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Past contraceptive method use and risk of ectopic pregnancy
ELSEVIER
Past Contraceptive Method Use and Risk of Ectopic Pregnancy Fabio Parazzini,**t Monica Ferraroni,$ Luca Tozzi,* Guido Benzi,? Gabriele Rossi,§ and Carlo La Vecchia*-$ The relationship between past contraceptive method use and risk of ectopic pregnancy has been analyzed in a casecontrol study conducted in Milan, Italy. Cases were 158 women with diagnosis of ectopic pregnancy confirmed by laparoscopy or laparotomy, admitted to a network of university and general hospitals of Milan. The first control group (obstetric controls) included 243 women who gave birth at term (more than 37 weeks’ gestation) to healthy infants at the same hospitals where the cases had been identified. The second control group (non-obstetric controls) was a random sample of 158 women admitted to the same network of hospitals where cases had been identified for diseases other than malignant, hormonal, or gynecological in origin. A total of 37 (23%) cases, 21 (9%) obstetric and 24 (15%) non-obstetric controls reported ever IUD use. The corresponding relative risk, RR, of ectopic pregnancy was 3.5 (95% confidence interval, CL 1.9-6.5) when obstetric and 2.4 (95% CI 1.3-4.6) when non-obstetric subjects were considered as control group. The risk of ectopic pregnancy increased with duration of IUD use: in comparison with obstetric and non-obstetric controls, the RR were 2.3 and 2.0 for users for less than 2 years and 4.3 and 2.6 for longer users. There was no clear relation between time since last IUD use and risk of ectopic pregnancy, and no evidence of a decline of risk with increasing time since stopping use. A total of 80 cases (51%), 115 obstetric (47%) and 70 non-obstetric controls (44%) were ever oral contraceptives users; these differences were not statistically significant (RR 1.1, 95% CI 0.7-1.7, in comparison with obstetric control and 1.2, 95% CI 0.8-2.0, in comparison with non-obstetric ones). Finally, 44 cases of ectopic pregnancy, 70 obstetric controls and 32 non-obstetric ones were ever users of barrier methods of contraception; in comparison with never users, the risk of ectopic pregnancy was 1.2 (95% CI 0.7-1.6) and 1.9 (95% CI 1.S3.4) for ever users, Vstituto di Ricerche Farmacologiche “Mario Negri”, via Eritrea 62, 20157 Milano. Italv: tPrima Clinica Ostetrico Ginecolooica. Universita di Milano. 20129 Milano, Italy: Slstituto di Statistica Medica e-Biometria. Universita di Milano, 20133 Milano, Italy; §Seconda Clinica Ostetrico Ginecologica. Universita di Milano. 20129 Milano. Italy Name and address for correspondence: Dr. Fabio Parazzini, lstituto di Ricerche Fanacologiche “Mario Negri,” via Eritrea, 62-20157 Milano, Italy. Tel. 02/39014.1; Fax 02/33200231 Submitted for publication August 5, 1994 Revised May 19, 1995 Accepted for publication May 19. 1995
Q 1995 Elsevier Science Inc. 655 Avenue of the Americas, New York,
NY 10010
respectively, when the comparison group was obstetric and non-obstetric controls. CONTRACEPTION 1995;52:93-98 KEY WORDS:
contraceptive
methods, ectopic pregnancy,
risk factors
Introduction he potential relation between past IUD use and the risk of ectopic pregnancy is still unclear.‘4 Past IUD users are at increased risk of pelvic infectior#; whether or not this in turn may increase the risk of ectopic pregnancy is still unclear.’ With regard to oral contraceptives (OC), there is general evidence that ever OC use does not increase risk of ectopic pregnancy and some studies have suggested a reduced risk,lpb* since OC may reduce the risk of pelvic disease.’ Most epidemiological evidence, however, derived from studies conducted in North American or Northern European countries, characterized by a higher prevalence of use of IUD and OC use than the Southem European ones, and different prevalence rates may be associated to different selective mechanism of use. To provide further information on the issue, we present here data on the relation between past contraceptive method use and risk of ectopic pregnancy from a case-control study conducted in Milan, Northem Italy.”
T
Materials and Methods Between September 1989 and March 1993 we conducted a case-control study on risk factors for ectopic pregnancy. The general design of this study has been described. lo Cases included in the study were women with a diagnosis of ectopic pregnancy confirmed by laparoscopy or laparotomy, admitted to the Clinica Mangiagalli and the IV Obstetric and Gynecologic Clinic of the University of Milan between September 1989 and February 1991 and to the I Obstetric and Gynecologic Clinic between March 1991 and March 1993. A total of 158 patients (median age 32 years, range 18-43) entered the study. ISSN OOlO-7624/95/$9.50 SSDI 0010-7824(95)00142-W
