One thousand initiated cycles of in vitro fertilization in women >40 years of age

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1 FERTILITY AND STERILITY VOL. 70, NO. 6, DECEMBER 1998 Copyright 1998 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A. One thousand initiated of in vitro fertilization in women >40 years of age Amir Lass, M.D.,* Carolyn Croucher, M.R.C.O.G., Suzanne Duffy, B.Sc., Karin Dawson, B.Sc., Raul Margara, M.D., and Robert M. L. Winston, F.R.C.O.G. Institute of Obstetrics and Gynecology, Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom Objective: To evaluate the results of IVF in women 40 years of age using their own oocytes. Design: Retrospective study. Setting: Wolfson and Royal Masonic in vitro fertilization units, London, United Kingdom. Patient(s): A total of 1,087 IVF were started in women 40 years of age. Intervention(s): Medical records of patient outcomes were reviewed. Main Outcome Measure(s): Clinical pregnancy, miscarriage, and delivery rates. Result(s): Of the 1,087 started in 471 women 40 years of age, 842 reached oocyte retrieval (77.5%) and 702 had embryos transferred (64.6%). The pregnancy rate (PR) was significantly lower in women 40 years of age than in a control group of women 40 years of age (11.3% versus 28.2%). It decreased sharply in women 42 years of age, and no women 45 years of age had a child. Women 40 years of age were more likely to miscarry (27% versus 12.7%). When only one embryo was available for transfer, the PR was 3.3%. When 2 embryos were available for transfer, the PR was similar whether 2 or 3 embryos were replaced. No triplet pregnancy occurred. Women 40 years of age achieved a cumulative PR of 30% after three with a cumulative take home baby rate of 21%. Conclusion(s): In vitro fertilization is a reasonable treatment for women 45 years of age using their own gametes. Those with a good response in their first attempt may be encouraged to complete three with an acceptable chance of conception. (Fertil Steril 1998;70: by American Society for Reproductive Medicine.) Key Words: Advanced female age, IVF outcomes, delivery rate, miscarriage rate Received February 27, 1998; revised and accepted July 24, Reprint requests: Amir Lass, M.D., Bourn Hall Clinic, Bourn, Cambridge, CB3 7TR, United Kingdom (FAX: ; * Present address: Bourn Hall Clinic, Bourn, Cambridge, United Kingdom. Present address: St. Helier Hospital, Carshalton, Surrey, United Kingdom /98/$19.00 PII S (98) As a woman ages, her fertility diminishes (1 5). More women are now choosing to delay starting a family in developed countries for various social reasons (6). As more couples delay the commencement of child-rearing, the age of those seeking infertility treatment will increase (7). Although many women are fertile into their late 40s, most are not; however, the precise reason for this loss of fertility is not understood. There are thought to be a number of factors, including the decline in the frequency of intercourse (7), decreasing numbers of primordial follicles (8), poorer oocyte quality (9), problems in the uterus (10), and embryo loss sometimes resulting from chromosomal abnormalities (11). Most women reach menopause by their early 50s. There is a significant decrease in the number of primordial follicles preceding this point, which accelerates around the age of 37 years on average. Biologic infertility is normal about years before menopause (12, 13). Declining fertility in the 40s is an individual event that cannot be predicted accurately before an IVF cycle is undertaken. Questions remain regarding the chance of successful pregnancy and delivery in this age group using a woman s own oocytes, the maximum female age at which IVF can be successful, and the appropriate number of that should be undertaken. This study summarizes our experience with a large series of patients 40 years of age who were treated with the same stimulation protocol to provide patients and medical teams with a realistic assessment of IVF success rates for women in their 40s as well as cumulative pregnancy and delivery rates for these women. 1030

