Risk factors for extrauterine pregnancy in women using an intrauterine device

Transcription

1 FERTILITY AND STERILITY VOL. 74, NO. 5, NOVEMBER 2000 Copyright 2000 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A. Risk factors for extrauterine pregnancy in women using an intrauterine device Jean Bouyer, Ph.D., a Emmanuelle Rachou, M.D., a Elisabeth Germain, Midwife, b Hervé Fernandez, M.D., a,c Joël Coste, M.D., Ph.D., a Jean-Luc Pouly, M.D., d and Nadine Job-Spira, M.D. a INSERM U292 (The French Institute of Health and Medical Research), Hôpital de Bicêtre, Le Kremlin-Bicêtre; Auvergne Ectopic Pregnancy Register, Centre Hospitalier Hôtel-Díeu, Clermont-Ferrand; and Hôpital Antoine Béclère, Clamart, France Received January 7, 2000; revised and accepted May 2, Supported by the clinical research department of Paris hospitals (Délégation à la Recherche Clinique, Assistance Publique Hôpitaux de Paris) (EMUL ), the National Register Committee (Comité National des Registres, INSERM, DGS), and SCHERING SA Company, France. Reprint requests: J. Bouyer, Ph.D., INSERM U292, Hôpital de Bicêtre, 82rueduGénéral Leclerc, Le Kremlin-Bicêtre Cedex, France (FAX: ; Bouyer@vjf.inserm.fr). a INSERM U292 (The French Institute of Health and Medical Research) Le Kremlin-Bicêtre, France. b Registre des GEU en Auvergne, Centre Hospitalier Hôtel-Dieu, Service d Epidémiologie et de Santé Publique, Clermont-Ferrand, France. c Hôpital Antoine Béclère, Service de Gynécologie- Obstétrique, Clamart, France. d Centre Hospitalier Hôtel-Dieu, Service de Gynécologie-Obstétrique, Clermont-Ferrand, France /00/$20.00 PII S (00) Objective: To identify the risk factors for ectopic pregnancy (EP) in women using an intrauterine device (IUD). Design: Case-control study. Setting: Auvergne region (France). Patient(s): Women using an IUD and suffering EP (243 cases) or having an intrauterine pregnancy (140 controls). Intervention(s): None. Main Outcome Measure(s): Sociodemographic characteristics, smoking, medical history, and medicines taken before the pregnancy. Type of IUD, duration of use, position and visibility of the thread at diagnosis, and presence of abnormal clinical signs. Result(s): Seven factors were associated with an increase in the risk of EP: histories of spontaneous abortion, IUD use, and tubal damage; progesterone IUD at the time of conception; insertion of an IUD during the month following a previous pregnancy; duration of use of the IUD in place at the time of conception; and pelvic pain resulting in medical consultation after the insertion of the IUD. Conversely, five factors were associated with a decrease in the risk of EP: history of treated low genital tract infection; history of contraception using the progestagen pill; use of paracetamol or aspirin before the pregnancy; and displacement of the IUD. Conclusion(s): This study suggests that the IUD itself may have an etiological role in EP (Fertil Steril 2000; 74: by American Society for Reproductive Medicine.). Key Words: Ectopic pregnancy, intrauterine device, risk factors, epidemiology Ectopic pregnancies (EPs) account for 1.5% of all reported pregnancies in western countries (1 3). The most important risk factor is a history of pelvic inflammatory disease (PID), with associated odds ratios (ORs) of 2 7.5, depending on the study (1, 4, 5). The risk attributable to this factor has been estimated at 50% (6). The second most important risk factor, on the basis of attributable risk values, is smoking at the time of conception, with ORs close to 2 and a dose-response relationship (7, 8). Other factors, less frequent and therefore responsible for a much smaller proportion of cases, have been identified: induction of ovulation by clomiphene, previous pelvic surgery, previous EP, and endometriosis. Aging, particularly for women over the age of 35, is also associated with a higher risk of EP (1), and past use of an intrauterine device (IUD) slightly increases the risk of EP (9 11). The proportion of EP cases in which the woman has an IUD differs between studies. In France, women with IUDs account for 25% 30% of all EP cases according to the data of the Auvergne register (12). A Norwegian study reported IUD use in 28% of EP cases (13), and a British study, in 14% (14). These differences may result from differences in the rate of IUD use for different populations. IUDs, like all contraceptive methods, decrease the risk of both intrauterine and extrauterine pregnancy. Thus, women using an IUD have a lower risk of EP than those not using contraception (15, 16). However, the IUD does not prevent ovulation, and it is more effective 899