94 Parazzini et al.
The first control group (obstetric controls) included women who gave birth at term (more than 37 weeks’ gestation) to healthy infants in the same hospitals where the cases had been identified. These control subjects were chosen on randomly selected days within one month of case ascertainment. A total of 243 controls (median age 3 1 years, range 17-44) were interviewed. Cases and controls were not strictly matched for age, but care was taken to obtain a reasonably comparable age distribution, checking regularly the accrual of cases and controls according to this variable. The second control group (non-obstetric controls) was a random sample of women interviewed in the same calendar year and hospital of cases in a casecontrol study of risk factors for benign and malignant gynecological diseases. l1 Included as controls in this study were women admitted to the same network of hospitals where cases had been identified for diseases other than malignant, hormonal, or gynecological in origin. They had not undergone hysterectomy, bilateral oophorectomy or surgical sterilization. The study protocol indicated that all eligible controls identified on selected days in the hospitals under surveillance should be interviewed. From the overall data set, 158 subjects (median age 31 years, range 18-44) were randomly extracted within strata of age of the cases and calendar year of interview. Of the controls, 26% were admitted for traumatic conditions (mostly fractures and sprains), 27% had non-traumatic orthopedic disorders (mostly low back pain and disk disorders), 20% were admitted for acute abdominal diseases that required surgery, and 27% had other illnesses, such as disorders of the eye, ear, nose and throat, or teeth. On average, less than 3% of elegible women refused to be interviewed. The catchment area of cases and controls were comparable, since over 90% of subjects lived in the same region, Lombardy. Trained interviewers used a standard questionnaire to obtain information on personal characteristics and habits, and gynecological and obstetric history. Cases and obstetric controls were asked about their contraceptive methods. No information was collected on number of IUD insertions and type of IUD used. Further, specific information was obtained on previous pelvic inflammatory diseases (PID)/salpingitis requiring medical consultation or treatment. Data Analysis
The odds ratios were computed as estimators of the relative risks (RR), of ectopic pregnancy according to use of various contraceptive methods, together with their 95% approximate confidence intervals (CI),
Contraception 1995;52:93-98
from data stratified for age by the Mantel-Haenszel procedure. I2 Further, to account simultaneously for the effects of several potential confounding factors, unconditional multiple logistic regression, with maximum likelihood fitting, was used.13 The regression equations included terms for contraceptive methods, age, marital status, parity, spontaneous and induced abortions, history of PID/salpingitis and smoking. Exclusion of history of PID/salpingitis, as well as the inclusion of history of infertility (i.e., two or more years of unsuccessful attempts at pregnancy), from the final model, two factors that may be related to past IUD use, did not markedly change any of the RR estimates. In the previous published analysis of this data-set, history of abdominal surgery and number of sexual partners were also associated with the risk of ectopic pregnancies. lo These two factors are not included in the multivariate analysis since these information were not collected for the non-obstetric controls. However, the inclusion of these factors for the
Table 1. Distribution of 158 cases of ectopic pregnancies, 243 obstetric controls and 158 non-obstetric controls according to selected factors; Milan, Italy, 1989-1993
Ectopic Pregnancy No. (%)
Controls Obstetric No. (%)
Non-obstetric No. (%)
Age (years) G25 26-30 3135 >35
Education “:yJ 212
Parity 0 21
Spontaneous abortions 0 a1
Induced abortions 0
25 (16’
46 (19)
25 51 51 31
(16’ (32’ (32’ (20’
z; [ii/ 31 (20)
;: /iii 39 (16’
64 (41’ 94 (59’
103 (42’ 140 (58’
:: I:;/
102 (65’ 56 (35’
139* (57’ 104 (43’
76 (48’ 82 (52’
113 (72’ 45 (28’
213 (88’ 30 (12’
140 (89’ 18 (11’
123 (78’ 35 (22’
214 (88’ 29 (12’
129 (82’ 29 (18’
139 (88’ 19 (12’
“?
154 (97’ 4 (3’
Histzv of PID/ salpingitis No
Yes Smoking Never Ever ‘Index
pregnancy
64 (41’ 94 (59’ excluded.
if’
124 (51’ 119 (49’
83 (53’ 75 (47’
Contraceptives and Ectopic Pregnancy 95
Contraception 1995;52:9%98
estimates comparing cases and obstetric not change the results of the analysis.
controls
did
