We found that smoking five cigarettes or less per day during the periconceptional period was associated with lower risk of NTDs, spina bifida, and anencephaly, while higher cigarette consumption (i.e., more than five cigarettes per day) was associated with lower risk of conotruncal heart defects, dTGA, and TOF in offspring. We also found that maternal intake of alcohol less than 1 day per week was associated with a 1.6- to 1.9-fold higher risk of NTDs, dTGA, and multiple CLP, while more frequent intake (i.e., at least 1 day per week) was associated with higher risk of NTDs and multiple CLP. Unlike a majority of the previous studies, we evaluated the effects of smoking and alcohol consumption simultaneously. This approach, however, did not yield estimates of risk of congenital anomalies that were substantially different from when these exposures were considered independently.
The decreased risks of NTDs and conotruncal heart defects associated with maternal smoking during the periconceptional period could be indicative of true risks or could be artifactual explained by the modestly elevated risk (i.e., relative risks of less than 1.5) of spontaneous abortion (Risch et al., 1988
; Armstrong et al., 1992
) among mothers who smoked during pregnancy. Complete ascertainment of NTDs among spontaneous abortions is essentially not possible. Thus, we can not disentangle whether the reduced risk is real or artifact. However, our finding of a reduced risk of NTDs in offspring associated with maternal smoking during the periconceptional period is consistent with the results of Shaw et al. (1996a)
, who reported risk estimates of 0.9 and 0.7 for mothers who smoked 1–19 cigarettes per day and ≥20 cigarettes per day, respectively. Both of these sets of results are contrary to those in earlier studies that have either reported an increase in the risk of NTDs (Kelsey et al., 1978
; Evans et al., 1979
; Suarez et al., 2007
) or have showed no association (McDonald et al., 1992
; Wasserman et al., 1996
). Our finding of a reduced risk of conotruncal heart defects associated with periconceptional smoking of more than five cigarettes per day is inconsistent with two previous studies that reported no association (Adams et al., 1989
; Wasserman et al., 1996
), and two others that reported ORs of 1.3 for mothers who smoked 20 cigarettes or less per day (Kelsey et al., 1978
) and 1.9 for mothers who smoked just 1–9 cigarettes per day (Shaw et al., 1992
). As these latter two studies examined conotruncal heart defects as a group and did not report results for the specific phenotypes, they do not offer a basis for comparison of our finding that maternal smoking was associated with a reduced risk of dTGA and TOF. Finally, our finding that maternal smoking during the periconceptional period does not play a significant role the etiology of orofacial clefts, with the possible exception of isolated CP, is supported by three studies (Evans et al., 1979
; Werler et al., 1990
; Lieff et al., 1999
), yet contradicted by several others (Kelsey et al., 1978
; Khoury et al., 1987
; Shaw et al., 1996b
; Chung et al., 2000
; Honein et al., 2007
). A number of our estimates of the risk of defects associated with maternal smoking are based on sparse data; therefore, the observed results might alternatively be attributable to random variation.
Our findings of elevated risk associated with periconceptional alcohol consumption are bolstered by experimental research that has suggested tenable mechanisms between alcohol and abnormal development (Pullarkat, 1991
; Shean and Duester, 1993
). Indeed, several studies have examined the link between maternal alcohol consumption and the risk for conotruncal heart defects in offspring, with conflicting findings. A population-based case-control study of California births between 1987 and 1988 noted that the risk of conotruncal heart defects in offspring was moderately elevated among women who consumed alcoholic beverages during the periconceptional period (Carmichael et al., 2003
). These results agree with two earlier studies (Shaw et al., 1992
; Tikkanen and Heinonen, 1992
), but are contradicted by two others that found no association (Adams et al., 1989
; Ferencz et al., 1997
). Our study findings are consistent with the former research: we observed a risk of conotruncal heart defects—particularly dTGA—that was nearly twofold higher among infants whose mothers reported alcohol consumption during the periconceptional period.
