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Second time around: a study of patients seeking second assisted reproduction pregnancies*
r FERTILITY AND STERILITY Copyright
Vol. 64, No.3, September 1995
Printed on acid·free paper in U. S. A.
1995 American Society for Reproductive Medicine
Second time around: a study of patients seeking second assisted reproduction pregnancies*
David Molloy, M.D.t Mary Louise Doody, B.Sc. Terrence Breen, B.Sc. Queensland Fertility Group, Watkins Medical Centre, Brisbane, Queensland, Australia
Objective: To investigate the outcomes of subsequent cycles of IVF-ET, GIFT, and frozen ET in patients who have already achieved at least one assisted reproductive technology (ART) pregnancy. Design: Retrospective cohort. Setting: Private infertility clinic, Brisbane, Queensland, Australia. Patients: From 1985 to 1992,4,860 patients underwent 13,106 ART oocyte retrieval cycles. One thousand nine hundred twenty-two patients achieved a pregnancy, and 784 returned for a second pregnancy. These 784 return patients were divided into two subgroups: group A (288 patients) took home at least one baby from their first pregnancy; group B (496 patients) had an unsuccessful first pregnancy. Main Outcome Measures: Pregnancy rate (PR), cumulative PR, pregnancy outcome. Results: Patients returning for second and third ART pregnancies had an increased chance of success. Pregnancy rates increased from 31.0% per transfer for patients attempting their first GIFT pregnancy, to 34.7% and 42.7% per transfer for patients attempting their second and third GIFT pregnancy. Cumulative PRs increased with subsequent pregnancy attempts. Groups A and B did not differ in PR, age, or indication of infertility but had significantly different live birth rates. The pregnancy outcomes of frozen ETs depended on the outcomes of the original cycle from which the embryos were derived. Conclusions: This study has important implications for the counseling of patients returning for subsequent ART pregnancies. Fertil Steril 1995;64:546-51 Key Words: Second ART pregnancy, cumulative pregnancy rate, secondary infertility
Prognostic factors such as maternal age (1-3), infertility etiology (3,4), and male factors (4-6) have been identified as predictive of assisted reproductive technology (ART) success. Primary and secondary infertility patients do not seem to have significantly different ART outcomes (4), and this suggests that the mechanism by which pregnancy occurs may be different in the ART patient. Haan et al. (7) illustrated that IVF results are dependent on a couple's previous history rather than on the female patient's
Received August 18, 1994; revised and accepted March 28, 1995. * Presented at the Fertility Society of Australia Conference, Sydney, New South Wales, Australia, November 2 to 6, 1993. t David Molloy, M.D., Queensland Fertility Group, Watkins Medical Centre, 225 Wickham Terrace, Spring Hill, Brisbane, Queensland 4000, Australia (FAX: 61-07-8398389).
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Molloy et aI. Second time around
history alone. Women with a previous pregnancy in an earlier relationship had an IVF success rate similar to that of women with primary infertility. In vitro fertilization results in both groups were significantly lower than for couples who had a previous natural pregnancy from the existing relationship. Investigation of the prognostic value of a patient's previous IVF history has concentrated largely on the effect of previous unsuccessful IVF treatments. A biochemical IVF pregnancy is a positive indicator for subsequent IVF pregnancy (8,9), and patients with an ectopic IVF pregnancy are at risk of another IVF ectopic (10). Simon et al. (11) showed that a previous IVF pregnancy is a better prognostic factor for subsequent IVF attempts than a previous natural pregnancy. This paper examines patients whose infertility has been reversed through ART. Such patients are Fertility and Sterility
now returning to ART clinics for second and higher order pregnancies and babies. As successful patients, they wish to know if their chances of success will be higher in subsequent attempts. In this study, the prognostic effect of a previous ART pregnancy on subsequent treatment cycle outcome is examined. Two populations are studied, those with a previous live birth and those with a previous pregnancy failure from ART treatment. MATERIALS AND METHODS
Patients in the study group underwent treatment cycles ofIVF-ET or GIFT. Stimulation protocols varied across the time frame, being predominately clomiphene citrate and hMG until 1992. Oocyte retrievals were performed by laparoscopy or ultrasound (US) scan. Excess high quality embryos from IVFET or GIFT were frozen to provide a subsequent treatment cycle of frozen ET. A total of 4,860 patients underwent 13,106 ART oocyte retrieval cycles between January 1985 and December 1992. During this time, 1,922 patients achieved a total of 2,324 pregnancies, a pregnancy rate (PR) of 17.7% per oocyte retrieval. These pregnancies resulted in 1,527 patients taking home at least one healthy baby, a take home baby rate of 65.7% per pregnancy. The remaining pregnancies resulted in losses from ectopic pregnancies (EPs) (4.8%), miscarriages (26.5%), and still birth or neonatal death (3.0%). This information provided the background statistics of our total ART population to be used for comparison with our study cohorts. Clinical pregnancies only were included in the study. Positive results were confirmed by US scan or histology. Biochemical pregnancies, pregnancies for which no confirmation was received by US scan, or pregnancies that aborted but did not require curettage were not included. Multiple pregnancies were counted as a single pregnancy event. Still births or neonatal deaths were not included in the live birth rate calculations. The live birth rate thus could be described more properly as a "take at least one baby home" rate. The prognostic effect of previous ART pregnancies on subsequent attempts was examined by comparing different groups of patients. The first group consisted of the total ART population of 4,860 patients, of whom 1,922 achieved a pregnancy. Of these successful patients, 1,138 did not or have not yet returned for a second pregnancy. The remaining 784 successful patients did return to attempt a second pregnancy (second group). One hundred thirty patients who successfully achieved a second pregnancy returned for a third pregnancy attempt (third Vol. 64, No.3, September 1995