2 at preventing intrauterine than extrauterine pregnancy (15 17). This accounts for most of the higher risk of EP for IUD users than for nonusers: IUDs prevent 99.5% of intrauterine pregnancies and only 95% of extrauterine pregnancies (18, 19). However, the reasons for implantation outside the uterus in women using IUDs are unknown. The aim of this work was to study the risk factors for ectopic implantation for pregnancies in women using an IUD by comparing the rates of EP with the rates of intrauterine pregnancies in IUD users, who are the appropriate controls. We assessed the contribution of three risk factor categories: factors associated with the woman herself (age, smoking, and surgical, gynecological, obstetric, and contraceptive history); medication before pregnancy; and IUD factors (type, duration of use, location, and abnormal clinical signs). The factors associated with the woman herself included, in particular, the classic EP risk factors identified in women not using IUDs, which have never been studied in women using IUDs. We studied the factors concerning medication taken before pregnancy for which an interaction with the IUD was suspected in a study of contraceptive failure in IUD users (20). The IUD factors have never before been investigated. PATIENTS AND METHODS This case-control study was conducted using data from the Auvergne EP register (central France) (21) and patients from the maternity unit of Antoine Béclère Hospital (Clamart, Paris suburbs). The population studied consisted of pregnant women using an IUD. Selection of Cases and Controls The case-patients were all women treated medically or surgically between September 1993 and August 1997 for an EP that occurred while an IUD was in place. All patients live permanently in the target area of the Auvergne register or were treated at Antoine Béclère Hospital. The women in the control group were IUD users with an intrauterine pregnancy (IUP) that ended either in delivery or induced abortion. The women in the control group were selected over the same time period as the case-patients. They were recruited at the maternity units and abortion clinics within the area covered by the register that agreed to participate in the study and at the abortion clinic and obstetrics department of Antoine Béclère Hospital. The five largest abortion clinics in the area covered by the register (which has 14 such clinics in total) took part in this study. All the induced abortion cases involving women using an IUD at these centers were included. The sample analyzed was made up of 243 cases (228 from the Auvergne register and 15 from Antoine Béclère Hospital) and 140 controls (112 induced abortions [IAs] and 28 deliveries, of which 100 and 16, respectively, came from the area covered by the register). Data Collection In each center, a trained investigator, either a midwife or a physician, was responsible for the selection of case-patients and women in the control group and data collection. The register has its own standard questionnaire, and this was used, with an additional form specific to this study. The same questionnaire was used for case-patients and women in the control group (except for questions related to the EP itself). The basic information collected from each woman included sociodemographic characteristics (age, geographic origin, education, and profession), smoking habits, sexual, gynecological, contraceptive and surgical history, and medicines taken during the 2 months preceding the conception. Information about the IUD in place at the time of conception was also collected: type of IUD, duration of use, position and visibility of the thread at diagnosis, and presence of abnormal clinical signs. Statistical Analysis The association between EP and the factors studied was measured by ORs. All analyses (including univariate analysis) were adjusted for the recruitment area (area covered by the Auvergne register or Antoine Béclère Hospital) and for the level of