- Email: [email protected]
Maternal periconceptional alcohol consumption and risk for orofacial clefts
M
Maternal periconceptional alcohol consumption and
risk for orofacial clefts Gary M. Shaw, DrPH, and Edward J. Lammer, MD
Objective: To investigate whether periconceptional maternal alcohol consumption increased the risk of delivering infants with orofacial cleft phenotypes. Design: Data were derived from a large population-based case control study of fetuses and infants among a cohort of California births from 1987 to 1989 (n = 548,844). Information concerning alcohol consumption was obtained by telephone interviews with mothers of 731 infants (84.7% of eligible) with orofacial clefts and of 734 (78.2%) infants in a nonmalformed control group. Results: Thirty-nine percent of mothers in the case group and 42% of mothers in the control group reported that they consumed alcohol during the period 1 month before through 3 months after conception. Relative to nonconsumers, women who reported alcohol consumption (
The constellation of birth defects and growth retardation described as fetal alcohol syndrome has been associated with women consuming large quanti-
ties of alcohol during pregnancy.1-3 Cleft palate and cleft lip with or without cleft palate have combined prevalences of 1 to 2 per 1000 livebirths4 and
From the March of Dimes Birth Defects Foundation, California Birth Defects Monitoring Program, Emeryville, California, and Division of Medical Genetics, Children’s Hospital, Oakland, California.
Partially supported by the Cigarette and Tobacco Surtax Fund of California Tobacco-Related Disease Research Program, University of California, 1RT466 and 3RT0413. Submitted for publication May 14, 1998; revisions received Aug 13, 1998, Nov 11, 1998; accepted Nov 23, 1998. Reprint requests: Gary M. Shaw, California Birth Defects Monitoring Program, 1900 Powell St, Suite 1050, Emeryville, CA 94608. Copyright © 1999 by Mosby, Inc. 0022-3476/99/$8.00 + 0 9/21/96099
298
appear to have heterogeneous but largely unknown etiologies.5 Epidemiologic studies suggest that exogenous factors such as maternal smoking and maternal periconceptional multivitamin use are associated with the occurrence of CP and CLP.8-12 Anecdotal clinical observations suggest that clefts may be a component of FAS in humans.1,2 Evidence can also be CLP CP FAS
Cleft palate Cleft lip with or without cleft palate Fetal alcohol syndrome
derived from experimental animal model systems.13 Despite these lines of evidence, however, few epidemiologic studies have included sufficient numbers of infants with CP or CLP to investigate whether these specific anomalies are associated with maternal alcohol consumption during pregnancy.7,14,15 We investigated whether periconceptional maternal alcohol consumption including “binge” drinking increased the risk of delivering infants with various orofacial cleft phenotypes. To investigate this potential association, we conducted a large population-based case control study of California infants born with orofacial clefts.
METHODS For this case control study, the case group or fetuses with an orofacial cleft were ascertained by reviewing medical records at all hospitals and genetic centers in a known geographic population base. Details of the study design have been described elsewhere.10,11 Eligible
SHAW AND LAMMER
THE JOURNAL OF PEDIATRICS VOLUME 134, NUMBER 3
Table I. Risk estimates for maternal alcohol consumption from 1 month before through 3 months after conception by cleft phenotypic subgroups
Maternal alcohol consumption*
No. of cases
Odds ratio†
95% CI
None
217 98 25 7 58 32 5 2 87 46 6 2 47 23 2 1 34 29 6 0
Reference 0.75 1.2 1.2 Reference 0.92 0.87 1.3 Reference 0.88 0.70 0.89 Reference 0.82 0.43 0.82 Reference 1.4 1.4 —
— 0.56-1.0 0.70-2.0 0.50-3.2 — 0.57-1.5 0.37-2.4 0.39-6.4 — 0.59-1.3 0.31-1.7 0.26-4.2 — 0.47-1.4 0.14-1.9 0.21-6.6 — 0.82-2.5 0.51-3.7 —
Isolated CLP (n = 348)‡
Multiple CLP (n = 99)‡
Isolated CP (n = 141)
Multiple CP (n = 74)‡
“Known syndrome” clefts (n = 69)
*Weekly corresponds to 1 to 4 drinking episodes per week and daily corresponds to maternal alcohol consumption approximately every day. †Alcohol use among control mothers was as follows: none, n = 424; <1 drink/week, n = 254; weekly, n = 42; daily, n = 11; Unknown, n = 3. ‡Alcohol consumption was unknown for 1 mother of isolated CLP case, 2 mothers of multiple CLP cases, and 1 mother of multiple CP case.
