Spontaneous conception after a successful attempt at in vitro fertilization/ intracytoplasmic sperm injection

Transcription

1 FERTILITY AND STERILITY VOL. 73, NO. 4, APRIL 2000 Copyright 2000 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A. Spontaneous conception after a successful attempt at in vitro fertilization/ intracytoplasmic sperm injection Bernadette Hennelly, S.R.N., Robert F. Harrison, M.D., Joan Kelly, S.R.N., Saji Jacob, M.R.C.O.G., and Tom Barrett, M.R.C.O.G. Human Assisted Reproduction Ireland, Rotunda Hospital, Dublin, Ireland Objective: To determine the incidence of spontaneous pregnancy in women who were not actively undergoing therapy after a successful attempt at IVF/intracytoplasmic sperm injection and to characterize its pattern of occurrence. Design: Retrospective postal questionnaire. Setting: An assisted reproduction unit at a university-based teaching hospital. Patient(s): Five hundred thirteen replies were received from 530 questionnaires mailed. Intervention(s): None Main Outcome Measure(s): Spontaneous pregnancy. Women who did and did not conceive spontaneously after successful IVF treatment were compared in terms of their age, duration of infertility, previous reproductive history, and indication for treatment at the time of assisted reproduction. Result(s): The rate of spontaneous conception among the survey respondents was 20.7%. Younger women ( 34 years of age) had a higher rate of spontaneous conception, as did those with a shorter duration of infertility. Women with unexplained infertility and endometriosis also were more likely to conceive. Few of those who had undergone intracytoplasmic sperm injection conceived, whereas 21.6% of those whose partners had had sperm quality sufficient for IVF later conceived spontaneously. Conclusion(s): The chances of spontaneous conception after successful ART therapy are significant in some groups of patients. This has implications for the practice of assisted reproduction and the obstetric care of patients who conceive with treatment. Contraceptive advice may need to be provided to couples who undergo IVF/intracytoplasmic sperm injection. (Fertil Steril 2000;73: by American Society for Reproductive Medicine.) Key Words: ART, success, incidence, subsequent, spontaneous conception Received September 25, 1999; revised and accepted November 8, Reprint requests: Robert F. Harrison, M.D., Human Assisted Reproduction Ireland, Rotunda Hospital, Dublin 1, Ireland (FAX: ) /00/$20.00 PII S (99) The positive placebo effect found in infertile couples undergoing investigation and treatment is well documented (1). It can even be seen in the pre and post end of the line therapy IVF/intracytoplasmic sperm injection (ICSI) (2 6). Much less well appreciated are the chances of spontaneous pregnancy after a successful attempt at assisted reproduction. The ability to supply such information would be an important part of the counseling process that should accompany all assisted reproductive technology (ART) procedures. Multiple pregnancy is a distinct possibility with IVF/ICSI (7). The unplanned, spontaneous conception of additional children at a later date could have unforeseen social and economic implications. These warrant consideration before therapy is initiated, particularly in older couples. Information in the literature is scant and diverse (8, 9). However, such an important detail should surely be included in the information given to patients as part of the decisionmaking process of informed consent. To remedy this situation at our center, we undertook this study to discover the subsequent reproductive history of couples who previously had achieved a live birth with us through IVF/ICSI and did not want any further fertility therapy. 774

2 MATERIALS AND METHODS Patients The study was approved by the Hospital Ethics Committee/Institutional Review Board. It included couples who had had successful pregnancies and birth as a result of IVF (10) or ICSI (11) cycles at the Human Assisted Reproduction Unit of the Rotunda Hospital in Dublin, Ireland, between July 1990 and March Patients who had conceived after subsequent IVF attempts were not included. The study was confined to couples who had indicated to us that they had finished active conceptive therapy. Four hundred sixty-nine such couples had conceived after an attempt at IVF. Another 44 had conceived after ICSI began to be used in Full results for both IVF and ICSI have been published annually in the Rotunda Hospital Reports since the clinic opened in October 1989 (12). Data Collection The information used in the study was derived from a questionnaire (available on request). This was drawn up with input from the medical, nursing, and counseling staff. It was initially pilot-tested on 30 women to ensure that they understood the questions asked and had no difficulty in responding. The questionnaire then was sent with an accompanying explanatory letter (to ensure informed consent) to each patient who was known to have been delivered of an infant after IVF or ICSI treatment at our hospital unit and who had not returned for further therapy. To ensure as comprehensive a survey as possible, when an initial reply was not received within 1 month, another questionnaire was mailed. When necessary, telephone calls were made and the questionnaire was completed over the phone. Data Processing and Statistical Analysis All the relevant answers to the questionnaire were entered into a Microsoft Excel (Redmond, WA) spreadsheet and analyzed using Data Desk version 6 (Data Desk, Ithaca, NY). Medians were used rather than means as most data were skewed. The 2 test was used for categorical outcomes. TABLE 1 Maternal age at the time of ART treatment and treatment outcome. Age (y) (%) (0.2) Note: , P Age at the Time of ART Success The median age of those respondents who did not conceive again after their ART success was 34 years, the same as that of those who did conceive again. The age-related frequency distribution is shown in Table 1. Younger patients were found to have a significantly higher chance of conceiving spontaneously than those who were older (P.0124). Duration of Infertility Before First ART Success The median duration of infertility before the successful attempt at IVF/ICSI was 4 years for respondents who conceived and also for those who did not conceive. However, as shown in Table 2, when the duration of infertility before conception was subdivided into 5-year intervals and the percentage of the column total was calculated, there was a trend toward conception among those who had not been trying as long (P.834). It is interesting to note that this trend occurred not just in the group of women who had been infertile for 5 years (the largest group), but also in the group who had been infertile for 5 9 years (also a large group). RESULTS General Five hundred thirty questionnaires were sent out. Five hundred thirteen (94%) replies were received and analyzed. One hundred six (20.7%) of the 513 respondents reported that they had had a subsequent spontaneous pregnancy. Ten of them had had two spontaneous pregnancies; in five cases, the first pregnancy ended in miscarriage and in two cases, it was ectopic. For the purposes of data analysis, only the first pregnancy was counted. Among the respondents who had had one subsequent pregnancy, 14 (13%) of those pregnancies ended in miscarriage and three (2.8%) were ectopic. All the pregnancies occurred within 2 years of the IVF/ICSI pregnancy success. TABLE 2 Duration of infertility before ART success and spontaneous pregnancy afterward. Duration of infertility (y) Note: 2.834, P.84. FERTILITY & STERILITY 775

