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* Department of Epidemiology and Biostatistics, University Medical Center, Nijmegen;
The National Institute for Public Health and the Environment, Bilthoven; and
** Department of Obstetrics and Gynaecology, Erasmus University Medical Center, Rotterdam, The Netherlands
2To whom correspondence should be addressed. E-mail: R.Steegers{at}epib.umcn.nl.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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24 mo after conception of the index pregnancy. Energy-adjusted mean nutrient intakes were compared, and odds ratios (OR) and 95% CI were calculated. Although mean nutrient intakes were comparable to the Dutch food consumption survey data, fat, cholesterol, iron, and folate intakes were below the 1998 Dutch Recommended Daily Allowances. Case mothers had significantly lower intakes of plant proteins (7%), polysaccharides (4%), fiber (7%), iron (6%), magnesium (6%), and niacin (4%) than control mothers. Mono- and disaccharide intakes were significantly higher (6%) in the case mothers than in control mothers. The adjusted OR (95% CI) in the lowest quartiles for plant proteins was 5.4 (2.3–12.4), for fiber 3.1 (1.5–6.8), for iron 3.5 (1.4–8.3), for magnesium 1.9 (0.9–4.1), and for niacin 2.5 (1.2–5.2). Mono- and disaccharide and polysaccharide intakes in the highest quartile had ORs (95% CI) of 2.9 (1.4–6.3) and 0.5 (0.3–1.0), respectively. The nutritional intake of Dutch women from food groups containing iron and folate seems to be compromised. Low preconceptional intakes of plant proteins, iron, magnesium, and niacin are associated with a 2- to 5-fold increased risk of spina bifida.
KEY WORDS: • folate • iron • neural tube defects
In the 1970s and 1980s, spina bifida and anencephaly were reported to be more frequent in the lower social classes (1,2). Nutritional intake is associated with social class, and poor nutrition was suggested to be an important risk factor for these central nervous system malformations (3). Smithells et al. (4) reported lower concentrations of RBC folate, white blood cell vitamin C, riboflavin saturation index, and serum vitamin A in blood samples of nonpregnant women in the lower social classes compared with women in the upper classes. Of interest was the finding that mothers of offspring with neural tube defects had lower RBC folate and white blood cell vitamin C concentrations in the first trimester of pregnancy than control mothers. Since that time, several groups have reported lower B vitamin concentrations, and folate in particular, in mothers of infants with neural tube defects (5,6).
B-vitamins are taken up from dietary sources such as green leafy vegetables, beans, liver, and dairy products. Thiamin is involved in carbohydrate metabolism and is essential for the decarboxylation of 
-keto acids (7). Studies in rats showed that thiamin deficiency results in the thinning of the intestinal microvillous membrane, aberration of intestinal function, and polyneuropathy (8). Riboflavin as FAD is an intermediate in cellular respiration and acts as a cofactor for methylenetetrahydrofolate reductase in which a polymorphism was shown to be a risk factor for spina bifida (9,10). Niacin and the active coenzymes NAD and NADPH are involved in energy-requiring and -generating cellular reactions, and in the regulation of the lipid status, i.e., cholesterol, apolipoprotein B, triglycerides, and lipoproteins. It was shown in diabetic patients that niacin supplementation is effective for the treatment of dyslipidemia, which is frequently observed in these patients (11). Pregnant mice with a cholesterol shortage exhibited severe growth retardation and defective closure of the neural tube in their offspring (12). Pyridoxine is involved in racemizations, amino acid side-chain modifications, and transamination reactions. It is a cofactor of cystathionine-ß-synthase, which converts homocysteine into cystathionine. Folate functions as a one-carbon carrier and as such is involved in purine and pyrimidine synthesis and methionine metabolism. Smithells et al. (13) were the first to suggest that maternal folate deficiency is associated with the occurrence of neural tube defects in the offspring. First, we demonstrated that maternal hyperhomocysteinemia, as a functional marker of folate status, is a risk factor for spina bifida in the offspring (14). Because hyperhomocysteinemia can be treated by folic acid supplementation, these findings are in line with the results of intervention studies showing that periconceptional vitamin supplementation reduces the occurrence and recurrence risk of spina bifida in the offspring (6,15,16). Cobalamin is involved in the conversion of methylmalonic acid into succinic acid and folate metabolism, acting as a cofactor for methionine synthase. A maternal cobalamin shortage resulting in a mild hyperhomocysteinemia was also associated with spina bifida (14,17).