were infants and fetuses with CP or CLP diagnosed within 1 year after birth among all births and fetal deaths (n = 552,601) between January 1987 and December 1989 to women residing in most California counties. Infants with diagnoses of bifid uvula, submucous cleft palate, notching of the alveolar ridge, vermillion border of the upper lip, or any cytogenetically diagnosed trisomy or Turner syndrome (45,X) were excluded (n = 81). Overall, 891 infants or fetuses were eligible (93% were liveborn infants). Cases were classified as “isolated” CP, “isolated” CLP, “multiple” CP, “multiple” CLP, and “known syndrome” cleft (most whose cause was likely attributable to a monogenic condition) based on the nature of any accompanying congenital anomalies. CP and CLP cases with no other major anomaly or with anomalies considered minor were classified as “isolated.” CP and CLP cases with at least 1 accom-
panying major anomaly or with a combination of phenotypic features suggestive of a “recognized pattern of malformation” or monogenic were considered to be either “multiple” or of “known syndrome.” A total of 972 infants for the control group were randomly selected from all infants born alive (n = 548,844) in the same geographic area and time period as the cases. Infants in the control group had no major structural malformations and were not individually matched to cases. Telephone interviews with mothers of infants in the case and control groups were conducted in English (91%) or Spanish. Women who only spoke languages other than English or Spanish (25 in case group and 33 in control group) or who died before interview contact (3 cases) were excluded. We interviewed 731 (84.7%) mothers in the case group and 734 (78.2%) mothers in the control group. The 731
cases consisted of 348 with isolated CLP, 141 with isolated CP, 99 with multiple CLP, 74 with multiple CP, and 69 with “known syndrome.” Information was unavailable from 3% of mothers who declined to be interviewed and from 13% of mothers in the case group and 18% of mothers in the control group who could not be located. Interviews were completed an average of 3.5 years for the case group and 3.6 years for the control group after the date of delivery. An interviewer assisted each woman with establishing a 4month time period from 1 month before through 3 months after conception to elicit information on exposures and events. Women were asked “During (the 4-month period) about how often did you have a beverage containing alcohol, whether it was wine, beer, whiskey, or any other drink: never, 1 to 3 times in period, 1 to 3 times per month, 1 to 4 times per week, about every day?” If the response was other 299
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THE JOURNAL OF PEDIATRICS MARCH 1999
Table II. Adjusted* risk estimates for maternal alcohol consumption from 1 month before through 3 months after conception by cleft phenotypic subgroups
Maternal alcohol consumption ≥1 drink/week†
<1 drink/week Odds ratio†
95% CI
Odds ratio‡
95% CI
1.1 0.76 1.1 0.87 § §
0.61-2.1 0.52-1.1 0.61-1.8 0.56-1.3
2.4 0.56 0.88 0.63 § §
0.86-6.4 0.27-1.2 0.32-2.4 0.28-1.4
Isolated CLP No multivitamins used Multivitamins used Multiple CLP Isolated CP Multiple CP “Known syndrome” clefts *Adjusted
for maternal race and ethnicity, education level, cigarette smoking, and use of multivitamin supplements (unless otherwise indicated). women with reported alcohol consumption of 1 to 4 times/week with those women who reported daily alcohol consumption. ‡Compared to maternal alcohol consumption = none. §Data were too sparse for model convergence. †Combines
than “never,” women were asked “About how often in this 4-month period would you say you had 5 or more drinks at one sitting: never, 1 to 3 times in period, 1 to 3 times per month, 1 to 4 times per week, about every day?” We further grouped consumption as “none,” “
which may not have been exactly known by some women in the study. Maternal cigarette smoking (0, 1 to 19, and >19 cigarettes per day during the 4-month periconceptional period), use of multivitamins containing folic acid (yes vs no from 1 month before through 2 months after conception), race and ethnic background (non-Hispanic white, Hispanic, black, Native American, Asian, other), and education level (less than a high school graduate, high school graduate, some college, college graduate) were considered as potential covariates.
RESULTS Race and ethnic distributions for CP (isolated and multiple phenotypes combined) cases, CLP cases, and controls in this study population were as follows, respectively: Hispanic, 23%, 30%, and 28%; non-Hispanic white, 66%, 59%, and 58%; black, 4%, 3%, and 3%; Asian, 5%, 3%, and 5%; and other race/ethnic group, 2%, 5%, and 5%. With respect to other demographic factors of the study population, compared with mothers in the control group, mothers in the CP case group were more likely to have been pregnant 4 or more times (27% vs 22%), to
have smoked cigarettes in the periconceptional period (30% vs 24%), and were less likely to have been employed (50% vs 57%) or to have used multivitamins containing folic acid in the periconceptional period (63% vs 70%). Mothers in the CLP case group were less likely to have attended or graduated college (11% vs 17%), were more likely to have male infants (62% vs 49%), were more likely to have smoked cigarettes in the periconceptional period (33% vs 24%), and were more likely to have had a history of epilepsy or seizures compared with mothers in the control group (3% vs 1%). Mothers in the CLP case group were less likely to have used multivitamins containing folic acid in the periconceptional period (53% vs 70%). Overall, 39% of mothers in the case group and 42% of mothers in the control group reported that they consumed any alcohol during the periconceptional period. The risks associated with maternal periconceptional alcohol consumption, that is,
SHAW AND LAMMER
THE JOURNAL OF PEDIATRICS VOLUME 134, NUMBER 3
Table III. Risk estimates for maternal alcohol consumption of 5 or more drinks per drinking occasion, from 1 month before through 3 months after conception, by cleft phenotypic subgroups
Isolated CLP (n = 348)†
Multiple CLP (n = 99)*
Isolated CP (n = 141)
Multiple CP (n = 74)*
“Known syndrome” clefts (n = 69)
Maternal alcohol consumption of ≥5 drinks/drinking occasion
No. of cases
Odds ratio†
95% CI
No occasion <1 occasion/week ≥1 occasion/week No occasion <1 occasion/week ≥1 occasion/week No occasion <1 occasion/week ≥1 occasion/week No occasion <1 occasion/week ≥1 occasion/week No occasion <1 occasion/week ≥1 occasion/week
321 17 8 89 5 3 133 7 1 67 6 0 59 7 3
Reference 0.86 3.4 Reference 0.91 4.6 Reference 0.85 1.0 Reference 1.5 — Reference 1.9 6.9
— 0.49-1.5 1.1-9.7 — 0.39-2.5 1.2-18.8 — 0.41-2.0 0.23-8.5 — 0.65-3.7 — — 0.89-4.6 1.9-28.6
*Information about consuming 5 or more drinks per drinking occasion was unknown for 2 mothers of isolated CLP cases, 2 mothers of multiple CLP cases, and 1 mother of multiple CP case. †Consumption of 5 or more drinks per drinking occasion among controls was as follows: No occasion, n = 681; <1 occasion/week, n = 42; ≥1 occasion/week, n = 5; and unknown, n = 6.