2 MATERIALS AND METHODS A total of 9,310 IVF using the woman s own gametes were started at Hammersmith Hospital and The Royal Masonic Hospital in the United Kingdom between 1988 and One thousand eighty-seven of these (11.7%) were performed in 471 women 40 years of age on the starting day of the cycle (group 1). Eight thousand two hundred twenty-two were performed in 4,602 women 40 years of age (group 2). All couples were treated using one standardized protocol, and the same clinical and embryologic team was involved in all treatments. The proportions of patients with tubal disease, male factor infertility, unexplained infertility, endometriosis, and ovulatory dysfunction were similar in each group. The difference between the two hospitals was that most patients at Hammersmith Hospital were in the public sector; those at The Royal Masonic Hospital were treated largely on a fee-paying private basis. Data supplied to the Human Fertilization and Embryo Authority (HFEA) (12) show that success rates at both these centers are virtually identical. The IVF unit at Hammersmith Hospital is licensed and regulated by the HFEA in the United Kingdom and is approved by the Institute of Obstetrics and Gynecology, Royal Postgraduate Medical School, Hammersmith Hospital. Follicle-stimulating hormone levels were measured immediately in the proliferative phase before treatment in women 36 years of age. Women whose FSH levels were consistently 15 miu/ml generally were excluded from IVF treatment. All the women had menstrual with no clinical signs of menopause. Before superovulation, all patients were treated with 1.5 mg/d of a GnRH agonist (buserelin acetate, Suprefact; Hoechst, Hounslow, United Kingdom) (13). This was administered from the second day of menstruation. Once complete ovarian suppression was confirmed (serum E 2 levels of 80 pmol/l and no follicles seen on ultrasound [US]), the ovaries were stimulated with hmg (Pergonal or Metrodin; Serono Laboratories, Welwyn Garden City, United Kingdom or Humegon, Orgafol, or Normegon; Organon Laboratories Ltd., Cambridge, United Kingdom, depending on the availability of the drug). Ovarian response was monitored daily from day 8 using vaginal US and serum E 2 assays. When at least three follicles of 17 mm in diameter were observed and E 2 levels had reached 3,000 pmol/l, 10,000 IU of hcg (Profasi; Serono Laboratories) was given by IM injection. Cycles were cancelled if these criteria for follicular development were not reached. Transvaginal aspiration of eggs was done approximately 34 hours after hcg injection. After fertilization under standardized culture conditions, ET was performed 2 or 3 days later. Previous analysis (14) showed that pregnancy rates (PRs) were not influenced by the day of ET. In about half the women 40 years of age, only two embryos were transferred per cycle. When IVF already had failed repeatedly or when the prognosis was considered to be particularly poor, three embryos were transferred. Pure progesterone in oil (25-mg IM injection) was given three times daily for the first 3 days and then once daily for 2 days after ET. Progesterone suppositories (200 mg) then were given daily for 10 days. A pregnancy was recorded when there was a rise in the -subunit of hcg of 20 IU on day 14 after oocyte retrieval together with evidence of a gestational sac seen on US after a further 2 weeks. The 2 test and Student s t-test for unpaired data were used to test for statistically significant differences in the fertilization rate or the PR (P.05) using the Stat View statistical package (Abacus Concepts Inc., Berkeley, CA). The cumulative PR was calculated for repeat attendees using life tables for patients whose first IVF attempt was conducted after the age of 40 years. It was calculated (15) using the following formula: cumulative pregnancy rate P% (100 S) (S P)/100 where S is the percentage of women who were not pregnant at the start of the cycle. RESULTS The rate of cancellation because of poor response to superovulation was higher in group 1 (22.5% versus 15.8%, P.001), but the women who were years of age had no greater risk of cancellation than the women who were 40 years of age (14.9%, P not significant). In the women 42 years of age, 28.4% of the were abandoned before oocyte retrieval (P.001, Table 1.) The PR decreased with age, and no woman who underwent her first IVF cycle at the age of 45 years or older had a live birth. Women 40 years of age were more likely to miscarry (27% versus 12.7%, P.001), and there was one elective pregnancy termination for Down syndrome in a 40-year-old woman. In all, there were 34 miscarriages, all but 4 occurred in women who required 60 ampules of hmg