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American Journal of Epidemiology Advance Access originally published online on March 14, 2008
American Journal of Epidemiology 2008 167(10):1164-1170; doi:10.1093/aje/kwn035
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American Journal of Epidemiology © The Author 2008. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

ORIGINAL CONTRIBUTIONS

Maternal Dietary Intake of Vitamin A and Risk of Orofacial Clefts: A Population-based Case-Control Study in Norway

Anne Marte W. Johansen1, Rolv T. Lie2, Allen J. Wilcox3, Lene F. Andersen1 and Christian A. Drevon1

1 Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
2 Department of Public Health and Primary Health Care, Section for Epidemiology and Medical Statistics, University of Bergen, Bergen, Norway
3 Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, NC

Correspondence to Anne Marte Wetting Johansen, Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1046, 0316 Oslo, Norway (e-mail: a.m.w.johansen{at}medisin.uio.no).

Received for publication October 16, 2007. Accepted for publication January 28, 2008.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
A population-based case-control study was carried out in Norway between 1996 and 2001. The aim was to evaluate the association between maternal intake of vitamin A from diet and supplements and risk of having a baby with an orofacial cleft. Data on maternal dietary intake were available from 535 cases (188 with cleft palate only and 347 with cleft lip with or without cleft palate) and 693 controls. The adjusted odds ratio for isolated cleft palate only was 0.47 (95% confidence interval: 0.24, 0.94) when comparing the fourth and first quartiles of maternal intake of total vitamin A. In contrast, there was no appreciable association of total vitamin A with isolated cleft lip with or without cleft palate. An intake of vitamin A above the 95th percentile was associated with a lower estimated risk of all isolated clefts compared with the 40th–60th percentile (adjusted odds ratio = 0.48, 95% confidence interval: 0.20, 1.14). Maternal intake of vitamin A is associated with reduced risk of cleft palate only, and there is no evidence of increased risk of clefts among women in our study with the highest 5% of vitamin A intake.

case-control studies; cleft lip; cleft palate; diet; Norway; pregnancy; vitamin A

Abbreviations: CI, confidence interval; OR, odds ratio


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Orofacial clefts are among the most prevalent birth defects worldwide, and Norway has a relatively high incidence (1). The emotional, medical, and economic costs are significant for the affected families and for the society. Cleft palate only and cleft lip with or without cleft palate are considered to be etiologically distinct types of clefts, because of embryonic and anatomic findings and distinct familial recurrence patterns (2). The etiology of clefting is multifactorial and complex, and most infants with clefts do not have additional malformations (3).

Previous studies of the influence of maternal diet on the prevalence of orofacial clefts have focused mainly on intake of folic acid and multivitamins. Several studies have demonstrated a protective effect of folic acid from supplements and folate from the diet (4, 5).

A recent article from the same study (5) showed that a daily intake of 400 µg or more of folic acid reduced the risk of isolated cleft lip with or without cleft palate by one third. A review of the effect of folic acid-containing multivitamins on congenital anomalies found a risk reduction of orofacial clefts in six of seven case-control studies (6). Riboflavin and niacin, iron, zinc, and the amino acids choline, methionine, and cysteine have also been reported to be associated with reduced risk of clefting (7, 8).

Vitamin A is known to play a crucial role in fetal development (9). Deficient and excessive intakes of vitamin A increase the risk of birth defects in animals as well as humans (4). The adult Norwegian population has a relatively high intake of vitamin A from diet and supplements (10); pregnant women are advised to take cod liver oil, a supplement that contains retinol. The epidemiologic studies of teratogenic effects have not been able to establish a threshold above which vitamin A is harmful. However, the body of evidence suggests that a vitamin A intake below 3,000 µg (10,000 IU)/day is safe. Some have argued that vitamin A intake up to 9,000 µg (30,000 IU)/day represents safe levels as well (11, 12).