only minimally influenced by the exclusion from analyses of those with a family history of clefting (defined as CLP or CP in mother, father, or previous sibling of the proband). Risk estimates were also only minimally influenced after simultaneous adjustment was done for maternal cigarette smoking, race and ethnicity, education, and multivitamin use (Table II). Because of small numbers, these analyses grouped women who reported weekly or daily alcohol consumption. For isolated CLP risk estimates for maternal alcohol consumption differed by whether mothers also used or did not use multivitamins in the periconception period. Although data were too sparse to adequately adjust simultaneously for these covariates for 2 cleft phenotypes, multiple CP and “known syndrome” clefts, single variable adjustment for each of these variables and for each phenotype did not reveal risk estimates substantially different from their unadjusted counterparts. Another analysis was designed to identify those women whose alcohol intake was greatest. We computed risk
estimates for women who consumed 5 or more drinks per drinking occasion. We compared these women with those who did not drink alcohol plus those who did but who did not consume 5 or more drinks per occasion (risks were similar when the comparison group was limited to women who reported no alcohol consumption in the periconceptional period, data not shown). These risk estimates are shown in Table III. Risks were substantially elevated for isolated CLP, multiple CLP, and “known syndrome” clefts. The elevated risks were primarily observed among women who consumed 5 or more drinks per drinking occasion on a weekly or more frequent basis during the periconceptional period (Table III). Among the 3 infants in the case group with known syndrome clefts whose mothers consumed ≥5 drinks per drinking occasion on a weekly or more frequent basis, 1 mother reported that her consumption stopped 2 weeks after conception. Exclusion of this infant still resulted in an elevated risk, OR = 4.6 (1.1 to 23.8). Single
variable (maternal cigarette smoking, race and ethnicity, education, and multivitamin use) adjusted risk estimates were similar to the unadjusted estimates shown in Table III for each of the 5 cleft phenotypes. The specific phenotypes of the 14 infants with isolated CLP (n = 8), multiple CLP (n = 3), and “known syndrome” clefts (n = 3) whose mothers consumed 5 or more drinks per drinking occasion on a weekly or more frequent basis (Table III) were further reviewed. We especially looked for mentions of short palpebral fissures and microcephaly. Among the 8 isolated CLP cases, no minor dysmorphic facial features considered to be a component of fetal alcohol syndrome were described in their medical records. One of these 8 infants had hypertelorism. None was identified as microcephalic. The birth weights (3140 g, 3827 g, 2756 g, 3005 g, 2920 g, 3130 g, and 3250 g; 1 birth weight unknown) of the 8 infants in the case group did not reveal evidence for intrauterine growth retardation. The other 6 infants 301
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in the case group were born within the average for gestational age birth weight range, lacked microcephaly, and were not identified as having short palpebral fissures.
DISCUSSION This large study included population-based ascertainment of infants in the case and control groups, high percentage participation, control of relevant confounders, and phenotypic subclassifications of orofacial clefts. Our results regarding maternal alcohol consumption of ≥5 drinks per drinking occasion and increased risk for cleft lip compare with a result of Werler et al.16 They observed a 3-fold increased risk for CLP among mothers who consumed an average of ≥5 drinks per drinking day. However, their consumption definition likely included more frequent binge episodes than were included in our definition. Our results are also consistent with the results by Laumon et al,15 who observed a 3-fold increased risk for all isolated clefts among women who consumed the daily alcohol equivalent of 500 mL of wine. However, this quantity of intake may be lower than the quantity defined in our study of ≥5 drinks per drinking occasion. We reasoned that if this higher quantity (≥5 drinks per drinking occasion) of maternal alcohol consumption caused cleft lip, then affected infants would probably also have common diagnostic features of FAS. The diagnostic criteria for FAS include prenatal or postnatal growth retardation, microcephaly, and a characteristic pattern of facial features. The facial phenotype comprises short palpebral fissures, short upturned nose with a tall, smooth philtrum, and thin upper vermillion of the lip. When an infant has a cleft lip, however, 3 of the 4 facial features cannot be assessed; thus the facial “gestalt,” often clinically advantageous for identifying FAS, cannot be ob302
THE JOURNAL OF PEDIATRICS MARCH 1999 served. We found no evidence of prenatal growth retardation, microcephaly, and short palpebral fissures among the 14 infants with cleft lip whose mothers reported the highest alcohol intake. None was found. Although our registry ascertainment likely collected accurate birth weight data for the infants in the case group, microcephaly and short palpebral fissures are not outcomes that registries will likely systematically collect. Those features might have been present among some of the 14 infants in the case group but not identified during medical record reviews by registry staff. If the association between cleft lip and high maternal alcohol consumption is causal, then the clefts appear to occur in the absence of the other signs of FAS that might be recognized when the cleft lip alters a part of the face often affected by FAS. Our results regarding maternal consumption of lesser amounts of alcohol are generally consistent with the lack of an increased risk observed by Khoury et al8 and Werler et al.14 They are, however, inconsistent with the recent results of Munger et al,18 who observed an increased CLP risk with increased monthly frequency of alcohol intake by women after conception. The frequency of maternal alcohol consumption of ≥1 drink per week for the 4-month periconceptional period was 7.3% among the mothers in the control group in our study and 9.2% among mothers in the isolated CLP case group, whereas the corresponding percentages in the Munger et al18 study, reflecting consumption after conception, were 2.6% and 8.4%, respectively. Thus the reported frequency of this pattern of maternal alcohol consumption was similar among mothers in the case groups in the 2 studies but higher among mothers in the control group in our study. One possible explanation for the contrasting results is that either the percentage of alcohol consumption of mothers in the control group in our study was artifactually high, or the
