1 Perinatal Epidemiological Research Unit, Department of Obstetrics and Gynaecology, Aarhus University Hospital, Aarhus, Denmark.
2 Department of Occupational Medicine, Aarhus University Hospital, Aarhus, Denmark.
3 Department of Growth and Reproduction, the National Hospital, Copenhagen, Denmark.
4 Reproductive Toxicology Unit, Institute of Anatomy, University of Aarhus, Aarhus, Denmark.
5 The Danish Epidemiology Science Center, University of Aarhus, Aarhus, Denmark.
Received for publication August 20, 2002; accepted for publication April 2, 2004.
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
abortion, spontaneous; alcohol drinking; embryo; follow-up studies
Abbreviations: Abbreviation: hCG, human chorionic gonadotropin.
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In humans, the association between alcohol consumption and clinically recognized or self-reported spontaneous abortion is less clear (413). Women with a very high alcohol intake have been shown to be at increased risk of preterm delivery and stillbirth, and a high intake during pregnancy may be teratogenic for some (14).
Early biochemically detected embryonal losses may account for as many as 4070 percent of all pregnancy losses (1518). Thus, studies of clinically recognized abortions may fail to reveal even very high risks if the exposure shifts the associated spontaneous abortions toward clinically undetectable abortions.
There are few studies on male alcohol intake and spontaneous abortions, and the published studies show no association (5, 12, 19). Alcohol consumption has been shown to be associated with aneuploidy in sperm cells (20), and spontaneously aborted embryos are frequently chromosomally abnormal (21). Alcohol is present in semen relatively shortly after ingestion, and it may also interfere directly with conception and thereby implantation (22). Thus, male alcohol intake may affect risk of early losses.
By follow-up of couples that attempted to conceive for the first time, we set out to study the association between female and male alcohol intakes and the risk of spontaneous abortion. We included early pregnancy loss, detected by measurement of human chorionic gonadotropin (hCG) in urine.
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
At enrollment, both partners completed a questionnaire on demographic, medical, reproductive, occupational, and lifestyle factors. Moreover, a monthly questionnaire on lifestyle factors completed 1421 days from the last menstrual bleeding was collected during follow-up. The women furthermore recorded vaginal bleeding and sexual intercourse in a diary. The time of questionnaire completion was estimated by the dates of returning questionnaires.
Alcohol intake was reported as the average number of drinks (glasses of wine, spirits, and bottles of beer of 0.33 liter, each corresponding to 12 g of alcohol) during the week before completion of the questionnaire. Wine and beer drinking were analyzed as separate exposures and subsequently combined into a compound measure together with spirits. Alcohol intake was categorized a priori into four categories (0, 14, 59, and 10 drinks/week).
The variables listed in table 1 were considered as potential confounders or modifiers. Caffeine intake was calculated from the reported daily consumption of coffee, tea, cola, and chocolate bars (24). Furthermore, the type of contraception last used, education, and hours at work were considered.
|
A total of 291 pregnancies were conceived. All cycles (n = 83 pregnancies) with no urinary sampling were excluded, because they were unavailable for detection of a potential early pregnancy loss. Only the womans first pregnancy conceived during the study period was considered, leaving 186 pregnancies for our analyses. A spontaneous abortion was defined as an involuntary loss within 28 weeks of the last menstrual period.
Statistics
In the analyses, the outcome was dichotomized: spontaneous abortion versus delivery. Since early biochemically detected pregnancy losses and clinically recognized abortions may not have the same etiology, separate analyses of each outcome were carried out before they were analyzed together. Survival curves were computed by the Kaplan-Meier method. Cox proportional hazards regression analyses were carried out with gestational age in completed weeks as the measure of time and abortion as the event of interest. Potential confounding factors were included in the regression analyses coded as shown in table 1. All pregnancies that continued beyond 28 completed weeks were right censored, as the women were no longer at risk of an abortion. The adjusted hazard ratios for abortion were present with 95 percent confidence intervals. Confounding factors were selected for the final model by the change-in-estimate method (26). Models were built for male and female alcohol intakes separately. Menstrual cycle length, maternal age, smoking, and caffeine intake were adjusted for in the final model. The two exposures were also tested in the same model with and without interaction terms. The level of statistical significance is defined as a two-sided p value of less than 5 percent.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
A high intake of alcohol by women or their partners was associated with a higher frequency of spontaneous abortions than was a low intake (table 1). Women who experienced a spontaneous abortion were older and had, on average, longer menstrual cycles, a higher caffeine intake, and partners with a higher caffeine intake than did women who gave birth (table 1). No association was found between spontaneous abortion and the partners smoking habits, partners age, body mass index, and partners reproductive illnesses; contraception last used; education for both man and woman; or hours at work for both partners.