education of the woman (to take into account possible differences in recruitment between the participating abortion clinics). We also systematically adjusted for age, because older women are likely to have been exposed more frequently to risk factors (especially those concerning gynecological history). As we investigated a large number of potential risk factors, we assigned them to five groups: [1] general characteristics of the woman; [2] surgical, gynecological, and obstetric history; [3] contraceptive history; [4] medicines taken during the 2 months preceding the conception, and [5] factors relating to the IUD. Univariate analyses were performed within these five groups to generate crude ORs. A two-stage multivariate analysis was then performed. First, logistic regression was performed within each group of factors, for variables with P.2, in univariate analysis. Variables with P.2 in these five partial analyses were then included in a global logistic regression analysis (22). Statistical analyses were performed with STATA software (23). As required by the French law, the design of this study was approved by the Commission Nationale de l Informatique et des Libertés. RESULTS Univariate Analysis General Characteristics of the Women The sociodemographic characteristics, smoking habits, and sexual behavior of the case-patients and women in the control group are reported in Table 1. Age and the proportion 900 Bouyer et al. Extrauterine pregnancy in IUD users Vol. 74, No. 5, November 2000

3 TABLE 1 General characteristics of the women. Controls (IUP with IUD) n a (%) Cases (EP with IUD) n a (%) Adjusted OR b P Age (years) (22.3) 45 (18.6) 1.36 c (39.6) 86 (35.5) (27.3) 91 (37.6) (10.8) 20 (8.3) Married or living in a couple relationship No 18 (12.9) 18 (7.4) 1 Yes 122 (87.1) 225 (92.6) Current professional activity No 31 (22.5) 53 (22.6) 1 Yes 107 (77.5) 181 (77.4) Full secondary or higher education No 22 (16.4) 21 (8.8) 1 Yes 112 (83.6) 217 (91.2) Smoking (number of cigarettes per day) 0 93 (67.4) 162 (67.8) 1.47 c (10.9) 29 (12.1) (10.1) 28 (11.7) (11.6) 20 (8.4) Total number of sexual partners 1 46 (35.7) 79 (36.7) 1.67 c (43.4) 107 (49.8) (20.9) 29 (13.5) Note: IUP, intrauterine pregnancy; EP, ectopic pregnancy; IUD, intrauterine device. a The sum does not necessarily equal the sample size for all the variables because of missing data. b OR adjusted for recruitment site and 95% confidence intervals. c P value for the trend test. Bouyer. Extrauterine pregnancy in IUD users. Fertil Steril of women living in a couple relationship were greater for case-patients than women in the control group, but the differences were not statistically significant. The proportion of women with a current professional activity and the proportion of smokers were almost identical in the two groups (32.2% smokers for case-patients, 32.6% for women in the control group). There was no difference between case-patients and women in the control group in the total number of sexual partners since first intercourse. Case-patients and women in the control group differed only in their level of education: the risk of EP in IUD users who had completed their secondary education or gone on to higher education was almost twice that of less educated women. Gynecological, Obstetric, and Surgical History All of the women except two case-patients had been pregnant at least once before. The EP risk was greater in women with a history of spontaneous abortion (OR 1.8 [ ], P.08). A history of PID, which is a major risk factor for EP in general, was not associated with EP in this sample, probably because it is a contraindication for IUD use. However, if histories of tubal surgery, EP, endometriosis, and salpingitis were grouped together (as tubal damage), the risk of EP was found to be higher (OR 1.8 [ ]). Contraceptive History The principal methods of contraception used in the past by the women in our sample were the combined estroprogestative pill, the progestagen pill, the miniprogestagen pill, and the IUD. The proportion of women who had previously used the combined pill was similar in the two groups: 72.8% for the case-patients and 72.5% for the women in the control group (Table 2). Previous use of the miniprogestagen pill was not associated with a risk of EP, and the risk of EP was much