From the Birth Defects and Genetic Diseases Branch, Division of
Birth Defects and Developmental Disabilities, National Center for
Environmental Health, Centers for Disease Control and Prevention,
Atlanta, Georgia.
Investigations of a possible association between women's
light-to-moderate alcohol consumption during pregnancy and congenital anomalies among their children have produced mixed results. Multiple adverse reproductive outcomes, including increased minor and/or major
congenital anomalies, have been reported from some cohort and
cross-sectional studies and clinical case series that have examined the
effect of moderate alcohol exposure in utero.1 Other studies have found no increase in congenital anomalies among infants with moderate in utero exposure to alcohol,4 but
many have reported a significant increase among infants with heavy exposure.9
The specific association between in utero alcohol exposure and renal
anomalies comes from several case reports and clinical case series in
humans,16 usually infants and children with fetal alcohol syndrome, and from experimental studies in
animals.20 Both the human and animal studies most often
examined the effects of heavy exposure. However, Taylor and
associates25 recently studied 84 individuals who had had
first trimester exposure of 2 or more absolute oz of alcohol per day
and did not find them to have an increased rate of renal anomalies.
Finally, a large cohort study reported by Mills and
Graubard,26 which evaluated the effects of moderate alcohol
exposure, found a dose-response relationship between in utero alcohol
exposure and genitourinary tract anomalies and raised the possibility
that there may be some malformations for which any drinking increases
the risk. The classification schema for the level of alcohol
consumption varied considerably among the studies we reviewed.
In this study, we evaluated the association between light-to-moderate
alcohol consumption during pregnancy and the birth prevalence of
selected renal anomalies among their offspring using data from a large
population-based, case-control study. To our knowledge, this is the
first population-based study to explore possible relationships between
renal anomalies and prenatal alcohol exposure.
METHODS 
Study Population
We used data originally collected as part of the Atlanta Birth
Defects Case-Control Study (ABDCCS), a large, population-based investigation conducted by the Centers for Disease Control and Prevention in 1982 and 1983. The purpose of the study was to identify risk factors for major birth defects; the study was primarily conducted
to determine whether men who had served in the US military in Vietnam
were at increased risk of fathering children with congenital anomalies.27
The case infants were 4918 infants who were initially ascertained by a
population-based birth defects surveillance system, the Metropolitan
Atlanta Congenital Defects Program.28 All case infants had
serious congenital anomalies diagnosed in the first year of life, were
either live born or stillborn at 20 weeks' gestation or later, were
born from 1968 through 1980, and had mothers who were residents of
metropolitan Atlanta at the time of delivery. The control group
comprised 3029 infants with no reported congenital anomalies. They were
randomly chosen from birth certificates and frequency matched to case
infants by race, year of birth, and hospital of birth. Information on
exposures just before and during the pregnancy was obtained during
parental telephone interviews conducted by trained interviewers unaware of the case-control status of the infant. These interviews were conducted in 1982 and 1983. Full details of this study are reported elsewhere.29
For the current study, an investigator (C.A.M.) with no knowledge of
the infants' in utero alcohol exposure reviewed case records of
infants from the ABDCCS who had been classified as having "renal
agenesis," "cystic kidney disease," "obstructive defects of the
urinary tract," or "atresia or stenosis of the urethra or
bladder." We included infants with congenital anomalies that fell
into one of the following categories: renal agenesis or hypoplasia,
hydronephrosis or hydroureter, renal or ureteral duplication, and renal
multicystic dysplasia. These renal defects have been associated with
alcohol exposure in previous reports and studies, and the numbers of
infants with these defects were sufficient for analyses. We included
infants with either unilateral or bilateral defects but excluded
infants with known syndromes, including chromosomal or single-gene
disorders. Only one included infant had the diagnosis of fetal alcohol
syndrome; we did not attempt to infer this diagnosis for other infants,
because the facial features of fetal alcohol syndrome are often minor
and may be underascertained in a birth defects surveillance system, and
we did not have access to cognitive or behavioral data for the
surviving infants. We classified infants as having multiple defects if
they had at least one other unrelated major congenital anomaly in
addition to the renal anomaly. Infants with additional minor congenital
anomalies or anomalies that were part of the oligohydramnios sequence
were classified as having isolated defects. There were 158 infants
whose renal defect(s) made them eligible for the study; sufficient
information on prenatal alcohol exposure was available for 148 of these
infants. We used two control groups. One group consisted of 2886 control infants from the ABDCCS who had no reported congenital
anomalies and on whom alcohol exposure information was available. The
second control group consisted of 4408 case infants from the ABDCCS who
had anomalies exclusive of the urinary tract and on whom we had alcohol
exposure information.
