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Maternal Nutritional Status and the Risk for Orofacial Cleft Offspring in Humans1,2

November 27, 2004

ABSTRACT

Periconceptional folate and folic acid intake prevents orofacial clefts (OFC) in the offspring. It has been suggested that other nutrients also play a role. We investigated the preconceptional intake of macronutrients (protein, fat, carbohydrate, fiber, and cholesterol), vitamins (vitamin A, retinol, β-carotene, ascorbic acid, and α-tocopherol), minerals (calcium, phosphorus, iron, magnesium, and zinc) and food groups in mothers of OFC children and controls. At ~14 mo after the index pregnancy, 206 mothers of a child with a nonsyndromic OFC and 203 control mothers completed a FFQ on current food intake and a general questionnaire. After exclusion of pregnant and lactating mothers, mothers who reported a change in diet compared with the preconceptional period, and those for whom periconceptional folic acid supplement use was unclear, 182 OFC mothers and 173 control mothers were evaluated. Macronutrient, vitamin, mineral, and food group intakes were compared. After adjustment for energy, quintiles of dietary nutrient intake and odds ratios with 95% Cl were calculated. The preconceptional intake of all macronutrients, vitamins, minerals, and food groups with the exception of milk (products), potatoes, pies/cookies were lower in OFC mothers than in controls. The energy- adjusted intakes of vegetable protein, fiber, β-carotene, ascorbic acid, α-tocopherol, iron, and magnesium were significantly lower in cases compared with controls. Increasing intakes of vegetable protein, fiber, ascorbic acid, iron, and magnesium decreased OFC risk. In conclusion, a higher preconceptional intake of nutrients predominantly present in fruits and vegetables reduces the risk of offspring affected by OFC. J. Nutr. 134: 3106-3113, 2004.

KEY WORDS: * ascorbic acid * cleft * iron * magnesium * nutrition

Orofacial clefts (OFC)5 are common birth defects in humans, occurring in 1-2/1000 live births. Its pathogenesis is multifactorial in that both genetic and lifestyle aspects such as nutrition are involved (1). Since the early 20th century, nutritional deficiencies have been associated with OFC in humans (2). Nutritional intake is related to socioeconomic status and the increased frequency of OFC among the offspring of less educated women emphasizes the importance of maternal nutritional status on reproductive outcome (3).

To date, research on the association between the maternal nutritional status and OFC risk has focused mainly on multivitamin and folic acid supplementation (4,5). Recently, van Rooij et al. (6,7) demonstrated that not only folic acid from supplements but also food folate significantly lowered the risk of OFC offspring. Our group also demonstrated that the dietary intake of several B vitamins and RBC zinc concentrations were significantly lower in mothers of OFC children compared with controls (8,9). Protective effects on OFC risk have been attributed to foods rich in β- carotene in humans (10), whereas a dietary excess of fat was postulated to potentiate the cleft palate-inducing effect of triamcinolone in mice (11). Maternal hyperglycemia and also low calcium concentrations are suggested to play a role in OFC pathogenesis (12,13). Of interest is that both low and high concentrations of vitamin A (14,15) and cholesterol (16,17) interfere with palatogenesis.

Research on other nutrients and OFC risk is not available. Neural tube defects (NTD) share similarities in the pathogenesis of OFC because both birth defects originate from disturbances in which neural crest cells are involved. Therefore, it is conceivable that nutritional factors implicated in NTD pathogenesis also apply to OFC. Groenen et al. (18) demonstrated that a low maternal dietary intake of vegetable protein, fiber, magnesium, and iron increased the risk for spina bifida 2- to 5-fold. A report of Shaw et al. (19) suggested a protective effect of a magnesium intake > 258 mg/d. In addition, the antioxidant α-tocopherol decreased the occurrence of valproic acid- and hyperglycemia-induced neural tube defects in mice (20,21). The aim of the current study was to investigate whether maternal preconceptional nutritional intake is associated with OFC in the offspring.