lower in women who had used the progestagen pill (OR 0.06 [ ]). Conversely, the risk of EP almost doubled for women who had previously used an IUD (OR 1.9 [ ]). Medication During the 2 Months Preceding Conception The proportion of women who had taken medicines (for at least 48 hours) during the 2 months preceding the conception was significantly lower for the case-patients (30%) than for the women in the control group (42%) (Table 3). The women reported having taken 35 medicines or groups of medicines. The medicines that women most frequently reported having taken were paracetamol (n 26), antibiotics (n 25), nonsteroidal antiinflammatory drugs (n 21), and aspirin (n 16). The case-patients used significantly less paracetamol than the women in the control group (4.6% vs. 11.2%, P.04). They also used less aspirin, but this difference was less clear cut (2.5% vs. 7.5%, P.22). Antiinflammatory drugs, whether considered as a whole or by group (aspirin, other nonsteroidal antiinflammatory drugs, corticosteroids), were not significantly associated with the risk of EP in women using an IUD. IUD Factors The women in our sample reported using seven types of IUD. The type most frequently used at the time of conception was the Nova T 200 (51%). The progesterone IUD (Progestasert) was used by 41 women (11%) and was associated with a greater risk of EP, with an OR of 1.9 [ ], close to statistical significance. No relationship was found between the risk of EP and the copper surface area or form ( T or other) of the IUD (Table 4), even if the women using Progestasert (which is in the form of a T ) were excluded from the analysis. The time for which the IUD had been in place at the time of conception was 1 75 months for the case-patients and FERTILITY & STERILITY 901

4 TABLE 2 Medical and contraceptive history of the women. History Controls (IUP with IUD) n a (%) Cases (EP with IUD) n a (%) Adjusted OR b P Medical History Appendectomy No 81 (57.9) 139 (57.7) 1 Yes 59 (42.1) 102 (42.3) 0.8 [ ].48 Delivery No 4 (2.9) 2 (0.8) 1 Yes 136 (97.1) 240 (99.2) 2.9 [ ].25 Spontaneous abortion No 123 (87.9) 197 (81.4) 1 Yes 17 (12.1) 45 (18.6) 1.8 [ ].08 Induced abortion No 105 (75.0) 183 (75.6) 1 Yes 35 (25.0) 59 (24.4) 0.9 [ ].58 EP No 140 (100.0) 235 (97.1) 1 Yes 0 (0) 7 (2.9) NC Tubal damage c No 127 (90.7) 205 (84.7) 1 Yes 13 (9.3) 37 (15.3) 1.8 [ ].10 Treated indection of the lower genital tract No 92 (65.7) 169 (70.1) 1 Yes 48 (34.3) 72 (29.9) 0.7 [ ].20 Female infertility ( 1 year) No 134 (97.1) 232 (96.3) 1 Yes 4 (2.9) 9 (3.7) 1.3 [ ].41 Contraceptive history Estroprogestative pill No 38 (27.5) 64 (27.2) 1 Yes 100 (72.5) 171 (72.8) 1.1 [ ].80 Progestative pill No 114 (82.6) 218 (92.8) d Mini-progestagen pill 9 (6.5) 15 (6.4) 0.7 [ ] Progestagen pill 15 (10.9) 2 (0.9) 0.06 [ ] IUD No 68 (50.7) 80 (33.9) 1 Yes 66 (49.3) 156 (66.1) 1.9 [ ].01 Note: IUP, intrauterine pregnancy; EP, ectopic pregnancy; IUD, intrauterine device; NC, not calculable. a The sum does not necessarily equal the sample size for all the variables because of missing data. b OR adjusted for recruitment site, level of education and age, and 95% confidence interval. c Tubal damage history of tubal surgery, extrauterine pregnancy, endometriosis, or salpingitis (clinical or serological). d Global test. Bouyer. Extrauterine pregnancy in IUD users. Fertil Steril months for the women in the control group. The mean duration was months for the case-patients and for the women in the control group (P.37). We classified the women into two groups on the basis of duration of use: ( 2 years and 2 years. The cutoff point was set at 2 years because this corresponds to a clear change in the OR for EP. After adjustment for the type of IUD (Progestasert vs. other IUDs), we found that the risk of EP in women who had had their current IUD for 2 years was about twice that of women who had had their current IUD for 2 years (OR 1.9 [ ]). The total duration of past IUD use (i.e., before insertion of the current IUD) was 0 18 years in the case-patients and women in the control group, with a mean of 46.6 months for the case-patients and 52.1 months for the women in the control group. The risk of EP was higher if the duration of past IUD use was more than 6 years. However, the difference 902 Bouyer et al. Extrauterine pregnancy in IUD users Vol. 74, No. 5, November 2000