We used data from a population-based case-control study to evaluate the association between maternal intake of vitamin A from diet and supplements and risk of having a baby with an orofacial cleft.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
All infants born in Norway with facial clefts are treated at government expense at plastic surgery centers located in Oslo and Bergen. In collaboration with these two surgical centers, we identified all babies born from 1996 to 2001 who were referred for treatment for either cleft lip with or without cleft palate or cleft palate only. Control subjects were recruited in the same period by randomly selecting four births per thousand from the National Medical Birth Registry covering all births in the country. These served as controls for both case groups, with the target of two controls per case of cleft lip with or without cleft palate (nearly four controls for each case of cleft palate only). Our present study was approved by a local ethics review board, the Norwegian Data Inspectorate, and the National Institute of Environmental Health Sciences Institutional Review Board. All the participating mothers provided informed consent.

Participants
There were 676 women in Norway who delivered infants requiring surgery for orofacial clefts during 1996–2001. We excluded 24 mothers who did not speak Norwegian or whose infant died after birth, leaving 652 eligible mothers. Of these, 88 percent (n = 573) agreed to participate in this study. We randomly selected 1,022 control mothers of livebirths via the national Medical Birth Registry within 6 weeks of delivery. After excluding 16 who were not Norwegian speakers or whose infant died, 1,006 control mothers were eligible, of whom 76 percent (n = 763) agreed to participate. Data on dietary intake were available for 93 percent (n = 535) of participating case mothers and 91 percent (n = 693) of participating control mothers (82 percent of eligible cases and 69 percent of eligible controls).

Data collection
Mothers completed a mailed questionnaire covering demographic characteristics, reproductive history, and exposures during pregnancy (including smoking, alcohol, medication, and occupational and household exposures). The median time from delivery to completion of the main questionnaire was 14 weeks for cases and 15 weeks for controls. After completing the main questionnaire, mothers were mailed a quantitative food frequency questionnaire. The 11-page questionnaire was designed to capture patterns of food intake among adults during the previous year; we customized the questionnaire slightly for women of reproductive age. The questionnaire includes questions on the frequency and amount eaten for about 180 food items grouped according to the Norwegian meal pattern. The questionnaire also includes questions about the frequency of use and dosage of seven types of dietary supplements, four of which contain vitamin A (cod liver oil, cod liver oil capsules, fish oil capsules, and multivitamins) and the rest of which do not (mineral mixtures, vitamin C, vitamin E, and iron). The original questionnaire has undergone tests of validity and reliability among several groups of Norwegian adults (13–15). The participants were asked to recall their diet during the first 3 months of pregnancy. English translations of the questionnaires are available online (dir.niehs.nih.gov/direb/studies/ncl/question.htm).

We used three data sources to identify the presence of other birth defects among the clefts cases: the Medical Birth Registry (based on delivery records and hospital records during the first week of life), medical records at the hospital performing the corrective surgery, and the mother's questionnaire.

Calculations of dietary intake
Data on dietary intake were entered by scanning, with the Teleform program, version 6.0 (Datascan, Oslo, Norway). Daily intakes of foods, energy, and nutrients were computed by use of a food database and software system developed at the Department of Nutrition, University of Oslo. The food database is based mainly on the official food composition table 16, which is continuously supplemented with data on new food items and nutrients. Calculations of nutrient intake were adjusted for losses during cooking. Vitamin A in the diet was estimated through "retinol equivalents," calculated as dietary retinol plus one twelfth of the estimated beta-carotene intake. Vitamin A from supplements consisted of retinol only.