The crude associations between female and male alcohol intakes and spontaneous abortion shown in figures 1 and 2 changed only slightly by adjustment for the confounders listed in table 2. Female alcohol intake was associated with a 23 times higher adjusted risk of spontaneous abortion compared with no intake, and male intake was associated with a 25 times increase in the adjusted risk. However, only the relative risks for male and female intakes of 10 or more drinks/week compared with no intake were statistically significant. We found a high correlation between male and female alcohol intakes. Additional adjustment for male intake revealed a lower risk of spontaneous abortion associated with female alcohol intake, whereas the higher risk associated with a high male alcohol intake changed only slightly following adjustment for female intake (table 2).
|
|
|
Only a few of the participants had an intake of spirits in the study period, and the associated risk of spontaneous abortion with alcohol could not be ascribed to a particular source, such as wine or beer. However, the size of our study did not allow us to fully explore each source of alcohol separately.
Alcohol consumption varied throughout the study period. We used information on alcohol intake from the cycle of conception as the primary exposure. Alcohol intake reported at the study entry was not statistically significantly associated with spontaneous abortion.
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Both partners reported their weekly alcohol intake in the cycle of conception on days 1421 from the last menstrual bleeding. Thus, the outcome of the cycle was unknown, and differential misclassification of alcohol intake is therefore unlikely. Most previous studies report average weekly consumption, which may be too imprecise. Accordingly, we found no association when alcohol intake reported at the time of pregnancy planning was studied. Other studies suffer from both selection bias and recall bias (27). Alcohol intake during early pregnancy may also be influenced by fetal death prior to an abortion, which may eliminate nausea and increase intake. Thus, if alcohol intake during conception is the proper exposure, it may explain why our estimates differ from those of previous studies. However, several studies with collection of information on alcohol intake in early pregnancy prior to recognition of clinical abortions have similar findings (8, 28). If our findings are causal, the possibility that female exposure may partly be a surrogate measure of male exposure also exists. None of the studies with information on alcohol intake in early pregnancy has collected information on male alcohol intake.
Some previous studies have reported a dose-response-like association between the number of drinks consumed and the risk of clinically recognized abortion (29). We found no dose-response relations that could be due to random misclassification of a light and moderate alcohol intake, because the exact number of drinks may be difficult to remember unless it is zero. If we grouped the light and the moderate consumers, a dose-response-like pattern was seen. The lack of a dose-response relation could also be due to our relatively small sample size and the concomitant imprecision.
No previous studies have investigated the combined effects of male and female alcohol intakes. In our study, a high intake of alcohol in both partners around the time of conception failed to increase the risk beyond that associated with male and female intakes separately.
If even small amounts of alcohol affect the conceptus and its survival immediately after the implantation, this may explain the male effect since seminal fluid has an alcohol content similar to what is found in blood (22). However, the male effect of alcohol on very early pregnancy losses may also be due to chromosomal abnormalities in the sperm cells, which condition is likely to occur some months prior to the conception. Unfortunately, we had no information on detailed cycle-specific alcohol intake during the cycles prior to the couples entry into the study, and a high proportion of our pregnancies occurred in the first couple of cycles during the study period. However, if alcohol intake is stable over time, our data are appropriate.
We tested a number of potential confounders but found that only menstrual cycle length, female caffeine intake, smoking, and age changed the estimated risks. Only some of these factors have been considered before (4, 810, 12, 30). Even with careful collection of and adjustment for potential confounding factors, residual confounding cannot completely be ruled out.
Self-reported information on lifestyle factors, such as alcohol intake, may underestimate the true consumption. If underreporting was present, it is unlikely to be differential, as the outcome of pregnancy in our study was unknown at the time of the reporting. Therefore, underreporting could indicate effects at biased low levels of intake or even obscure an association between alcohol intake and spontaneous abortion.
We emphasized that participants should have no prior knowledge about their fecundity, including no pregnancies or previous attempts to become pregnant. Thus, selection of couples with known problems related to fertility is unlikely, as is bias due to specific selection of subfertile couples with a very high or low alcohol intake. We also avoided enrollment of couples who may have changed their alcohol intake and other lifestyle factors because of previous pregnancy experience or because of a loss in the beginning of the study period by including only first pregnancies. Furthermore, 100 percent follow-up was obtained.
Our sample is not a representative sample of the population (23). However, it is unlikely that this will bias our estimates of the association between alcohol intake and spontaneous abortion. We have previously shown that women in this study with a moderate or high alcohol intake have an increased waiting time to pregnancy (31). However, our estimated risk of spontaneous abortion associated with female alcohol consumption would only partly explain the decreased fecundability. This suggests that the effects of alcohol on female fecundability are mediated through different mechanisms, and early pregnancy loss is only one of those. Our analyses of time to pregnancy, however, did not indicate an increased risk of spontaneous abortion associated with male alcohol intake. Thus, time to clinically recognized pregnancy is a rather insensitive measure of the risk of early pregnancy loss.
In conclusion, we found that both male and female alcohol intakes during the week of conception increased the risk of spontaneous abortion, including biochemically detected pregnancy loss.
![]() |
ACKNOWLEDGMENTS |
---|
The authors thank Dr. Allen J. Wilcox for fruitful discussions during the design of the study and Dr. Ulrik Kesmodel for valuable comments on a previous version of the manuscript.
![]() |
NOTES |
---|
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|