3 TABLE 3 Cause of infertility in 513 women in whom ART treatment was successful. Cause of infertility Male factor* Tubal factor Unexplained Anovulation Endometriosis Cervical factor Note: , P * Includes 44 patients who underwent ICSI; 2 became. Presence of Primary Infertility at the Time of ART Therapy Four hundred seven (79%) of the 513 respondents had not had a previous pregnancy before their successful ART attempt. This parameter appeared to have no role in the occurrence of a subsequent spontaneous pregnancy ( , P.1). Relation to Clinical Indication for ART Of the 513 respondents, 153 had had unexplained infertility before their ART attempt. A tubal factor was present in 128 cases and significant endometriosis was present in 92 cases. Forty-five of the women were anovulatory and 5 were thought to have a cervical factor. In 95 cases, a male factor was identified. As Table 3 shows, statistically significant differences were found in the occurrence of subsequent spontaneous pregnancies (P.0535) when the various main causes of infertility that necessitated the use of IVF/ICSI were considered. Those who were most likely to conceive spontaneously had unexplained infertility or endometriosis. Patients who had a tubal factor were less likely to conceive again. Of the overall group, 13.7% of the respondents who underwent ART for male factor infertility conceived again. However, these data include patients who underwent ICSI after it was introduced in 1995, 4.6% of whom subsequently conceived spontaneously (Table 4). This is significantly worse than the rate of spontaneous pregnancy in the overall group (P.0058). Among the 51 patients who underwent IVF alone before 1995, the rate of spontaneous pregnancy was 21.6%. Unlike the ICSI group, which contained patients with severe male factor infertility (11), many of whom would not have been considered for IVF before 1995, the patients who were treated before ICSI was available had poor spermiograms but adequate sperm after swim-up to allow for IVF. TABLE 4 Comparison of pregnancies achieved after a successful IVF and ICSI were performed for male factor infertility. Type of treatment (%) DISCUSSION ICSI 2 (4.55) 42 (95.5) 44 IVF 104 (22.2) 365 (77.8) Note: , P Most couples who want to conceive children are happy however it happens. Those who have achieved this goal through IVF/ICSI (13) and then suddenly conceive without aid also are extremely happy. But these feelings can be tinged with surprise and apprehension. Many of these patients thought that the reproductive chapter of their lives was closed. They had put the pain of childlessness behind them. An unexpected pregnancy may raise many issues. These individuals did not contemplate this situation when they sought treatment with ART, and it may take time for them to come to terms with it. In the Human Assisted Reproduction Unit at Rotunda Hospital in Dublin, in accord with the guidelines of the Medical Council of Ireland (14), patients enter the program only if they have a valid clinical indication for IVF/ICSI. They must have undergone a full infertility investigation and explored all other therapeutic options. These patients truly undertake IVF as a last resort. Therefore, it was surprising to find that 20.7% of those for whom IVF proved successful later conceived spontaneously. This incidence is much higher than that reported from France (8). Olivennes et al. reported that 8.9% of their patients had spontaneous pregnancies after the birth of a child conceived through IVF. A recent Japanese study found a cumulative pregnancy rate of 18% at 60 months after the delivery of an infant conceived through IVF (9). The figure we obtained is likely to be a true representation of our clinic population. Our survey response rate of 94% was much higher than others have obtained (15) and the population our clinic serves is very stable. Only patients who live in Ireland are recruited to our program, and for much of the study period, it was the only ART program that was operating full-time in the Republic of Ireland. Our standard protocol (10, 11) involves thorough counseling and a high degree of contact between patient and staff throughout the treatment period. The rapport that develops through this approach ensures a high degree of feedback in regard to treatment outcome, even from couples who later move to another address. 776 Hennelly et al. Spontaneous conception after ART success Vol. 73, 4, April 2000