percentage in the study by Munger et al18 was artifactually low. The percentage observed in our study was probably slightly inflated by the inclusion of women who consumed alcohol in the 1 month before conception and subsequently reduced their alcohol consumption after they found out they were pregnant. However, this potential exposure misclassification should have contributed equally to mothers in the case and control groups. We do not know whether mothers in the control group compared with mothers in the case group might have differentially stopped alcohol consumption shortly after conception (and therefore were misclassified as alcohol consumers). It is also unknown whether alcohol consumption among mothers in the control group (during pregnancy) in the study by Munger et al18 study was artifactually low, particularly given the relatively low participation (54.6% of eligible) among mothers in the control group. Comparisons between studies of alcohol consumption during early pregnancy are complicated by differences in study methods, schemes for quantifying alcohol consumption, and the accuracy of women’s reports of their alcohol consumption. It is difficult to predict from our study whether mothers in the case group compared with mothers in the control group would be more or less likely to report alcohol consumption correctly. For comparison to our retrospectively obtained consumption estimates among mothers in the control group, we examined data from a recent prospective cohort study of California women.19 Women in their first trimester of pregnancy were queried about their consumption of alcohol. A total of 6.5% of women reported consumption of ≥1 drink per week, a percentage similar to the percentage of mothers in the control group (7.3%) in our study who reported alcohol consumption in the periconceptional period. The accuracy of self-reported consumption of alcohol during pregnancy likely depends on many factors including a
SHAW AND LAMMER
THE JOURNAL OF PEDIATRICS VOLUME 134, NUMBER 3 woman’s perceived risk for sharing such information with an interviewer. Women who participated were assured that all information collected about pregnancies would be considered confidential and used only by research staff for summary purposes. Questions about alcohol consumption were made approximately midway through the interview, well after a rapport had been established between the interviewee and interviewer. Nevertheless, reporting bias cannot be ruled out as a possible explanation of our results, given the potential social stigmata that may be associated with excess alcohol consumption during pregnancy. The observations of a lack of increased risks of clefts for relatively low quantities of consumption and the observations of increased risks of clefts for higher quantities of maternal alcohol consumption are intriguing. Although the observations that women who consume higher quantities of alcohol are at increased risk build on the results of 2 previous epidemiologic studies, several issues must be further addressed before a secure inference can be made regarding maternal alcohol consumption during pregnancy and infant clefting risk. First, the number of infants exposed to these higher quantities of alcohol in utero is relatively small, making it difficult to adequately control for potential confounders. It has been demonstrated that women who consume these quantities in the periconception period are also more likely to report use of other substances such as cigarettes, marijuana, and cocaine, substances that may also pose potential teratogenic risks to fetuses.20 Second, if cleft lip is caused by high maternal consumption of alcohol, it is difficult to identify the charac-
teristic facial phenotype of FAS, and this may further contribute to the difficulty in establishing a causal connection between the two. We are grateful to Dr Marie Tolarova for her expert review and classification of cases, to Verne Nelson for his analytic activities, and to Jennifer Stiling for article preparation.
10.
11.
REFERENCES 1. Jones KL, Smith DW, Ulleland CN, Streissguth AP. Pattern of malformation in offspring of chronic alcoholic mothers. Lancet 1973;1:1267-71. 2. Hanson JW, Jones KL, Smith DL. Fetal alcohol syndrome. Experience with 41 patients. JAMA 1976;235:1458-60. 3. Jones KL. Smith’s recognizable patterns of human malformations. 4th ed. Philadelphia: WB Saunders; 1988. p. 491-4. 4. Shaw GM, Croen LA, Curry CJ. Isolated oral cleft malformations: associations with maternal and infant characteristics in a California population. Teratology 1991;43:225-8. 5. Wyszynski DF, Beaty TH. Review of the role of potential teratogens in the origin of human nonsyndromic oral clefts. Teratology 1996;53:309-17. 6. Czeizel A, Nagy E . A recent aetiological study on facial clefting in Hungary. Acta Pediatr Hungarica 1986;27:145-66. 7. Khoury MJ, Weinstein A, Panny S, Holtzman NA, Lindsay PK, Farrel K, et al. Maternal cigarette smoking and oral clefts: a population-based study. Am J Pub Health 1987;77:623-5. 8. Khoury MJ, Gomez-Farias M, Mulinare J. Does maternal cigarette smoking during pregnancy cause cleft lip and palate in offspring? Am J Dis Child 1989;143:333-7. 9. Hwang SJ, Beaty TH, Panny SR, Street NA, Joseph JM, Gordon S, et al. Association study of transforming growth factor alpha (TGFa) TaqI polymorphism and oral clefts: indication of gene-environment interaction in a population-based sample of infants