SUBJECTS AND METHODS

We performed a case-control study at the Department of Epidemiology and Biostatistics of the University Medical Center Nijmegen in Nijmegen in the Netherlands from 1998 to 2001. This study was described in detail by Van Rooij et al. (6,7). Mothers (n = 206) of a child with a nonsyndromic OFC were recruited in collaboration with the 9 largest cleft lip and palate centers ~14 mo after the delivery of the index child; 203 mothers who had a healthy child of the same age and unrelated to the cases served as controls. They were recruited in the population domain of the case group, through acquaintances, friends, or neighbors of the mothers of OFC children and through public nurseries and health care centers. Mothers who were known to be pregnant, lactating, or those who reported a change in the diet since the preconceptional period were excluded for analysis. Also excluded were those whose folic acid supplement use during the periconceptional period was unclear. Thus, 182 OFC and 173 control mothers (59.5% recruited by the cases, e.g., acquaintances, friends, and neighbors of mothers of OFC children and 40.5% by public nurseries and health care centers) were evaluated. The OFC group was made up of 153 mothers of a child with a cleft lip with or without cleft palate (CLP) and of 29 mothers of a child with a cleft palate only (CPO). Case and control mothers were all Dutch Caucasians. The Medical Ethical Committees of all participating hospitals approved the study protocol and written informed consent was obtained from every participant.

Dietary intake was assessed using a validated FFQ developed for the Dutch cohorts of the European Prospective Investigation into Cancer and Nutrition (EPIC) study (22,23). The FFQ accounted for at least 90% of the population mean intake of food groups and nutrients of interest. We collected the dietary intake data ~14 mo after the delivery of the index child. At that time, the diagnosis of the child with nonsyndromic OFC had been confirmed. Our assumption was that nutritional habits in general are rather constant, with the exception of periods of dieting and periods with increased needs such as pregnancy and lactation. The validity of the data are strengthened by the time at which the FFQ was filled out, i.e., ~14 mo after the birth of the index child, which is 24 mo after the preconceptional period and in the same season of the year as the preconceptional period.

The FFQ was mailed to the subjects and filled out at home. In the FFQ, subjects could indicate their answers in frequency per day, per week, per month or per year, or never. For several food items, additional questions were asked about the frequency of consumption and preparation methods, including the addition of condiments and spices. The amount consumed was estimated in commonly used units by using household measures or colored photographs of foods showing different portion sizes. During the hospital visit at the University Medical Center Nijmegen or through a telephone interview, we verified the completeness and consistency of the FFQ in a standard way. Mean daily nutrient intake was estimated by multiplying the frequency of consumption of the food items by the portion size and the nutrient content per gram. Total energy intake, the intake of macronutrients, vitamins, minerals, and food groups were calculated by using the computerized version of the 1996 Dutch food composition table (24). A validation study of our questionnaire demonstrated that the reproducibility and validity of food groups and nutrients was acceptable and comparable to other FFQs (22,23).

Furthermore, all mothers filled out a general questionnaire from which data such as age, education, nausea and/or vomiting in the first trimester of pregnancy, parity, previous OFC children, and periconceptional lifestyle factors such as smoking, alcohol consumption, and the use of vitamins were extracted. The periconceptional period was defined as the period 3 mo before until 3 mo after the conception of the index child. Education was categorized into low (primary/lower vocational/intermediate secondary/intermediate vocational) and high education (higher secondary/higher vocational, or university). Nausea was characterized by duration, period, and severity. Because of the potential influence on dietary intake, severe nausea and/or vomiting was defined as starting after wk 1 of pregnancy and resulting in a change or decrease in food intake. Mothers were considered smokers or to consume alcohol during the periconceptional period when any smoking (cigarettes, cigars, or pipe) or alcohol consumption was reported. Data on vitamin supplements comprised information on the contents (folic acid only or multivitamins), dosage, frequency of intake, and specification in which weeks the supplements were taken before and during pregnancy. The periconceptional use of supplements was defined as the daily intake from 4 wk before through 8 wk after conception of the index pregnancy.

