1 Perinatal Epidemiological Research Unit, Department of Obstetrics and Gynaecology, Aarhus University Hospital, 8200 Aarhus N, Denmark.
2 Department of Paediatrics, Aarhus University Hospital, 8200 Aarhus N, Denmark.
3 Maternal Nutrition Group, Danish Epidemiology Science Centre, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen S, Denmark.
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ABSTRACT |
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alcohol drinking; fetal death; infant mortality; pregnancy
Abbreviations: CI, confidence interval
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INTRODUCTION |
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Intake of one or more alcoholic drinks per day during pregnancy has consistently been shown to be associated with reduced birth weight and intrauterine growth restriction (5, 6
), and heavy maternal alcohol consumption is consistently found to be associated with malformations (7
), mental retardation (8
), and behavioral and psychosocial problems in childhood and adolescence (9
, 10
). Still, the question of whether there is a safe level of drinking during pregnancy remains controversial (8
, 11
, 12
).
Results regarding the relation of alcohol drinking to stillbirth and perinatal, neonatal, and infant mortality have been few and highly inconsistent (1321
). Many studies used retrospective information on alcohol intake (13
18
) or did not adequately account for competing risk factors (19
21
). Excessive alcohol consumption during pregnancy is potentially preventable; therefore, clarification of the relation between alcohol drinking and infant mortality is important.
We examined the association between maternal alcohol consumption during pregnancy and the risk of stillbirth and death during the first year of life in a Danish cohort of pregnant women. We used information on alcohol intake that had been collected prospectively during pregnancy and took into account a variety of other lifestyle factors, maternal risk factors, and obstetric risk factors.
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MATERIALS AND METHODS |
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Information on stillbirths, including causes of death, was obtained from one of the birth registration forms and from the Danish Medical Birth Register through record linkage, using the mother's unique personal identification number. Information on deaths occurring during the first year of life was obtained from the Registry of Causes of Death, which is administered by the Danish National Board of Health, and from the Civil Registration System. Four children listed as deceased according to the Civil Registration System were not registered in the Registry of Causes of Death. The medical records were checked, and according to the records all four children were dead.
Stillbirth was defined as delivery of a dead fetus at 28 completed weeks of gestation or later in pregnancy. Infant death was defined as death within the first year of life among liveborn babies. Causes of stillbirth were categorized according to the classification suggested by Andersen et al. (22), based on categorizations suggested by Cole et al. (23
) and Hey et al. (24
). The classification identifies the factor which probably initiated the chain of events leading to death (22
). In Danish data, this categorization was previously shown to yield fewer unexplained deaths than the categorization suggested by Cole et al. (22
, 23
), as well as a more detailed description of the category labeled "antepartum asphyxia" in the classification by Hey et al. (22
, 24
). For deaths that could not be unambiguously classified on the basis of the register data, the medical records and autopsy reports were consulted before classification.
Danish women with singleton pregnancies who did not have an induced abortion and who completed the questionnaire for the medical record were eligible for this study (n = 25,788). We excluded the following types of pregnancies from the study: pregnancies that ended with a spontaneous abortion (defined as delivery of a dead fetus before 28 completed weeks of gestation) (n = 346); pregnancies included in the cohort after birth had occurred (n = 7); and pregnancies for which there was no information on alcohol intake (n = 667). This left 24,768 pregnancies for analysis (116 stillbirths, 119 infant deaths). All livebirths, including infant deaths, were included in the analyses irrespective of gestational age at the time of delivery. For analysis of infant deaths, stillbirths were excluded from the denominator. All participants in the study had filled in the questionnaire for the medical record, whereas 18,287 (74 percent) had filled in the research questionnaire.
In the medical-record questionnaire, the following question on alcohol intake was asked: "How many drinks do you approximately drink per week (one drink is the equivalent of one [bottle of] beer, one glass of wine, or one schnapps)?" This question has been shown to yield information comparable to that obtained from a more extensive research questionnaire (25), and it has been validated in a study comparing it with an extensive interview and with diaries (26
). Possible responses to the question on alcohol consumption were precoded as <1, 12, 34, 59, 1014, 1519, 2029, 3039, and
40 drinks/week. Because of small numbers in the highest alcohol intake categories (table 1), information on alcohol intake was categorized into four groups for these analyses (<1, 12, 34, and
5 drinks/week). The definition of a drink followed the definition of the Danish National Board of Health: One drink contains 12 g or 15 ml of pure alcohol, the equivalent of one normal beer, one glass of wine, or 4 cl (40 ml) of spirits. Caffeine intake was calculated from average daily consumption of coffee (one cup = 104 mg), tea (one cup = 46 mg), liquid chocolate (one cup = 13 mg), and cola (one bottle or 250 ml = 45 mg) (27
). Potentially confounding factors were categorized as shown in table 2.