of IUD use; in comparison with obstetric and nonobstetric controls, the RRs were 2.3 and 2.0, respectively, for users for less than 2 years, and 4.3 and 2.6 for longer users (CTtrend 16.97, p< 0.05, vs. obstetric and 7.04, p< 0.05, vs. non-obstetric controls). There was no clear relation between time since last IUD use and risk of ectopic pregnancy, and no evidence of a decline of risk with increasing time since stopping use. No case or obstetric control was current OC user at conception of the index pregnancy, but 17 nonobstetric controls were OC users at interview. A total of 80 cases (51%), 115 obstetric (47%) and 70 (44%) non-obstetric controls were past OC users; these differences were not significant. Likewise, no relation emerged between duration of OC use and risk of ectopic pregnancy. Forty-four (28%) cases of ectopic pregnancy, 70 (29%) obstetric controls and 32 (20%) non-obstetric ones were ever barrier methods of contraception users: in comparison with never users, the risk of ectopic pregnancy was 1.2 (95% CI 0.7-1.7) and 1.9 (95% CI 0.9-3.4) for ever users, respectively, when the comparison group was obstetric and non-obstetric controls. The relation between IUD use and risk of ectopic pregnancy was further analyzed in strata of potential
Results The distribution of cases and controls according age and selected covariates is shown in Table 1. Cases were more frequently nulliparae and reported more frequently spontaneous or induced abortions, history of PID/salpingitis and smoking than both control groups. No difference emerged between cases or controls with reference to education. Table 2 considers the relation between ectopic pregnancy risk and contraceptive habits. No case or obstetric control was current IUD users at conception of the index pregnancy, but 5 non-obstetric controls were IUD users at interview. A total of 37 cases (23%), 21 obstetric (9%) and 24 non-obstetric controls ( 15%) reported ever IUD use, the corresponding RR of ectopic pregnancy being 3.5 (95% CI 1.9-6.5) when obstetric and 2.4 (95% CI 1.3-4.6) when non-obstetric subjects were considered as control group. Multivariate RRs were somewhat higher than the crude ones, the major modifying factor being parity. For example, the age-adjusted RRs for IUD use were 3.2 and 1.7 for obstetric and non-obstetric controls, and 3.5 and 2.4 when entered terms for age and parity in the model. The risk of ectopic pregnancy increased with duration
Table 2. Distribution of cases of ectopic pregnancy and controls according to various measures of IUD, oral contraceptive and barrier method of contraceptive use in the past; Milan, Italy, 1989-1993
IUD use Never users
Ever users Duration of use (years) <2 22
Controls
RR (95% CI)t
Ectopic Pregnancy
Obstetric
Non-obstetric
121 37
222 21
134 24
9 28
8 13
19 18
Never users Ever users Duration of use (months) ~18 ~18 Barrier methods of contraception Never users Ever users
Non-obstetric
3.5 (lL.5)
2.4 (l%4.6)
7 17
2.3 (0.8-6.3) 4.3 (2.0-9.0)
2.0 (0.7-6.0) 2.6 (1.3-5.4)
9 12
14’ 6
4.3 (1.8-10.3) 2.9 (1.3-6.4)
2.1 (0.9-4.7) 4.5 (1.6-12.7)
78 80
128 115
88 70*
1” 1.1 (0.7-1.7)
1.2 &~2.0)
36 44
34 81
28 42
1.8 (1.0-3.1) 0.9 (0.5-1.4)
1.5 (0.8-2.7) 1.2 (0.7-2.0)
110’ 44
173 70
126 32
1.2 (0%.6)
1.9 (x3.4)
Time since last use (years) <2 23 contraceptive use Oral
Obstetric
‘The sum does not add up to the total because of missing tAdjusted for age, marital status, parity, abortions, history “Reference category. SCurrent users are included in the analysis.
values. of PID/salpingitis,
smoking
and, in two,
the above listed variables.
96
Parazzini
et al
Contraception 1995;52:9%98
covariates (Table 3); no difference emerged in RR estimates. In particular, the RRs of ectopic pregnancy for ever IUD users were 3.2 and 1.7 in comparison with the obstetric and non-obstetric control group, respectively, in women who reported a history of pelvic inflammatory disease, and 2.0 and 3.1 in those who did not.
Discussion This study suggests that past use of IUD increases the risk of ectopic pregnancy, and the risk increases with duration of use. The risk was still about double three years or more after last IUD use. No consistent association was found between OC and barrier methods of contraceptive use and risk of the disease, but the estimated RR for barrier method use in comparison non-obstetric controls was higher than unity and of borderline statistical significance. The choice of the control group is a key problem in any case-control study on the relation between past contraceptive methods and risk of ectopic pregnancy.14 The choice as controls of women who completed full-term pregnancies may lead one to overestimate the RR, since parous women may report a different rate of contraceptive use as compared to 3. Relative risk of ectopic pregnancy for ever IUD use in strata of selected covariates; Milan, Italy, 1989-1993 Table
RR for Ever IUD’ Obstetric Controls
Covariate
Ageb=l
c30 >30 Education (years) Cl2 212
Parity 0 31
Spontaneous abortions 0 ==l
Induced abortion 0 21
History of pelvic inflammatory disease/salpingitis No Yes Smoking Never Ever ‘RR
= relative
risk, adjusted
Non-obstetric Controls
3.8 (1.5-10.0) 2.9 (1 A-6.0)
1.9 (0.8-4.9) 1.6 (0.8-3.3)
1.6 (0.7-3.8) 6.5 (2.7-15.8)
1.1 (0.5-2.5) 3.2 (1.2-8.5)
4.3 ( 1 h-1 1.3) 3.6 (1.6-7.9)
7.7 (1.7-34.8) 1.5 (0.7-3.2)
4.1 (2.1-8.0) 1.6 (0.3-3.8)
2.1 (1.1-3.9) 0.9 (0.2-3.9)
2.7 (1.3-5.6) 3.6 (1.1-11.4)
1.6 (0.7-3.3) 1.9 (0.7-5.3)
9.1 (1.7-5.8) 2.0 (0.2-21.2)
1.7 (0.9-3.0) 3.1 (0.8-6.3)
5.5 (1.9-15.6) 2.3 (1.1-4.8)
1.5 (0.6-3.5) 2.1 (0.94.8)
for age. Comparison
group:
never IUD
users.