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with birth defects. Am J Epidemiol 1995;141:629-36. Shaw GM, Wasserman CR, Lammer EJ, O’Malley CD, Murray JC, Basart AM, et al. Orofacial clefts, parental cigarette smoking, and transforming growth factor-alpha gene variants. Am J Hum Genet 1996;58:551-61. Shaw GM, Lammer EJ, Wasserman CR, O’Malley CD, Tolarova MM. Risks of orofacial clefts in children born to women using multivitamins containing folic acid periconceptionally. Lancet 1995;345:393-6. Tolarova MM, Harris JA. Reduced recurrence of orofacial clefts after periconceptional supplementation with high-dose folic acid and multivitamins. Teratology 1995;51:71-8. Kotch LE, Sulik KK. Experimental fetal alcohol syndrome: proposed pathogenic basis for a variety of associated facial and brain anomalies. Am J Med Genet 1992;44:168-76. Werler MM, Lammer EJ, Rosenberg L, Mitchell AA. Maternal alcohol use in relation to selected birth defects. Am J Epidemiol 1991;134:691-8. Laumon B, Martin JL, Bertucat I, Verney MP, Robert E. Exposure to organic solvents during pregnancy and oral clefts: a case-control study. Repro Toxicol 1996;10:15-9. EGRET. Statistics and Epidemiology Research Corporation, Seattle: 1991. Gustafson TL. Epistat, Richardson, Texas, 1986. Munger RG, Romitti PA, DaackHirsch S, Burns T, Murray JC, Hanson J. Maternal alcohol use and risk of orofacial cleft birth defects. Teratology 1996;54:27-33. Windham GC, Von Behren J, Fenster L, Schaefert C, Swan SH. Moderate alcohol consumption and risk of spontaneous abortion. Epidemiol 1997;8:509-14. Gladstone J, Levy M, Nulman I, Koren G. Characteristics of pregnant women who engage in binge alcohol consumption. Can Med Assoc J 1997;156:789-94.
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Maternal periconceptional alcohol consumption and
risk for orofacial clefts Gary M. Shaw, DrPH, and Edward J. Lammer, MD
Objective: To investigate whether periconceptional maternal alcohol consumption increased the risk of delivering infants with orofacial cleft phenotypes. Design: Data were derived from a large population-based case control study of fetuses and infants among a cohort of California births from 1987 to 1989 (n = 548,844). Information concerning alcohol consumption was obtained by telephone interviews with mothers of 731 infants (84.7% of eligible) with orofacial clefts and of 734 (78.2%) infants in a nonmalformed control group. Results: Thirty-nine percent of mothers in the case group and 42% of mothers in the control group reported that they consumed alcohol during the period 1 month before through 3 months after conception. Relative to nonconsumers, women who reported alcohol consumption (
The constellation of birth defects and growth retardation described as fetal alcohol syndrome has been associated with women consuming large quanti-
ties of alcohol during pregnancy.1-3 Cleft palate and cleft lip with or without cleft palate have combined prevalences of 1 to 2 per 1000 livebirths4 and
From the March of Dimes Birth Defects Foundation, California Birth Defects Monitoring Program, Emeryville, California, and Division of Medical Genetics, Children’s Hospital, Oakland, California.
Partially supported by the Cigarette and Tobacco Surtax Fund of California Tobacco-Related Disease Research Program, University of California, 1RT466 and 3RT0413. Submitted for publication May 14, 1998; revisions received Aug 13, 1998, Nov 11, 1998; accepted Nov 23, 1998. Reprint requests: Gary M. Shaw, California Birth Defects Monitoring Program, 1900 Powell St, Suite 1050, Emeryville, CA 94608. Copyright © 1999 by Mosby, Inc. 0022-3476/99/$8.00 + 0 9/21/96099
298
appear to have heterogeneous but largely unknown etiologies.5 Epidemiologic studies suggest that exogenous factors such as maternal smoking and maternal periconceptional multivitamin use are associated with the occurrence of CP and CLP.8-12 Anecdotal clinical observations suggest that clefts may be a component of FAS in humans.1,2 Evidence can also be CLP CP FAS
Cleft palate Cleft lip with or without cleft palate Fetal alcohol syndrome
derived from experimental animal model systems.13 Despite these lines of evidence, however, few epidemiologic studies have included sufficient numbers of infants with CP or CLP to investigate whether these specific anomalies are associated with maternal alcohol consumption during pregnancy.7,14,15 We investigated whether periconceptional maternal alcohol consumption including “binge” drinking increased the risk of delivering infants with various orofacial cleft phenotypes. To investigate this potential association, we conducted a large population-based case control study of California infants born with orofacial clefts.
METHODS For this case control study, the case group or fetuses with an orofacial cleft were ascertained by reviewing medical records at all hospitals and genetic centers in a known geographic population base. Details of the study design have been described elsewhere.10,11 Eligible
SHAW AND LAMMER
THE JOURNAL OF PEDIATRICS VOLUME 134, NUMBER 3
Table I. Risk estimates for maternal alcohol consumption from 1 month before through 3 months after conception by cleft phenotypic subgroups
Maternal alcohol consumption*
No. of cases
Odds ratio†
95% CI
None
217 98 25 7 58 32 5 2 87 46 6 2 47 23 2 1 34 29 6 0
Reference 0.75 1.2 1.2 Reference 0.92 0.87 1.3 Reference 0.88 0.70 0.89 Reference 0.82 0.43 0.82 Reference 1.4 1.4 —
— 0.56-1.0 0.70-2.0 0.50-3.2 — 0.57-1.5 0.37-2.4 0.39-6.4 — 0.59-1.3 0.31-1.7 0.26-4.2 — 0.47-1.4 0.14-1.9 0.21-6.6 — 0.82-2.5 0.51-3.7 —
Isolated CLP (n = 348)‡
Multiple CLP (n = 99)‡
Isolated CP (n = 141)
Multiple CP (n = 74)‡
“Known syndrome” clefts (n = 69)
*Weekly corresponds to 1 to 4 drinking episodes per week and daily corresponds to maternal alcohol consumption approximately every day. †Alcohol use among control mothers was as follows: none, n = 424; <1 drink/week, n = 254; weekly, n = 42; daily, n = 11; Unknown, n = 3. ‡Alcohol consumption was unknown for 1 mother of isolated CLP case, 2 mothers of multiple CLP cases, and 1 mother of multiple CP case.