for ovarian stimulation. Women 40 years of age who required 60 ampules of hmg (75 IU) to produce adequate superovulation were more likely to conceive. In general, these women also tended to produce higher peak E 2 levels and more oocytes. Women who were poor responders (i.e., who required 100 ampules of hmg) had poor outcomes (Table 2). Although poor responders produced fewer oocytes, their eggs had a relatively normal chance of fertilization. Seven hundred two in women 40 years of age reached the stage of ET (64.6%) (Table 3). Of the 125 women who failed to reach oocyte collection during their first IVF attempt, 51 returned for a second cycle (40.8%); 27 FERTILITY & STERILITY 1031

3 TABLE 1 In vitro fertilization outcome in different age groups. Age group (y) patients initiated oocyte recovery (cancellation rate)* Implantation miscarriages 40 4,602 8,233 6, ,321 (28.2) 295 (12.7) (14.0) 13 (21.7) (13.8) 11 (28.2) (10.6) 4 (23.5) (6.6) 4 (66.6) (4.1) 1 (33.3) (2.0) 1 (100.0) * The cancellation rate was higher in women 42 years of age than in women 42 years of age (P.001). The pregnancy rate was higher in women 42 years of age than in women 42 years of age (P.001). of these reached egg collection (52.9%), 17 obtained embryos (33.3%), and 6 (11.8%) became pregnant. Three of these produced phenotypically normal infants (5.9%) and three ended in spontaneous abortion. When 2 embryos were available, the 2 with the most normal morphology were chosen for transfer; these women had a significantly higher chance of pregnancy. Half the patients had three embryos transferred, but there were no triplet ; only six sets of twins were born. Tables 4 and 5 show the cumulative clinical PRs and delivery rates, respectively. DISCUSSION The age of the female partner is an important factor in the outcome of IVF. Previous studies report reduced chances of pregnancy after the age of years (16, 17). In our study, women 42 years of age had a 7% chance of pregnancy. There were no viable after 45 years of age. Data from the HFEA (18) include a live birth rate of 8.1% per ET in women years of age. Our experience is similar, with a live birth rate of 8.7%. However, this was per TABLE 2 Correlation between total number of hmg ampules administered and IVF cycle outcome. ampules Age (y) E 2 level (pmol/l)* oocytes* Fertilization clinical , (18.9) , (10.3) , (4.5) * P.001 between each group. The pregnancy rate was significantly lower in patients who required medium or high doses of hmg (P.002). treatment cycle commenced and included not just those women who reached ET. The PR for women 40 years of age in the first three was the same in each treatment cycle. This contrasts with the data of the HFEA and of Guzick et al. (19), which indicate a decrease in the success rate with each subsequent IVF cycle. The lower PRs seen among older women seem to be due partly to a worsening response to superovulation. In spite of increased dosages of hmg, fewer oocytes were obtained from older women and more of these women had their egg collection cancelled because of poor ovarian response. Women who need massive amounts of hmg ( 100 ampules) seldom become pregnant (4.5%). Van Kooij et al. (16) found that the number of oocytes collected or embryos available did not correlate significantly with the implantation rate. When fewer oocytes and embryos were available, PRs and delivery rates were lower in our study. Once a pregnancy was established, women who had required 60 ampules to stimulate their ovaries were no more likely to miscarry than those who had required a lower, more physiologic dose of hmg. Many patients consider undergoing multiple of treatment; consequently, calculation of the cumulative PRs and live birth rates is necessary to assess their chances of success and to compare IVF with other treatments, such as tubal surgery. Our cumulative PR rose to 31% after three ; there was no further increase thereafter. Dor et al. (20) made similar observations, but the cumulative PR in their study was 13%. Given the results of our study, we believe that if two or more embryos were available in a previous cycle in a woman 39 years of age, it is reasonable to attempt further treatment, up to three in all. Oocyte donation from younger women is an option for older patients when high doses of hmg fail to yield sufficient oocytes. This reduces the chance of failure resulting from inadequate ovarian response and embryonic abnormalities resulting from maternal age Lass et al. IVF in women 40 years of age Vol. 70, No. 6, December 1998

