Fertility outcome after ectopic pregnancy and use of an intrauterine device at the time of the index ectopic pregnancy

A. Bernoux1, N. Job-Spira1, E. Germain2, J. Coste1 and J. Bouyer1,3

1 INSERM U292, Hôpital de Bicêtre, 82 rue du Général Leclerc, 94276 Le Kremlin-Bicêtre Cedex and 2 Centre Hospitalier Hôtel-Dieu, Service Epidémiologie, Prévention et Economie de la Santé, Clermont-Ferrand, France


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Fertility after ectopic pregnancy (EP) was investigated in a non-selected population taking into account intrauterine device (IUD) use at the time of the EP. Between January 1992 and June 1996, 647 women listed in the EP register of Auvergne (France) were followed up. The analysis included only the 328 women who were seeking to become pregnant: 23 women using IUD at the time of the index EP (IUD users) and 305 IUD non-users. Among IUD users, there was no recurrence of EP, and the 1 year cumulative rate was 87% [95% confidence interval (CI): 73–100%] for intrauterine pregnancies and 86% (95% CI: 72–100%) for deliveries. Among IUD non-users, the 2 year cumulative rate for recurrence of EP was 28% (95% CI: 17–39%), and the 1 year cumulative rates were 60% (95% CI: 53–66%) for intrauterine pregnancies and 44% (95% CI: 38–56%) for deliveries. The adjusted intrauterine pregnancy rate of IUD users was not significantly different from that of IUD non-users. However, IUD non-users had more miscarriages, so their delivery rate was lower.

Key words: ectopic pregnancy/epidemiology/fertility/intrauterine device/prospective study


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Ectopic pregnancies (EP) account for 1.5% of all reported pregnancies in western countries (Hemminki and Heinonen, 1987Go; Mäkinen, 1987Go; Coste et al., 1994Go). Several risk factors have been identified: pelvic inflammatory disease (PID), especially with Chlamydia trachomatis, smoking at the time of conception, induction of ovulation by clomiphene, previous pelvic surgery, previous EP and age (Chow and Daling, 1987; Coste et al., 1991Go; Fernandez et al., 1991Go; Job Spira et al., 1993Go). In developed countries, improvements in the diagnosis and management of ectopic pregnancies have shifted clinicians' concerns away from the immediate health of the woman, towards preserving her subsequent fertility. Adverse effects of EP on subsequent reproductive performance include low fertility and a high recurrence rate (De Cherney et al., 1982Go; Tuomivaara and Kauppila, 1988Go; Mäkinen et al., 1989Go). Conflicting results have been obtained concerning fertility after EP (Clausen, 1996Go), with proportions of pregnancies after EP of 24% (Sultana et al., 1992) to 89% (Lindblom et al., 1990Go) reported. These differences may be due to selection in the populations studied, because in most studies, fertility is evaluated in a hospital-based population after a specific treatment: conservative surgery (De Cherney et al., 1982Go; Langer et al., 1990Go; Vermesh and Presser, 1992Go), radical surgery (Dubuisson et al., 1990Go; Oelsner et al., 1994Go), methotrexate (Fernandez et al., 1993Go; Stoval et al., 1991Go) or prostaglandin treatment (Lindblom et al., 1990Go), laparotomy (Sherman et al., 1982Go; Ory et al., 1993Go) or laparoscopy (Tuomivaara and Kauppila, 1988Go; Silva et al., 1993Go; Langebrekke et al., 1993Go). Moreover, several previous studies did not consider whether the women were seeking to become pregnant, and classified women not seeking to become pregnant as infertile. In-vitro fertilization (IVF) has seldom been dealt with separately from spontaneous fertility. Women using an intrauterine device (IUD) at the time of EP have rarely been analysed separately from women not using contraception although these two groups of women differ in reproductive risk factors (Pouly et al., 1991Go) and probably also differ in subsequent fertility levels.