4 In this study, all the spontaneous pregnancies reported occurred during the 2 years after the ART birth success. This is similar to the findings of Shimizu et al. (9), who also noted that most such pregnancies occurred within 2 years. The mean interval from the delivery of the infant conceived through IVF to the last menstrual period before the spontaneous conception was 14.8 months. It is of interest that the cumulative rate of conception leading to live birth is 14.3% at 12 months in untreated infertile couples (1). The report from Olivennes et al. (8) does not include such information. However, they do state that 40% conceived again through another attempt at IVF. The way in which this figure was calculated and the initial pregnancy rate the first time conception occurred after IVF are not given. Other data (16) suggest that a previously successful IVF cycle is a positive prognostic indicator for a second IVF attempt compared with a previous natural conception (31% vs. 19.4%). Like Shimizu et al. (9), we found no relation between a natural conception before the IVF success and a spontaneous pregnancy afterward. This differs from studies on IVF therapy (17), which report that patients with secondary unexplained infertility have a significantly better chance of success. We found no statistically significant differences in the rates of positive outcomes among patients undergoing ART for various indications (18). Patients with unexplained infertility and those with endometriosis were most likely to have a spontaneous pregnancy after IVF success in this study. This finding calls into question the early use of ART in the management of unexplained infertility because spontaneous conception can be readily expected in these cases (1). In patients with endometriosis, subsequent spontaneous pregnancy could be the result of the known effect pregnancy itself has on endometriosis. When we analyzed couples in which the woman had a tubal factor and her male partner had a severe male factor (the ICSI group), we found a much lower rate of spontaneous conception. In the study by Shimizu et al. (9), patients with severe male factor infertility (sperm count of / ml) were not included. Before ICSI was introduced in 1995 (11), only men who had subnormal semen parameters (19) but a sperm density of /ml and a good swim-up result (20) would have been considered for IVF (21). In such cases, the prognosis for spontaneous conception after IVF success was 21.6% in this study, compared with 4.6% for the ICSI group. These findings call into question the present definition of male factor infertility. Further revision of sperm parameters downward is indicated (19). In this study, age was significantly correlated with the chance of spontaneous conception. This is in agreement with the findings of Shimizu et al. (9). It also fits with what is known about the chance of spontaneous conception with (22, 23) or without (1) IVF treatment. The chance of a spontaneous pregnancy after a successful IVF cycle should be considered when the number of embryos to be transferred is determined for younger women. This is particularly important today when the detrimental impact of multiple pregnancy is widely recognized (7) and in units like ours where selective reduction is not an option (24). The duration of infertility undoubtedly is related to age, albeit not entirely. In the population we serve, marriage is frequently postponed until the couple are in their 30s. However, the interplay between age and duration of infertility may explain why, despite a definite trend, statistical analysis of the duration of infertility did not quite reveal significance. This is somewhat different from studies of IVF therapy itself (22, 23). There is a perception among patients who conceive through IVF/ICSI that they cannot conceive in any other way. Our data clearly show that this is not true for as many as one in five couples, particularly those who are younger and have been infertile for a shorter period, women with endometriosis, couples with unexplained infertility, and men with a mild male factor problem. The volume of data collected and the incidence documented warrant the inclusion of the chance of subsequent spontaneous pregnancy in discussions with couples who are considering the use of ART. Contraceptive advice also may need to be given, particularly when multiple pregnancy has resulted from previous ART treatment. There also are implications for obstetric practice, particularly the mode of delivery. Many infants conceived through ART are delivered by cesarean section (25). This may be due in part to a belief that a scar in the uterus is inconsequential because the patient will not become again. In our unit, the positive placebo effect of being placed on the waiting list for ART treatment and conceiving after an unsuccessful IVF attempt was already evident. To this information, we now add the chance of spontaneous pregnancy occurring after a successful ART outcome. However, the number of such pregnancies that would have occurred without the prior success is unknown. These spontaneous pregnancies may be related to the ovarian stimulation given in the past or to the physiologic effects of pregnancy on the pituitary and endocrine systems. The most likely cause, however, is the relief from stress (13) that undoubtedly occurs after an infertile couple finally has a child. References 1. Collins JA, Burrows EA, Wilan AR. The prognosis for live birth among untreated infertile couples. Fertil Steril 1995;64: Ben-Rafael Z, Mashiach S, Dor J, Rudak E, Goldman B. Treatmentindependent pregnancy after an in vitro fertilization and embryo transfer trial. 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