group). This stratification was continued for fourth and fifth pregnancy attempts (20 and 3 patients, respectively), but these pregnancy attempts were not included in statistical analysis because of small numbers. The three study groups were compared by means of PR per oocyte retrieval and by life table analysis. Over the term of the study, the PRs for IVF-ET and GIFT procedures in our clinic did not alter significantly. The PR for GIFT procedures ranged from 30.1 % to 34.8%, and averaged 33.0%. For IVF-ET procedures, the PR averaged 12.2%, with a range of 11.6% to 13.1%. Changes in PR with pregnancy order in the study cohort was considered to be attributable to the cohort characteristics and not to changing PRs. Because of the higher PR associated with GIFT compared with IVF-ET, PRs for these two procedures were examined separately. Comparative life table analysis was carried out according to the methods used by Guzick and Kovacs (12-14) using follicular aspiration as the denominator. The 784 patients of the return group were subdivided into women whose first pregnancy resulted in a live baby (group A, 288 patients) and those whose first pregnancy failed (group B, 496 patients). Subsequent pregnancy outcomes in these groups were examined. The results of 154 frozen ETs undertaken by 117 of the return group of 784 patients were examined. Groups A and B were compared for the PR per frozen ET cycle and for the pregnancy outcomes of the frozen ET cycles with reference to the results of the stimulation cycle from which the embryos were derived. All statistical analyses were carried out using the Statistical Package for the Social Sciences (SPSS Inc., Chicago, IL). Two-sided X 2 and t-tests were used as appropriate. RESULTS Pregnancy Rates
Pregnancy rates per oocyte retrieval for patients attempting their first, second, or third pregnancy are shown in Table 1. Pregnancy rates are presented for GIFT and IVF-ET procedures separately. There is an increasing PR with pregnancy order for GIFT procedures. The PR per oocyte retrieval is higher for subsequent pregnancies than for the first pregnancy, with a significantly higher (P < 0.05) PR for first and second pregnancies in comparison to first pregnancies for both treatment methods. This result suggests that a previous ART pregnancy is a positive indicator for success in a subsequent attempt. Molloy et al. Second time around
547
r Table 1 Pregnancy Rates per Oocyte Retrieval for Patients Attempting Their First, Second, or Third ART Pregnancy
First pregnancy Second pregnancy Third pregnancy
GIFT procedures
NF-ET procedures
913/2,941 * (31.0) 207/597 (34.7)t 41/96 (42.7)§
937/8,082 (11.6) 154/929 (16.6)+ 22/139 (15.8)t
* Number of pregnancies per number of oocyte retrieval cycles. Values in parentheses are percentages. t Significantly different from the PR for patients attempting their first pregnancy, P < 0.05. t Significantly different from the PR for patients attempting their first pregnancy, P < 0.001. § Significantly different from the PR for patients attempting their first pregnancy, P < 0.01.
Pregnancy rates per retrieval are one method of describing the results of treatment attempts. Life table analysis estimates the proportion of patients who will conceive after any given number of treatment episodes and may be a better indicator of performance than per retrieval PR (12). Life table analysis for GIFT procedures is presented in Figure 1. A feature of the life table graph is the increasing "first pass" success rate for first, second, and third pregnancies. Mter one oocyte retrieval cycle, 34.3% of all patients attempting their first GIFT pregnancy were successful. The first cycle success rate is 39.7% for patients returning for their second pregnancy and 53.6% for patients attempting a third pregnancy. The difference between these three "first pass" success rates is statistically significant (P < 0.001). This initial improvement in success rate for second and third pregnancies is not sustained, with curves for first and second pregnancies converging by the fourth attempt. These curves plateau at approximately 92%, and the curve for the third pregnancy plateaus at a lower 83%. These plateaus represent the proportion of all patients who have conceived a pregnancy. Examination of the life table curve for IVF-ET procedures shows the same pattern: an initial increasing first pass success rate (12.1%, 18.1%, and 21.4% for first, second, and third pregnancies, respectively), which is not sustained for subsequent attempts. Pregnancy Outcome
Of the 1,922 successful patients, 1,138 have not returned for attempts at a second pregnancy. The most likely reason for this exit from treatment is a very high live birth rate in this group, with 977 (86%) of the patients taking home at least one healthy baby. Many of the 784 patients who returned for further ART treatment did so because of a high preg548
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Second time around
nancy failure rate. Of the first pregnancies achieved by the 784 return patients, 288 (36.7%) resulted in a take home baby. This left 386 (49.2%) miscarriages, 71 (9.1%) EPs, and 39 (5.0%) still births and neonatal deaths. These rates are all significantly different (P < 0.05) from those of the general ART population. Some patients returned for a third (130 patients), fourth (20 patients), and fifth (3 patients) pregnancy and provide an opportunity to examine the prognostic effect of pregnancy outcome on the course of subsequent ART pregnancies. The cohort of 784 return patients was therefore considered as two groups: group A being the 288 patients whose first pregnancy had a successful live birth outcome; group B is the remaining 496 patients whose first pregnancy did not have a successful live birth outcome. The subsequent ART history of the two groups is compared in light of their first ART pregnancy outcome. There was no significant difference between groups A and B with respect to etiology of infertility, stimulation protocol, numbers of oocytes retrieved, oocytes replaced, or embryos transferred. The average age of patients achieving their first ART pregnancy was 31 years for group A and 32 years for group B and for both groups the age at the time of the third pregnancy was 34 years. Any difference in pregnancy outcome for the two groups was not considered to be as a result of advanced maternal age. There is no significant difference in PRs for the two groups. However, there is a significantly differ-
CUMULATIVE PREGNANCY RATE
100r------------------------------------.