Stat\istical methods. Maternal age at delivery and age of the child at the time of study are presented as means SD and compared between the groups using Student’s t tests. Significant differences in frequency of a low level of maternal education, severe nausea and/ or vomiting in the first trimester of pregnancy, parity and periconceptional lifestyle factors such as smoking, the consumption of alcohol and the use of nutritional supplements were tested using χ^sup 2^ tests. When the tables of the variables contained cells with expected counts

Vitamin A retinol equivalents were computed as retinol + (β- carotene/6) and the intake of unsaturated fat by adding the amounts of monounsaturated and polyunsaturated fat consumed. The distributions of most food groups and nutrients were positively skewed. The skewness of the data on food groups remained after logarithmic transformation. Therefore, we present these data as medians with 5th and 95th percentiles, and the difference between cases and controls were evaluated by Wilcoxon’s rank-sum tests. The macronutrient, vitamin, and mineral intakes were log-transformed and presented as geometric means with 5th and 95th percentiles, and differences between cases and controls were evaluated by Student’s t tests.

We used the nutrient residual method to adjust for total energy intake as described by Willet et al. (25). 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 (9186 kJ/d). 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 evaluated using Student’s t tests.

For the nutrients that remained significantly different between cases and controls after energy adjustment, quintiles of the dietary intake were computed from the continuous variables of the control mothers. The risk for OFC offspring was estimated by odds ratios (OR) and 95% CI for each quintile of dietary intake of the nutrient with the lowest quintile as a reference in an unconditional logistic regression model. Trends across the quintiles were evaluated, in which the quintiles were modeled after inclusion of the continuous variables in 5 categories ranging from 1 (Reference) to 5 (highest quintile of dietary intake). Adjustments were made for potential confounders such as maternal age and periconceptional smoking, alcohol, and folic acid supplement use by logistic regression analyses. We did not adjust for maternal body mass, because it was not feasible to collect valid data on body weight and length by standardized measurements for all participants.

Because CLP and CPO are considered etiologically to be 2 distinct diagnostic entities, we conducted separate analyses for both types of clefts. Because periconceptional vitamin supplement use and especially folic acid supplementation is suggested to reduce OFC, we also performed a stratified statistical analysis for periconceptional folic acid supplement use.

Differences were considered significant when P ≤ 0.05. All statistical analyses were performed using SAS Statistical Analysis System version 6.12 (SAS Institute).

RESULTS

The educational level was significantly lower in mothers of OFC children, who tended to use less folic acid supplements than controls (P = 0.07) (Table 1). Three OFC mothers had a previous liveborn OFC-affected child (Fisher’s Exact Test, 2-tailed P = 0.25). The dietary intake of energy, all macro-nutrients, vitamins, and minerals was lower in mothers of OFC children than in controls (Table 2). To assess the adequacy of the maternal diet during the period of data collection (1998-2000), the dietary intakes were compared with the most recent Dutch recommended daily allowances (RDAs) for nonpregnant women in the reproductive age (26-28). The RDAs used for energy, protein, and saturated fat were established in 2001 (26), those for calcium in 2000 (27), and those for fiber, vitamin A, ascorbic acid, α-tocopherol, phosphorus, iron, magnesium, and zinc in 1989 (28). The nutrient intake levels were compared with the data of the Dutch food consumption survey (FCS) held in 1997-1998 (29) for nonpregnant women aged 22-50 y. With the exception of energy, saturated fat, fiber, and iron, all geometric mean dietary intakes met the RDAs and were in line with the Dutch FCS 1997-1998. In cases and controls, the geometric mean dietary intake of energy, fiber, and iron were below the RDA, whereas the percentage of energy derived from saturated fat (15%) exceeded the Dutch recommendation of 10% (26). After adjustment for energy intake, the dietary intake of vegetable protein (P = 0.002), fiber (P = 0.0005), β-carotene (P = 0.04), ascorbic acid (P = 0.008), α-tocopherol (P = 0.04), iron (P = 0.002), and magnesium (P = 0.004), remained significantly different in mothers of OFC children compared with controls. On the food group level, cases had lower intakes of vegetables (P = 0.04), eggs (P = 0.02), fruit (P = 0.0003), fat (P = 0.009), grain products (P = 0.02), bread (P = 0.06), herbs (P = 0.0003), cheese (P = 0.07), and soy products (P = 0.03) and tended to consume more potatoes (P = 0.08) compared with controls.