were infants and fetuses with CP or CLP diagnosed within 1 year after birth among all births and fetal deaths (n = 552,601) between January 1987 and December 1989 to women residing in most California counties. Infants with diagnoses of bifid uvula, submucous cleft palate, notching of the alveolar ridge, vermillion border of the upper lip, or any cytogenetically diagnosed trisomy or Turner syndrome (45,X) were excluded (n = 81). Overall, 891 infants or fetuses were eligible (93% were liveborn infants). Cases were classified as “isolated” CP, “isolated” CLP, “multiple” CP, “multiple” CLP, and “known syndrome” cleft (most whose cause was likely attributable to a monogenic condition) based on the nature of any accompanying congenital anomalies. CP and CLP cases with no other major anomaly or with anomalies considered minor were classified as “isolated.” CP and CLP cases with at least 1 accom-
panying major anomaly or with a combination of phenotypic features suggestive of a “recognized pattern of malformation” or monogenic were considered to be either “multiple” or of “known syndrome.” A total of 972 infants for the control group were randomly selected from all infants born alive (n = 548,844) in the same geographic area and time period as the cases. Infants in the control group had no major structural malformations and were not individually matched to cases. Telephone interviews with mothers of infants in the case and control groups were conducted in English (91%) or Spanish. Women who only spoke languages other than English or Spanish (25 in case group and 33 in control group) or who died before interview contact (3 cases) were excluded. We interviewed 731 (84.7%) mothers in the case group and 734 (78.2%) mothers in the control group. The 731
cases consisted of 348 with isolated CLP, 141 with isolated CP, 99 with multiple CLP, 74 with multiple CP, and 69 with “known syndrome.” Information was unavailable from 3% of mothers who declined to be interviewed and from 13% of mothers in the case group and 18% of mothers in the control group who could not be located. Interviews were completed an average of 3.5 years for the case group and 3.6 years for the control group after the date of delivery. An interviewer assisted each woman with establishing a 4month time period from 1 month before through 3 months after conception to elicit information on exposures and events. Women were asked “During (the 4-month period) about how often did you have a beverage containing alcohol, whether it was wine, beer, whiskey, or any other drink: never, 1 to 3 times in period, 1 to 3 times per month, 1 to 4 times per week, about every day?” If the response was other 299
SHAW AND LAMMER
THE JOURNAL OF PEDIATRICS MARCH 1999
Table II. Adjusted* risk estimates for maternal alcohol consumption from 1 month before through 3 months after conception by cleft phenotypic subgroups
Maternal alcohol consumption ≥1 drink/week†
<1 drink/week Odds ratio†
95% CI
Odds ratio‡
95% CI
1.1 0.76 1.1 0.87 § §
0.61-2.1 0.52-1.1 0.61-1.8 0.56-1.3
2.4 0.56 0.88 0.63 § §
0.86-6.4 0.27-1.2 0.32-2.4 0.28-1.4
Isolated CLP No multivitamins used Multivitamins used Multiple CLP Isolated CP Multiple CP “Known syndrome” clefts *Adjusted
for maternal race and ethnicity, education level, cigarette smoking, and use of multivitamin supplements (unless otherwise indicated). women with reported alcohol consumption of 1 to 4 times/week with those women who reported daily alcohol consumption. ‡Compared to maternal alcohol consumption = none. §Data were too sparse for model convergence. †Combines
than “never,” women were asked “About how often in this 4-month period would you say you had 5 or more drinks at one sitting: never, 1 to 3 times in period, 1 to 3 times per month, 1 to 4 times per week, about every day?” We further grouped consumption as “none,” “
which may not have been exactly known by some women in the study. Maternal cigarette smoking (0, 1 to 19, and >19 cigarettes per day during the 4-month periconceptional period), use of multivitamins containing folic acid (yes vs no from 1 month before through 2 months after conception), race and ethnic background (non-Hispanic white, Hispanic, black, Native American, Asian, other), and education level (less than a high school graduate, high school graduate, some college, college graduate) were considered as potential covariates.
