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
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Abstract |
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Key words: ectopic pregnancy/epidemiology/fertility/intrauterine device/prospective study
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Introduction |
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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., 1996). 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).
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Materials and methods |
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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., 1989). 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., 1989
; Saada et al., 1997
). 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, 1958). 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., 1996) were taken into account by multivariate analysis using the Cox model (Cox and Oakes, 1984
).
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Results |
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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 I. 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.
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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): 1739%].
Intrauterine pregnancy
The 23 IUD users who tried to become pregnant again waited a mean of 8.5 months (95% CI: 4.812.2) after EP, whereas the mean waiting time was 3.0 months (95% CI: 2.53.6) for the 305 IUD non-users.
Spontaneous intrauterine pregnancy rates were significantly different between IUD users and non-users (Figure 1). The 1 year cumulative rates were 87% (95% CI: 73100%) for IUD users and 60% (95% CI: 5366%) for non-users. The crude hazard ratio for IUP was 2.1 (1.33.5) (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 II
). If these fertility factors were taken into account as confounders, the difference between IUD users and non-users was not significant (Table II
): the adjusted hazard ratio for IUP was 1.2 (95% CI: 0.692.2; P = 0.48).
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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 2): the 1 year cumulative delivery rate was 86% (95% CI: 72100%) for IUD users, and 44% (95% CI: 3856%) for IUD non-users. The crude hazard ratio was 2.9 (95% CI: 1.84.9; P < 0.001). If fertility factors and IVF were taken into account as confounders, the difference was also significant (Table III
): the adjusted hazard ratio was 1.8 (95% CI: 1.03.2; 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: 0.170.64; P < 0.01).
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Discussion |
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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: 5669%). 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., 1988; Mäkinen et al., 1989
; Pouly et al., 1991
). 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., 1982, Pouly et al., 1991
; Silva et al., 1993
; Job-Spira et al., 1996
). 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., 1991
) 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., 1989
; Fedele et al., 1989
; Saada et al., 1997
), 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., 1997
) 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., 1987), 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, 1992
). 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.
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Acknowledgments |
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Notes |
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References |
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Submitted on October 7, 1999; accepted on January 18, 2000.