TABLE 1

Characteristics of mothers and their children with nonsyndromic OFC and control mothers and their children1

For the energy-adjusted nutrient intakes that demonstrated a significant difference between cases and controls, the risk for OFC was assessed by increasing the nutrient intakes throughout the quintiles. A trend toward decreased OFC risk with increasing dietary intake was demonstrated for vegetable protein (P = 0.004), fiber (P = 0.002), ascorbic acid (P = 0.04), iron (P = 0.008), and magnesium (P = 0.003) (Table 3). The most important risk reductions were observed for ascorbic acid and magnesium above the RDA and for fiber and iron equal to the RDA. Separate adjustment for maternal age, parity, periconceptional smoking, alcohol consumption, or folic acid supplement use altered the odds ratios only marginally.

Although CLP and CPO are 2 separate diagnostic entities with different etiologies, the results for the CLP group were comparable to those from the OFC group. The CPO group differed with significantly lower intakes of meat/poultry (P = 0.04), eggs (P = 0.04), fruit (P = 0.002), and sweets (P = 0.02) compared with the controls. After energy adjustment, the dietary intake of fat (P = 0.05), saturated fat (P = 0.009), cholesterol (P = 0.03), fiber (P = 0.006), iron (P = 0.005), and zinc (P = 0.02) remained significantly different between CPO mothers and controls. The CPO risk decreased with increasing dietary intake of fiber (P = 0.03), saturated fat (P = 0.05), cholesterol (P = 0.05), and iron (P = 0.04).

In a separate stratified analysis for maternal periconceptional folic acid supplement use, all significant trends for a reduced risk for OFC by increasing dietary intake could be demonstrated only in folic acid supplement users, with the exception of vegetable protein. (Table 4). Similar results were obtained for CLP, whereas in the CPO group, no conclusions could be drawn due to the small numbers.

DISCUSSION

This study demonstrates that the preconceptional dietary intakes of energy and all macronutrients, vitamins, and minerals were lower in mothers of OFC children compared with controls. A few differences in nutrient intake could be explained by lower energy intake in mothers of OFC children. After energy adjustment, the intake of vegetable protein, fiber, β-carotene, ascorbic acid, α- tocopherol, iron, and magnesium remained significantly different between the groups. On the food group level, this coincided with lower intakes of vegetables, eggs, fruit, grain products, bread, herbs, cheese, and soy products. The intake of vegetable protein, fiber, ascorbic acid, iron, and magnesium reduced OFC risk with increasing dietary intake. With the exception of vegetable protein, these significant trends toward OFC risk reductions could be demonstrated only in women using folic acid supplements periconceptionally.

With the exceptions of an excess of saturated fat and a relative lack of fiber and iron, the overall diet was adequate for both mothers of OFC children and controls and met the Dutch RDA and FCS of 1997-1998 (26-29). Careful interpretation of these comparisons is warranted because the FFQ categorizes individuals in groups of low or high dietary intake, making it less suitable for comparisons with absolute values. The RDA for energy is based on the mean low activity level of the Dutch adults, which should be taken into account in the interpretation of the results (26). Our data can be extrapolated to the Dietary Reference Intake values used in the United States except for α-tocopherol, which would be considered deficient because the value is higher than the Dutch one (30-33).

