about the interrelations among elevated prepregnancy obesity, weight gain during pregnancy, and early pregnancy nutrient intake. We examined data from a large population-based case-control study to investigate a possible association between weight gain during pregnancy and NTD among offspring. This potential association was investigated controlling for the influences of prepregnant obesity, nutrient intake, and a variety of other possible covariates.
Materials and Methods
For this population-based case-control study, details of which have been reported previously,5,13 infants or fetuses with NTD were ascertained by the California Birth Defects Monitoring Program14 by reviewing medical records, including ultrasonography, at all hospitals and genetic clinics for those infants/ fetuses who were delivered in and whose mother was a resident in California. Eligible were singleton fetuses and liveborn infants diagnosed with NTD among the cohort of 708 129 births (includes fetal deaths) between June 1989 and May 1991. Fetuses diagnosed prenatally with NTD and electively terminated between February 1989 and January 1991 were also eligible. Eligibility was restricted to infants/fetuses with anencephaly, spina bifida cystica, craniorachischisis, or iniencephaly. Ascertained were 653 singleton infants/fetuses with an eligible NTD diagnosis. Controls were randomly selected from each area hospital in proportion to the hospital's estimated contribution to the total population of infants born alive in a given month from June 1989 to May 1991. Considered eligible were 644 singleton infants who were born alive without a reportable congenital anomaly14 and whose mother was a California resident.
Women who only spoke languages other than English or Spanish or who had a previous NTD-affected pregnancy were excluded, leaving 613 cases and 611 controls. In-person interviews were completed with mothers of 538 (87.8%) cases and of 539 (88.2%) controls within an average of 5 months after the actual or projected date of term delivery. Non-participants were similar to study participants in race/ethnicity and age. The 538 cases included 217 with anencephaly, 296 with spina bifida, and 25 with other NTD.
An interviewer presented each woman with an individualized calendar marked by four time periods: 3 months before conception, 3 months post-conception, and the subsequent two trimesters of pregnancy. Date of conception was determined using gestational age estimated primarily from date of last menstrual period, and in some circumstances from ultrasound results and physical examination. The average 2-hour interview elicited information from each woman on medical, reproductive, and family history as well as aspects about her employment, hobbies, vitamin intake, prepregnant weight, height, and activities associated with various lifestyle factors. With respect to weight gained or lost during pregnancy, each woman was asked: How much weight did you gain or lose during this pregnancy? Body mass index (BMI) was estimated for each woman from information on her reported prepregnant weight and height using the algorithm,15 kilograms weight/(metres height2).
A 100-item food frequency questionnaire was used to assess nutrient intake from diet.16 Study women themselves completed this food frequency questionnaire in English or Spanish with the interviewer present. Each woman was instructed to estimate her usual frequency and portion size of the food items she consumed during the 3 months before conception. Average daily intake of various nutrients was computed using analytical software developed for the survey instrument.16 Of the 1077 women who completed an interviewer-administered questionnaire, 1004 (93.2%) completed a food frequency questionnaire; of these, 916 revealed suitable data based on error checks built into the analytical software.
Effects were described by odds ratios (OR) and their 95% CI. Analyses were performed to estimate the risks of delivering infants with NTD by women who gained 4kg, 59, 1014, 2024, and >24 kg, using weight gain of 1519 kg as the referent category. Potential maternal covariates considered included: age, race/ethnicity, education, gravidity, alcohol use, diabetes, any use of a vitamin containing folic acid in the period 3 months before or after conception, cigarette smoking, exercise, indicators of low socioeconomic status, obesity, diet to lose weight, nausea, and dietary intake of folate, zinc, fat, protein, methionine, carbohydrate, and energy. Obesity was defined using the Institute of Medicine's15 cutpoint for obesity, i.e. BMI >29 kg/m2.
Most analyses were limited to pregnancies 38 weeks gestation and thus excluded 305 NTD cases (most were electively terminated) and 41 controls. To evaluate the impact that these excluded pregnancies may have had on the computed risk estimates, we included them in analyses that estimated NTD risk based on categories of weekly weight gain during gestation. These categories have been used elsewhere to estimate risk for preterm delivery.17 The categories were <0.27 (low), 0.270.52 (average), and >0.52 kg/week (high gain).