5 TABLE 3 Medicines used during the 2 months preceding conception. Controls (IUP with IUD) n a (%) Cases (EP with IUD) n a (%) Adjusted OR b P Treated with medicines during the 2 months preceding the conception No 78 (58.2) 169 (70.1) 1 Yes 56 (41.8) 72 (29.9) 0.5 [ ].01 Paracetamol No 119 (88.8) 230 (95.4) 1 Yes 15 (11.2) 11 (4.6) 0.47 [ ].05 Antibiotics No 125 (93.3) 225 (93.4) 1 Yes 9 (6.7) 16 (6.6) 0.9 [ ].79 Aspirin No 124 (92.5) 235 (97.5) 1 Yes 10 (7.5) 6 (2.5) 0.5 [ ].22 Other nonsteroidal antiinflammatory drugs No 126 (94.0) 228 (94.6) 1 Yes 8 (6.0) 13 (5.4) 1.0 [ ].93 Corticosteroids No 133 (99.2) 238 (98.8) 1 Yes 1 (0.8) 3 (1.2) 1.8 [ ].64 Note: IUP, intrauterine pregnancy; EP, ectopic pregnancy; IUD, intrauterine device. a The sum does not necessarily equal the sample size for all the variables because of missing data. b OR adjusted for recruitment site, level of education and age, and 95% confidence interval. Bouyer. Extrauterine pregnancy in IUD users. Fertil Steril was not significant after stratification for the variable history of IUD use. Thus, the factor associated with EP risk is IUD use in the past, and not the duration of use. The risk of EP was much lower (OR 0.2 [ ]) in cases of displacement of the IUD (i.e., if the IUD was not in the uterus or if its thread was not visible at diagnosis). The proportion of women who had consulted their doctor during the month after insertion of the IUD for pelvic pain and/or discomfort was greater for the case-patients than for the women in the control group (OR 5.4 [ ]). Case-patients reported metrorrhagia more frequently than women in the control group during the 6 months preceding the pregnancy (13.0% vs. 5.9%, P.08). Final Multivariate Analysis The variables from the initial analyses retained for the final multivariate analysis are listed in Table 5. Age was also included to take into account possible selection bias (see Materials and Methods). Although tobacco use was not found to be associated with the risk of EP in univariate analysis (Table 1), we retained it in the final analysis as a dichotomous variable (smoker/nonsmoker), as tobacco is generally recognized as playing a role in the epidemiology of EP. Finally, the variable medical treatment was considered to be too general and was replaced in the final analysis by the variables aspirin use and paracetamol use, which were considered to be more relevant. In the multivariate analysis, seven factors were found to be associated with a significant or almost significant (P.07) increase in the risk of EP: history of spontaneous abortion, history of tubal damage, history of IUD use, use of a progesterone IUD at the time of conception, the insertion of an IUD during the month following a previous pregnancy, duration of use of the IUD in place at the time of conception of 2 years, and pelvic pain or discomfort resulting in medical consultation during the month following insertion of the IUD. Conversely, five factors were found to be associated with a significant or almost significant (P.07) decrease in the risk of EP: a history of treated lower genital tract infection, history of contraception using the progestagen pill, use of paracetamol or of aspirin in the 2 months preceding the conception and, displacement of the IUD. DISCUSSION Most of the epidemiological studies that have contributed to our knowledge of the risk factors for EP have been case-control studies focusing on women who had planned FERTILITY & STERILITY 903

6 TABLE 4 Characteristics of the IUD in use at the time of conception. Controls (IUP with IUD) n a (%) Cases (EP with IUD) n a (%) Adjusted OR b P IUD in use at the time of conception Progesterone IUD (Progestasert) No 109 (92.4) 177 (84.7) 1 Yes 9 (7.6) 32 (15.3) 1.9 [ ].13 T -form IUD c No 11 (9.3) 14 (6.7) 1 Yes 107 (90.7) 195 (93.3) 1.4 [ ].42 Cooper surface area 300 mm 2d No 26 (24.1) 53 (29.9) 1 Yes 82 (75.9) 124 (70.1) 0.9 [ ].63 IUD inserted during the month after a previous pregnancy No 133 (97.8) 223 (93.3) 1 Yes 3 (2.2) 16 (6.7) 2.7 [ ].13 Total duration of past IUD use 6 years 113 (84.3) 172 (72.9) 1 6 years 21 (15.7) 64 (27.1) 1.8 [ ].06 IUD displaced e No 62 (47.7) 177 (85.5) Yes 68 (52.3) 30 (14.5) 0.2 [ ] 10 3 Consultation for pain or discomfort