TABLE 2

Preconceptional energy and nutrient intake in mothers of nonsyndromic OFC children and control mothers1

The results of this study are in line with recommendations of the Dutch Nutrition Center that emphasize the importance of the consumption of a diet rich in fruit and vegetables. These foods are important sources of essential nutrients and dietary fiber (34). Fiber stimulates the transport of ingested food through the bowel, thereby minimizing the toxic effects of some dietary compounds. Thus, a low intake of fiber could indirectly lead to increased maternal and, subsequently, embryonic and fetal exposure to toxic compounds.

The WHO revealed that in Europe, 10% of women have hemoglobin values below th\e norm before conception (35). This fits with our finding of lower dietary iron intakes in both nonpregnant OFC mothers and controls. A low preconceptional iron status increases the risk for anemia during pregnancy (36). This is of interest because anemia was associated with cleft palate in the offspring of mice (37). Iron is essential for hematopoiesis and nucleic acid metabolism, and it plays a role in multiple enzyme reactions (38,39). A low iron status was also suggested to adversely affect important regulators of growth and development (40). Nutritional sources of iron are meat/poultry, fish, cereals, bread, and green vegetables. Thus, our results also confirm the difficulty women have in meeting their iron requirements by dietary intake. Iron status could be optimized by increasing the bioavailability of food iron or fortifying a food staple with iron. The concerns raised about the risk of cancer and heart disease, especially in individuals with high iron stores support the current recommendation to meet dietary iron requirements and not to exceed them (41).

Magnesium is found mainly in grain products and green vegetables and is essential for energy-requiring processes and the mediation of immune responses. This trace element is also involved in protein synthesis, and membrane and nucleic acid stability (34,42). Ascorbic acid, found mainly in vegetables and fruit is an important antioxidant, but it is also important in the synthesis of collagen, carnitine, and catecholamines, and in the metabolism of cholesterol, lipids, folate, and iron. Moreover, ascorbic acid plays a role in the functioning of detoxification enzymes and in the immune system (34,42). Despite the adequacy of magnesium and ascorbic acid intake in our study groups, an intake above the RDA at 375.9-502.9 and 97.9- 295.8 mg/d, respectively, substantially decreased OFC risk, values that are closer to the RDAs of magnesium (300-360 mg/d) and ascorbic acid (90 mg/d) for pregnant women (28). This may indicate that the RDAs for these nutrients are insufficient for women of reproductive age and further strengthen our recommendation to further optimize maternal nutritional status before conception. Although the toxicity of high dietary intakes of these nutrients is considered to be low, other studies will have to replicate our findings before these results contribute to an evaluation of the RDAs.

Our study has some limitations that must be recognized. We standardized the study moment at ~14 mo after delivery to reflect the preconceptional period of the index pregnancy and assumed that nutritional habits in general remain constant, with the exception of periods of dieting and periods of increased needs such as pregnancy and lactation. Several authors support this assumption. Devine et al. (43) demonstrated that, in general, no difference occurs in dietary patterns between the beginning of pregnancy and 1 y postpartum. Leck et al. (44) showed that RBC folate concentrations in early pregnancy correlated well with those 1 y after delivery. Moreover, Riboli et al. (45) 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. These data are further supported by our studies, in which we demonstrated that nutritional preconceptional biochemical values, including myo- inositol, glucose, zinc, and folate, were not significantly different from those determined ~14 mo after the index-pregnancy (46,47).

TABLE 3

Risk for OFC in offspring in association with the preconceptional dietary maternal intake of several nutrients