RESULTS Race and ethnic distributions for CP (isolated and multiple phenotypes combined) cases, CLP cases, and controls in this study population were as follows, respectively: Hispanic, 23%, 30%, and 28%; non-Hispanic white, 66%, 59%, and 58%; black, 4%, 3%, and 3%; Asian, 5%, 3%, and 5%; and other race/ethnic group, 2%, 5%, and 5%. With respect to other demographic factors of the study population, compared with mothers in the control group, mothers in the CP case group were more likely to have been pregnant 4 or more times (27% vs 22%), to
have smoked cigarettes in the periconceptional period (30% vs 24%), and were less likely to have been employed (50% vs 57%) or to have used multivitamins containing folic acid in the periconceptional period (63% vs 70%). Mothers in the CLP case group were less likely to have attended or graduated college (11% vs 17%), were more likely to have male infants (62% vs 49%), were more likely to have smoked cigarettes in the periconceptional period (33% vs 24%), and were more likely to have had a history of epilepsy or seizures compared with mothers in the control group (3% vs 1%). Mothers in the CLP case group were less likely to have used multivitamins containing folic acid in the periconceptional period (53% vs 70%). Overall, 39% of mothers in the case group and 42% of mothers in the control group reported that they consumed any alcohol during the periconceptional period. The risks associated with maternal periconceptional alcohol consumption, that is,
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THE JOURNAL OF PEDIATRICS VOLUME 134, NUMBER 3
Table III. Risk estimates for maternal alcohol consumption of 5 or more drinks per drinking occasion, from 1 month before through 3 months after conception, by cleft phenotypic subgroups
Isolated CLP (n = 348)†
Multiple CLP (n = 99)*
Isolated CP (n = 141)
Multiple CP (n = 74)*
“Known syndrome” clefts (n = 69)
Maternal alcohol consumption of ≥5 drinks/drinking occasion
No. of cases
Odds ratio†
95% CI
No occasion <1 occasion/week ≥1 occasion/week No occasion <1 occasion/week ≥1 occasion/week No occasion <1 occasion/week ≥1 occasion/week No occasion <1 occasion/week ≥1 occasion/week No occasion <1 occasion/week ≥1 occasion/week
321 17 8 89 5 3 133 7 1 67 6 0 59 7 3
Reference 0.86 3.4 Reference 0.91 4.6 Reference 0.85 1.0 Reference 1.5 — Reference 1.9 6.9
— 0.49-1.5 1.1-9.7 — 0.39-2.5 1.2-18.8 — 0.41-2.0 0.23-8.5 — 0.65-3.7 — — 0.89-4.6 1.9-28.6
*Information about consuming 5 or more drinks per drinking occasion was unknown for 2 mothers of isolated CLP cases, 2 mothers of multiple CLP cases, and 1 mother of multiple CP case. †Consumption of 5 or more drinks per drinking occasion among controls was as follows: No occasion, n = 681; <1 occasion/week, n = 42; ≥1 occasion/week, n = 5; and unknown, n = 6.
only minimally influenced by the exclusion from analyses of those with a family history of clefting (defined as CLP or CP in mother, father, or previous sibling of the proband). Risk estimates were also only minimally influenced after simultaneous adjustment was done for maternal cigarette smoking, race and ethnicity, education, and multivitamin use (Table II). Because of small numbers, these analyses grouped women who reported weekly or daily alcohol consumption. For isolated CLP risk estimates for maternal alcohol consumption differed by whether mothers also used or did not use multivitamins in the periconception period. Although data were too sparse to adequately adjust simultaneously for these covariates for 2 cleft phenotypes, multiple CP and “known syndrome” clefts, single variable adjustment for each of these variables and for each phenotype did not reveal risk estimates substantially different from their unadjusted counterparts. Another analysis was designed to identify those women whose alcohol intake was greatest. We computed risk
estimates for women who consumed 5 or more drinks per drinking occasion. We compared these women with those who did not drink alcohol plus those who did but who did not consume 5 or more drinks per occasion (risks were similar when the comparison group was limited to women who reported no alcohol consumption in the periconceptional period, data not shown). These risk estimates are shown in Table III. Risks were substantially elevated for isolated CLP, multiple CLP, and “known syndrome” clefts. The elevated risks were primarily observed among women who consumed 5 or more drinks per drinking occasion on a weekly or more frequent basis during the periconceptional period (Table III). Among the 3 infants in the case group with known syndrome clefts whose mothers consumed ≥5 drinks per drinking occasion on a weekly or more frequent basis, 1 mother reported that her consumption stopped 2 weeks after conception. Exclusion of this infant still resulted in an elevated risk, OR = 4.6 (1.1 to 23.8). Single
variable (maternal cigarette smoking, race and ethnicity, education, and multivitamin use) adjusted risk estimates were similar to the unadjusted estimates shown in Table III for each of the 5 cleft phenotypes. The specific phenotypes of the 14 infants with isolated CLP (n = 8), multiple CLP (n = 3), and “known syndrome” clefts (n = 3) whose mothers consumed 5 or more drinks per drinking occasion on a weekly or more frequent basis (Table III) were further reviewed. We especially looked for mentions of short palpebral fissures and microcephaly. Among the 8 isolated CLP cases, no minor dysmorphic facial features considered to be a component of fetal alcohol syndrome were described in their medical records. One of these 8 infants had hypertelorism. None was identified as microcephalic. The birth weights (3140 g, 3827 g, 2756 g, 3005 g, 2920 g, 3130 g, and 3250 g; 1 birth weight unknown) of the 8 infants in the case group did not reveal evidence for intrauterine growth retardation. The other 6 infants 301
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in the case group were born within the average for gestational age birth weight range, lacked microcephaly, and were not identified as having short palpebral fissures.