nulliparae. This effect, however, is not marked in Italy.15J16 Non-pregnant women may differ from cases in terms of reduced fertility, and less fertile women are less frequently users of contraceptive. The exclusion from the non-obstetric control group of current contraceptive users would be incorrect, since noncontraceptive users would more easily experience difficulty in conception owing, in part, to past IUD use. In this series, however, exclusion of non-contraceptive current users did not change the estimated RR (data not shown). Thus, various potential biases are difficult to overcome and are applicable both to hospital-based and population-based control groups. Most of these biases, however, should tend to overestimate the RR of OC use and barrier methods, too. To address, at least in part, these problems, we have chosen to consider as controls both women who delivered a live-born child and non-pregnant hospitalized women. Other potential sources of bias should be less important in this study. Cases and controls were drawn from the same network of hospitals and had similar participation rates of nearly 100%. It is possible that women with an ectopic pregnancy might be more sensitized towards recalling potential risk factors for the disease (including IUD use] than women in hospital for other conditions. However, the potential association between ectopic pregnancy and IUD use did not receive widespread attention from the lay press in Italy, and the question on contraceptive methods use was included in a questionnaire including several medical (particularly gynecological and obstetric) questions. Further, the prevalence of OC, IUD and barrier methods of contraceptive use in the control group was largely consistent with the few data of prevalence of contraceptive methods in Italy, the low prevalence of use being partly attributable to the use of coitus interruptus and rhythmic methods in Italy. Recall bias should not be a major problem also for potential covariates. In Italy, induced abortion has been legal since 1978 and only a small proportion of induced abortion is performed outside recognized structures in this area of Italy.” Thus, in consideration of the time frame of data collection, it is unlikely that women tended systematically to report induced abortion as spontaneous. With regard to the role of other factors, allowance for potential distorting factors, including marital status, socioeconomic indicators and other major known or potential determinants (such as PID, smoking, or induced abortion) of ectopic gestation, did not change the estimated RR. Further, the estimated RRs for ever IUD use were largely consistent across strata of various covariates. The only possible exception was the
Contraceptives
Contraception 1995;52:9%98
observation that the RRs were higher in non-educated women, but contraceptive methods use in Italy is generally more frequent among women of higher social class.16 Several studies have analyzed the relation between prior to conception IUD use and risk of ectopic pregnancy. ‘-M’J’J~ However, the evidence is not completely consistent. Data from the Oxford Family Planning Contraceptive study,16 and a large multicentric study conducted by the World Health Organization3 reported no increased risk of ectopic pregnancy in exIUD users. However, case-control studies found an elevate risk of ectopic pregnancy, the estimated RR ranging from 1.5 to 4.0.‘~2~4~6’7Selective mechanisms should be carefully considered in the interpretation of these apparent differences. However, the durationrisk relationship observed in some studies4 gives some support to the hypothesis of a causal link. In biological terms the association has been interpreted in terms of increased risk of clinical or subclinical tubal or pelvic infection (due to several microorganisms, such as Chlamydia, Actomyces israelii) in IUD users,” that, in turn, may increase the risk of ectopic pregnancy. In this study, the increased risk persisted also after exclusion from the multivariate equation of a history of PID and in strata of subjects with and without history of PID/salpingitis, but only PID with clinical diagnoses have been considered. It has also been suggested that tubal damage unrelated to sexually transmitted disease may occur in IUD users. Changes in cilia of fallopian tubes have been observed in IUD users, but the duration of the changes is unclear.20#21 Ever OC use was not related to the risk of ectopic pregnancy. These findings are in general agreement with most of the published studies.1*68s22 A specific interest of this analysis derives from the fact that the study was based on a population with low prevalence of OC use, where different potential selective mechanisms are conceivable, in comparison to those from populations with more widespread use. This offers further indirect support to the association observed with IUD use. Ever use of barrier methods was associated with a borderline statistically significant increased risk of ectopic pregnancy in comparison with non-obstetric controls in the analysis. This finding was not confirmed when obstetric controls were considered, and may be in first hypothesis attributable to chance. In any case, it must be considered cautiously as a potential indicator of higher contraceptive method use in the non-obstetric control group. In conclusion, the possible association observed in this study between past IUD use and the risk of ectopic pregnancy, if confirmed, together with the per-
and Ectopic
Pregnancy
97
sistence of the risk several years after stopping use, would have relevant public health implications in the ultimate assessment of benefits and risks related to various contraceptive methods.
Acknowledgments This work was conducted within the framework of the CNR (Italian National Research Council) Applied Project “Fattori di Rischio di Malattia” (sottoprogetto “Fattori di Malattia nella Patologia Matemo Infantile”). The authors wish to thank Ivana Garimoldi, Judy Baggott and the G.A. Pfeiffer Memorial Library staff for editorial assistance.
References 1. Chow WH, Daling JR, Gates W, Greenberg R. Epidemi-
ology of ectopic pregnancy. Epidemiol Rev 1987;9:7& 94. 2. Ory HW. The women’s health study. Ectopic pregnancy
and intrauterine contraceptive devices: New perspectives. Obstet Gynecol 1981;57:137-44. 3. World Health Organization. Task Force on Intrauterine Devices for Fertility Regulation. A multi-national casecontrol study of ectopic pregnancy. Clin Reprod Fertil 1985;3:131-. 4. Rossing MA, Daling JR, Weiss NS, et al. Past use of an
intrauterine
device and risk of tubal pregnancy. Epide-
miology 1993;4:245-5 1. 5. Kaufman DW, Watson J, Rosenberg L, et al. The effect of different types of intrauterine devices on the risk of pelvic inflammatory disease. JAMA 1983;250:759-62. 6. Coste J, Job-Spira N, Femandez H, Papiemik E, Spira A. Risk factors for ectopic pregnancy: A case-control study in France, with special focus on infectious factors. Am J Epidemiol 1991;133:839-49. 7. Marchbanks PA, Annegers JF, Coulam CB, Strathy JH, Kurland LT. Risk factors for ectopic pregnancy. A population-based study. JAMA 1988;259: 1823-7. 8. Kalandidi A, Doulgerakis M, Tzonou A, Hsieh CC, Aravandinos D, Trichopoulos D. Induced abortions, contraceptive practices, and tobacco smoking as risk factors for ectopic pregnancy in Athens, Greece. Br J Obstet Gynaecol 1991;98:207-13. 9. Rubin GL, Ory HW, Layde PM. Oral contraceptives and pelvic inflammatory disease. Am J Obstet Gynaecol 1982;144:630-5. 10. Parazzini F, Tozzi L, Ferraroni M, Bocciolone L, La Vecchia C, Fedele L. Risk factors for ectopic pregnancy: An Italian case-control study. Obstet Gynecol 1992;80: 821-6. 11. Parazzini F, Negri E, La Vecchia C, Fedele L, Rabaiotti M, Luchini L. Oral contraceptive use and risk of uterine fibroids. Obstet Gynecol 1992;79:430-3. 12. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Nat1
Cancer Inst 1959;22:71948. 13. Baker RJ, Nelder JA. The GLIM system, release 3. Oxford: 1978. 14. Weiss NS, Daling JR, Chow WH. Control definition in
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15. 16. 17. 18. 19.