50
40 ~LL----~--~----~--~----~--~L----U
2
3
4 5 ATIEMPT NUMBER
6
7
8
Figure 1 Life table analysis of GIFT procedures for all patients attempting their first (*), second (0), and third (D) pregnancies.
Fertility and Sterility
ent pregnancy outcome pattern. When the outcome of the first pregnancy in each group was ignored and the live birth rate was recalculated, there still was a significantly higher live birth rate for second and higher order pregnancies of 74.2% in group A compared with 62.1% in group B (P < 0.01). There was no significant difference in the ectopic PR or perinatal death rate for subsequent pregnancies, but there was a significantly higher miscarriage rate in group B (30.4%) compared with 19.5% for group A (P < 0.01). This higher take home baby rate in group A compared with group B persists when each pregnancy number is examined in turn and suggests that the outcome of a pregnancy is predictive of subsequent pregnancy outcomes.
differen1l- at 12.9% and 15.6%, respectively, and on average two embryos were replaced in each group. However the frozen ET pregnancy outcomes for each group had significantly different patterns. Of the 11 frozen ET pregnancies achieved by group A, only 1 pregnancy resulted in a miscarriage, giving a take home baby rate of90.9%. Group B achieved 24 frozen ET pregnancies but had a significantly lower (P < 0.01) take home baby rate of 41.7%, with 10 live babies, an EP, 12 miscarriages, and a neonatal death. This pattern of frozen ET outcomes is consistent with groups A and B having nearly equal chances of conceiving but of having a quite different pregnancy course and outcome.
Frozen ET
Although it seems that a previous natural pregnancy confers no positive benefit for subsequent ART attempts, there have been suggestions in the literature that a patient who has conceived previously with IVF has a greater chance of IVF success than a patient presenting for treatment for the first time. Simon et al. (11) concluded that the reproductive performance of IVF -only patients is different from previous in vivo conception patients. Other studies (8, 9, 15, 16) investigating very early pregnancy loss found that preclinical abortions in IVF patients were a positive indication for a future IVF pregnancy, possibly by indicating that the stages of reproduction leading to implantation are intact. In general these studies used limited patient numbers in their analysis. This paper investigates the ART history of a large cohort of 784 patients who have achieved one ART pregnancy and have returned for subsequent treatment attempts. It confirms that PRs for second and third conceptions are significantly higher than for first pregnancies for IVF-ET and GIFT procedures. The cumulative PR curve for patients attempting their first pregnancy is similar to cumulative PRs in other centers (17), but the cumulative PRs for cycles leading to second and third pregnancies are considerably higher, at least for the first three cycles. The positive advantage bestowed on second and third pregnancy patients does not seem to persist for more than the first few attempts. Application of the two-parameter model of Guzick and Rock (14) shows that 70% of IVF-ET patients are pregnant by their fifth cycle, and this holds true for first, second, and third pregnancies. This indicates that, despite an increasing "first pass" success rate with higher order pregnancies, the proportion of patients in each pregnancy who are cured by the IVF-ET procedure does not improve with higher order pregnancies. Similar results are obtained for GIFT procedures.
Frozen ET allows the investigation of factors involved in achieving an ART pregnancy and the outcome of that pregnancy because embryos from the same cohort are transferred during the original stimulation cycle and later under more physiological conditions. The patient can be used as her own control in the investigation of pregnancy and live baby rates by comparing original cycles and subsequent frozen ET cycles. Results from original ART and subsequent frozen ET cycles were compared in 154 cases to determine if a previous pregnancy in the initial treatment cycle was predictive of pregnancy. Where the original cycle did not result in a pregnancy (88 patients), 21 (24%) of the frozen ETs did achieve a pregnancy. If the original cycle resulted in a pregnancy (66 patients), 13 (20%) of the frozen ETs achieved a pregnancy. These PRs per frozen ET cycle are not significantly different and indicate that a pregnancy in the original cycle does not predict a pregnancy for the related frozen ET. However, the outcomes of the original cycle do seem to influence the outcomes of related frozen ET pregnancies. If the original cycle did not result in a pregnancy, 53% ofthe frozen ET pregnancies ended in a miscarriage. If the original cycle resulted in a healthy take home baby, most of the frozen ET pregnancies had successful live baby outcomes, with no losses. Original cycle EPs did not predict frozen ET EPs. Original cycle miscarriage pregnancies resulted in a significantly lower (P = 0.05) frozen ET PR of 9.7% compared with a rate of 25.2% for other original cycle-frozen ET cycle groups. The results of frozen ETs for groups A and B were consistent with the observation that original cycle outcome exerts an influence on the outcome of the related frozen ET pregnancy. The PRs per frozen ET cycle for the two groups were not significantly Vol. 64, No.3, September 1995
DISCUSSION
Molloy et al. Second time around
549