during the month following insertion of the IUD No 135 (97.8) 216 (91.5) 1 Yes 3 (2.2) 20 (8.5) 5.4 [ ].02 Metrorrhagia during the last 6 months No 127 (94.1) 207 (87.0) 1 Yes 8 (5.9) 31 (13.0) 2.1 [ ].07 IUD used in the past History of pregnancy with IUD use No 132 (95.0) 215 (90.3) 1 Yes 7 (5.0) 23 (9.7) 1.9 [ ].17 Duration of use of IUD in place at time of conception 2 years 102 (74.4) 154 (64.7) 1 2 years 35 (25.6) 84 (35.3) 1.9 f [ ].03 Note: IUP, intrauterine pregnancy; EP, ectopic pregnancy; IUD, intrauterine device. a The sum does not necessarily equal the sample size for all the variables because of missing data. b OR adjusted for recruitment site, level of education and age, and 95% confidence interval. c The IUDs in the form of a T were Nova T 200, Gyne T 380, Progestasert, and TCu 200. d The IUDs with a copper surface area 300 mm 2 were Nova T 200, MLCu 250, and TCu 200A. e IUD outside the uterus and/or thread not visible. f OR adjusted for type of IUD (progesterone IUD vs. other IUDs). Bouyer. Extrauterine pregnancy in IUD users. Fertil Steril their pregnancies. Women using contraception at the time of conception (essentially women using an IUD) were excluded, principally as a means of avoiding selection bias (24). This study is the first to focus specifically on EP in women using an IUD, with an appropriate control group (IUD users with an IUP). The principal source of bias in this study is the selection and recruitment of women in the control group. The control group did not include women whose pregnancy ended in spontaneous abortion, although a nonnegligible proportion of IUPs in women using IUDs end in this way. These women were not included partly because it is impossible to identify and recruit them in an exhaustive manner and partly because they involve pathological pregnancies. For Auvergne, the cases comprised all of the EPs in women using IUDs in the region, whereas the control group included only a fraction of IUPs in women using IUDs. However, all the women using IUDs who underwent IA at the clinics participating in the study were included. Thus, any possible bias is linked only to differences in recruitment between participating and non- 904 Bouyer et al. Extrauterine pregnancy in IUD users Vol. 74, No. 5, November 2000

7 TABLE 5 Final multivariate analysis. Adjusted OR a P General characteristics Age (years; reference: 30 years).94 b [ ] [ ] [ ] Full secondary or higher education 2.3 [ ].10 Married or living in a couple relationship 0.6 [ ].43 Smoker ( 1 cigarette/day) 0.8 [ ].51 Surgical, gynecological, and obstetric history History of spontaneous abortion 2.3 [ ].07 History of tubal damage c 3.7 [ ].03 Treated infection of the lower genital tract 0.5 [ ].04 Contraceptive history Progesterone-only pill (reference: no history of use of this type of pill).01 Mini-progestagen pill 0.4 [ ] Progestagen pill 0.02 [ ] Previous IUD use 2.4 [ ].02 Medicines taken during the 2 months preceding the conception Paracetamol 0.2 [ ].02 Aspirin 0.2 [ ].07 Variables associated with the IUD in place Progesterone IUD (Progestasert) 2.5 [ ].06 IUD inserted during the month following a previous pregnancy 9.9 [1.0 99].05 Duration of use of the IUD in place at the time of conception 2 years 2.9 [ ].01 IUD displaced d 0.2 [ ] 10 3 Consultation for pain or discomfort during the month following insertion 27.6 [ ].01 Note: IUD, intrauterine device. OR adjusted for the variables in the table and recruitment site and 95% confidence interval. P value of the trend test. c Tubal damage history of tubal surgery, ectopic pregnancy, endometriosis, or salpingitis (clinical or serological). d IUD outside the uterus and/or thread not visible. Bouyer. Extrauterine pregnancy in IUD users. Fertil Steril participating clinics. The systematic adjustment for the level of education of the women (proxy variable for socioeconomic level) was designed to take into account this potential source of bias. The loss of statistical power, due to fewer women being in the control group than initially planned, was modest because the power was nonetheless greater than 80% for demonstrating an OR of 2 for risk factors with a prevalence of 20% 70% in the population. A number of factors were associated with EP in women with IUDs. Some increased the risk of EP and others