1 INSERM U569, IFR69 (The French Institute of Health and Medical Research), Le Kremlin-Bicêtre, France.
2 Centre Hospitalier Hôtel-Dieu, Service de Gynécologie-Obstétrique, Clermont-Ferrand, France.
3 Hôpital Antoine Béclère, Service de Gynécologie-Obstétrique, Clamart, France.
4 Service dEpidémiologie et de Santé Publique, Clermont-Ferrand, France.
Received for publication February 15, 2002; accepted for publication August 28, 2002.
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ABSTRACT |
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abortion, induced; case-control studies; infertility, female; pregnancy, ectopic; registries; risk factors; sexually transmitted diseases; tobacco
Abbreviations: Abbreviation: CI, confidence interval.
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INTRODUCTION |
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Several risk factors for ectopic pregnancy have been identified (3, 68) including pelvic inflammatory disease, smoking, and, previous ectopic pregnancy. Other factors, such as age, surgical history, and obstetric history, are also thought to be involved. However, the role played by these factors remains unclear because of problems with the sample size or the design of previous studies. Published meta-analyses of ectopic pregnancy risk factors (911) only partly answered the questions addressed, mainly because their ability to adjust for confounders was limited (12, 13). This problem is particularly severe in analyses of ectopic pregnancy, which has a large number of highly correlated risk factors. The selection of studies to be included in the meta-analysis and assessment of their quality may also cause difficulties. Strikingly, in the two most recent meta-analyses on this subject, two different sets of studies were selected (9, 10).
The ectopic pregnancy register of Auvergne (France) (14) and associated case-control studies provide an opportunity to analyze the risk factors for ectopic pregnancy in a large sample, representative of a geographically defined population. Results concerning women using contraception at the time of conception have already being published (15). This study focuses on women not using contraception at the time of conception. It aimed to provide a comprehensive analysis of the ectopic pregnancy risk factors in these women.
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MATERIALS AND METHODS |
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Each case of ectopic pregnancy in a woman not using contraception was associated with two controls: women who gave birth at the center at which the case was treated and women whose delivery occurred very shortly after treatment of the case. For some cases, only one control was interviewed, and no control was associated with cases retrieved at the end of the year when the completeness of the register was checked. The same questionnaire was used for cases and controls, except for items relating directly to the diagnosis and treatment of ectopic pregnancy. Between September 1993 (beginning of recruitment of controls) and December 2000, a total of 1,065 cases and 1,881 controls were collected.
Women who underwent induced abortion were not included in the control group because, in France, these women are referred to specialist centers not connected with maternity hospitals. However, a certain proportion of cases might have undergone induced abortion had their pregnancy been intrauterine. We attempted to take this into account by the method recommended by Weiss et al. (16), which involves restricting the analysis to women married (or living as a couple) and not using contraception at the time of conception (803 cases and 1,683 controls). As stated by Weiss et al., this restriction should make cases and controls more comparable, reducing the magnitude of the bias present when evaluating variables associated with induced abortion.
Statistical analysis
We carried out a two-stage analysis as a large number of potential risk factors were investigated. We first assigned the risk factors to four groups: 1) sociodemographic characteristics, 2) surgical, gynecologic, and obstetric history, 3) potential exposure to infectious factors, and 4) contraceptive history and fertility markers. Univariate analyses were performed to generate crude odds ratios. Logistic regressions were then performed within each group, including variables with p values of 0.2 in univariate analysis (17). Finally, variables with p values of
0.2 in these four partial analyses were included in a global logistic regression analysis. The assignment of a factor to a particular group was a matter of debate in some instances. We checked that the assignment of such factors to particular groups had no influence on the final logistic regression analysis.
For quantitative variables, such as age or time since the previous pregnancy, the association with ectopic pregnancy risk was plotted using fractional polynomials (18), a simple and powerful way of modeling nonlinear relations.