Maternal alcohol consumption during the period between 1 month before
and 3 months after conception was determined from telephone interviews
with the infants' mothers. We derived the number of drinks consumed
per week during the critical period from questions regarding frequency
and dose. We defined binge drinking as drinking five or more drinks of
beer, wine, or hard liquor on one occasion. We classified levels of
consumption as light for less than 3 drinks per week, moderate for 3 to
13 drinks per week, and heavy for 14 or more drinks per week; these
levels were derived from the classification system used to report
alcohol consumption patterns in the United States in the 1983 and 1988 alcohol supplements of the National Health Interview
Survey.30
Statistical Methods and Analyses
We compared case and control infants with respect to maternal
alcohol consumption. We calculated odds ratios (ORs) and 95% confidence intervals and used unconditional logistic regression to
adjust for potential confounders. Potential confounders included maternal age (<20, 20-34, and 
35 years), education, and race; whether mothers smoked, had diabetes mellitus, or used vitamins between
3 months before and the first 3 months after conception; and period of
birth. We included vitamin use as a confounder because multivitamin use
among pregnant women in their first trimester was recently reported to
have a protective effect against congenital urinary tract anomalies
among their children.31,32 Because there were no
significant differences between the models with and without these
potential confounders, we present the results of the crude analyses. We
also present the results of crude analyses for some subgroups of
defects (eg, renal agenesis and hypoplasia, multiple with anal atresia)
that occurred too infrequently for meaningful analysis by logistic
regression.
We calculated the attributable fraction (AF, the
fraction of cases of a disease in a population attributed to a
particular risk factor) using the formula of Miettinen33
[AF = fc(R 
1)/R], where fc is the fraction of
cases with the moderate in utero alcohol exposure, and R is
the OR.34
RESULTS
Table 1 shows the association between maternal
light-to-moderate alcohol consumption and the occurrence of selected
renal anomalies. Infants exposed in utero to 14 or more drinks per week (heavy consumption) were included in this table, but data are sparse.
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Table 1.
Association Between Selected Renal Anomalies and Mothers'
Light-to-Moderate Alcohol Consumption During Pregnancy: Atlanta Birth
Defects Case-Control Study, 1968 Through 1980
[View Table]
|
Of the 2886 mothers of control infants with no anomalies, 847 (29.3%)
reported consuming more than zero but fewer than three drinks per week,
whereas of the 148 mothers of infants with renal anomalies, only 34 (22.3%) reported drinking that amount, thus showing no significant
association between this low level of in utero alcohol exposure and
renal anomalies. In addition, we found no significant association
between this level of in utero exposure and any of the subgroups of
renal anomalies. The OR for multicystic dysplasia was elevated at 2.4;
however, four infants with this defect were excluded because of missing
variables necessary to calculate the number of drinks that their
mothers consumed per week. Other variables indicate that these mothers
were probably nondrinkers; thus the OR may be falsely elevated.
Of the 2886 mothers of control infants with no anomalies, 428 (14.8%)
reported consuming from 3 to 13 drinks per week. Of the 148 mothers of
case infants, 32 (21.6%) reported a similar exposure, which yielded an
OR of 1.5, which was not significant. On subgroup analysis, only renal
agenesis was significantly associated with moderate in utero exposure
(OR, 2.5; 95% confidence interval, 1.2 to 5.1).
We further subdivided the hydroureter or hydronephrosis group according
to the level or type of obstructive lesion (ie, ureteropelvic junction
and ureter, ureterovesicular junction, bladder neck and posterior
urethra, posterior urethral valves, and unspecified). However, no level
of in utero alcohol exposure was significantly associated with any of
these subgroups, and the results are not presented in this article.