Minerals have also been implicated in the pathogenesis of neural tube defects. Lower maternal serum and hair concentrations of zinc were associated with neural tube defects (18–20). Moreover, zinc affects folate status as a cofactor for methionine synthase and 
-glutamyl hydrolase. Calcium is a second messenger in the inositol-triphosphate signaling pathway responsible for gene transcription, muscle contraction, and differentiation of cells. A reduced availability of cellular calcium induces abnormalities in neural tissues in experimental studies (21). Intracellular magnesium is a cofactor for ATP-requiring enzymes, such as hexokinase, which phosphorylates glucose. Of interest is that Shaw et al. (22) demonstrated that maternal periconceptional intake of magnesium decreased the risk of offspring with neural tube defects.
The aim of the current study was to investigate the independent effects of preconceptional maternal intake of various macronutrients, vitamins, and minerals on the risk of spina bifida in the offspring.
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SUBJECTS AND METHODS |
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In general, the individual nutritional pattern is rather constant (25) and is influenced only by episodes of temporary dieting, illnesses, nausea, and increased needs due to growth such as in pregnancy and breast-feeding (26,27). Under the assumption that the nutritional pattern after pregnancy is a proxy for the preconceptional nutritional pattern, mothers filled out a validated FFQ covering the intake 3 mo before the study moment. Some questions referred to the intakes of the preceding year (28,29). The frequency in which mothers used the food groups could be indicated per day, per week, month, year, or never. They were also asked about the preparation methods, additions, and portion sizes. All FFQs were individually checked for completeness and consistency at the hospital or by phone by the researcher. Consequently, the average daily nutrient intake was estimated by multiplying the frequency of consumption of food items by the portion size and nutrient content per gram based on the 1998 electronic version of the Dutch food-composition table except for folate and cobalamin, which were based on the 2001 electronic version (30,31). Additionally, mothers provided information on environment and lifestyle factors such as the use of folic acid supplements and smoking, in the periconceptional period that was defined as the period from 3 mo before until 3 mo after conception.
Eighteen of the 132 case-mothers and 38 of 236 control mothers, respectively, were excluded due to excessive vomiting and/or a change in nutritional intake in the periconceptional period compared with the study moment; 4 case mothers and 4 controls were excluded from the analyses because information on periconceptional excessive vomiting and/or change in nutritional pattern was lacking. Finally, the FFQ of 4 case and 13 control mothers was not completed properly, resulting in 106 case and 181 control questionnaires entering the analyses. The study protocol was approved by the Institutional Review Board of the University Medical Center Nijmegen in the Netherlands.
Statistical analysis. We used the nutrient residual (energy-adjusted) method to adjust for total energy intake as described by Willet et al. (32). Briefly, the crude nutrient intakes of the individuals were log-transformed and regressed on their total energy intake. This regression equation was used to calculate the expected mean nutrient log-intake for the mean total energy intake of the study population. The energy-adjusted log-intake of each individual was calculated by adding the expected mean nutrient log-intake of the study population to the individual residual that was derived from the regression analysis. Differences in energy-adjusted log-nutrient intakes between the groups were tested using Student’s t test. The energy-adjusted nutrient log-intakes were back-transformed to present energy-adjusted summary measures on the original scale.
The association between maternal nutrient intake and spina bifida in the offspring was stratified by the use of periconceptional folic acid–containing supplements because of the modification of the risk of spina bifida (15).
The energy-adjusted nutrient intakes were divided into quartiles based on the control mothers. The risk of spina bifida was estimated using odds ratios (OR)3 with 95% CI by comparing each quartile of a nutrient intake with the highest one in a logistic model. Multiple logistic regression analysis was performed to adjust for potential confounding factors, i.e., periconceptional smoking, alcohol consumption, and periconceptional use of folic acid–containing supplements. Control mothers appeared to be better educated than case mothers. Education is considered a proxy for social class and thereby nutritional habits (3). Adjustment for education would lead to an overcorrection of the data and may eliminate relevant significant differences in the nutritional pattern.