We have previously investigated fertility by studying the rate of intrauterine pregnancies after EP in the women listed in the French EP register of the Auvergne region, a non-selected population (Job-Spira et al., 1996Go). The large number of registered EP and the long duration of follow-up enabled us to extend this investigation. We investigated other fertility indicators such as EP recurrence and delivery (with or without IVF). Women were also studied separately according to the circumstances of conception for the index EP (whether an IUD was used).


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Study population
The methodology of the Auvergne EP register has been described elsewhere (Coste et al., 1994Go). Briefly, a register was established in January 1992 in three départements (districts) of the Auvergne region in the centre of France (Allier, Cantal and Puy-de-Dôme). All women between 15 and 44 years of age who lived permanently in the target area and who had had either surgical or medical treatment for ectopic pregnancy were registered and followed up until the age of 45 years, all reproductive outcomes being recorded. In each medical centre in the area (15 public or private maternity hospitals and 12 surgical units) a trained investigator, either a midwife or a physician, was responsible for case identification, follow-up and data collection. The basic information collected for each woman included: socio-demographic characteristics, sexual, gynaecological, reproductive and surgical history, conditions at conception (use of contraception, ovulation induction, IVF), smoking habits, results of Chlamydia trachomatis serology tests, characteristics of the EP (site, tubal rupture, haemoperitoneum), and the treatment given. The completeness of the register has been estimated to be around 90% (Coste et al., 1995Go).

The women were interviewed as follows about reproductive events by telephone every 6 months after EP: the desire for a new pregnancy, cumulative period of trying to become pregnant, pregnancies achieved, treatments for infertility and use of contraception.

Each EP was recorded independently, so an individual woman with several successive EP had several records in the register. For this study, we used the first EP record (called `index EP') and included any other EP in the follow-up data.

This study was conducted on the 835 women registered between January 1992 and June 1996. 115 were excluded from follow-up because they had undergone contraceptive sterilization or therapeutic bilateral salpingectomy (with no desire to become pregnant again), and 70 of the remaining women (9.7%) were lost to follow-up and three women were followed up for less than 6 months. The remaining 647 women were followed up for at least 6 months after treatment for index EP, until June 1997. Women who had been using oral contraception at the time of the index EP (n = 32) were excluded from the analysis because they were too few in number. Women who had been using an intrauterine device at the time of the index EP (n = 181, called IUD users) were analysed separately from other women (n = 434, called IUD non-users). Only a fraction of the women followed were seeking to become pregnant: 23 IUD users (13%) and 305 IUD non-users (70%). These women were younger and had fewer children than those who had not sought to become pregnant. Fertility was therefore finally studied in these 328 women.

Epidemiological indicators of fertility
The classical epidemiological indicator of fertility is the cumulative pregnancy rate, which is the probability of becoming pregnant within a given time (Sandvei et al., 1989Go). This rate measures the biological ability to procreate but does not take into account the outcome of the pregnancy. It therefore does not consider EP recurrences and miscarriages, which frequently occur after EP (Mäkinen et al., 1989Go; Saada et al., 1997Go). Moreover, it is restricted to spontaneous pregnancy whereas a large proportion of women undergo IVF after EP.

We therefore considered three indicators of fertility in this study: the rate of EP recurrence; the rate of spontaneous intrauterine pregnancy (IUP), to account for pregnancy outcome; and the rate of delivery after spontaneous pregnancy or IVF, which is a more global indicator, closer to the concerns of women and clinicians.

Statistical methods
Cumulative pregnancy (EP or IUP) and delivery rates were calculated with Kaplan-Meier estimators (Kaplan and Meier, 1958Go). This required knowledge of the actual period of time for which women had been trying to become pregnant.

For EP recurrence and IUP, the time period was calculated by summing all the periods of time during which the woman was trying to become pregnant, until the event of interest occurred (EP or IUP). The follow-up of women entering IVF programmes was censored, because the event of interest was spontaneous pregnancy. For intrauterine pregnancy rates, any recurrent EP was ignored, but the time during which the woman was pregnant was excluded from the time taken to seek a pregnancy, because the woman was not exposed to the `risk of intrauterine pregnancy'.