Finally, attributable risks were calculated for each risk factor. Attributable risks provide an additional dimension to risk factors that is useful for public health purposes. The odds ratio gives the individual increase in risk of ectopic pregnancy for a woman exposed to that risk, whereas the attributable risk indicates the burden of this risk factor at the population level. Attributable risks were adjusted for the other risk factors as described by Bruzzi et al. (19). For age, the category 2529 years was taken as the reference because this corresponds to the mean age for delivery in France at the time of the study. Thus, the odds ratio and attributable risk were calculated with this category considered as "nonexposed."
A woman experiencing several ectopic pregnancies during the study period generated multiple case entries, one for each ectopic pregnancy. In this study, 43 women experienced two ectopic pregnancies and four women experienced three ectopic pregnancies, that is, 12 percent of all ectopic pregnancies. Although this proportion was relatively small, the potential nonindependence of the data induced was taken into account using a random effects model (17) in the multivariate analysis; incidentally, we observed that the results were quite similar to those obtained with a usual logistic model.
Statistical analyses were performed with STATA software (20).
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RESULTS |
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Surgical and obstetric history
Most of the items recorded in the patients obstetric histories were associated with ectopic pregnancy (table 2). However, the age of the woman and previous intrauterine device use accounted for the crude association with prior delivery. We therefore did not include the variable "prior deliveries" in the final multivariate analysis to avoid overadjustment. Although the association with prior ectopic pregnancies was very strong, this variable was not included in the final multivariate analysis. Instead, we included a broader variable, "tubal surgery," which covered all indications for tubal surgery, not just ectopic pregnancy treatment.
Prior spontaneous abortions increased the risk of ectopic pregnancy, especially for women with three or more spontaneous abortions (tables 2 and 5).
The risk of ectopic pregnancy was higher in women with previous induced abortions. However, the odds ratio differed according to the method used for abortion (table 2). The results were similar after adjustment (table 5): With prior surgical abortion only, the odds ratio = 1.1 (95 percent confidence interval (CI): 0.8, 1.6), whereas the odds ratio in women with prior medical abortion only (mifepristone and misoprostol) was 2.8 (95 percent CI: 1.1, 7.2).
Infectious history
Infectious history was studied through direct items, such as prior sexually transmitted diseases, or indirect items, such as the age at first intercourse and the number of sexual partners, which were considered to be markers of potential risk of sexually transmitted disease.
The indirect factors were associated with a risk of ectopic pregnancy in univariate analysis (table 3) but not in multivariate analysis. Prior sexually transmitted diseases were associated with a risk of ectopic pregnancy, with an adjusted odds ratio of 3.4 (95 percent CI: 2.4, 5.0) for prior confirmed pelvic infectious disease (table 5). If infectious history and prior tubal surgery (frequently performed because of infection) were considered together, their adjusted attributable risk was 0.33 (table 6).
Contraceptive history and fertility markers
Previous use of oral contraception was associated with a decreased risk of ectopic pregnancy. In contrast, previous use of an intrauterine device was associated with an increased risk of ectopic pregnancy. The induction of ovulation with clomiphene citrate was associated with a risk of ectopic pregnancy in univariate analysis, but this association disappeared after adjustment for prior infertility. A history of infertility was strongly associated with the risk of ectopic pregnancy, with a dose-response relation and an adjusted odds ratio for more than 2 years of infertility of 2.7 (95 percent CI: 1.8, 4.2).
The crude relation between time since previous pregnancy and risk of ectopic pregnancy gave a J-shaped curve (table 4). However, time since previous pregnancy was closely associated with the womans age, infertility, and previous use of an intrauterine device. To avoid overadjustment, we did not include this variable in the multivariate analysis.
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DISCUSSION |
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Almost all the women living in the Auvergne region who were treated for ectopic pregnancy during the study period were included in this study, with the completeness of the Auvergne ectopic pregnancy register estimated at about 90 percent (21, 26). Controls were selected from the same geographic population as cases.