case-control studies of ectopic pregnancy. Am J Public Health 1985;75:67-8. D’Avanzo B, Luchini L, Parazzini P, Negri E, La Vecchia C. Descriptive epidemiology of induced abortion in Italy 1979-1990. Contraception 1992;46:549-59. La Vecchia C, Decarli A, Parazzini F, Gentile A, Negri E, Frances&i S. Determinants of oral contraceptive use in Northern Italy. Contraception 1986;34:145-56. Vessey M, Meisler L, Flavel R, et al. Outcome of pregnancy in women using different methods of contraception. Am J Obstet Gynaecol 1979;86:548-56. Chow WI-I, Dahng JR, Weiss NS, Moore DE, SoderStrom RM, Metch BJ. IUD use and subsequent tubal ectopic pregnancy. Am J Public Health 1986;76:536-9. Valicenti JF, Pappas AA, Graber CD, Williamson HO,
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Wills NF. Detection and prevalence of IUD-associated Actinomyces colonization and related morbidity: A prospective study of 69,925 cervical smears. JAMA 1982;247: 1149-52. 20. Wollen AL, Flood PR, Sandvei R. Altered ciliary substructure in the endosalpinx in women using an IUCD. Acta Obstet Gynecol Stand 1990;69:307-12. 21. Wollen AL, Flood PR, Sandvei R, Steier JA. Morphological changes in tubal mucosa associated with the use of intrauterine contraceptive devices. Br J Obstet Gynaeco1 1984;91:1123-8. 22. Li DK, Daling JR, Stergachis AS, Chu J, Weiss NS. Prior condom use and the risk of tubal pregnancy. Am J Public Health 1990;80:964-6.
Past Contraceptive Method Use and Risk of Ectopic Pregnancy Fabio Parazzini,**t Monica Ferraroni,$ Luca Tozzi,* Guido Benzi,? Gabriele Rossi,§ and Carlo La Vecchia*-$ The relationship between past contraceptive method use and risk of ectopic pregnancy has been analyzed in a casecontrol study conducted in Milan, Italy. Cases were 158 women with diagnosis of ectopic pregnancy confirmed by laparoscopy or laparotomy, admitted to a network of university and general hospitals of Milan. The first control group (obstetric controls) included 243 women who gave birth at term (more than 37 weeks’ gestation) to healthy infants at the same hospitals where the cases had been identified. The second control group (non-obstetric controls) was a random sample of 158 women admitted to the same network of hospitals where cases had been identified for diseases other than malignant, hormonal, or gynecological in origin. A total of 37 (23%) cases, 21 (9%) obstetric and 24 (15%) non-obstetric controls reported ever IUD use. The corresponding relative risk, RR, of ectopic pregnancy was 3.5 (95% confidence interval, CL 1.9-6.5) when obstetric and 2.4 (95% CI 1.3-4.6) when non-obstetric subjects were considered as control group. The risk of ectopic pregnancy increased with duration of IUD use: in comparison with obstetric and non-obstetric controls, the RR were 2.3 and 2.0 for users for less than 2 years and 4.3 and 2.6 for longer users. There was no clear relation between time since last IUD use and risk of ectopic pregnancy, and no evidence of a decline of risk with increasing time since stopping use. A total of 80 cases (51%), 115 obstetric (47%) and 70 non-obstetric controls (44%) were ever oral contraceptives users; these differences were not statistically significant (RR 1.1, 95% CI 0.7-1.7, in comparison with obstetric control and 1.2, 95% CI 0.8-2.0, in comparison with non-obstetric ones). Finally, 44 cases of ectopic pregnancy, 70 obstetric controls and 32 non-obstetric ones were ever users of barrier methods of contraception; in comparison with never users, the risk of ectopic pregnancy was 1.2 (95% CI 0.7-1.6) and 1.9 (95% CI 1.S3.4) for ever users, Vstituto di Ricerche Farmacologiche “Mario Negri”, via Eritrea 62, 20157 Milano. Italv: tPrima Clinica Ostetrico Ginecolooica. Universita di Milano. 20129 Milano, Italy: Slstituto di Statistica Medica e-Biometria. Universita di Milano, 20133 Milano, Italy; §Seconda Clinica Ostetrico Ginecologica. Universita di Milano. 20129 Milano. Italy Name and address for correspondence: Dr. Fabio Parazzini, lstituto di Ricerche Fanacologiche “Mario Negri,” via Eritrea, 62-20157 Milano, Italy. Tel. 02/39014.1; Fax 02/33200231 Submitted for publication August 5, 1994 Revised May 19, 1995 Accepted for publication May 19. 1995
Q 1995 Elsevier Science Inc. 655 Avenue of the Americas, New York,
NY 10010
respectively, when the comparison group was obstetric and non-obstetric controls. CONTRACEPTION 1995;52:93-98 KEY WORDS:
contraceptive
methods, ectopic pregnancy,
risk factors
Introduction he potential relation between past IUD use and the risk of ectopic pregnancy is still unclear.‘4 Past IUD users are at increased risk of pelvic infectior#; whether or not this in turn may increase the risk of ectopic pregnancy is still unclear.’ With regard to oral contraceptives (OC), there is general evidence that ever OC use does not increase risk of ectopic pregnancy and some studies have suggested a reduced risk,lpb* since OC may reduce the risk of pelvic disease.’ Most epidemiological evidence, however, derived from studies conducted in North American or Northern European countries, characterized by a higher prevalence of use of IUD and OC use than the Southem European ones, and different prevalence rates may be associated to different selective mechanism of use. To provide further information on the issue, we present here data on the relation between past contraceptive method use and risk of ectopic pregnancy from a case-control study conducted in Milan, Northem Italy.”