A more pragmatic approach was also adopted, studying the occurrence of delivery. We considered the time period from the point at which the woman first began trying to become pregnant until the first pregnancy ending in a delivery, whatever the intervening events (temporary interruptions in trying to conceive, IVF, recurrent EP or spontaneous abortion). However, women pregnant at the cut-off date were excluded if they had been pregnant for less than 3 months because an early miscarriage was still possible.

We compared crude cumulative fertility rates for IUD users and non-users by calculating hazard ratios with 95% confidence intervals and using log rank tests. Potential confounding effects of known fertility factors (Job-Spira et al., 1996Go) were taken into account by multivariate analysis using the Cox model (Cox and Oakes, 1984Go).


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The 70 women lost to follow-up included fewer IUD users than did the group followed (12 versus 29%), but there was no difference between the two groups for the main fertility factors except tubal damage, which was more frequent in women lost to follow-up (50 versus 30%, not significant).

The characteristics, including IUD use, at the time of the index EP of the 328 women who were trying to become pregnant are shown in Table IGo. The percentage of women with a history of infertility or tubal damage was significantly lower for IUD users than for non-users. Parity was significantly higher in IUD users. There were no significant differences between IUD users and non-users for socio-demographic characteristics, prior miscarriage and EP treatment.


View this table:
[in this window]
[in a new window]
 
Table I. Characteristics at the time of the index ectopic pregnancy (EP) of the women trying to become pregnant (n = 328), according to IUD use at the time of the index EP
 
The mean follow-up time was 28 months (range: 5–61) and was similar (P = 0.13) for IUD users (28 months) and non-users (32 months).

Recurrent ectopic pregnancy
None of the IUD users experienced a recurrence of EP, whereas 32 IUD non-users (10%) suffered another EP after the index EP. The 2 year cumulative rate of EP recurrence for IUD non-users was 28% [95% confidence interval (CI): 17–39%].

Intrauterine pregnancy
The 23 IUD users who tried to become pregnant again waited a mean of 8.5 months (95% CI: 4.8–12.2) after EP, whereas the mean waiting time was 3.0 months (95% CI: 2.5–3.6) for the 305 IUD non-users.

Spontaneous intrauterine pregnancy rates were significantly different between IUD users and non-users (Figure 1Go). The 1 year cumulative rates were 87% (95% CI: 73–100%) for IUD users and 60% (95% CI: 53–66%) for non-users. The crude hazard ratio for IUP was 2.1 (1.3–3.5) (P < 0.01). The incidence of IUP decreased with increasing age of the woman, and was lower if the women had a history of infertility or tubal damage whereas it was higher for women with high parity (Table IIGo). If these fertility factors were taken into account as confounders, the difference between IUD users and non-users was not significant (Table IIGo): the adjusted hazard ratio for IUP was 1.2 (95% CI: 0.69–2.2; P = 0.48).



View larger version (13K):
[in this window]
[in a new window]
 
Figure 1. Cumulative intrauterine pregnancy rate according to IUD use at the time of the index ectopic pregnancy.

 

View this table:
[in this window]
[in a new window]
 
Table II. Adjusted hazard ratios for intrauterine pregnancies after ectopic pregnancy (EP)
 
Delivery
At the cut-off date, 24 women were pregnant. The 10 women who had been pregnant for less than 3 months were excluded from this part of the analysis (see above). The remaining 14 women were grouped with the women who gave birth.

The cumulative rate of miscarriage was significantly higher (P < 0.01) for IUD non-users (26%) than for IUD users (5%). Twenty of the 23 IUD users (87%) and 150 of the 305 IUD non-users (49%) gave birth. The pregnancies of the IUD users were all spontaneous whereas 52 of the pregnancies of the IUD non-users were achieved by IVF. The cumulative delivery rates were significantly different for IUD users and non-users (Figure 2Go): the 1 year cumulative delivery rate was 86% (95% CI: 72–100%) for IUD users, and 44% (95% CI: 38–56%) for IUD non-users. The crude hazard ratio was 2.9 (95% CI: 1.8–4.9; P < 0.001). If fertility factors and IVF were taken into account as confounders, the difference was also significant (Table IIIGo): the adjusted hazard ratio was 1.8 (95% CI: 1.0–3.2; P < 0.05). The cumulative birth rate was significantly lower for women treated by IVF than for those with spontaneous pregnancies, the adjusted hazard ratio being 0.33 (95% CI: 0.17–0.64; P < 0.01).