Statistical methods
Maternal energy intake, age, height, weight, body mass index, and vitamin A intake were compared by use of the Student t test. Differences in educational level, father's income, employment, smoking, frequency of other birth defects, and supplement use were evaluated with {chi}2 tests. Dietary vitamin A intake was categorized in quartiles based on the distribution among controls. The risk of having an offspring with an orofacial cleft was estimated by odds ratios with 95 percent confidence intervals for each quartile of nutrient intake, with the lowest quartile as a reference category in an unconditional logistic regression model. Trends across the quartiles were evaluated, with the first quartile (lowest) as the reference. Potential adverse effects of a high vitamin A intake on the estimated risk of cleft lip with or without cleft palate and cleft palate only were evaluated by comparing a high intake (>95th percentile) with a median intake (40th–60th percentile). The percentiles used to define levels of intake were based on the distribution of intake among controls. Adjustments were made for potential confounders, that is, father's income (ordinal linear with six categories), mother's education (categorized as less than high school and high school or more), mother's employment in early pregnancy (yes or no), mother's consumption of alcohol in early pregnancy (abstained in early pregnancy or not), mother's smoking (ordinal linear with five categories; none, passive only, 1–5, 6–10, and ≥11 cigarettes per day), dietary folate (continuous), folic acid supplement (400 µg/day, yes or no), energy intake (continuous), and year of birth. Because cleft lip with or without cleft palate and cleft palate only are considered to be two etiologically distinct categories of cases, we conducted separate analyses for each category. Separate analyses were also performed for isolated clefts (i.e., excluding those with accompanying defects). Because oral clefts are relatively rare birth defects, odds ratios are close approximations of relative risks. All statistical analyses were performed with SPSS, version 14.0, software (SPSS, Inc., Chicago, Illinois).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Data on dietary intake were available for 693 mothers of controls and 535 mothers of cases (347 in the cleft lip with or without cleft palate category and 188 in the cleft palate-only category). Subgroup analysis was carried out for isolated clefts, comprising 287 cases of cleft lip with or without cleft palate and 115 cases of cleft palate only. Table 1 shows the characteristics of mothers and fathers of cases and controls. Mothers in the cleft lip with or without cleft palate category were taller, had less education, had a lower vitamin A intake, and were more likely to be smokers or unemployed during the first trimester, as compared with the control group. The frequency of other birth defects was 39, 17, and 5 percent among infants with cleft palate only, cleft lip with or without cleft palate, and controls, respectively. Mothers in the isolated cleft palate only category had lower energy and vitamin A intakes, whereas mothers in the isolated cleft lip with or without cleft palate category used folic acid or multivitamin supplement less frequently and were more often smokers compared with the controls. As presented in table 2, cod liver oil, liver paste, carrots, and multivitamin supplements were the main contributors to vitamin A. Cod liver oil alone contributed 21 percent of total vitamin A intake on average, whereas liver paste, carrots, and multivitamins provided 17, 12, and 11 percent, respectively.


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  		TABLE 1. Characteristics of mothers and fathers of cases and controls, Norway, 1996–2001{dagger}

 

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  		TABLE 2. Main dietary sources of total vitamin A intake, Norway, 1996–2001*{dagger}

 
Table 3 shows the odds ratio of having an infant with orofacial cleft for each quartile of maternal vitamin A and beta-carotene intake. The highest quartile of vitamin A intake was associated with a reduced odds ratio of isolated cleft palate only compared with the lowest quartile (adjusted odds ratio (OR) = 0.47, 95 percent confidence interval (CI): 0.24, 0.94). There was a dose-dependent reduction in risk with increasing intake of vitamin A in all three subanalyses of cleft palate only (table 3).


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  		TABLE 3. Crude and adjusted odds ratios and 95% confidence intervals for the association between maternal total intake of vitamin A (diet and supplements) and beta-carotene (diet) in early pregnancy and orofacial clefting in the offspring, Norway, 1996–2001

 
When comparing the highest with the lowest quartile of beta-carotene intake, the odds ratio of isolated cleft palate only was reduced by 49 percent (adjusted OR = 0.51, 95 percent CI: 0.26, 0.97). The adjusted analyses of beta-carotene suggested a dose-response trend (ptrend = 0.10) (table 3). The trend was stronger for retinol alone (ptrend = 0.05) (data not shown). There was a slight association of vitamin A with the crude risk of cleft lip with or without cleft palate but no evidence of dose response in the adjusted analysis (p = 0.59).