T
Materials and Methods Between September 1989 and March 1993 we conducted a case-control study on risk factors for ectopic pregnancy. The general design of this study has been described. lo Cases included in the study were women with a diagnosis of ectopic pregnancy confirmed by laparoscopy or laparotomy, admitted to the Clinica Mangiagalli and the IV Obstetric and Gynecologic Clinic of the University of Milan between September 1989 and February 1991 and to the I Obstetric and Gynecologic Clinic between March 1991 and March 1993. A total of 158 patients (median age 32 years, range 18-43) entered the study. ISSN OOlO-7624/95/$9.50 SSDI 0010-7824(95)00142-W
94 Parazzini et al.
The first control group (obstetric controls) included women who gave birth at term (more than 37 weeks’ gestation) to healthy infants in the same hospitals where the cases had been identified. These control subjects were chosen on randomly selected days within one month of case ascertainment. A total of 243 controls (median age 3 1 years, range 17-44) were interviewed. Cases and controls were not strictly matched for age, but care was taken to obtain a reasonably comparable age distribution, checking regularly the accrual of cases and controls according to this variable. The second control group (non-obstetric controls) was a random sample of women interviewed in the same calendar year and hospital of cases in a casecontrol study of risk factors for benign and malignant gynecological diseases. l1 Included as controls in this study were women admitted to the same network of hospitals where cases had been identified for diseases other than malignant, hormonal, or gynecological in origin. They had not undergone hysterectomy, bilateral oophorectomy or surgical sterilization. The study protocol indicated that all eligible controls identified on selected days in the hospitals under surveillance should be interviewed. From the overall data set, 158 subjects (median age 31 years, range 18-44) were randomly extracted within strata of age of the cases and calendar year of interview. Of the controls, 26% were admitted for traumatic conditions (mostly fractures and sprains), 27% had non-traumatic orthopedic disorders (mostly low back pain and disk disorders), 20% were admitted for acute abdominal diseases that required surgery, and 27% had other illnesses, such as disorders of the eye, ear, nose and throat, or teeth. On average, less than 3% of elegible women refused to be interviewed. The catchment area of cases and controls were comparable, since over 90% of subjects lived in the same region, Lombardy. Trained interviewers used a standard questionnaire to obtain information on personal characteristics and habits, and gynecological and obstetric history. Cases and obstetric controls were asked about their contraceptive methods. No information was collected on number of IUD insertions and type of IUD used. Further, specific information was obtained on previous pelvic inflammatory diseases (PID)/salpingitis requiring medical consultation or treatment. Data Analysis
The odds ratios were computed as estimators of the relative risks (RR), of ectopic pregnancy according to use of various contraceptive methods, together with their 95% approximate confidence intervals (CI),
Contraception 1995;52:93-98
from data stratified for age by the Mantel-Haenszel procedure. I2 Further, to account simultaneously for the effects of several potential confounding factors, unconditional multiple logistic regression, with maximum likelihood fitting, was used.13 The regression equations included terms for contraceptive methods, age, marital status, parity, spontaneous and induced abortions, history of PID/salpingitis and smoking. Exclusion of history of PID/salpingitis, as well as the inclusion of history of infertility (i.e., two or more years of unsuccessful attempts at pregnancy), from the final model, two factors that may be related to past IUD use, did not markedly change any of the RR estimates. In the previous published analysis of this data-set, history of abdominal surgery and number of sexual partners were also associated with the risk of ectopic pregnancies. lo These two factors are not included in the multivariate analysis since these information were not collected for the non-obstetric controls. However, the inclusion of these factors for the
Table 1. Distribution of 158 cases of ectopic pregnancies, 243 obstetric controls and 158 non-obstetric controls according to selected factors; Milan, Italy, 1989-1993
Ectopic Pregnancy No. (%)
Controls Obstetric No. (%)
Non-obstetric No. (%)
Age (years) G25 26-30 3135 >35
Education “:yJ 212
Parity 0 21
Spontaneous abortions 0 a1
Induced abortions 0
25 (16’
46 (19)
25 51 51 31
(16’ (32’ (32’ (20’
z; [ii/ 31 (20)
;: /iii 39 (16’
64 (41’ 94 (59’
103 (42’ 140 (58’
:: I:;/
102 (65’ 56 (35’
139* (57’ 104 (43’
76 (48’ 82 (52’
113 (72’ 45 (28’
213 (88’ 30 (12’
140 (89’ 18 (11’
123 (78’ 35 (22’
214 (88’ 29 (12’
129 (82’ 29 (18’
139 (88’ 19 (12’
“?