As shown in Table 2, light in utero exposure to alcohol
was not significantly associated with renal agenesis and hypoplasia, but moderate exposure was. In this analysis, infants were further subdivided into those with unilateral or bilateral defects and those in
whom the defects were isolated or single components of multiple
congenital anomalies. No association between light consumption and any
subgroup of renal agenesis or hypoplasia was seen. However, among
children of mothers with histories of moderate consumption, ORs were
elevated for all subgroups of defects but were significantly elevated
only in the bilateral and multiple subgroups.
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Table 2.
Association Between Renal Agenesis and Hypoplasia and Mothers'
Light-to-Moderate Alcohol Consumption During Pregnancy: Atlanta Birth
Defects Case-Control Study, 1968 Through 1980
[View Table]
|
Table 3 shows the association between binge drinking
among moderate drinkers and their risk of having children with renal agenesis or hypoplasia. There was a significant association between binge drinking and all renal agenesis or hypoplasia. Although the ORs
were elevated for each of the subgroups of this class of anomaly, they
were statistically significant only for bilateral defects and multiple
congenital anomalies. However, among mothers of both case and control
infants, those who were binge drinkers had a higher number of drinks
per week than those who did not binge. Therefore, it is difficult to
disentangle the effect of quantity of alcohol from the binge pattern.
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Table 3.
Association Between Renal Agenesis and Hypoplasia and Binge Drinking
Among Mothers Who Were Light-to-Moderate Drinkers During Pregnancy:
Atlanta Birth Defects Case-Control Study, 1968 Through 1980
[View Table]
|
The association of various combinations of structural anomalies with
light-to-moderate maternal alcohol consumption is shown in Table
4. Only major anomalies that were unrelated to the renal anomalies and occurred more than once in the exposed infants are shown.
Combinations that are not shown because they occurred only once in the
exposed infants included tracheoesophageal fistula, unilateral lung
agenesis, omphalocele, unspecified accessory digits, and agenesis of
the gallbladder. Only anal atresia and major cardiac defects in
conjunction with renal agenesis or hypoplasia showed a significant
association with moderate exposure. The types of cardiac defects were
varied and included unspecified ventricular septal defects in two
infants and coarctation of the aorta, an atrial septal defect, and
aortic and mitral valve hypoplasia in only one infant each. Of the two
infants with cardiac defects, one also had anal atresia, and another
had hemivertebrae. No multiple defect combination was significantly
associated with light maternal alcohol consumption.
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Table 4.
Association Between Multiple Congenital Anomalies with Renal Agenesis
and Hypoplasia and Mothers' Light-toModerate Alcohol Consumption
During Pregnancy: Atlanta Birth Defects Case-Control Study, 1968 Through 1980
[View Table]
|
For all analyses, we used a second control group composed of infants
with congenital anomalies exclusive of the urinary tract. The results
of the analyses with this second control group were not appreciably
different from those with the first group, and they are not included in
this report.
The attributable fractions for moderate alcohol exposure and two
subgroups of renal agenesis and hypoplasia, bilateral and multiple
defects, were 33% and 22%, respectively. If the association between
renal agenesis or hypoplasia and moderate maternal alcohol consumption
during pregnancy is causal, we estimate that 22% of the multiple
anomaly cases and 33% of bilateral defect cases may be attributed to
this exposure.
DISCUSSION
The main finding of this study was a significant association
between a pregnant woman's reported moderate alcohol consumption and
renal agenesis or hypoplasia among her offspring. This association was
stronger for infants with bilateral defects and for infants who have
multiple congenital anomalies, in particular anal atresia and major
cardiac defects. However, given the rarity of renal agenesis or
hypoplasia in the general population,35 the absolute risk
for this defect among offspring of women who consume moderate amounts
of alcohol during the first trimester is less than 1 in 1000 exposed
births. There were no significant associations with other studied renal
anomalies and reported moderate consumption and no significant
associations between any category of renal anomalies and reported light
consumption. Reported heavy consumption was rare in the study
population; therefore, no conclusions could be reached for this
consumption category because of sparse data.