decreased it. This situation rarely occurs in epidemiology and makes interpretation of the results more complicated. We will deal with these factors in two groups: IUD factors and factors common to all EPs. IUD Factors This group of factors is made up of the following: the use of medicines that have been reported to interact with the IUD (20), the type of IUD, the conditions in which it was inserted, and the duration of its use. The displacement of the IUD was associated with a decreasing risk of EP. Because the displacement of the IUD reduces its contraceptive efficacy (25), it may make it possible for an egg to implant normally in the uterus. Thus, for pregnancies occurring in women with a displaced IUD, there is a relative increase in the number of IUPs over EP, in other words, a decrease in the risk of EP. Therefore, displacement of the IUD would increase the risk of IUP more than it increases the risk of EP. The decrease in the risk of EP in women who took aspirin during the 2 months preceding the conception (close to the significance threshold: OR 0.2 [ ]) may be from the antiinflammatory properties of aspirin, which reduce inflammation of the endometrium, leading to a decrease in the contraceptive efficacy of the IUD. However, these results should be interpreted with caution given that we found no such protective effect with other antiinflammatory drugs and that paracetamol use was also associated with a decreased risk of EP (OR 0.2 [ ]). Alternatively, paracetamol and aspirin may be used to treat the same common factor (migraine, for example) or aspirin may facilitate implanta- FERTILITY & STERILITY 905

8 tion as has been observed in women with repeated spontaneous abortions (26 28) and in women undergoing in vitro fertilization (29). We observed no link between EP risk and the form or copper surface area of the IUD. In contrast, the progesterone IUD, Progestasert, was associated with an increase in the risk of EP (OR 2.5 [ ]). This result, although of only borderline significance, is consistent with those of other studies on the undesirable side effects of IUDs (30, 31). The underlying mechanism is probably a direct effect of the local liberation of progesterone, decreasing tubal motility to a greater extent than occurs with copper. This is the other side of the coin: the greater contraceptive efficacy of Progestasert is linked to an increase in the risk of EP. The time for which the current IUD had been in place at the time of conception was associated with EP risk, the risk being higher if the IUD had been in place for more than 2 years. This may be because intrauterine inflammation increases over time from the continuing presence of a foreign body, the IUD, resulting in a decrease in the number of IUPs relative to the number of EPs. Women who consulted for pelvic pain or discomfort during the month following IUD insertion had a much higher risk of EP, probably because these symptoms were signs of pelvic infection. This idea is consistent with the results of Farley et al. (32), showing that the risk of PID associated with the IUD is greatest during the first 20 days after its insertion. Some authors have suggested that prophylactic antibiotic treatment should be given to decrease the risk of infection, but clinical trials have not been convincing (33). If infection associated with the insertion of the IUD does occur, ectopic implantation would be favored by the associated tubal inflammation. Factors Common to All EPs It was difficult a priori to demonstrate an association for some of the classic risk factors for EP in this study because of the particular indications for contraception by IUD. Thus, we found no increase in the risk of EP with age, in contrast to most studies of EP in the absence of contraception (34, 35, 6). This may result from the limited age range of the women in our sample, the IUD being most frequently used toward the end of a woman s reproductive life. Similarly, given that the IUD is not prescribed for women with a history of infection, it is not surprising that a history of salpingitis or Chlamydia trachomatis infection was not associated with the risk of EP. We found few women with these risk factors in our sample: 6 women (1.6%) had a history of salpingitis, and 33 (8.6%) tested positive for C. trachomatis. However, tubal