154 (97’ 4 (3’
Histzv of PID/ salpingitis No
Yes Smoking Never Ever ‘Index
pregnancy
64 (41’ 94 (59’ excluded.
if’
124 (51’ 119 (49’
83 (53’ 75 (47’
Contraceptives and Ectopic Pregnancy 95
Contraception 1995;52:9%98
estimates comparing cases and obstetric not change the results of the analysis.
controls
did
of IUD use; in comparison with obstetric and nonobstetric controls, the RRs were 2.3 and 2.0, respectively, for users for less than 2 years, and 4.3 and 2.6 for longer users (CTtrend 16.97, p< 0.05, vs. obstetric and 7.04, p< 0.05, vs. non-obstetric controls). There was no clear relation between time since last IUD use and risk of ectopic pregnancy, and no evidence of a decline of risk with increasing time since stopping use. No case or obstetric control was current OC user at conception of the index pregnancy, but 17 nonobstetric controls were OC users at interview. A total of 80 cases (51%), 115 obstetric (47%) and 70 (44%) non-obstetric controls were past OC users; these differences were not significant. Likewise, no relation emerged between duration of OC use and risk of ectopic pregnancy. Forty-four (28%) cases of ectopic pregnancy, 70 (29%) obstetric controls and 32 (20%) non-obstetric ones were ever barrier methods of contraception users: in comparison with never users, the risk of ectopic pregnancy was 1.2 (95% CI 0.7-1.7) and 1.9 (95% CI 0.9-3.4) for ever users, respectively, when the comparison group was obstetric and non-obstetric controls. The relation between IUD use and risk of ectopic pregnancy was further analyzed in strata of potential
Results The distribution of cases and controls according age and selected covariates is shown in Table 1. Cases were more frequently nulliparae and reported more frequently spontaneous or induced abortions, history of PID/salpingitis and smoking than both control groups. No difference emerged between cases or controls with reference to education. Table 2 considers the relation between ectopic pregnancy risk and contraceptive habits. No case or obstetric control was current IUD users at conception of the index pregnancy, but 5 non-obstetric controls were IUD users at interview. A total of 37 cases (23%), 21 obstetric (9%) and 24 non-obstetric controls ( 15%) reported ever IUD use, the corresponding RR of ectopic pregnancy being 3.5 (95% CI 1.9-6.5) when obstetric and 2.4 (95% CI 1.3-4.6) when non-obstetric subjects were considered as control group. Multivariate RRs were somewhat higher than the crude ones, the major modifying factor being parity. For example, the age-adjusted RRs for IUD use were 3.2 and 1.7 for obstetric and non-obstetric controls, and 3.5 and 2.4 when entered terms for age and parity in the model. The risk of ectopic pregnancy increased with duration
Table 2. Distribution of cases of ectopic pregnancy and controls according to various measures of IUD, oral contraceptive and barrier method of contraceptive use in the past; Milan, Italy, 1989-1993
IUD use Never users
Ever users Duration of use (years) <2 22
Controls
RR (95% CI)t
Ectopic Pregnancy
Obstetric
Non-obstetric
121 37
222 21
134 24
9 28
8 13
19 18
Never users Ever users Duration of use (months) ~18 ~18 Barrier methods of contraception Never users Ever users
Non-obstetric
3.5 (lL.5)
2.4 (l%4.6)
7 17
2.3 (0.8-6.3) 4.3 (2.0-9.0)
2.0 (0.7-6.0) 2.6 (1.3-5.4)
9 12
14’ 6
4.3 (1.8-10.3) 2.9 (1.3-6.4)
2.1 (0.9-4.7) 4.5 (1.6-12.7)
78 80
128 115
88 70*
1” 1.1 (0.7-1.7)
1.2 &~2.0)
36 44
34 81
28 42
1.8 (1.0-3.1) 0.9 (0.5-1.4)
1.5 (0.8-2.7) 1.2 (0.7-2.0)
110’ 44
173 70
126 32
1.2 (0%.6)
1.9 (x3.4)
Time since last use (years) <2 23 contraceptive use Oral
Obstetric
‘The sum does not add up to the total because of missing tAdjusted for age, marital status, parity, abortions, history “Reference category. SCurrent users are included in the analysis.
values. of PID/salpingitis,
smoking
and, in two,
the above listed variables.
96
Parazzini
et al
Contraception 1995;52:9%98
covariates (Table 3); no difference emerged in RR estimates. In particular, the RRs of ectopic pregnancy for ever IUD users were 3.2 and 1.7 in comparison with the obstetric and non-obstetric control group, respectively, in women who reported a history of pelvic inflammatory disease, and 2.0 and 3.1 in those who did not.
Discussion This study suggests that past use of IUD increases the risk of ectopic pregnancy, and the risk increases with duration of use. The risk was still about double three years or more after last IUD use. No consistent association was found between OC and barrier methods of contraceptive use and risk of the disease, but the estimated RR for barrier method use in comparison non-obstetric controls was higher than unity and of borderline statistical significance. The choice of the control group is a key problem in any case-control study on the relation between past contraceptive methods and risk of ectopic pregnancy.14 The choice as controls of women who completed full-term pregnancies may lead one to overestimate the RR, since parous women may report a different rate of contraceptive use as compared to 3. Relative risk of ectopic pregnancy for ever IUD use in strata of selected covariates; Milan, Italy, 1989-1993 Table
RR for Ever IUD’ Obstetric Controls
Covariate
Ageb=l
c30 >30 Education (years) Cl2 212
Parity 0 31
Spontaneous abortions 0 ==l
Induced abortion 0 21
History of pelvic inflammatory disease/salpingitis No Yes Smoking Never Ever ‘RR
= relative
risk, adjusted
Non-obstetric Controls
3.8 (1.5-10.0) 2.9 (1 A-6.0)
1.9 (0.8-4.9) 1.6 (0.8-3.3)
1.6 (0.7-3.8) 6.5 (2.7-15.8)
1.1 (0.5-2.5) 3.2 (1.2-8.5)
4.3 ( 1 h-1 1.3) 3.6 (1.6-7.9)
7.7 (1.7-34.8) 1.5 (0.7-3.2)
4.1 (2.1-8.0) 1.6 (0.3-3.8)
2.1 (1.1-3.9) 0.9 (0.2-3.9)
2.7 (1.3-5.6) 3.6 (1.1-11.4)
1.6 (0.7-3.3) 1.9 (0.7-5.3)
9.1 (1.7-5.8) 2.0 (0.2-21.2)
1.7 (0.9-3.0) 3.1 (0.8-6.3)
5.5 (1.9-15.6) 2.3 (1.1-4.8)
1.5 (0.6-3.5) 2.1 (0.94.8)
for age. Comparison
group:
never IUD
users.