Results
Case mothers as compared to control mothers were more likely to be Hispanic (49% versus 36%), to be <25 years of age (42% versus 33%), less likely to have graduated from college (17% versus 28%), and to have consumed alcohol during the first trimester (28% versus 34%). Among the 538 case mothers interviewed, 28 were missing information on weight gained or lost during pregnancy. Of the remaining 512 case mothers, 60% had gestations <38 weeks and 40% had gestations 38 weeks. Among the 539 interviewed control mothers, 16 were missing weight gain or loss information, and 92% had gestations
38 weeks.
Effect estimates for delivering an infant with NTD associated with maternal weight gain categories, among pregnancies 38 weeks gestation, are displayed in Table 1
. Relative to women who gained 1519 kg during their pregnancies, 2.5- to 5-fold increased risks for delivering infants with NTD were observed for women who gained <10kg. Among those women who reported weight gains of <5 kg, 11 case and 4 control mothers reported no gains or net weight losses during pregnancy. The OR for these women was 9.0 (95% CI : 2.828.3) relative to women who gained 1519 kg. Increased or decreased risks were not observed for women who gained
20 kg relative to those who gained 1519 kg.
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Other potential explanations were explored for the increased NTD risk among women who gained <10 kg during pregnancy. Average birthweights of infants delivered by women who gained <10 kg (among those 38 weeks gestation) were similar between NTD cases (mean = 3.4 kg) and controls (mean = 3.4 kg). These averages were also similar to infant birthweights among women who gained
10 kg during pregnancy (cases = 3.4 kg, controls = 3.6 kg). In addition, excluding women with any type of diabetes (including gestational diabetes) did not substantially alter the OR for the comparison between women who gained <10 kg to those
10 kg. Case mothers in the <10 kg group were also not more likely to have a reported history of particular illnesses such as bladder infection or fever during the periconceptional period (3 months before to 3 months after conception) compared to control women in the <10 kg group. The increased risk was not substantially influenced by excluding cases with recognized NTD syndromes (three cases trisomy 13, 18, or another chromosomal aberration). The elevated risk was also not attributable to women having a history of NTD-affected pregnancy because the 12 women (11 case mothers) who reported such a history were excluded from all analyses. Nor was the elevated risk associated with reported pica-related behaviours, i.e. eating freezer frost, clay, dirt, corn starch or laundry starch.
The above analyses were limited to term pregnancies (i.e. 38 weeks gestation) and thus excluded 305 NTD cases and 41 controls owing to the fact that they were diagnosed and electively terminated (cases) or were prematurely delivered (cases or controls). We evaluated the impact that these excluded pregnancies may have had on the computed risk estimates by including them in analyses using average weekly weight gain during pregnancy. Compared to women who gained 0.270.52 kg/week, women who gained <0.27 kg/week were at substantially increased risk of having had an NTD-affected pregnancy (Table 3
). These increased risks were observed for all women in the study, including those who delivered before 38 weeks gestation, and those who delivered at
38 weeks gestation.
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These data revealed more than a threefold risk for delivering infants with NTD associated with maternal pregnancy weight gain of <10 kg. We were unable to identify specific factors that explained this elevated risk despite the fact that numerous potentially relevant covariates were examined. In particular, neither numerous measured dietary parameters nor prepregnant obesity appeared to substantially contribute to this elevated risk.
This is the first epidemiological study that we are aware of to fully explore lowered weight gain as a potential risk factor for NTD. Two other investigations, however, have specifically offered some preliminary evidence for an association with NTD. Robert et al.9 presented data from Sweden showing an elevated risk of NTD among women who gained <10 kg, although the observed OR of 1.4 (95% CI : 1.02.1) was considerably less than the OR of 3.2 observed here for the same comparison. Mendelsohn et al.18 reported (abstract only) an association between lowered weight gain and elevated NTD risk in a small study population in Minnesota. In addition, some anecdotal observations have been reported (case reports) that suggested a potential association between lack of weight gain in early pregnancy and congenital anomaly risk.9,19,20 Relative to previous studies and case reports, our study was advantaged by its large size, its population-based ascertainment of cases (including elective terminations) and controls, its high participation of eligible case and control mothers, its ability to examine a variety of potential covariables including maternal obesity, and its ability to investigate variation in dietary intake of several nutrients as possible contributors to increased NTD risks. Nevertheless, our findings are preliminary and are subject to a number of considerations.