Table 4 shows the odds ratio of having an infant with an orofacial cleft for women in the highest 5 percent of vitamin A, retinol, and beta-carotene intake (>95th percentile) compared with median intake (40th–60th percentile). Women in the highest group had an intake of vitamin A exceeding 3,763 µg (12,518 IU). The high-intake category of vitamin A was still associated with a lower estimated risk of all isolated clefts (adjusted OR = 0.48, 95 percent CI: 0.20, 1.14). The adjusted odds ratio was 0.51 (95 percent CI: 0.19, 1.38) for isolated cleft lip with or without cleft palate and 0.34 (95 percent CI: 0.07, 1.68) for isolated cleft palate only. When comparing a high with a median intake of retinol and beta-carotene separately, we found that the adjusted odds ratios of all isolated clefts were 0.40 (95 percent CI: 0.15, 1.02) and 0.41 (95 percent CI: 0.17, 0.97), respectively (table 4).


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  		TABLE 4. Crude and adjusted odds ratios for the association of a high compared with a medium intake of total vitamin A, retinol, and beta-carotene and isolated clefts, Norway, 1996–2001*

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
Our data show a substantial protective association between high maternal intake of vitamin A and risk of cleft palate only in her offspring. Vitamin A intake in the highest quartile reduced the risk of cleft palate only by half compared with an intake in the lowest quartile. The crude risk of cleft lip with or without cleft palate was more weakly associated with vitamin A intake; adjustment for covariates removed the risk altogether. The contrasting effects of vitamin A intake on the two types of clefts are in line with evidence that cleft palate only and cleft lip with or without cleft palate are etiologically distinct forms of clefting (5). The two subgroups of clefts rarely occur in the same family, suggesting separate genetic etiology (16). An analysis from the same study found that maternal intake of folic acid supplement reduced the odds ratio of cleft lip with or without cleft palate but not for cleft palate only (5), indicating different environmental sensitivity. Moreover, fusion of the lip and the palate takes place at different time points during the embryonic development (3), also suggesting that there might be different underlying mechanisms and causal factors.

Additional analysis failed to show any evidence of increased risk among women getting the highest quantities of vitamin A. An intake above the 95th percentile reduced the odds ratio of all isolated clefts by approximately 50 percent compared with a median intake. Separate analyses of retinol and beta-carotene both showed that the highest intake reduced the odds ratio of having a baby with isolated clefts.

It has previously been suggested that a maternal intake of retinol above 3,000 µg (10,000 IU) may be harmful for the fetus (17), while others have argued that an intake up to 9,000 µg (30,000 IU) is safe (11, 12). We find no evidence of an increased risk of clefting with an intake of total vitamin A or retinol of more than 3,000 µg (10,000 IU). As shown in table 4, all odds ratios were reduced when comparing a high with a median intake of vitamin A, retinol, or beta-carotene. The low number of cases in the high-intake category and the many variables included in the analyses produce wide confidence intervals.

Rothman et al. (17) found a 3.5-fold increase in risk of birth defects associated with cranial-neural-crest tissue when comparing a retinol intake of more than 4,500 µg from diet and supplements with an intake of less than 1,500 µg. An intake exceeding 3,000 µg from supplements alone increased the risk 4.8-fold compared with an intake below 1,500 µg (17). In our data, the mean intake of retinol from supplements (477 µg) accounts for approximately one third of the total intake of retinol (1,210 µg) and is thus of less importance than dietary retinol for the total intake of retinol. Only two individuals had an intake of retinol from supplements exceeding 3,000 µg, which made it unfeasible for us to replicate the analysis of Rothman et al. However, we were able to compare an intake of more than 3,000 µg of retinol from diet and supplement with an intake of less than 1,500 µg, the cutoffs Rothman et al. used with retinol from supplement. In this comparison, the risk of all isolated clefts (all cases) was still substantially lower in the high exposed category (OR = 0.55, 95 percent CI: 0.33, 0.92). However, the mean intake in the highest category was considerably lower in our study than in that of Rothman et al. (17). The different findings can also be due to differences in bioavailability. The lipid-soluble retinol present in diet and supplements in Norway is more slowly bioavailable than the water-soluble retinol in the American study (18). In addition, Rothman et al. (17) studied a broader range of birth defects and did not present results for vitamin A intake and orofacial clefts specifically.