View larger version (12K):
[in this window]
[in a new window]
 
Figure 2. Cumulative delivery rates according to IUD use at the time of the index EP.

 

View this table:
[in this window]
[in a new window]
 
Table III. Adjusted hazard ratios for deliveries
 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Our study population included all the women living in the Auvergne region who experienced EP, not just those who chose to be treated in a particular hospital or clinic. Moreover, there were very few selection effects because around 90% of the women experiencing EP in the Auvergne region were included in the register (Coste et al., 1995Go). Few women (9.7%) were lost to follow-up and these women differed only slightly from the women who were followed up. The results presented are therefore probably not biased. Women were interviewed every 6 months, the details of reproductive events after EP were precisely known, and recall bias, which occurs frequently in retrospective studies, was therefore limited.

Our results show that, on a population basis, only 53% of the women were seeking to become pregnant after EP. The overall 1-year cumulative intrauterine pregnancy rate was 62% (95% CI: 56–69%). The most important finding of this study was that IUD users were very different from the other women in terms of their reproductive behaviour and fertility after EP. Few IUD users were trying to become pregnant again (13%) and those who were had delayed their decision for a mean of 8.5 months after EP. None of these women had another EP. Their 1 year cumulative intrauterine pregnancy rate was 87%, similar to that reported in several other studies (Thorburn et al., 1988Go; Mäkinen et al., 1989Go; Pouly et al., 1991Go). In contrast, 70% of IUD non-users were trying to become pregnant and the mean length of time after index EP before trying to become pregnant again was short (3.0 months). The frequency of second EP within 2 years was 28% and the 1 year cumulative intrauterine pregnancy rate for these women was 60%.

Factors such as a history of infertility, tubal damage and age were associated with low fertility, as shown in previous studies (De Cherney et al., 1982Go, Pouly et al., 1991Go; Silva et al., 1993Go; Job-Spira et al., 1996Go). The prevalence of these factors differed between IUD users and non-users. IUD users had lower rates of previous infertility, EP and pelvic inflammatory diseases (PID) (Pouly et al., 1991Go) because previous PID is a contraindication for IUD. These differences in prior fertility factors may account for the differences between IUD users and non-users in terms of subsequent fertility. This was the case in this study for intrauterine pregnancies: if known prior fertility factors were taken into account, the difference in subsequent intrauterine pregnancy rates between IUD users and non-users was not significant. This was not true for delivery rates, which differed significantly between IUD users and non-users after adjustment for known prior fertility factors. The difference between the results for intrauterine pregnancy and delivery rates may be partly due to the apparently high rate of miscarriage among IUD non-users (26%). This rate, consistent with previous reports (Coulam et al., 1989Go; Fedele et al., 1989Go; Saada et al., 1997Go), was higher than that for the general population (10 to 15%) and significantly higher (P < 0.01) than that for IUD users (5%). Although it is unclear why the miscarriage rate is so low in IUD users, this result supports our previous suggestion (Saada et al., 1997Go) that EP and miscarriage may have common risk factors or mechanisms. IVF was also a potential source of difference. However, the difference between the pregnancy rates of IUD users and non-users would have been even greater if IVF pregnancies had been excluded because only the IUD non-users received IVF treatment.

In conclusion, fertility after EP cannot be entirely described by a single indicator. At least three indicators appear to be necessary: EP recurrence, intrauterine pregnancy and delivery. Women should be classified according to IUD use at the time of the index EP. EP recurrence is rare in IUD users, and the adjusted intrauterine pregnancy rate for these women does not significantly differ from that of IUD non-users. However, they have fewer miscarriages, so their delivery rate is higher. For these women, EP should be considered as a failure of contraception (Chow et al., 1987Go), demonstrating high fertility. In contrast, for IUD non-users, EP should be considered as a reproductive failure that may reflect a low level of fertility, probably due to persistent organic tubal lesions (Tran and Leroy, 1992Go). This study contributes to the identification of two clinical and epidemiological entities: EP due to contraceptive failure and EP due to reproductive failure. Further analysis is required to determine whether the risk factors and management of these two categories of EP are different.