r The PR for higher order pregnancies is not dependent upon the outcome of the previous ART pregnancies: the PR for group A patients whose first ART conception resulted in a take home baby had the same PR as group B patients whose first pregnancy resulted in a loss. It seems that those patients who respond well to ART intervention will continue to achieve ART pregnancies, and that this is not affected by the success or failure of those pregnancies. To a patient, success is a healthy baby, and our results show that pregnancy outcome is a clear prognostic indicator of the outcomes of subsequent pregnancies. The return group of 784 patients is successful in that the stages leading to implantation are intact, and they continue to conceive second and subsequent pregnancies. The different performances of the subgroups A and B must reflect a fundamental difference in their reproductive competence because the process of implantation seems to be intact in both groups, as reflected by similar PRs. Two alternative theories can be presented to explain the difference in pregnancy outcome in the two groups. Poor embryo quality in group B could allow for implantation but may result in a nonviable pregnancy, Alternately, deficient uterine performance could doom a viable embryo to failure (19). The frozen ET results help to clarify these alternate suggestions. Our frozen ET results do not support the observation of other workers (18) that a pregnancy in an original cycle is predictive of a pregnancy in the related frozen ET cycle. The chance of achieving a frozen ET pregnancy is independent of the results of the original cycle, but the outcome of an original cycle pregnancy does influence the results of the related frozen ET pregnancy. These frozen ET results may provide an explanation for the difference between the groups A and B. The PRs for both groups are the same per oocyte retrieval, suggesting that implantation is equally successful in both groups. Yet the pregnancy outcome pattern for the two groups is very different. Group B may be a group of patients whose uterine environment may be hostile, leading to a tendency to early pregnancy losses or, later, to still births and neonatal deaths. Alternatively, both groups may have similar uterine environments after stimulation, but group B may have poorer quality embryos, which implant but fail to sustain a viable pregnancy. In the first scenario, the more favorable physiological uterine conditions of a frozen ET cycle should allow both groups to attain the same pregnancy outcome results, with few losses. In the second scenario, it is the quality of the embryo cohort that will determine the outcome of the transfer, and the difference between groups A and B as observed in the original cycle should be 550
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Second time around
maintained. Our results tend to support the second hypothesis. The PRs after frozen ET are the same for groups A and B, suggesting that implantation is taking place equally well in both groups. However, the pregnancy loss pattern for frozen ET pregnancies in group B is similar to the pattern of loss under the less physiologically favorable conditions of a stimulation cycle. The conclusion can be drawn that it is embryo quality rather than the state of the uterine environment at implantation that is the important factor in deciding the outcome of an ART conception. Pregnancy in an ART cycle is therefore a good prognostic indicator of pregnancy in a subsequent cycle, and pregnancy outcome also predicts the outcome of any future ART conception. With this information, more intensive preterm counseling of "at risk" women can be implemented, thus modifying the risk of an unsuccessful outcome. With such care, there may be a better long-term chance of a positive outcome of any ART pregnancy. REFERENCES 1. Harrison K, Breen T, Hennessey J, Hynes M, Keeping J, Kilvert G, et al. Patient age and success in a human NF programme. Aust NZ J Obstet Gynaecol 1989;29:326-7. 2. Romeu A, Muasher SJ, Acosta AA, Veeck LL, Diaz J, Jones GS, et al. Results of in vitro fertilization attempts in women 40 years of age and older: the Norfolk experience. Fertil Steril 1987;47:130-6. 3. Wilkes C, Rosenwaks Z, Jones D, Jones H. Pregnancy related to infertility diagnosis, number of attempts, and age in a program of in vitro fertilization. Obstet Gynecol 1885; 66:350-2. 4. Wood C, McMaster R, Rennie G, Trounson A, Leeton J. Factors influencing pregnancy rates following in vitro fertilization and embryo transfer. Fertil Steril 1985;43:245-50. 5. Cohen J, Edwards R, Fehilly C, Fishel S, Hewitt J, Purdy J, et al. In vitro fertilization: a treatment for male infertility. Fertil Steril 1985;43:422-32. 6. Mahadevan MM, Trounson AO. The influence of seminal characteristics on the success rate of human in vitro fertilization. Fertil Steril 1984;42:400-5. 7. Haan G, Bernardus RE, Hollanders JMG, Leerentveld RA, Prak FM, Naaktgeboren N. Results ofNF from a prospective multicentre study. Hum Reprod 1991;6:805-10. 8. Levy T, Goldman JA, Dicker D, Axhkenazi J, Feldberg D. Very early pregnancy wastage in in vitro fertilization and embryo transfer OVF-ET) J In Vitro Fert Embryo Transf 1991;8:250-3. 9. Barlow P, Lejeune B, Puissant F, Englert Y, Van Rysselberge M, Vekemans M, et al. Early pregnancy loss and obstetrical risk after in-vitro fertilisation and embryo replacement. Hum Reprod 1988;3:671-5. 10. Karande VC, Flood JT, Heard N, Veeck L, Muaxher SJ. Analysis of ectopic pregnancies resulting from in-vitro fertilisation and embryo transfer. Hum Reprod 1991;6:446-9. 11. Simon A, Ronit C, Lewin A, Mordel N, Zajicek G, Laufer N. Conception rate after in vitro fertilization in patients who conceived in a previous cycle. Fertil Steril 1993;59:343-7. 12. Guzick DS, Wilkes C, Jones HW Jr. Cumulative pregnancy rates for in vitro fertilization. Fertil Steril 1986;46:663-7.
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13. Kovacs GT, Rogers P, Leeton JF, Trounson AO, Wood C, Gordon Baker HW. In-vitro fertilisation and embryo transfer: prospects of pregnancy by life-table analysis. Med J Aust 1986; 144:682-3. 14. Guzick D, Rock J. Estimation of a model of cumulative pregnancy following infertility therapy. Am J Obstet Gynecol 1984; 140:573-5. 15. Liu H, Rosenwaks Z. Early pregnancy wastage in IVF (in vitro fertilization) patients (review). J In Vitro Fert Embryo Transf 1991;8:65-72.
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16. Levy 't, Dicker D, Ashkenazi J, Feldberg D, Shelef M, Goldman JA. The prognostic value and significance of preclinical abortions in in vitro fertilization-embryo transfer programs. Fertil Steril 1991;56:71-4. 17. Cohen J. The efficiency and efficacy of IVF and GIFT. Hum Reprod 1991;6:613-8. 18. Toner JP, Veeck LL, Acosta AA, Muasher SJ. Predictive value of pregnancy during original in vitro fertilization cycle on implantation and pregnancy in subsequent cryothaw cycles. Fertil Steril 1991;56:505-8.