damage, the variable grouping together histories of tubal surgery, salpingitis, EP, and endometriosis, was associated with a four times higher risk of EP (OR 3.7 [ ]. This confirms the direct etiological effect of these factors (if fertilization occurs, the changes in the tube associated with these factors prevents the descent of the egg into the uterus) and shows that it persists even at low doses. A history of treated infection of the lower genital tract was associated with a decrease in the risk of EP (adjusted OR 0.5 [ ]). This relationship appears paradoxical given that a history of salpingitis (a complication of STDs) is the principal risk factor for EP (5, 6). It may arise from a selection effect, in the choice of women given an IUD. Women with a history of PID are underrepresented in our sample because this is a contraindication for IUD use. This results in the overrepresentation of women with a lower genital tract infection in this sample. Among these women, the risk of EP is lower for women who have received treatment. We found that smoking was not associated with the risk of EP, whereas it generally gives an OR of around 2 with a dose-dependent relationship (7, 8). It is possible that the direct and indirect toxic effects of nicotine on the cilia and tubal contractions (36, 37) are masked here by the larger effect of the IUD on the fallopian tube (38). This study demonstrates an effect of two risk factors that were thought to be associated with the risk of EP: a history of spontaneous abortion and previous use of an IUD. The effect of these factors may not have been detectable in previous studies because of the presence of other stronger factors for which the confounding effect was not completely taken into account (a history of PID in particular). Women using IUDs are very similar in age, obstetric history, and history of infection. Thus, these factors have few if any confounding effects, making the effects of other factors more obvious. A relationship between recurrent spontaneous abortion and recurrent EP has been reported in several studies (39 42), whereas a relationship between a history of spontaneous abortion and the risk of EP does not seem to have been clearly established (43). This relationship, significant in this study, probably results from there being a common risk factor, such as a chromosomal abnormality in the egg (44) or a hormonal imbalance, that may cause both miscarriages and ectopic implantation of the egg (45). In most studies showing an increase in the risk of EP in women who have used an IUD in the past, the ORs are moderate (around 1.4 according to Xiong s meta-analysis (11)) and can be accounted for by associated PID. Several studies have shown excellent fertility in women after contraception with an IUD in place (46, 47) and in women who have suffered an EP while using an IUD (13, 48 51), suggesting that tubal inflammation (in the absence of infection) is immediately reversible on removal of the IUD. Our results on the associations between a history of IUD use, the duration of use of the current IUD, and the risk of EP suggest instead that the IUD itself has an effect, via the tubal inflammation that it causes. Finally, a history of contraception using the progestagen 906 Bouyer et al. Extrauterine pregnancy in IUD users Vol. 74, No. 5, November 2000

9 pill was associated with a very large decrease in the risk of EP and this relationship remained significant after adjustment for the other factors (OR 0.2 [ ]). The reason for this relationship is unclear. CONCLUSION These results should be interpreted with caution because this is the first study on EP dealing with women suffering EP while an IUD was in place. For the most part, this study tries to suggest hypotheses and put forward possible explanations. Other studies in other populations are required to confirm these results, concerning, for example, the role of the IUD itself and of contraception using the standard-dose progesterone-only pill. Acknowledgment: We thank Julie Knight for her careful review of the English version of this paper. References 1. Chow WH, Daling JR, Cates W, Greenberg RS. Epidemiology of ectopic pregnancy. Epidemiol Rev 1987;9: Coste J, Bouyer J, Job-Spira N. 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