A case-control study by Mitchell et al. (19) found an association of high intake of vitamin A from liver with reduced risk of cleft lip with or without cleft palate but not cleft palate only. After adjustments for multivitamin intake, the association of vitamin A was weakened. They estimated intake of vitamin A from liver products and multivitamins only and included fewer cases (n = 302) than in our present study (n = 535) (19).

Several other case-control studies have evaluated the teratogenic effect of retinol from supplements. A large population-based case-control study concluded that low-to-moderate doses of vitamin A (<3,000 µg) from supplements did not increase the risk of birth defects but, rather, provided a protective effect (20). Two other studies reported a possible increase in risk of malformations (21, 22), although these studies were short of statistical power. Finally, three studies found no increase in risk of orofacial clefts or other major birth defects with exposure to retinol from supplements (23–25).

Our study has the strength of being population based with a high participation rate among cases and controls. Moreover, the study population is relatively homogeneous, and the sample size is large compared with previous studies. Potential confounding factors such as maternal smoking and folic acid intake were included in the logistic regression model. Adjusted odds ratios differed only slightly from the unadjusted odds ratios. The food frequency questionnaire we used to assess the diet has been extensively validated and is designed to give detailed information on total dietary intake. The questionnaire was sent out 3–4 months postpartum, which is a relatively short time after the birth of the index child and might improve recall accuracy.

The participation rate was, however, somewhat higher among cases than among controls. This may reflect differential participation and creates the possibility of selection bias. Recall may also have been different between case mothers and control mothers. However, it is not likely that these potential biases would appear in analyses of cleft palate only but not in analyses of cleft lip with or without cleft palate. In the analysis of folic acid intake using data from the same study, there was an association between intake of folic acid and cleft lip with or without cleft palate, but not for cleft palate only. Thus, a bias in our information on dietary intake does not appear to affect a specific case category.

Adjustment for energy intake was carried out by including energy intake as a continuous variable in the regression model. Relative adjustment methods such as the residual method (26) were discussed but not preferred, because we considered the absolute intake of vitamin A to be more biologically relevant for fetal development.

The protective association of vitamin A with cleft palate might be explained by vitamin A itself, by closely associated nutrients, or by a generally healthier diet. Vitamin A consists of retinol and beta-carotene. Retinol is found in animal products such as meat, liver, margarine, and cheese, which are rich in protein and fat, while beta-carotene comes from vegetables (table 2). We did not observe any effect of either total fat, types of fat, or protein intake on the risk of developing cleft palate only. There was no substantial association of cleft palate with intake of vegetables after adjustments for vitamin A intake. On the basis of the role of vitamin A in cell growth and differentiation, combined with the evidence that both deficient and excessive amounts of retinoic acid cause congenital malformations in experimental animals, it seems likely that vitamin A plays an independent role in the pathogenesis of cleft palate only, rather than simply being a marker for other nutritional factors.

In summary, our data show that maternal vitamin A intake from diet and supplements is associated with decreased risk of cleft palate only, with much less evidence for an association with cleft lip with or without cleft palate. Moreover, there is no increased risk of clefting by a vitamin A intake above the 95th percentile (3,763 µg). Thus, eating foods rich in vitamin A during early pregnancy may be essential for fetal health and should not be discouraged.


   ACKNOWLEDGMENTS
 
The work was funded by the Research Council of Norway (166026/V50); the Freia Foundation; the Throne-Holst Foundation; and the thematic area of perinatal nutrition, Faculty of Medicine, University of Oslo, Oslo, Norway.

The authors thank Dr. Kari Solvoll for taking part in the planning and work with the dietary assessment.

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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