Molloy et at Second time around
551
Vol. 64, No.3, September 1995
Printed on acid·free paper in U. S. A.
1995 American Society for Reproductive Medicine
Second time around: a study of patients seeking second assisted reproduction pregnancies*
David Molloy, M.D.t Mary Louise Doody, B.Sc. Terrence Breen, B.Sc. Queensland Fertility Group, Watkins Medical Centre, Brisbane, Queensland, Australia
Objective: To investigate the outcomes of subsequent cycles of IVF-ET, GIFT, and frozen ET in patients who have already achieved at least one assisted reproductive technology (ART) pregnancy. Design: Retrospective cohort. Setting: Private infertility clinic, Brisbane, Queensland, Australia. Patients: From 1985 to 1992,4,860 patients underwent 13,106 ART oocyte retrieval cycles. One thousand nine hundred twenty-two patients achieved a pregnancy, and 784 returned for a second pregnancy. These 784 return patients were divided into two subgroups: group A (288 patients) took home at least one baby from their first pregnancy; group B (496 patients) had an unsuccessful first pregnancy. Main Outcome Measures: Pregnancy rate (PR), cumulative PR, pregnancy outcome. Results: Patients returning for second and third ART pregnancies had an increased chance of success. Pregnancy rates increased from 31.0% per transfer for patients attempting their first GIFT pregnancy, to 34.7% and 42.7% per transfer for patients attempting their second and third GIFT pregnancy. Cumulative PRs increased with subsequent pregnancy attempts. Groups A and B did not differ in PR, age, or indication of infertility but had significantly different live birth rates. The pregnancy outcomes of frozen ETs depended on the outcomes of the original cycle from which the embryos were derived. Conclusions: This study has important implications for the counseling of patients returning for subsequent ART pregnancies. Fertil Steril 1995;64:546-51 Key Words: Second ART pregnancy, cumulative pregnancy rate, secondary infertility
Prognostic factors such as maternal age (1-3), infertility etiology (3,4), and male factors (4-6) have been identified as predictive of assisted reproductive technology (ART) success. Primary and secondary infertility patients do not seem to have significantly different ART outcomes (4), and this suggests that the mechanism by which pregnancy occurs may be different in the ART patient. Haan et al. (7) illustrated that IVF results are dependent on a couple's previous history rather than on the female patient's
Received August 18, 1994; revised and accepted March 28, 1995. * Presented at the Fertility Society of Australia Conference, Sydney, New South Wales, Australia, November 2 to 6, 1993. t David Molloy, M.D., Queensland Fertility Group, Watkins Medical Centre, 225 Wickham Terrace, Spring Hill, Brisbane, Queensland 4000, Australia (FAX: 61-07-8398389).
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history alone. Women with a previous pregnancy in an earlier relationship had an IVF success rate similar to that of women with primary infertility. In vitro fertilization results in both groups were significantly lower than for couples who had a previous natural pregnancy from the existing relationship. Investigation of the prognostic value of a patient's previous IVF history has concentrated largely on the effect of previous unsuccessful IVF treatments. A biochemical IVF pregnancy is a positive indicator for subsequent IVF pregnancy (8,9), and patients with an ectopic IVF pregnancy are at risk of another IVF ectopic (10). Simon et al. (11) showed that a previous IVF pregnancy is a better prognostic factor for subsequent IVF attempts than a previous natural pregnancy. This paper examines patients whose infertility has been reversed through ART. Such patients are Fertility and Sterility
now returning to ART clinics for second and higher order pregnancies and babies. As successful patients, they wish to know if their chances of success will be higher in subsequent attempts. In this study, the prognostic effect of a previous ART pregnancy on subsequent treatment cycle outcome is examined. Two populations are studied, those with a previous live birth and those with a previous pregnancy failure from ART treatment. MATERIALS AND METHODS
Patients in the study group underwent treatment cycles ofIVF-ET or GIFT. Stimulation protocols varied across the time frame, being predominately clomiphene citrate and hMG until 1992. Oocyte retrievals were performed by laparoscopy or ultrasound (US) scan. Excess high quality embryos from IVFET or GIFT were frozen to provide a subsequent treatment cycle of frozen ET. A total of 4,860 patients underwent 13,106 ART oocyte retrieval cycles between January 1985 and December 1992. During this time, 1,922 patients achieved a total of 2,324 pregnancies, a pregnancy rate (PR) of 17.7% per oocyte retrieval. These pregnancies resulted in 1,527 patients taking home at least one healthy baby, a take home baby rate of 65.7% per pregnancy. The remaining pregnancies resulted in losses from ectopic pregnancies (EPs) (4.8%), miscarriages (26.5%), and still birth or neonatal death (3.0%). This information provided the background statistics of our total ART population to be used for comparison with our study cohorts. Clinical pregnancies only were included in the study. Positive results were confirmed by US scan or histology. Biochemical pregnancies, pregnancies for which no confirmation was received by US scan, or pregnancies that aborted but did not require curettage were not included. Multiple pregnancies were counted as a single pregnancy event. Still births or neonatal deaths were not included in the live birth rate calculations. The live birth rate thus could be described more properly as a "take at least one baby home" rate. The prognostic effect of previous ART pregnancies on subsequent attempts was examined by comparing different groups of patients. The first group consisted of the total ART population of 4,860 patients, of whom 1,922 achieved a pregnancy. Of these successful patients, 1,138 did not or have not yet returned for a second pregnancy. The remaining 784 successful patients did return to attempt a second pregnancy (second group). One hundred thirty patients who successfully achieved a second pregnancy returned for a third pregnancy attempt (third Vol. 64, No.3, September 1995
