Eligible cases were all newborn infants with orofacial cleft defects born in Norway in May 1996 to October 2001 and referred for surgical treatment. In Norway, all surgery for clefts is paid for by the government and takes place at one of two surgical centers (Oslo and Bergen). An infant with a cleft is routinely referred for surgery shortly after birth. Our study office was notified of all referrals, at which time a letter of invitation was sent to the family. We randomly selected controls (with a probability of about 4 per 1,000) from all livebirths recorded in the Medical Birth Registry of Norway from September 1996 to April 2001. Families of selected controls were mailed an invitation to participate. These infants served as controls for both cleft case groups, with control-case ratios of about 2:1 for cleft lip with or without cleft palate and 4:1 for cleft palate. Study materials were in Norwegian; mothers who did not speak Norwegian were excluded. The study was approved by the Norwegian Data Inspectorate, the Regional Medical Ethics Committee of Western Norway, and the Institutional Review Board of the US National Institute of Environmental Health Sciences. Parents provided informed consent.
Mothers completed a self-administered, mailed questionnaire on demographic characteristics, medical history, family history of clefts, cigarette smoking, alcohol consumption, and other exposures during pregnancy. Questions pertaining to maternal exposures and diet were asked specifically for the first 3 months of pregnancy, the relevant exposure period for early facial development. During this time period, the structures that form the embryonic lip and palate fuse: closure of the lip occurs during weeks 5 and 6 postconception, followed by closure of the palatal shelves during weeks 7–10 (15
). Median time from the infant's delivery to the mother's completion of the main questionnaire was 14 weeks for cases and 15 weeks for controls. After returning the main questionnaire, mothers completed a quantitative food frequency questionnaire (16
) on dietary habits during the first 3 months of pregnancy, including the types of alcoholic beverages (beer, wine, and liquor) consumed. The study questionnaires (with English translations) are available online at http://www.niehs.nih.gov/research/atniehs/labs/epi/studies/ncl/question.cfm
Information on noncleft birth defects was collected from three sources: the mother's questionnaire, the infant's medical records at the time of cleft repair surgery, and the Medical Birth Registry, which contains information from the infant's delivery records and hospital records during the first week of life. Cases with any accompanying birth defect or syndrome were categorized as nonisolated.
Information on maternal alcohol consumption was collected for the first 3 months of pregnancy and the time period before the pregnancy. Mothers were asked to recall the average number of days per week or month they drank alcohol, and the average number of drinks consumed on each occasion. Total number of drinking days in the first trimester was estimated by extrapolating weekly or monthly drinking frequency over the 3-month period. Total number of alcoholic beverages consumed in the first trimester was estimated by multiplying the total number of drinking days by the average number of drinks per occasion. Categorical variables were used to summarize total drinks (1–3, 4–6, ≥7), number of drinking days (1–2, 3–6, ≥7), and average number of drinks per occasion (1, 2–4, ≥5) in the first trimester. The categories were defined to ensure adequate case numbers within categories and to capture binge-level drinking (defined as an average of ≥5 drinks per sitting.) An additional categorical variable was used to examine number of drinks and frequency of consumption simultaneously: one to four drinks on one to two occasions, one to four drinks on three or more occasions, five or more drinks on one to two occasions, and five or more drinks on three or more occasions. Nondrinkers served as the referent group for all measures of first-trimester alcohol exposure.
We calculated odds ratios and 95 percent confidence intervals for the associations between infant clefts and maternal alcohol consumption. Because cleft outcomes are rare, the odds ratios are close approximations of risk ratios and can be interpreted as such. We conducted separate analyses of cleft lip with or without cleft palate, and cleft palate only. We calculated separate estimates for infants with isolated and with nonisolated cleft defects. Multivariable logistic regression models were used to estimate odds ratios adjusted for child's year of birth, mother's age group (<25, 25–29, 30–34, ≥35 years), education (less than high school, high school, technical college, 2–4-year college, university), first-trimester smoking (none; passive only; active, 1–5 cigarettes per day; active, 6–10 cigarettes per day; active, ≥11 cigarettes per day), household per capita income (≤50,000, 50,001–75,000, 75,001–100,000, 100,001–150,000, ≥150,001 kroner), and family history of clefts among parents or grandparents (yes/no). Dummy variables were used for variables with more than two levels. Further adjustment for mother's marital status, parity, employment during the first trimester, folic acid supplement use, dietary folate, multivitamin use, and prepregnancy body mass index did not substantially change the estimates.
We explored the possible effect of heavy drinking before the pregnancy by restricting analysis to mothers who drank an average of five or more alcoholic beverages per sitting before pregnancy but reported no drinking during pregnancy. We calculated the risk of infant clefts among these women compared with women who abstained from drinking alcohol both before and during their pregnancies.
Pearson chi-square tests were used to compare the percentages of beer, wine, and liquor drinkers among the women who reported an average of five or more drinks per sitting and those who reported four or fewer. To assess possible differences in infant cleft risk by the type(s) of alcohol the mothers consumed, separate multivariable logistic regression models were conducted to examine beer/wine consumption (alone or in combination) and liquor consumption (alone or in combination with beer or wine).