Before interpreting these results, it is important to consider the
strengths and limitations of the study. Because we derived our data
from a population-based study with a relatively large number of births,
it was not subject to the selection bias found in most clinic- or
hospital-based studies, and there were enough participants in the study
to detect small excess risks. The diagnosis data were based on multiple
sources of ascertainment, and because the data were collected before
there was widespread use of prenatal diagnosis, there was probably
little bias introduced by pregnancies being selectively terminated
before 20 weeks' gestation. Additionally, the interview data were
collected before there was widespread knowledge of alcohol-related
congenital anomalies, knowledge that could perhaps cause a woman to be
reluctant to disclose her alcohol consumption during pregnancy.
The study has several limitations. Renal anomalies are variably
ascertained and classified; however, 67% of the infants in the renal
agenesis or hypoplasia group did have autopsies. In addition, infants
with other major congenital anomalies and those who are stillborn or
die shortly after birth may be studied more completely than those with
isolated and/or unilateral defects. The renal defects studied are most
likely heterogeneous in both cause and pathogenesis, and one or more of
the case infants may have had an undiagnosed genetic syndrome. There
were small numbers of case infants, especially in the subgroups with
additional anomalies.
The level of alcohol exposure is difficult to quantitate. The structure
of the questionnaire does not allow for easy determination of the
amount of absolute alcohol ingested per week. There were variable
periods between exposure and administration of the questionnaire. In
addition, we are relying on self-reported exposure data, which may be
subject to recall bias. However, the results of analyses with a control
group of infants with congenital anomalies indicate that this was not a
significant problem in this study. Comparing the results of this study
with those of other studies is complicated by the variation in alcohol
consumption classification.
Animal studies give some support to the biological plausibility of the
study finding. In mice, Gage and Sulik20 demonstrated that
ethanol caused excessive cell death in the region of the developing
mesonephric duct just proximal to the cloaca and in the premigratory
neural crest cell located just proximal to the posterior neuropore.
However, the resultant defects in these mice were hydronephrosis and
hydroureter, not renal agenesis or hypoplasia. In light of our elevated
OR for renal or ureteral duplication, it is interesting that the
hydronephrosis was commonly caused by duplicate ureteral lumens. In
monkeys, Mukherjee and Hodgen36 observed that maternal
ethanol exposure in the third trimester induced transient impairment of
umbilical circulation and resultant fetal hypoxia. Human umbilical
blood vessels from full-term pregnancies were subsequently reported to
spasm when exposed to ethanol.37 Whether this effect could
be produced earlier in pregnancy and to a sufficient degree to cause
hypoperfusion of the developing kidney and other organs is unknown.
Previous studies of the relationship between maternal alcohol
consumption and renal anomalies have produced varying results, as
discussed previously. We found that prenatal alcohol exposure was most
highly associated with renal agenesis or hypoplasia in conjunction with
bilateral defects and/or multiple congenital anomalies. Because infants
with these anomalies are more likely to be stillborn or to die shortly
after death (74% in this study), studies that ascertain cases after
the neonatal period will miss an association between moderate alcohol
exposure and these defects.
The literature is also divided on the effect that maternal binge
drinking has on a child's risk of congenital anomalies in general.
Studies with both positive and negative results are
reported.8,12,14 Although among women who drank moderately
we found a significant association between binge drinking and their
children's risk of renal agenesis or hypoplasia, we cannot interpret
this finding with the available data.
Even in view of the limitations of this study, we think that the
findings are important and warrant further investigation in studies
with better measures of both exposure and outcome. If our results are
confirmed by other studies, moderate alcohol consumption during
pregnancy could be identified as an important determinant of renal
agenesis or hypoplasia.
Reprint requests to (C.A.M.) Centers for Disease Control and
Prevention, National Center for Environmental Health, Division of Birth
Defects and Developmental Disabilities, 4770 Buford Hwy, F-45, Atlanta,
GA 30341-3724.
We thank the Metropolitan Atlanta Congenital Defects Program
abstracters, Charlie Mae Peters, Connie Thompson, Debbie Nurmi, Joan
Garcia, Joann Donaldson, Jo Anne Croghan, Carolyn Sullivan, and Melissa
Johnson, for their superior data collection efforts.
ABSTRACT