    Acknowledgments
 
This study was supported by Fondation pour la Recherche Médicale and by grants from the National Register Committee (Comité National des Registres – INSERM – DGS) and the French National Social Security Organisation (CNAMTS, convention number 3AM044). We thank Julie Knight for her careful review of the English version of this paper.


    Notes
 
3 To whom correspondence should be addressed Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Chow, W.H., Daling, J.R., Cates, W. and Greenberg, R.S. (1987) Epidemiology of ectopic pregnancy. Epidemiol. Rev., 9, 70–94.[ISI][Medline]

Clausen, I. (1996) Conservative versus radical surgery for tubal pregnancy. A review. Acta Obstet. Gynecol. Scand., 75, 8–12.[ISI][Medline]

Coste, J., Job-Spira, N., Fernandez, H. et al. (1991) Risk factors for ectopic pregnancy: a case control study in France, with special focus on infectious factors. Am. J. Epidemiol., 133, 839–849.[Abstract]

Coste, J., Job-Spira, N., Aublet-Cuvelier, B. et al. (1994) Incidence of ectopic pregnancy. First results of a population-based register in France. Hum. Reprod., 9, 742–745.[Abstract]

Coste, J., Aublet-Cuvelier, B., Bouyer, J. et al. (1995) Evaluation de l'exhaustivité du registre des grossesses extra-utérines d'Auvergne par la méthode capture-recapture. Rev. Epidemiol. Santé Publique, 43 (S1), 10.

Coulam, C.B., Johnson, P.M., Ramsden, G.H. et al. (1989) Occurrence of ectopic pregnancy among women with recurrent spontaneous abortion. Am. J. Reprod. Immununol., 21, 105–107.

Cox, D.R. and Oakes, D. (eds) (1984) Analysis of Survival Data. Chapman and Hall, London.

De Cherney, A.H., Maheaux, R. and Naftolin, F. (1982) Salpingostomy for ectopic pregnancy in the sole patent oviduct: reproductive outcome. Fertil. Steril., 37, 619–622.[ISI][Medline]

Dubuisson, J.B., Aubriot, F.X., Foulot, H. et al. (1990) Reproductive outcome after laparoscopic salpingectomy for tubal pregnancy. Fertil. Steril., 53, 1004–1007.[ISI][Medline]

Fedele, L., Acaia, B., Parazzini F. et al. (1989) Ectopic pregnancy and recurrent spontaneous abortion: two associated reproductive failures. Obstet. Gynecol., 73, 206–208.[Abstract]

Fernandez, H., Coste, J. and Job-Spira, N. (1991) Controlled ovarian hyperstimulation as a risk factor for ectopic pregnancy. Obstet. Gynecol., 78, 656–659.[Abstract]

Fernandez, H., Benifla, J.L., Lelaidier, C. et al. (1993) Methotrexate treatment of ectopic pregnancy: 100 cases treated by primary transvaginal injection under sonographic control. Fertil. Steril., 59, 773–777.[ISI][Medline]

Hemminki, E. and Heinonen, P.K. (1987) Time trends of ectopic pregnancies. Br. J. Obstet. Gynaecol., 94, 322–327.[ISI][Medline]

Job-Spira, N., Collet, P., Coste, J. et al. (1993) Facteurs de risque de la grossesse extra-utérine. Résultats d'une enquête cas-témoins dans la région Rhône-Alpes. Contracept. Fertil. Sex., 21, 307–312.[ISI][Medline]

Job-Spira, N., Bouyer, J., Pouly, J.L. et al. (1996) Fertility after ectopic pregnancy: first results of a population-based cohort study in France. Hum. Reprod., 11, 99–104.[Abstract]

Kaplan, E.L. and Meier, P. (1958) Non-parametric estimation from incomplete observations. J. Am. Stat. Assoc., 53, 457–481.[ISI]