group). This stratification was continued for fourth and fifth pregnancy attempts (20 and 3 patients, respectively), but these pregnancy attempts were not included in statistical analysis because of small numbers. The three study groups were compared by means of PR per oocyte retrieval and by life table analysis. Over the term of the study, the PRs for IVF-ET and GIFT procedures in our clinic did not alter significantly. The PR for GIFT procedures ranged from 30.1 % to 34.8%, and averaged 33.0%. For IVF-ET procedures, the PR averaged 12.2%, with a range of 11.6% to 13.1%. Changes in PR with pregnancy order in the study cohort was considered to be attributable to the cohort characteristics and not to changing PRs. Because of the higher PR associated with GIFT compared with IVF-ET, PRs for these two procedures were examined separately. Comparative life table analysis was carried out according to the methods used by Guzick and Kovacs (12-14) using follicular aspiration as the denominator. The 784 patients of the return group were subdivided into women whose first pregnancy resulted in a live baby (group A, 288 patients) and those whose first pregnancy failed (group B, 496 patients). Subsequent pregnancy outcomes in these groups were examined. The results of 154 frozen ETs undertaken by 117 of the return group of 784 patients were examined. Groups A and B were compared for the PR per frozen ET cycle and for the pregnancy outcomes of the frozen ET cycles with reference to the results of the stimulation cycle from which the embryos were derived. All statistical analyses were carried out using the Statistical Package for the Social Sciences (SPSS Inc., Chicago, IL). Two-sided X 2 and t-tests were used as appropriate. RESULTS Pregnancy Rates
Pregnancy rates per oocyte retrieval for patients attempting their first, second, or third pregnancy are shown in Table 1. Pregnancy rates are presented for GIFT and IVF-ET procedures separately. There is an increasing PR with pregnancy order for GIFT procedures. The PR per oocyte retrieval is higher for subsequent pregnancies than for the first pregnancy, with a significantly higher (P < 0.05) PR for first and second pregnancies in comparison to first pregnancies for both treatment methods. This result suggests that a previous ART pregnancy is a positive indicator for success in a subsequent attempt. Molloy et al. Second time around
547
r Table 1 Pregnancy Rates per Oocyte Retrieval for Patients Attempting Their First, Second, or Third ART Pregnancy
First pregnancy Second pregnancy Third pregnancy
GIFT procedures
NF-ET procedures
913/2,941 * (31.0) 207/597 (34.7)t 41/96 (42.7)§
937/8,082 (11.6) 154/929 (16.6)+ 22/139 (15.8)t
* Number of pregnancies per number of oocyte retrieval cycles. Values in parentheses are percentages. t Significantly different from the PR for patients attempting their first pregnancy, P < 0.05. t Significantly different from the PR for patients attempting their first pregnancy, P < 0.001. § Significantly different from the PR for patients attempting their first pregnancy, P < 0.01.
Pregnancy rates per retrieval are one method of describing the results of treatment attempts. Life table analysis estimates the proportion of patients who will conceive after any given number of treatment episodes and may be a better indicator of performance than per retrieval PR (12). Life table analysis for GIFT procedures is presented in Figure 1. A feature of the life table graph is the increasing "first pass" success rate for first, second, and third pregnancies. Mter one oocyte retrieval cycle, 34.3% of all patients attempting their first GIFT pregnancy were successful. The first cycle success rate is 39.7% for patients returning for their second pregnancy and 53.6% for patients attempting a third pregnancy. The difference between these three "first pass" success rates is statistically significant (P < 0.001). This initial improvement in success rate for second and third pregnancies is not sustained, with curves for first and second pregnancies converging by the fourth attempt. These curves plateau at approximately 92%, and the curve for the third pregnancy plateaus at a lower 83%. These plateaus represent the proportion of all patients who have conceived a pregnancy. Examination of the life table curve for IVF-ET procedures shows the same pattern: an initial increasing first pass success rate (12.1%, 18.1%, and 21.4% for first, second, and third pregnancies, respectively), which is not sustained for subsequent attempts. Pregnancy Outcome
Of the 1,922 successful patients, 1,138 have not returned for attempts at a second pregnancy. The most likely reason for this exit from treatment is a very high live birth rate in this group, with 977 (86%) of the patients taking home at least one healthy baby. Many of the 784 patients who returned for further ART treatment did so because of a high preg548
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nancy failure rate. Of the first pregnancies achieved by the 784 return patients, 288 (36.7%) resulted in a take home baby. This left 386 (49.2%) miscarriages, 71 (9.1%) EPs, and 39 (5.0%) still births and neonatal deaths. These rates are all significantly different (P < 0.05) from those of the general ART population. Some patients returned for a third (130 patients), fourth (20 patients), and fifth (3 patients) pregnancy and provide an opportunity to examine the prognostic effect of pregnancy outcome on the course of subsequent ART pregnancies. The cohort of 784 return patients was therefore considered as two groups: group A being the 288 patients whose first pregnancy had a successful live birth outcome; group B is the remaining 496 patients whose first pregnancy did not have a successful live birth outcome. The subsequent ART history of the two groups is compared in light of their first ART pregnancy outcome. There was no significant difference between groups A and B with respect to etiology of infertility, stimulation protocol, numbers of oocytes retrieved, oocytes replaced, or embryos transferred. The average age of patients achieving their first ART pregnancy was 31 years for group A and 32 years for group B and for both groups the age at the time of the third pregnancy was 34 years. Any difference in pregnancy outcome for the two groups was not considered to be as a result of advanced maternal age. There is no significant difference in PRs for the two groups. However, there is a significantly differ-
CUMULATIVE PREGNANCY RATE
100r------------------------------------.