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The study was approved by the regional ethics committee, the Danish Data Protection Agency, and the Danish National Board of Health.
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RESULTS |
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Stillbirth
Bivariate analyses showed that the risk of stillbirth increased with increasing alcohol intake across alcohol categories (Mantel-Haenszel 2 test for trend: p = 0.02; test for departure from a linear trend: p > 0.2). Women who consumed
5 drinks/week had a risk of stillbirth nearly three times greater than that of women who consumed <1 drink/week (table 2). Restricting analyses to each woman's first pregnancy registered in the cohort during the study period did not change this conclusion. There was no interaction with smoking (p > 0.1) or effect modification by smoking (p > 0.1) at any alcohol intake level. Multivariate logistic regression analysis, which included maternal smoking habits, caffeine intake, age, prepregnancy body mass index (weight (kg)/height (m)2), marital status, occupational status, education, parity, and sex of the child, yielded comparable results (table 3). For comparison, the unadjusted and adjusted odds ratios for the subset of women with no missing information on any of the potential confounders are also shown in table 3. Alcohol may increase the risk of low birth weight and preterm delivery, and these factors may also increase the risk of stillbirth (table 2); yet stratification by birth weight and preterm delivery (dichotomized) did not change the conclusions (all p's > 0.1), nor did inclusion of these variables in the regression model (the odds ratio for women who consumed
5 drinks/week was 2.69 (95 percent confidence interval (CI): 1.14, 6.31)).
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The risk of stillbirth due to fetoplacental dysfunction increased across alcohol categories, from 1.37 per 1,000 for women consuming <1 drink/week to 8.83 per 1,000 for women consuming 5 drinks/week (table 4). When we included only stillbirths due to fetoplacental dysfunction in the analyses, the adjusted odds ratios for women consuming 12, 34, and
5 drinks/week were 1.45 (95 percent CI: 0.67, 3.11), 1.79 (95 percent CI: 0.60, 5.37), and 7.92 (95 percent CI: 2.80, 22.40), respectively. The increased risk of stillbirth did not seem to be mediated through an increased risk of malformations (table 4).
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Multivariate logistic regression analyses with adjustment for potential confounding by maternal smoking, caffeine intake, age, prepregnancy body mass index, marital status, occupational status, education, parity, and sex of the child yielded comparable results (table 5), as did inclusion of birth weight and preterm delivery in the regression model (the odds ratio for women consuming 5 drinks/week was 1.39 (95 percent CI: 0.49, 3.95)).
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DISCUSSION |
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Previous studies of mortality have yielded highly inconsistent results (1321, 32). One study which used prospective information on alcohol intake showed a 2.5 times increased risk of stillbirth for women consuming >3 drinks/day (32); another study showed a linear relation for stillbirth and infant mortality, each drink increasing the risk of stillbirth by 1 percent (16
). However, the unadjusted data from the latter study suggest a threshold effect for both outcomes at a level of approximately 6 drinks/week rather than a linear relation. Yet another study showed an increased risk of intrapartum stillbirth (13
) and perinatal mortality (13
, 20
) for abstainers. Other studies have found no association between alcohol and stillbirth (14
, 15
, 17
, 19
, 21
), perinatal mortality (21
), early neonatal (17
) or neonatal (19
, 21
) mortality, or sudden infant death syndrome (18
). However, in most of these studies, investigators used retrospective information on alcohol intake (collected after death had occurred) (13
18
), and in some of the studies they did not adequately control for potentially confounding factors (19
21
).
Preterm delivery and low birth weight are important contributors to neonatal mortality (33, 34
). We previously found that alcohol was associated with increased risk of preterm delivery (35
), and it has consistently been found that alcohol is associated with increased risk of low birth weight (5
, 6
). However, our analyses suggested that the association of stillbirth with alcohol consumption was not mediated by an effect of alcohol on preterm delivery and birth weight, nor did it seem to be mediated by an effect of alcohol on malformations.