Langebrekke, A., Sornes, T. and Urnes, A. (1993) Fertility outcome after treatment of tubal pregnancy by laparoscopic laser surgery. Acta Obstet. Gynecol. Scand., 72, 547–549.[ISI][Medline]

Langer, R., Raziel, A., Ron-El, R. et al. (1990) Reproductive outcome after conservative surgery for unruptured tubal pregnancy. A 15-year experience. Fertil. Steril., 53, 227–231.[ISI][Medline]

Lindblom, B., Hahlin, M., Lundorff, P. et al. (1990) Treatment of tubal pregnancy by laparoscope-guided injection of prostaglandin F2alpha. Fertil. Steril., 54, 404–408.[ISI][Medline]

Mäkinen, J.I. (1987) Ectopic pregnancy in Finland 1967–83: a massive increase. Br. Med. J., 294, 740–741.[ISI][Medline]

Mäkinen, J.I., Salmi, T.A., Nikkanen, V.P.J. and Koskinen, E.Y.J. (1989) Encouraging rates of fertility after ectopic pregnancy. Int. J. Fertil., 34, 46–51.[ISI][Medline]

Oelsner, G., Goldenberg, M., Admon, D. et al. (1994) Salpingectomy by operative laparoscopy and subsequent reproductive performance. Hum. Reprod., 9, 83–86.[Abstract]

Ory, S.J., Nnadi, E., Herrmann, R. et al. (1993) Fertility after ectopic pregnancy. Fertil. Steril., 60, 231–235.[ISI][Medline]

Pouly, J.L., Chapron, C., Canis, M. et al. (1991) Grossesses extra-utérines sur stérilet. Caractéristiques et fertilité ultérieure. J. Gynecol. Obstet. Biol. Reprod., 20, 453–460.

Saada, M., Job-Spira, N., Bouyer, J. et al. (1997) Etude épidémiologiques des facteurs liés à la récidives de la grossesse extra-utérine. Contracept. Fertil. Sex., 25 (6), 457–462.[Medline]

Sandvei, R., Bergsjo, P. and Brun, O. (1989) Computation of fertility rates following a defined reproductive risk event, by the life table method, with ectopic pregnancy used as an example. Acta Obstet. Gynecol. Scand., 68, 319–322.[ISI][Medline]

Sherman, D., Langer, R., Sadovsy, G. et al. (1982) Improved fertility following ectopic pregnancy. Fertil. Steril., 37, 497–502.[ISI][Medline]

Silva, P.D., Schaper, A.M. and Rooney, B. (1993) Reproductive outcome after 143 laparoscopic procedures for ectopic pregnancy. Obstet. Gynecol., 81, 710–715.[Abstract]

Stoval, T.G., Ling, F.W., Gray, L.A. et al. (1991) Methotrexate treatment of unruptured ectopic pregnancy: a report of 100 cases. Obstet. Gynecol., 77, 749–753.[Abstract]

Sultana, C.J. and Easley, K.C.R.L. (1992) Outcome of laparoscopic versus traditional surgery for ectopic pregnancies. Fertil. Steril., 57, 285–289.[ISI][Medline]

Thorburn, J., Philipson, M. and Lindblom, B. (1988) Fertility after ectopic pregnancy in relation to background factors and surgical treatment. Fertil. Steril., 49, 595–601.[ISI][Medline]

Tran, D.K. and Leroy, J.L. (1992) Rôle des lésions tubaires dans la génèse des grossesses extra-utérines. Hypothèses pathogéniques. Contracept. Fertil. Sex., 20, 864–867.[ISI]

Tuomivaara, L. and Kauppila, A. (1988) Radical or conservative surgery for ectopic pregnancy? A follow-up of fertility of 323 patients. Fertil. Steril., 50, 580–583.[ISI][Medline]

Vermesh, M. and Presser, S.C. (1992) Reproductive outcome after linear salpingostomy for ectopic gestation: a prospective 3-year follow-up. Fertil. Steril., 57, 682–684.[ISI][Medline]

Submitted on October 7, 1999; accepted on January 18, 2000.