The potential association between alcohol intake during early pregnancy and NTDs was first described in a clinical study 25 years ago (Freidman, 1982
). Our results, however, are consistent with several subsequent epidemiologic studies (Mills and Graubard, 1987
; McDonald et al., 1992
; Shaw et al., 1996a
), each of which found no significant increase in NTD risk associated with maternal alcohol use during early pregnancy. Similarly, our finding that maternal alcohol consumption during the periconceptional period was not associated with an elevated risk of most of the cleft phenotypes is generally consistent with previous studies (Werler et al., 1991
; Shaw and Lammer, 1999
). We did observe an increase in the risk of multiple CLP, unlike Munger et al. (1996)
, who found an effect only for isolated CLP. Our findings also suggested that binge drinking is associated with a higher risk of multiple CLP, but not other cleft phenotypes, which is in contrast to the findings of Werler et al. (1991)
and Shaw and Lammer (1999)
. With the exception of isolated CLP (where no association was observed), however, our study lacked power to accurately estimate risks of clefts associated with binge drinking.
Any similarities and differences in results should be considered with caution given variation across studies in the definition of the periconceptional period, the methods for quantifying smoking and alcohol consumption, and the time period over which data were collected (and as a result, the interval between exposure and interview). For example, given the low prevalence of smoking in our study population, we were unable to replicate the broad smoking categories that were employed in previous studies (Shaw et al., 1992
; Wasserman et al., 1996
; Suarez et al., 2007
; Honein et al., 2007
), thus making direct comparison difficult. Similarly, we cannot easily compare our findings on alcohol consumption with previous studies, as we considered both the frequency (number of drinking days per week) and amount of alcohol consumption (number of drinks per drinking day), whereas several of the previous studies used a more limited classification of alcohol intake, for example, simply distinguishing between those who consumed alcohol and those who did not.
Another important consideration is the decline in the prevalence of smoking and alcohol consumption in the US during the past few decades: the share of the adult population in the US that smoked dropped by 38% between 1979 and 2004 (NCHS, 2006
), while the share that consumed alcohol dropped by 13% between 1978 and 2003 (NIAAA, 2004
). Among pregnant mothers, the decline in smoking prevalence was even steeper: 48% between 1989 (the first year for which data were reported) and 2004 (NCHS, 2006
). According to data from two cross-sectional National Health and Nutrition Examination Surveys conducted in 1988–1994 and 1999–2002, the average number of cigarettes smoked per day fell by nearly 15% during this time period (O’Connor et al., 2006
). The sales of high-tar and -nicotine delivery cigarettes have also dropped significantly since 1978, whereas sales of medium- and low-delivery cigarettes increased over the same time frame (NIAAA, 2004
). Although the overall prevalence of smoking and alcohol consumption has declined, our results—that maternal alcohol consumption during the periconceptional period continues to increase risk of NTDs, dTGA, and multiple CLP, whereas maternal smoking decreases risk for NTDs and conotruncal heart defects—are consistent with earlier studies that were conducted when these exposures were more common.
A further issue to bear in mind is the potential impact of reporting bias. The behaviors that mothers of cases report could be influenced by increased public awareness of the potential teratogenic effects of smoking and alcohol consumption during pregnancy. Mothers may be inclined to underestimate their exposures, denying a possible causal role. On the other hand, they may overestimate their exposures, believing there is a causal role. Previous studies have suggested that for many chronic exposures, reporting bias is likely to be minimal in studies of congenital anomalies (Werler et al., 1989
; Swan et al., 1992
; Khoury et al., 1994
). To help gauge whether such a bias exists in our study, we examined data from the National Birth Defects Prevention Study (NBDPS), an ongoing, multistate, case-control study of environmental and genetic risk factors for major birth defects. According to NBDPS data from 1999–2004, the percentage of control mothers in California who smoked ranged from 12% 2 months before pregnancy to 8% 2 months after conception—versus 11 and 5%, respectively, in our study. The prevalence of alcohol intake among the NBDPS control mothers ranged from 22% 2 months before pregnancy to 8% 2 months after conception—versus 27 and 6%, respectively, in our study. The comparison, therefore, reveals only modest differences in the prevalence of these exposures and offers no specific evidence that the mothers in our study may have over- or under-reported smoking and alcohol consumption.
Finally, we also cannot rule out residual confounding as a possible explanation for our findings. Although all of the analyses were ultimately adjusted for several covariates known to be associated with both exposures and the selected birth defects, it is possible that the omission of additional unmeasured confounders contributed to our results.
In summary, this large, population-based, case-control study revealed that even limited maternal alcohol intake during the periconceptional period was associated with a higher risk of select congenital anomalies—especially NTDs, dTGA, and multiple CLP—in offspring. By contrast, no such effects were observed in regards to maternal smoking, which was actually associated with a lower risk of conotruncal heart defects and NTDs in offspring.