For stillbirth, the test for departure from a linear trend (based on unadjusted data) did not yield a significant result, which suggests a linear effect rather than a threshold effect. On the other hand, considering that the risk for women consuming 12 and 34 drinks/week was only insignificantly increased in comparison with women drinking less, and considering that the linear trend seemed less evident when the adjusted estimates were examined (table 3), one should be cautious when interpreting the apparent linear dose-response relation. Moreover, although underreporting usually has little effect on the association between exposure and outcome (if the reference group is large) (36), underreporting of alcohol intake may mask a true threshold effect as a dose-response relation (36
). Indeed, it is well-known that alcohol intake is usually underreported in questionnaires and interviews as compared with diaries (37
). When we compared our questionnaire data with information on alcohol intake obtained from a more elaborate questionnaire specifying subtypes of alcohol (25
) and with information from an elaborate personal interview and from diaries specifying alcohol subtypes and different time periods during pregnancy, we found a slight tendency towards underreporting in the questionnaire data (26
). Therefore, considering that slight underreporting is likely to have occurred (26
), a threshold for the effect of alcohol on stillbirth also seems to be a plausible interpretation of our data. In any case, both interpretations are possible because of the small numbers in the highest alcohol intake group.
We had information on alcohol intake at only one point in time during pregnancy, and therefore we were not able to account for different patterns of drinking. Our data did not allow us to distinguish between total abstainers and women reporting an intake of >0 but <1 drink/week. However, a distinction between these two groups of women would be inappropriate in our data in any case. In a recent study, when we focused on low-to-moderate intake, we found that a very large group of women (544 percent) who reported being total abstainers on the questionnaire actually reported consuming small amounts of alcohol (>0 but <1 drink/week) in interviews or diaries, and vice versa (26).
Although this was one of the largest studies of this topic to date, the number and distribution of drinkers limited the analytical possibilities. Very few women reported consuming more than 14 drinks/week, which made it impossible to independently assess effects above this level, and the findings for women who consumed 5 drinks/week were all based on low numbers.
Women consuming 5 drinks/week were older, were more often smokers, had a higher caffeine intake, were more educated, and were more often multiparous than women with a lower alcohol intake. Women with a high alcohol intake may also differ with regard to other sociodemographic factors not included in these analyses, and thus bias from unadjusted confounding may be present. Furthermore, information was missing for some women, particularly with respect to caffeine intake, occupation, and education. However, in order for these variables to act as confounders they must be associated with both alcohol intake and death. Although caffeine intake and education were associated with alcohol intake (based on information obtained from the participants), none of the variables were significantly associated with death (table 2). In any case, causal inferences should be made with caution.
We used the definition of stillbirth that was used officially during the study periodthe definition of the Danish Medical Birth Register. We obtained supplementary data on spontaneous abortions occurring in the 27th and 28th weeks of gestation from the Danish National Patient Registry. Including these fetal deaths in the analyses did not change the conclusions: Adjusted odds ratios for women consuming 12, 34, and 5 drinks/week were 1.28 (95 percent CI: 0.82, 1.99), 1.26 (95 percent CI: 0.64, 2.49), and 2.69 (95 percent CI: 1.20, 6.05), respectively, in comparison with women consuming <1 drink/week.
We found an increased risk of stillbirth that was mainly due to fetoplacental dysfunction, including placental infarction, complications related to the umbilical cord, intrauterine growth retardation, and antepartum asphyxia (22). Animal models have shown that increasing alcohol intake may increase the risk of severe intravascular coagulation (38
) and decrease blood flow in the placenta (39
). A recent study in humans suggested that alcohol abuse among nonpregnant surgical patients may change hemostatic function (40
). Other possible pathophysiologic mechanisms may include increased production of prostaglandins, including prostaglandins of the E series (41
, 42
). Prostaglandins increase cyclic 3',5'adenosine monophosphate activity, thereby decreasing cell division (42
), and it is possible that increased levels of prostaglandin E2 and prostaglandin F2
cause fetal death (43
). Finally, alcohol drinking may cause hypoglycemia (44
), and an association has been found between hypoglycemia and perinatal mortality (45
).
Our data suggest that there is an increasing risk of stillbirth with increasing moderate alcohol intake. The data show that women consuming 5 drinks/week have a 23 times increased risk of stillbirth that is attributable mainly to fetoplacental dysfunction.
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ACKNOWLEDGMENTS |
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NOTES |
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REFERENCES |
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