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40 ~LL----~--~----~--~----~--~L----U
2
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4 5 ATIEMPT NUMBER
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Figure 1 Life table analysis of GIFT procedures for all patients attempting their first (*), second (0), and third (D) pregnancies.
Fertility and Sterility
ent pregnancy outcome pattern. When the outcome of the first pregnancy in each group was ignored and the live birth rate was recalculated, there still was a significantly higher live birth rate for second and higher order pregnancies of 74.2% in group A compared with 62.1% in group B (P < 0.01). There was no significant difference in the ectopic PR or perinatal death rate for subsequent pregnancies, but there was a significantly higher miscarriage rate in group B (30.4%) compared with 19.5% for group A (P < 0.01). This higher take home baby rate in group A compared with group B persists when each pregnancy number is examined in turn and suggests that the outcome of a pregnancy is predictive of subsequent pregnancy outcomes.
differen1l- at 12.9% and 15.6%, respectively, and on average two embryos were replaced in each group. However the frozen ET pregnancy outcomes for each group had significantly different patterns. Of the 11 frozen ET pregnancies achieved by group A, only 1 pregnancy resulted in a miscarriage, giving a take home baby rate of90.9%. Group B achieved 24 frozen ET pregnancies but had a significantly lower (P < 0.01) take home baby rate of 41.7%, with 10 live babies, an EP, 12 miscarriages, and a neonatal death. This pattern of frozen ET outcomes is consistent with groups A and B having nearly equal chances of conceiving but of having a quite different pregnancy course and outcome.
Frozen ET
Although it seems that a previous natural pregnancy confers no positive benefit for subsequent ART attempts, there have been suggestions in the literature that a patient who has conceived previously with IVF has a greater chance of IVF success than a patient presenting for treatment for the first time. Simon et al. (11) concluded that the reproductive performance of IVF -only patients is different from previous in vivo conception patients. Other studies (8, 9, 15, 16) investigating very early pregnancy loss found that preclinical abortions in IVF patients were a positive indication for a future IVF pregnancy, possibly by indicating that the stages of reproduction leading to implantation are intact. In general these studies used limited patient numbers in their analysis. This paper investigates the ART history of a large cohort of 784 patients who have achieved one ART pregnancy and have returned for subsequent treatment attempts. It confirms that PRs for second and third conceptions are significantly higher than for first pregnancies for IVF-ET and GIFT procedures. The cumulative PR curve for patients attempting their first pregnancy is similar to cumulative PRs in other centers (17), but the cumulative PRs for cycles leading to second and third pregnancies are considerably higher, at least for the first three cycles. The positive advantage bestowed on second and third pregnancy patients does not seem to persist for more than the first few attempts. Application of the two-parameter model of Guzick and Rock (14) shows that 70% of IVF-ET patients are pregnant by their fifth cycle, and this holds true for first, second, and third pregnancies. This indicates that, despite an increasing "first pass" success rate with higher order pregnancies, the proportion of patients in each pregnancy who are cured by the IVF-ET procedure does not improve with higher order pregnancies. Similar results are obtained for GIFT procedures.
Frozen ET allows the investigation of factors involved in achieving an ART pregnancy and the outcome of that pregnancy because embryos from the same cohort are transferred during the original stimulation cycle and later under more physiological conditions. The patient can be used as her own control in the investigation of pregnancy and live baby rates by comparing original cycles and subsequent frozen ET cycles. Results from original ART and subsequent frozen ET cycles were compared in 154 cases to determine if a previous pregnancy in the initial treatment cycle was predictive of pregnancy. Where the original cycle did not result in a pregnancy (88 patients), 21 (24%) of the frozen ETs did achieve a pregnancy. If the original cycle resulted in a pregnancy (66 patients), 13 (20%) of the frozen ETs achieved a pregnancy. These PRs per frozen ET cycle are not significantly different and indicate that a pregnancy in the original cycle does not predict a pregnancy for the related frozen ET. However, the outcomes of the original cycle do seem to influence the outcomes of related frozen ET pregnancies. If the original cycle did not result in a pregnancy, 53% ofthe frozen ET pregnancies ended in a miscarriage. If the original cycle resulted in a healthy take home baby, most of the frozen ET pregnancies had successful live baby outcomes, with no losses. Original cycle EPs did not predict frozen ET EPs. Original cycle miscarriage pregnancies resulted in a significantly lower (P = 0.05) frozen ET PR of 9.7% compared with a rate of 25.2% for other original cycle-frozen ET cycle groups. The results of frozen ETs for groups A and B were consistent with the observation that original cycle outcome exerts an influence on the outcome of the related frozen ET pregnancy. The PRs per frozen ET cycle for the two groups were not significantly Vol. 64, No.3, September 1995
DISCUSSION