Multicollinearity, due to the large number of highly correlated ectopic pregnancy risk factors, was dealt with in several ways including adjustment for confounders in multivariate analyses, the building of synthetic variables (for instance, prior sexually transmitted diseases), the removal of certain variables corresponding to possible intermediate factors from subsequent analysis (for instance, time since the last pregnancy), and the choice of variables closer to possible causal factors (for instance, age of the woman and previous intrauterine device use rather than prior delivery). This careful consideration of all potential factors and the large sample in this study resulted in a comprehensive study of the risk factors for ectopic pregnancy, whether previously known or only suspected.
Prior genital infections and tubal surgery
Tubal surgery may be a direct consequence of prior tubal infection and may therefore be considered with infectious factors. The importance of infectious factors in ectopic pregnancy is well documented (3, 6, 27, 28). There is probably a causal link. In Sweden, declining rates of chlamydial infections, attributed to preventive policies, have been accompanied by a fall in the risk of ectopic pregnancy (29). The other variables suggestive of a higher probability of exposure to sexually transmitted diseases (age at first intercourse and number of sexual partners) were associated with a risk of ectopic pregnancy in univariate analysis. However, this association was not significant after adjustment for diagnosed prior sexually transmitted diseases. This indicates both that these factors are not risk factors per se and that they are good markers of exposure to sexually transmitted diseases.
Finally, the adjusted attributable risk of ectopic pregnancy for both infectious factors and tubal surgery was 0.33 (table 6), making these the most important risk factors for ectopic pregnancy.
Smoking
A strong association between tobacco use and ectopic pregnancy has been demonstrated by several studies (3, 8, 28, 30, 31). Our study confirmed this association, demonstrating a dose-effect relation. This is probably a causal relation (32), and tobacco use may play a role at various stages in reproduction: ovulation, fertilization, viability, and implantation (3336). Smoking cessation reduces the risk of ectopic pregnancy to a level intermediate between that of current smokers and that of women who have never smoked. However, no trend was observed for time since cessation.
Although the magnitude of the effect of smoking on ectopic pregnancy risk is sometimes poorly appreciated, it is striking to note the parallelism between smoking and infectious factors. The odds ratios, trends, and attributable risks are of similar magnitude (tables 5 and 6). Therefore, smoking is a risk factor for ectopic pregnancy that is almost as important as infectious factors.
Age
Age has long been suspected to play a role in ectopic pregnancy risk, but studies have provided conflicting results (1, 2, 6, 8, 29, 37, 38). In our study, after careful adjustment, we found a significant relation between age and ectopic pregnancy. Therefore, unlike certain other authors (37, 38), we conclude that it is unlikely that the higher probability of exposure to most risk factors in older women accounts for the higher risk of ectopic pregnancy. The physiologic effect on ectopic pregnancy risk of an advanced maternal age at conception remains unclear. It is unlikely to involve an increase in chromosomal abnormalities in the trophoblastic tissue (39, 40). Age-related changes in tubal function may delay ovum transport and result in tubal implantation. However, these hypotheses remain to be tested (41).
Prior spontaneous abortions
The results concerning prior spontaneous abortion differ among studies (3, 11, 42, 43). We found a "dose"-response relation with prior spontaneous abortions, the adjusted risk of ectopic pregnancy being particularly high in women with three or more previous spontaneous abortions. Spontaneous abortions may have a causal effect, possibly mediated by infection (42). However, there may also be common risk factors for ectopic pregnancy and spontaneous abortions, such as chromosomal abnormalities (39, 44) or hormonal factors (45, 46). The available evidence suggests that the chromosomal abnormalities may be ruled out (40), but hormonal factors require further study, together with other factors including immunologic factors.
Previous use of an intrauterine device
In previous studies, odds ratios greater than one were obtained for current intrauterine device use, but odds ratios were generally not significant for previous intrauterine device use (6, 4749). A meta-analysis produced an odds ratio slightly greater than one, but adjustment for confounders is necessarily imperfect. In this study, the significant adjusted odds ratio for previous intrauterine device use (table 5) confirms that previous intrauterine device use has an etiologic role in ectopic pregnancy per se, not only through an association with infection as previously suggested (50, 51). We did not know the duration of past intrauterine device use, and we could not study the type of intrauterine device used because all but four of the women had used copper devices.