An important consideration about this study is that we did not have information on weight gain during early pregnancy. Because weight gain during the relevant embryological period for NTD (first month post-conception) is relatively small and often variable, it seems less likely that elevated NTD risks indicate a causal association between lowered weight gain throughout pregnancy and abnormal development of the neural tube. It seems somewhat more likely that lowered weight gain is a consequence of carrying an NTD-affected fetus. However, how this consequence is brought about and why risk was substantially larger for anencephaly is unknown; lowered birthweights of NTD infants were not the explanation. One might speculate that lowered weight gain and NTD risk could result from a common factor. For example, ketoacidosis induced by maternal weight loss in early pregnancy has been suggested as a risk factor for NTD.9 We cannot rule out ketoacidosis as a possible causative factor because we did not know whether women who were less likely to gain weight were also more likely to have been ketoacidotic during early pregnancy.
Gaining <10 kg during pregnancy may result from an innate metabolic abnormality, or may result from lifestyle factors (e.g. diet, exercise, or stress) that limit weight gain. Thus, it is possible that lowered weight gain is a reflection of other factors that we did not measure, though what these factors might be is unknown. Factors considered most likely to contribute to such an association, given their postulated role in the occurrence of NTD, were in fact measured. They included maternal use of vitamins containing folic acid, maternal dietary intake of folates and selected other nutrients, and prepregnant obesity. However, none of these factors fully accounted for the elevated risks (Table 2).
We could not completely determine whether low weight gain was a risk factor for all NTD, not just those whose gestational ages were 38 weeks. We analysed the case infants/fetuses who were <38 weeks by a categorization of weekly gain and found low weight gain/week among all NTD-affected pregnancies. Because weekly weight gain is not uniform throughout pregnancy and is likely to be lower during the first compared to later trimesters,15,21 it is possible that NTD-affected pregnancies may have been overrepresented in the lower weekly weight gain category given they were more likely to be diagnosed and terminated at mid-pregnancy. However, most of the NTD-affected pregnancies <38 weeks that were terminated (207 cases) were well beyond the first trimester at the time of termination (average = 20.4 gestational weeks).
Validity of maternal report of weight gained during pregnancy has not been measured and thus the extent of bias resulting from differential reporting accuracy of weight gain by case and control mothers in this study is unknown. Nevertheless, we do not suspect that NTD case mothers were more likely to underestimate or that control mothers were more likely to overestimate their weight gain. At the time of data collection for this study, lowered weight gain was not considered a risk factor for having an NTD-affected pregnancy. Moreover, a recent study demonstrated that maternal recall of height and prepregnant weight was highly accurate.22 Other investigators have found that women tend to underestimate their weight at delivery which could possibly result in an underestimate of their weight gain further resulting in women being misclassified to lower weight gain categories.23 If weight gain reporting inaccuracies occurred independent of case/control status, such misclassification would have resulted in our underestimating, not overestimating, NTD risk. We observed about 10% of control women gained 7.3 kg, about 20% gained
10 kg, and the median weight gain for control mothers was 13.6 kg. These measures compare reasonably well with other published data.15,24 Thus, the observed elevated risks were unlikely due to a lower proportion of control mothers in the current study reporting that they gained <10 kg. Further, we have indirect evidence that supports our suspicion that case and control mothers may not have reported their weight gain differentially. We analysed data from another dataset (described in25,26) that also included NTD as well as conotruncal heart defects, limb anomalies, and orofacial clefts. Despite the fact that the control group was the same for each of the studied anomalies, we observed elevated risks for weight gain of <5 kg only for NTD and not for the other groups of anomalies.
Ideal weight gain during pregnancy is complex in that increased risks have been observed for other pregnancy outcomes associated with either lowered or elevated weight gains during pregnancy.15,17,27,28 The current Institute of Medicine recommendations for weight gain during pregnancy are based on prepregnant BMI. For 40-week gestations those guidelines are: low BMI, 2840 pounds; average BMI 2535 pounds; and high BMI 1525 pounds. For the most part, the risks we observed for NTD correspond to weight gains below the guidelines. These findings are provocative and their follow-up may prove helpful in gaining a better understanding of the complex aetiologies of these serious birth defects.
Acknowledgments
We are grateful to Dr Ellen Velie for preparing many of the data used in these analyses, and to Jennifer Stiling for manuscript preparation.
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