Another issue to consider is that the control group were acquaintances, friends, and neighbors of mothers of OFC children (59.5%) and were also recruited from local public nurseries and health care centers (40.5%). The educational level differed substantially between these 2 control groups, i.e., 62.1 and 25.7%, respectively, were poorly educated. We therefore compared the dietary intakes of these control groups separately with the OFC group. When the OFC group was compared with controls recruited by case mothers, an increasing dietary intake of cholesterol significantly reduced OFC risk. The comparison of controls recruited by public health centers and nurseries revealed that higher intakes of vegetable protein, protein, fiber, β-carotene, ascorbic acid, phosphorus, iron, magnesium, and zinc were associated with a decreased OFC risk. Higher intakes of monounsaturated fat, however, increased OFC risk. Although these differences indicate confounding by education in the association between dietary intake and OFC risk, adjustment for education only marginally affected the conclusions. Furthermore, it is not likely that regional differences between OFC mothers and controls as a consequence of the recruitment method significantly affected the results because regional differences in populations are very small in the Netherlands. In addition, confounding was minimized by restriction of the analyses to Dutch Caucasian mothers only.

Although OFC risk reductions were also apparent in the highest quintiles of dietary intake in those not using folic acid supplements, our results merely demonstrated that a trend toward a higher dietary intake of fiber, ascorbic acid, iron, and magnesium particularly reduced OFC risk in periconceptional folic acid supplement users. This may point to a different attitude toward health and nutrition in these mothers. Lyle et al. (48) reported that supplement users are more health conscious and have higher dietary intakes of fiber, thiamin, riboflavin, folate, α- carotene, β-carotene, α-tocopherol, ascorbic acid, iron, and zinc compared with nonsupplement users. Others demonstrated, however, that supplement users were more likely to report physical conditions, which contradicts their suggested superior health (49).

The CLP and CPO are considered to be 2 distinct etiologic entities according to the pioneering work of Fogh-Anderson (50). Most children in our population had a CLP (84%), which probably explains the similar results compared with the total group of OFC. In the CPO group, higher dietary intakes of fiber, cholesterol, iron, and, surprisingly, saturated fat were significantly associated with a decreased CPO risk. Cholesterol is essential for normal embryonic development (51). Offspring from individuals with aberrant cholesterol metabolism, as observed in the Smith-Lemli-Opitz syndrome, have multiple congenital malformations including cleft palate (16). Fat is an important source of the fat-soluble vitamins A, D, α-tocopherol, and K. With the exception of vitamin A, none of these vitamins have been associated with CPO. Thus, the role of saturated fat intake in CPO pathogenesis remains unclear. Due to the rather limited number of CPO cases, however, strong conclusions cannot be drawn and more research should focus on CPO in the future.

TABLE 4

Preconceptional maternal dietary intake of nutrients by periconceptional maternal folic acid supplement use and OFC risk

The data on BMI were known for only 83 OFC mothers and 81 controls. Despite the questionable validity of these data because no standardized measurements were carried out, these OFC mothers had a higher BMI (mean SD: 25.2 4.4 kg/m^sup 2^) compared with controls (23.7 4.4 kg/m ) and a lower energy intake [geometric mean energy intake (5th-95th percentile)] of 8391 (5697-11500) kJ/d compared with controls [8880 (6030-12182) kj/d]. The case mothers were less educated than controls, which has been associated with a higher degree of energy underreporting (52). This could have led to an overestimation of these results. Other factors not evaluated in the current study, such as physical activity, metabolic and genetic background, could also be involved. We dealt with physical activity, BMI, and metabolism to some degree by adjusting the data for energy intake. The frequency of dieting was comparable in OFC mothers and controls. A lower intake of dietary fiber reduces the transfer of nutrients into the gastrointestinal tract, thereby increasing the absorption of nutrients, which may contribute to an increased body weight.

In conclusion, this study demonstrates differences in the dietary intake of energy, macronutrients, vitamins, minerals, and food groups in mothers of OFC children compared with controls. Of particular interest is the protective effect of a higher dietary intake of vegetable protein, fiber, ascorbic acid, iron, and magnesium on OFC risk. These data may suggest that an imbalance between dietary intake of macronutrients, vitamins, and minerals contributes to the pathogenesis of complex birth defects such as OFC. Groenen et al. (18) supported this finding in a similar study focused on spina bifida offspring. This hypothesis should therefore be investigated in more detail and emphasizes that preconceptional counseling of pregnant women toward a healthier lifestyle, which includes a diet rich in plant sources and iron may be important in the prevention of nonsyndromic OFC offspring.