4 TABLE 3 Correlation between number of embryos replaced and IVF cycle outcome. embryos transferred (no. available) Variable 1 (1) 2 (2) 2 ( 2) 3 (3) 3 ( 3) Total initiated clinical 4 (3.3)* 13 (11.4) 26 (24.8) 14 (14.4) 62 (23.4) 119 (17.0) miscarriages 2 (50.0) 6 (46.2) 5 (19.2) 5 (35.7) 15 (24.2) 33 (27.7) twin deliveries 1 (25.0) 0 1 (3.8) 1 (7.1) 3 (4.8) 6 (5.0) * The clinical pregnancy rate was significantly lower when only one embryo was transferred (P.05). The clinical pregnancy rate was significantly lower when only two embryos were available (P.017). Twin pregnancy and miscarriage rates were similar in all groups. Up to three embryos may legally be transferred simultaneously in the United Kingdom (21). Three hundred sixtythree women in this study had three embryos transferred, but there were no triplet. Svendsen et al. (22) reported a 0.3% rate of triplet pregnancy at 20 weeks gestation when three embryos were transferred in younger women. In women 40 years of age, there was an increase in twin pregnancy, and the risks of multiple gestations must be considered in these women (23). We therefore do not advocate a further increase in the number of embryos transferred. We found a lower miscarriage rate in women years of age (22% 28%) than did Harrison et al. (40% at 40 years and 83% at 41 years) (24) or Padilla and Garcia (2) (50% at 40 years). Abdulla et al. (25) found that the miscarriage rate increased with donor age in an egg donation cycle, being 14% when the donor was years of age and rising to 44.5% when the donor was 35 years of age. The relatively low miscarriage rate in our series is encouraging. Although genetic abnormalities may occur more frequently in the conceptuses of older women (10), these figures imply that they are not so common as to inhibit older patients from considering IVF as a serious option. Accurate assessment for poor ovulatory response before IVF would help to identify those women who are more suitable candidates for the alternatives of either IVF or donor oocytes. Roest et al. (26) suggested recently that ovarian response was a more useful predictor of pregnancy than was age alone. Decreased ovarian volume is associated with decreased ovarian performance (27). This generally is detectable before basal FSH levels are elevated and usually predicts a poor response to superovulation (28, 29). For physicians to refuse treatment on the arbitrary basis of age alone in women 45 years of age is illogical. Better methods to predict the response to superovulation are clearly valuable. Assessment after the first IVF cycle in older women is helpful, providing useful information about potential future superovulatory response. In this study, only 3 of the 51 women who failed to reach oocyte collection but who then attempted a second cycle gave birth to a live infant. It is relevant that all the patients we treated had more or less normal early follicular FSH levels immediately before treatment. It follows that measurement of basal FSH alone would have been of little value in predicting subsequent failure to superovulate. There is evidence to suggest the treatment regimen used in this study produces a reasonably good PR (13). Moreover, the cancellation rate due to poor response or premature LH surges was relatively low. However, evidence about the most TABLE 4 Cumulative clinical pregnancy rate for women 40 years of age. TABLE 5 Cumulative delivery rate for women 40 years of age. Cycle no. initiated Pregnancy Cumulative pregnancy rate Cycle no. initiated deliveries Delivery Cumulative delivery rate FERTILITY & STERILITY 1033

5 effective management of women 40 years of age is still vague and more studies are needed. In summary, IVF can be successful in women 40 years of age. Treatment with IVF is an option for women 45 years of age. Those with a good response in their first attempt may be encouraged to complete three with an acceptable chance of conception (a take home baby rate of 21%). However, it is vital for women to know that the incidence of poor response to treatment increases dramatically with advancing age. References 1. Bopp BL, Alper MM, Thompson IE, Mortola J. Success rates with gamete intrafallopian transfer and in vitro fertilization in women of advanced maternal age. Fertil