nulliparae. This effect, however, is not marked in Italy.15J16 Non-pregnant women may differ from cases in terms of reduced fertility, and less fertile women are less frequently users of contraceptive. The exclusion from the non-obstetric control group of current contraceptive users would be incorrect, since noncontraceptive users would more easily experience difficulty in conception owing, in part, to past IUD use. In this series, however, exclusion of non-contraceptive current users did not change the estimated RR (data not shown). Thus, various potential biases are difficult to overcome and are applicable both to hospital-based and population-based control groups. Most of these biases, however, should tend to overestimate the RR of OC use and barrier methods, too. To address, at least in part, these problems, we have chosen to consider as controls both women who delivered a live-born child and non-pregnant hospitalized women. Other potential sources of bias should be less important in this study. Cases and controls were drawn from the same network of hospitals and had similar participation rates of nearly 100%. It is possible that women with an ectopic pregnancy might be more sensitized towards recalling potential risk factors for the disease (including IUD use] than women in hospital for other conditions. However, the potential association between ectopic pregnancy and IUD use did not receive widespread attention from the lay press in Italy, and the question on contraceptive methods use was included in a questionnaire including several medical (particularly gynecological and obstetric) questions. Further, the prevalence of OC, IUD and barrier methods of contraceptive use in the control group was largely consistent with the few data of prevalence of contraceptive methods in Italy, the low prevalence of use being partly attributable to the use of coitus interruptus and rhythmic methods in Italy. Recall bias should not be a major problem also for potential covariates. In Italy, induced abortion has been legal since 1978 and only a small proportion of induced abortion is performed outside recognized structures in this area of Italy.” Thus, in consideration of the time frame of data collection, it is unlikely that women tended systematically to report induced abortion as spontaneous. With regard to the role of other factors, allowance for potential distorting factors, including marital status, socioeconomic indicators and other major known or potential determinants (such as PID, smoking, or induced abortion) of ectopic gestation, did not change the estimated RR. Further, the estimated RRs for ever IUD use were largely consistent across strata of various covariates. The only possible exception was the
Contraceptives
Contraception 1995;52:9%98
observation that the RRs were higher in non-educated women, but contraceptive methods use in Italy is generally more frequent among women of higher social class.16 Several studies have analyzed the relation between prior to conception IUD use and risk of ectopic pregnancy. ‘-M’J’J~ However, the evidence is not completely consistent. Data from the Oxford Family Planning Contraceptive study,16 and a large multicentric study conducted by the World Health Organization3 reported no increased risk of ectopic pregnancy in exIUD users. However, case-control studies found an elevate risk of ectopic pregnancy, the estimated RR ranging from 1.5 to 4.0.‘~2~4~6’7Selective mechanisms should be carefully considered in the interpretation of these apparent differences. However, the durationrisk relationship observed in some studies4 gives some support to the hypothesis of a causal link. In biological terms the association has been interpreted in terms of increased risk of clinical or subclinical tubal or pelvic infection (due to several microorganisms, such as Chlamydia, Actomyces israelii) in IUD users,” that, in turn, may increase the risk of ectopic pregnancy. In this study, the increased risk persisted also after exclusion from the multivariate equation of a history of PID and in strata of subjects with and without history of PID/salpingitis, but only PID with clinical diagnoses have been considered. It has also been suggested that tubal damage unrelated to sexually transmitted disease may occur in IUD users. Changes in cilia of fallopian tubes have been observed in IUD users, but the duration of the changes is unclear.20#21 Ever OC use was not related to the risk of ectopic pregnancy. These findings are in general agreement with most of the published studies.1*68s22 A specific interest of this analysis derives from the fact that the study was based on a population with low prevalence of OC use, where different potential selective mechanisms are conceivable, in comparison to those from populations with more widespread use. This offers further indirect support to the association observed with IUD use. Ever use of barrier methods was associated with a borderline statistically significant increased risk of ectopic pregnancy in comparison with non-obstetric controls in the analysis. This finding was not confirmed when obstetric controls were considered, and may be in first hypothesis attributable to chance. In any case, it must be considered cautiously as a potential indicator of higher contraceptive method use in the non-obstetric control group. In conclusion, the possible association observed in this study between past IUD use and the risk of ectopic pregnancy, if confirmed, together with the per-
and Ectopic
Pregnancy
97
sistence of the risk several years after stopping use, would have relevant public health implications in the ultimate assessment of benefits and risks related to various contraceptive methods.
Acknowledgments This work was conducted within the framework of the CNR (Italian National Research Council) Applied Project “Fattori di Rischio di Malattia” (sottoprogetto “Fattori di Malattia nella Patologia Matemo Infantile”). The authors wish to thank Ivana Garimoldi, Judy Baggott and the G.A. Pfeiffer Memorial Library staff for editorial assistance.
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