DISCUSSION This large study included population-based ascertainment of infants in the case and control groups, high percentage participation, control of relevant confounders, and phenotypic subclassifications of orofacial clefts. Our results regarding maternal alcohol consumption of ≥5 drinks per drinking occasion and increased risk for cleft lip compare with a result of Werler et al.16 They observed a 3-fold increased risk for CLP among mothers who consumed an average of ≥5 drinks per drinking day. However, their consumption definition likely included more frequent binge episodes than were included in our definition. Our results are also consistent with the results by Laumon et al,15 who observed a 3-fold increased risk for all isolated clefts among women who consumed the daily alcohol equivalent of 500 mL of wine. However, this quantity of intake may be lower than the quantity defined in our study of ≥5 drinks per drinking occasion. We reasoned that if this higher quantity (≥5 drinks per drinking occasion) of maternal alcohol consumption caused cleft lip, then affected infants would probably also have common diagnostic features of FAS. The diagnostic criteria for FAS include prenatal or postnatal growth retardation, microcephaly, and a characteristic pattern of facial features. The facial phenotype comprises short palpebral fissures, short upturned nose with a tall, smooth philtrum, and thin upper vermillion of the lip. When an infant has a cleft lip, however, 3 of the 4 facial features cannot be assessed; thus the facial “gestalt,” often clinically advantageous for identifying FAS, cannot be ob302
THE JOURNAL OF PEDIATRICS MARCH 1999 served. We found no evidence of prenatal growth retardation, microcephaly, and short palpebral fissures among the 14 infants with cleft lip whose mothers reported the highest alcohol intake. None was found. Although our registry ascertainment likely collected accurate birth weight data for the infants in the case group, microcephaly and short palpebral fissures are not outcomes that registries will likely systematically collect. Those features might have been present among some of the 14 infants in the case group but not identified during medical record reviews by registry staff. If the association between cleft lip and high maternal alcohol consumption is causal, then the clefts appear to occur in the absence of the other signs of FAS that might be recognized when the cleft lip alters a part of the face often affected by FAS. Our results regarding maternal consumption of lesser amounts of alcohol are generally consistent with the lack of an increased risk observed by Khoury et al8 and Werler et al.14 They are, however, inconsistent with the recent results of Munger et al,18 who observed an increased CLP risk with increased monthly frequency of alcohol intake by women after conception. The frequency of maternal alcohol consumption of ≥1 drink per week for the 4-month periconceptional period was 7.3% among the mothers in the control group in our study and 9.2% among mothers in the isolated CLP case group, whereas the corresponding percentages in the Munger et al18 study, reflecting consumption after conception, were 2.6% and 8.4%, respectively. Thus the reported frequency of this pattern of maternal alcohol consumption was similar among mothers in the case groups in the 2 studies but higher among mothers in the control group in our study. One possible explanation for the contrasting results is that either the percentage of alcohol consumption of mothers in the control group in our study was artifactually high, or the
percentage in the study by Munger et al18 was artifactually low. The percentage observed in our study was probably slightly inflated by the inclusion of women who consumed alcohol in the 1 month before conception and subsequently reduced their alcohol consumption after they found out they were pregnant. However, this potential exposure misclassification should have contributed equally to mothers in the case and control groups. We do not know whether mothers in the control group compared with mothers in the case group might have differentially stopped alcohol consumption shortly after conception (and therefore were misclassified as alcohol consumers). It is also unknown whether alcohol consumption among mothers in the control group (during pregnancy) in the study by Munger et al18 study was artifactually low, particularly given the relatively low participation (54.6% of eligible) among mothers in the control group. Comparisons between studies of alcohol consumption during early pregnancy are complicated by differences in study methods, schemes for quantifying alcohol consumption, and the accuracy of women’s reports of their alcohol consumption. It is difficult to predict from our study whether mothers in the case group compared with mothers in the control group would be more or less likely to report alcohol consumption correctly. For comparison to our retrospectively obtained consumption estimates among mothers in the control group, we examined data from a recent prospective cohort study of California women.19 Women in their first trimester of pregnancy were queried about their consumption of alcohol. A total of 6.5% of women reported consumption of ≥1 drink per week, a percentage similar to the percentage of mothers in the control group (7.3%) in our study who reported alcohol consumption in the periconceptional period. The accuracy of self-reported consumption of alcohol during pregnancy likely depends on many factors including a
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THE JOURNAL OF PEDIATRICS VOLUME 134, NUMBER 3 woman’s perceived risk for sharing such information with an interviewer. Women who participated were assured that all information collected about pregnancies would be considered confidential and used only by research staff for summary purposes. Questions about alcohol consumption were made approximately midway through the interview, well after a rapport had been established between the interviewee and interviewer. Nevertheless, reporting bias cannot be ruled out as a possible explanation of our results, given the potential social stigmata that may be associated with excess alcohol consumption during pregnancy. The observations of a lack of increased risks of clefts for relatively low quantities of consumption and the observations of increased risks of clefts for higher quantities of maternal alcohol consumption are intriguing. Although the observations that women who consume higher quantities of alcohol are at increased risk build on the results of 2 previous epidemiologic studies, several issues must be further addressed before a secure inference can be made regarding maternal alcohol consumption during pregnancy and infant clefting risk. First, the number of infants exposed to these higher quantities of alcohol in utero is relatively small, making it difficult to adequately control for potential confounders. It has been demonstrated that women who consume these quantities in the periconception period are also more likely to report use of other substances such as cigarettes, marijuana, and cocaine, substances that may also pose potential teratogenic risks to fetuses.20 Second, if cleft lip is caused by high maternal consumption of alcohol, it is difficult to identify the charac-
teristic facial phenotype of FAS, and this may further contribute to the difficulty in establishing a causal connection between the two. We are grateful to Dr Marie Tolarova for her expert review and classification of cases, to Verne Nelson for his analytic activities, and to Jennifer Stiling for article preparation.
10.
11.
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