Infertility
We found that the adjusted risk of ectopic pregnancy increased with the duration of infertility, and this relation persisted if the analysis was restricted to women whose pregnancy was not induced. It is therefore likely that a history of infertility per se (independently of infertility drug use) is associated with ectopic pregnancy risk. However, as ectopic pregnancy is known to be a risk factor for subsequent infertility (24, 52, 53), the links between ectopic pregnancy and infertility, which seem to be mutual risk factors, are likely to be complex. Common risk factors for both conditions should be sought.
Previous induced abortions
Conflicting results have been reported in previous studies on this issue (54). This study, including a larger number of cases and controls, found an association between previous induced abortions and ectopic pregnancy, with an adjusted odds ratio of 1.9 (95 percent CI: 1.0, 3.8) for women with two or more prior induced abortions. The main source of bias may derive from ascertainment of the number of previous induced abortions, which may be underreported by the subject herself (55). In France, estimates of the number of induced abortions for the year 1988 range from 22 to 30 per 100 births (56, 57). If we took into account the number of induced abortions for each woman, we note a slightly lower ratio in our control sample (15 declared induced abortions for 100 births). Similar results were obtained by Daling et al. (58) in the United States. Misclassification bias could account for the observed relation only if it were differential and concerned mainly controls but not cases (or to a lesser extent). Holt et al. (59) found such a differential bias but in the reverse direction. Although a differential misclassification bias cannot be excluded, we think it unlikely that its magnitude or direction could account for our results.
In a previous study on another French population, we found an association between induced abortion and ectopic pregnancy (54). We interpreted the association as the consequence of uterine injuries or infections following abortion because most, if not all, of the abortions in this previous study were surgical. This interpretation was not confirmed by the study presented here: The risk of ectopic pregnancy was higher only for women who underwent medical abortions. However, the hypothesis that induced abortion leads to a higher risk of ectopic pregnancy as a result of infection cannot be rejected. The association with medical abortion may be accounted for by the absence of systematic antibiotic prophylaxis in this group of women, whereas such prophylaxis is more routinely given in cases of surgical abortion.
Research perspectives
The total attributable risk of ectopic pregnancy for the known risk factors is around 70 percent. This figure should be interpreted with caution (60, 61), but there are clearly other factors that may cause ectopic pregnancy. The search has turned toward possible common risk factors for ectopic pregnancy and spontaneous abortion or infertility. It has been suggested that ectopic pregnancy is linked to chromosomal abnormalities (44, 62) or exposure to antineoplastic drugs (63). Specific studies were conducted, which did not support these hypotheses (39, 40, 64). Hormonal factors have also been suspected (45), and immunologic factors may be involved.
Conclusion
Although several risk factors for ectopic pregnancy are known, the cause of a large proportion of ectopic pregnancies remains unknown. Our new findings on the association between previous medical induced abortion and ectopic pregnancy should be confirmed by further results. On the other hand, as ectopic pregnancy and infertility or spontaneous abortion have been found to be tightly linked, further research may concern both ectopic pregnancy epidemiology and the wider field of infertility. Increasing our knowledge of risk factors for ectopic pregnancy may improve our understanding of the causes of infertility.
In terms of public health, increasing awareness of the role of smoking may be useful in the formulation of ectopic pregnancy prevention policies. It would also be interesting to evaluate the effects on the incidence of ectopic pregnancy (and other infertility parameters) of the increase in sexually transmitted disease incidence observed in recent months or years (65, 66).
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ACKNOWLEDGMENTS |
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The authors thank Julie Sappa for her careful review of the English version of this paper.
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REFERENCES |
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NOTES |
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REFERENCES |
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