ACKNOWLEDGMENTS

We thank the participating cleft lip and palate teams and their coordinators at the: Rijnstate Hospital Arnhem, Dr. W. Brussel; Free University Hospital Amsterdam and Erasmus MC University Medical Center Rotterdam, Prof. B. Prahl-Andersen; University Medical Center Groningen, Prof. S. M. Goorhuis-Brouwer; Medical Center Leeuwarden, Dr. J. J. van der Biezen; University Medical Center Nijmegen, Prof. A. M. Kuijpers-Jagtman; St. Elisabeth Hospital Tilburg, Dr. J. G. Daggers; University Medical Center Utrecht, Dr. A. M. Mink van der Molen; and Sophia Hospital Zwolle, Dr. P. Houpt. We acknowledge the nurseries and public health centers for their participation in the recruitment of control mothers. We are very grateful to M. van der Doelen and Dr. C. van Oostrom, chief nurse officer and head of the outpati\ent pediatric clinic University Medical Center Nijmegen, respectively, for their assistance, Dr. C. Vermeij-Keers for the opportunity to use the standardized registration form of the OFC of the Dutch Association for Cleft Palate and Craniofacial Anomalies, A. Pellegrino and L. Lemmens for data entry, W. Lemmens for data management, and R. Bretveld, P. Peer, and H. Straatman for their support in the statistical analysis.

0022-3166/04 $8.00 2004 American Society for Nutritional Sciences.

Manuscript received 21 May 2004. Initial review completed 29 June 2004. Revision accepted 2 September 2004.

1 Presented in part at NWO Werkgemeenschap Voeding, Papendal, October 2003, The Netherlands [Krapels, I. (2003) Preconceptional nutritional intake and the risk of schisis]; at the 7th European Craniofacial Congress, November 2003, Bologna, Italy [Krapels, I. P., van Rooij, I., Kuijpers-Jagtman, A.-M., West, C., Ock, M., van der Horst, C. & Steegers-Theunissen, R. (2003) Periconceptional maternal nutrient intake and the risk for orofacial cleft offspring]; and [Krapels, I. P., van Rooij, I., Ock, M. & Steegers- Theunissen,R. (2004) A high preconceptional intake of fruits and vegetables reduces the risk for orofacial clefts in the offspring. J. Soc. Gynecol. Investig. 11 (suppl. 2): 388A (abs.)].

2 Supported by the Royal Netherlands Academy of Arts and Sciences (KNAW), Amsterdam, The Netherlands, 1997.

5 Abbreviations used: CLP, cleft lip with or without cleft palate; CPO, cleft palate only; FCS, food consumption survey; OFC, orofacial cleft; RDA, recommended daily allowance.

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Ingrid P. C. Krapels,*[dagger] Iris A.L.M. van Rooij,* Marga C. Ocke,[double dagger] Clive E. West,**[dagger][dagger]3 Chantai M.A.M. van der Horst,[double dagger][double dagger] and Rgine P. M. Steegers-Theunissen*#4

Departments of * Epidemiology and Biostatistics, [dagger] Orthodontics and Oral Biology and ** Department of Gastroenterology, University Medical Center Nijmegen, Nijmegen, The Netherlands; [double dagger] Department of Chronic Disease Epidemiology, National Institute for Public Health and the Environment, Bilthoven, The Netherlands; [dagger][dagger] Department of Human Nutrition, Wageningen University, Wageningen, The Netherlands; [double dagger][double dagger] Department of Plastic and Reconstructive Surgery, Academic Medical Center Amsterdam, The Netherlands; and # Department of Obstetrics and Gynecology, Erasmus MC University Medical Center, Rotterdam, The Netherlands

3 Deceased.

4 To whom correspondence should be addressed. E-mail: R.Steegers@epib.umcn.nl.

Copyright American Institute of Nutrition Nov 2004




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