Steril 1995;63: Padilla SL, Garcia JE. Effect of maternal age and number of in vitro fertilization procedures on pregnancy outcome. Fertil Steril 1989;52: Arthur ID, Anthony FW, Masson GM, Thomas EJ. The selection criteria on an IVF program can remove the association between maternal age and implantation. Acta Obstet Gynecol Scand 1994;73: Alsalili M, Yuzpe AA, Tummon IS, Parker J, Martin JS, Nisker JA, et al. Confounding variables in IVF success: a decade of experience. J Assist Reprod Genet 1995;12: Dicker D, Goldman JA, Ashkenazi J, Feldberg D, Shelef M, Levy T. Age and pregnancy rates in in vitro fertilization. J In Vitro Fert Embryo Transfer 1991;8: Speroff L. The effect of aging on fertility. Curr Opin Obstet Gynecol 1994;6: Leeton J. Patient selection for assisted reproduction. Baillieres Clin Obstet Gynaecol 1992;6: Richardson SJ, Senikas V, Nelson JF. Follicular depletion during the menopausal transition: evidence for accelerated loss and ultimate exhaustion. J Clin Endocrinol Metab 1987;65: Wallach EE. Pitfalls in evaluating ovarian reserve. Fertil Steril 1995; 63: Abdalla HI, Baber R, Kirkland A, Leonard T, Power M, Studd JW. A report on 100 of oocyte donation: factors affecting the outcome. Hum Reprod 1990;5: Munne S, Alikani M, Tomkin G, Grifo J, Cohen J. Embryo morphology, developmental rates, and maternal age are correlated with chromosome abnormalities. Fertil Steril 1995;64: Human Fertilization and Embryo Authority. The patients guide to DI and IVF clinics. London: Human Fertilization and Embryo Authority Rutherford AJ, Subak-Sharpe RJ, Dawson KJ, Margara RA, Franks S, Winston RML. Improvement of in-vitro fertilization after treatment with buserelin, an agonist of luteinising hormone releasing hormone. Br Med J 1988;296: Dawson KJ, Conaghan J, Ostera GR, Winston RML, Hardy K. Delaying transfer to the third day post-insemination, to select non-arrested embryos, increases development to the fetal heart stage. Hum Reprod 1995;10: Kovacs GT, Rogers P, Leeton JF, Trouson AO, Wood C, Gordon Baker HW. In-vitro fertilization and embryo transfer. Prospects of pregnancy by life-table analysis. Med J Aust 1986;144: Van Kooij RJ, Looman CW, Habbema JD, Dorland M, te Velde ER. Age-dependent decrease in embryo implantation rate after IVF. Fertil Steril 1996;66: Jenkins JM, Davies DW, Devonport H, Anthony FW, Gadd SC, Watson RH, et al. Comparison of poor responders with good responders using a standard buserelin/human menopausal gonadotrophin regime for IVF. Hum Reprod 1991;6: Templeton A, Morris JK, Parslow W. Factors that affect outcome of in-vitro fertilization treatment. Lancet 1996;348: Guzick DS, Wilkes C, Jones HW. Cumulative pregnancy rates for in vitro fertilization. Fertil Steril 1986;46: Dor J, Seidman DS, Ben-Shlomo I, Levran D, Ben-Rafael Z, Mashiach S. Cumulative pregnancy rate following in-vitro fertilization: the significance of age and infertility etiology. Hum Reprod 1996;11: Human Fertilization and Embryo Authority. Manual for centers. Version 2.1. London: Human Fertilization and Embryo Authority Svendsen TO, Jones D, Butler L, Muasher SJ. The incidence of multiple gestations after IVF is dependent on the number of embryos transferred and maternal age. Fertil Steril 1996;65: Levene MI, Wild J, Steer P. Higher multiple births and the modern management of infertility in Britain. Br J Obstet Gynaecol 1992;99: Harrison KL, Breen TM, Hennessey JF, Hynes MJ, Keeping JP, Kilvert GT. Patient age and success in a human IVF program. Aust NZJ Obstet Gynaecol 1989;29: Abdulla HI, Burton G, Kirkland A, Johnson MR, Leonard T, Brooks AA, et al. Age, pregnancy and miscarriage: uterine versus ovarian factors. Hum Reprod 1993;8: Roest J, van Heusden AM, Mous H, Zeilmaker GE, Verhoeff A. The ovarian response as a predictor for successful IVF treatment after the age of 40 years. Fertil Steril 1996;66: Lass A, Skull J, McVeigh E, Margara R, Winston RM. Measurement of ovarian volume by transvaginal sonography before ovulation induction with human menopausal gonadotrophin for IVF can predict poor response. Hum Reprod 1997;12: Toner JP, Philput CB, Jones GS, Muassher SJ. Basal follicular stimulating hormone level is a better predictor of IVF performance than age. Fertil Steril 1991;55: Scott RT, Hoffmann GE. Prognostic assessment of ovarian reserve. Fertil Steril 1995;63: Lass et al. IVF in women 40 years of age Vol. 70, No. 6, December 1998