To construct a composite variable for macronutrients (total protein, total fat, and total carbohydrates), minerals (calcium, phosphorus, iron, magnesium, and iron), and vitamins (thiamin, riboflavin, niacin, pyridoxine, folate, and cobalamin), we summarized the Z-scores of the underlying variables. The individual Z-scores were calculated by subtracting the mean intake of the individual intake and dividing it by the SD. A high Z-score thus indicates that an individual has a relatively high intake of all of the nutrients in a given nutrient group compared with their peers. Additionally, ratios between protein intake from plant and animal sources, between saturated and nonsaturated fats, and between mono- and disaccharides and polysaccharides were calculated because they may be indicative of clinically relevant differences in nutritional patterns. All statistical analyses were performed using the SAS System for Windows version 8 (SAS Institute). Difference with P-values < 5% were considered significant.
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The overall dietary intakes of the mothers in both groups were comparable to the FCS of 1998 for women of reproductive age (20–55 y) (30). However, the mean intakes of fiber, all minerals, and vitamin C exceeded the data of the FCS of 1998 by 15% or more, indicating that our FFQ may not have estimated these minerals with enough precision. Therefore, comparing the results to the RDA may not be appropriate. Nevertheless, internal comparisons remain valid. The intakes of fats, cholesterol, iron, and folate were lower than the RDA, which are institutional values that aim to pursue an optimal nutrient status in a given population. Mean nutrient intakes that are roughly equal to the RDA indicate an adequate nutritional status. By contrast, higher mean nutrient intakes represent excessive intakes, possibly leading to adverse outcomes such as the association between fat intake and risk of cardiovascular disease. Lower mean nutrient intakes represent inadequate intakes and point to a subgroup at risk of nutritional deficiencies. The geometric means of folate and iron intakes were below the RDA which means that >50% of our study population is at risk of folate and iron deficiency. Although this may not lead to clinical symptoms, the risk of spina bifida in the offspring may increase when nutritional needs increase. It is important to realize that the values estimated by our FFQ are not absolute values; therefore, they have to be carefully compared and interpreted in relation to the RDA values. During the last 3 years, the Dutch RDAs have been revised and several guidelines were changed. Because our study population was determined before the revision of some RDA values, we used the old guidelines. For completeness, we have added the new RDAs as a footnote to Table 2.
Maternal niacin intake 
15.7 mg/d was associated with a 2.5-fold (95% CI: 1.2–5.2) increased risk of spina bifida in the offspring. It is noteworthy that the increased risk is observed at a niacin intake slightly above the RDA. This may indicate that the RDA for niacin intake in women of reproductive age, 17 mg/d during pregnancy, is insufficient. The relatively low niacin intake in mothers of offspring with spina bifida may be explained in part by the lower bread consumption. Closer investigation of the intakes of the other B vitamins suggests that the overall intake of B vitamins tended to be lower in case mothers than in controls (P = 0.11). Although the underlying mechanism of niacin on closure of the neural tube is not clear, the effect of niacin shortage on cholesterol-lipoprotein metabolism may be of interest in this regard (34). In experimental studies, pregnant knockout mice lacking a specific enzyme involved in the pathway of the biosynthesis of cholesterol exhibited severe growth retardation and defective closure of the neural tube in the offspring (35). In humans, inborn errors of cholesterol metabolism have been associated with abnormal development of the brain such as a 7-dehydrocholesterol reductase deficiency (36). Therefore, polymorphisms in related genes may contribute to the development of spina bifida.
A deficient iron intake of <12.6 mg/d was associated with a 3.5- to 4.6-fold increased risk of spina bifida. Although nonpregnant women may not suffer from clinical symptoms due to deficient iron intake, it may well become a problem during pregnancy when the needs are greatly enhanced. This is supported by the frequently observed microcytic anemia in the 2nd and 3rd trimesters of pregnancy. Iron deficiency present in the first trimester may therefore play a role in the pathogenesis of spina bifida, although literature relating dietary iron intake and spina bifida is scarce.