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r The PR for higher order pregnancies is not dependent upon the outcome of the previous ART pregnancies: the PR for group A patients whose first ART conception resulted in a take home baby had the same PR as group B patients whose first pregnancy resulted in a loss. It seems that those patients who respond well to ART intervention will continue to achieve ART pregnancies, and that this is not affected by the success or failure of those pregnancies. To a patient, success is a healthy baby, and our results show that pregnancy outcome is a clear prognostic indicator of the outcomes of subsequent pregnancies. The return group of 784 patients is successful in that the stages leading to implantation are intact, and they continue to conceive second and subsequent pregnancies. The different performances of the subgroups A and B must reflect a fundamental difference in their reproductive competence because the process of implantation seems to be intact in both groups, as reflected by similar PRs. Two alternative theories can be presented to explain the difference in pregnancy outcome in the two groups. Poor embryo quality in group B could allow for implantation but may result in a nonviable pregnancy, Alternately, deficient uterine performance could doom a viable embryo to failure (19). The frozen ET results help to clarify these alternate suggestions. Our frozen ET results do not support the observation of other workers (18) that a pregnancy in an original cycle is predictive of a pregnancy in the related frozen ET cycle. The chance of achieving a frozen ET pregnancy is independent of the results of the original cycle, but the outcome of an original cycle pregnancy does influence the results of the related frozen ET pregnancy. These frozen ET results may provide an explanation for the difference between the groups A and B. The PRs for both groups are the same per oocyte retrieval, suggesting that implantation is equally successful in both groups. Yet the pregnancy outcome pattern for the two groups is very different. Group B may be a group of patients whose uterine environment may be hostile, leading to a tendency to early pregnancy losses or, later, to still births and neonatal deaths. Alternatively, both groups may have similar uterine environments after stimulation, but group B may have poorer quality embryos, which implant but fail to sustain a viable pregnancy. In the first scenario, the more favorable physiological uterine conditions of a frozen ET cycle should allow both groups to attain the same pregnancy outcome results, with few losses. In the second scenario, it is the quality of the embryo cohort that will determine the outcome of the transfer, and the difference between groups A and B as observed in the original cycle should be 550
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maintained. Our results tend to support the second hypothesis. The PRs after frozen ET are the same for groups A and B, suggesting that implantation is taking place equally well in both groups. However, the pregnancy loss pattern for frozen ET pregnancies in group B is similar to the pattern of loss under the less physiologically favorable conditions of a stimulation cycle. The conclusion can be drawn that it is embryo quality rather than the state of the uterine environment at implantation that is the important factor in deciding the outcome of an ART conception. Pregnancy in an ART cycle is therefore a good prognostic indicator of pregnancy in a subsequent cycle, and pregnancy outcome also predicts the outcome of any future ART conception. With this information, more intensive preterm counseling of "at risk" women can be implemented, thus modifying the risk of an unsuccessful outcome. With such care, there may be a better long-term chance of a positive outcome of any ART pregnancy. REFERENCES 1. Harrison K, Breen T, Hennessey J, Hynes M, Keeping J, Kilvert G, et al. Patient age and success in a human NF programme. Aust NZ J Obstet Gynaecol 1989;29:326-7. 2. Romeu A, Muasher SJ, Acosta AA, Veeck LL, Diaz J, Jones GS, et al. Results of in vitro fertilization attempts in women 40 years of age and older: the Norfolk experience. Fertil Steril 1987;47:130-6. 3. Wilkes C, Rosenwaks Z, Jones D, Jones H. Pregnancy related to infertility diagnosis, number of attempts, and age in a program of in vitro fertilization. Obstet Gynecol 1885; 66:350-2. 4. Wood C, McMaster R, Rennie G, Trounson A, Leeton J. Factors influencing pregnancy rates following in vitro fertilization and embryo transfer. Fertil Steril 1985;43:245-50. 5. Cohen J, Edwards R, Fehilly C, Fishel S, Hewitt J, Purdy J, et al. In vitro fertilization: a treatment for male infertility. Fertil Steril 1985;43:422-32. 6. Mahadevan MM, Trounson AO. The influence of seminal characteristics on the success rate of human in vitro fertilization. Fertil Steril 1984;42:400-5. 7. Haan G, Bernardus RE, Hollanders JMG, Leerentveld RA, Prak FM, Naaktgeboren N. Results ofNF from a prospective multicentre study. Hum Reprod 1991;6:805-10. 8. Levy T, Goldman JA, Dicker D, Axhkenazi J, Feldberg D. Very early pregnancy wastage in in vitro fertilization and embryo transfer OVF-ET) J In Vitro Fert Embryo Transf 1991;8:250-3. 9. Barlow P, Lejeune B, Puissant F, Englert Y, Van Rysselberge M, Vekemans M, et al. Early pregnancy loss and obstetrical risk after in-vitro fertilisation and embryo replacement. Hum Reprod 1988;3:671-5. 10. Karande VC, Flood JT, Heard N, Veeck L, Muaxher SJ. Analysis of ectopic pregnancies resulting from in-vitro fertilisation and embryo transfer. Hum Reprod 1991;6:446-9. 11. Simon A, Ronit C, Lewin A, Mordel N, Zajicek G, Laufer N. Conception rate after in vitro fertilization in patients who conceived in a previous cycle. Fertil Steril 1993;59:343-7. 12. Guzick DS, Wilkes C, Jones HW Jr. Cumulative pregnancy rates for in vitro fertilization. Fertil Steril 1986;46:663-7.
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13. Kovacs GT, Rogers P, Leeton JF, Trounson AO, Wood C, Gordon Baker HW. In-vitro fertilisation and embryo transfer: prospects of pregnancy by life-table analysis. Med J Aust 1986; 144:682-3. 14. Guzick D, Rock J. Estimation of a model of cumulative pregnancy following infertility therapy. Am J Obstet Gynecol 1984; 140:573-5. 15. Liu H, Rosenwaks Z. Early pregnancy wastage in IVF (in vitro fertilization) patients (review). J In Vitro Fert Embryo Transf 1991;8:65-72.
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16. Levy 't, Dicker D, Ashkenazi J, Feldberg D, Shelef M, Goldman JA. The prognostic value and significance of preclinical abortions in in vitro fertilization-embryo transfer programs. Fertil Steril 1991;56:71-4. 17. Cohen J. The efficiency and efficacy of IVF and GIFT. Hum Reprod 1991;6:613-8. 18. Toner JP, Veeck LL, Acosta AA, Muasher SJ. Predictive value of pregnancy during original in vitro fertilization cycle on implantation and pregnancy in subsequent cryothaw cycles. Fertil Steril 1991;56:505-8.
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