Maternal magnesium intake of <378 mg/d was associated with a 2- to 3-fold higher risk of spina bifida in the offspring. Although the RDA for magnesium seems appropriate for nonpregnant women, a higher magnesium intake during pregnancy may prevent spina bifida. Shaw et al. (22) showed a 0.7 lower risk of neural tube defects in mothers with a magnesium intake > 258 mg/d. In the present study, an OR of 0.9 was observed in mothers with an intake > 407.4 mg magnesium/d. The difference between the 25% cutoff values of control mothers in our study and that of Shaw et al. (22) is striking: <330 mg and <258 mg of magnesium, respectively. Differences in nutritional habits and lifestyles between the investigated countries and populations may explain these findings.
Although these data are informative, the following limitations of this study have to be addressed. First, FFQs give an average intake over a long time period, and aberrations in individual nutritional patterns will therefore not severely influence the results. Our assumption was that the nutritional pattern is rather constant and is influenced by episodes of illnesses, dieting, and increased needs due to pregnancy and breastfeeding. This was confirmed by 2 studies in which nutrition, the continuity and change in women’s weight, and lifestyle practices through pregnancy and the postpartum period were studied (26,27). If nutritional changes occurred in our study, this would have affected the nutritional "biochemical" variables. In a longitudinal pregnancy study, we measured serum myo-inositol and glucose and RBC zinc concentrations at various time points before, during, and after pregnancy. The preconceptional values and those determined 24 mo after the index pregnancy, as a part of the present study, were not significantly different (23). In another longitudinal pregnancy study (37), we determined folate concentrations in serum and RBC preconceptionally and in the study described by Van Rooij et al. (38), months after the index pregnancy. The folate concentrations were comparable at both time points, again supporting our hypothesis. In addition, Riboli et al. (25) demonstrated reasonable correlations between FFQ data determined at baseline and 2–4 y later in a subgroup of women enrolled in the NYU Women’s Health Study. By definition, the data collected by the FFQ are semiquantitative, meaning that although the high and low differences can be distinguished, the exact difference is measured with moderate precision. This implies that the associations observed in this study are likely to be stronger. The inferences drawn from Table 3 may be slightly biased because of the categorization of the exposure from a continuous variable that is subjective to measurement error (39). We therefore recalculated the risk of spina bifida in the offspring by using the continuous nutrient intakes according to Flegal et al. (39). The results of this analysis were in line with the categorized approach (data not shown) and strengthen the observed gradual effect of nutrient intake and spina bifida risk. It was shown that deranged folate metabolism is associated with spina bifida (14). Alcohol abuse, smoking, and oral contraceptive use decrease folate status and increase plasma homocysteine concentrations, which may be the result of impairment of the activity of folate reductase or methionine synthase or by induction of folate clearance (40,41). Based on data in Table 3, we conclude that these factors did not confound the results.
The intakes of many nutrients are correlated (42). Simultaneous adjustment of the intake of 1 nutrient for all others may lead to difficulties in interpretation due to multicollinearity. To overcome this problem, we calculated summary measures for macronutrients, minerals, and vitamins by summing Z-scores. These Z-scores revealed that case mothers had lower mineral and vitamin intakes than controls. In addition, we investigated the association of nutritional intake and spina bifida risk by comparison of ratios between nutrients to reveal differences in food patterns. The ratios suggested that case mothers had higher intakes of animal proteins and mono- and disaccharides compared with controls, which may reflect an imbalance of macro- and micronutrients intakes.
In summary, mothers of a child with spina bifida had lower intakes of iron, magnesium, and niacin compared with controls. Overall intakes, however, were comparable to the Dutch FCS and RDA except for the intakes of iron and folate. These findings strengthen the advice that women of child-bearing age should consume a balanced diet, rich in vegetables and fruits. In addition, this study shows the importance of periconceptional use of folic acid supplements because the average Dutch diet does not provide adequate amounts of this nutrient.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: FCS, Food Consumption Survey; OR, odds ratio; RDA, Recommended Daily Allowances.
Manuscript received 22 October 2003. Initial review completed 9 December 2003. Revision accepted 11 March 2004.
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LITERATURE CITED |
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