Outcome of treatment subsequent to the elective cryopreservation of all embryos from women at risk of the ovarian hyperstimulation syndrome

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1 Human Reproduction vol.7 no.7 pp.929, 1992 Outcome of treatment subsequent to the elective cryopreservation of all embryos from women at risk of the ovarian hyperstimulation syndrome I.Wada' 2, P.L.Matson 1 * 2, S.A.Troup', S.Hughes 2, P.Buck 2 and B.A.Lieberman 1 2 'Manchester Fertility Services, BUPA Hospital Russell Road, Manchester M1 8AJ and 2 RegionaI IVF Unit, St Mary's Hospital, Whitworth Park, Manchester M1 OJH, UK 'To whom correspondence should be addressed at: Bourn Hall Clinic, Bourn, Cambridge, CB 7TR, UK From 1st June 1989 to 1st May 1991, 78 women with a serum oestradiol level >500 pg/ml on the day of the ovulatory trigger, following pituitary suppression with buserelin and ovarian stimulation with human menopausal gonadotrophins (HMG), had all their embryos electively cryopreserved at the pronucleate stage to minimize the risk of developing ovarian hyperstimulation syndrome (OHS). Treatment with buserelin was continued in the luteal phase. A median of 19 oocytes (range 74) was obtained and 12 embryos (range 17) frozen per cycle. Twentyone (27%) women developed OHS (six severe). Women developing OHS had higher (P < 0.05) serum oestradiol concentrations on the 7th day after oocyte retrieval, compared to those who did not. differences were found for any of the following criteria: aetiology of infertility, age, total dose of HMG, number of oocytes, fertilization rate or freezethaw survival of embryos. Subsequently, 125 frozenthawed embryo replacements have been undertaken, using buserelin and hormone replacement therapy (HRT) (n = 9) or natural cycles (n = ). The overall freezethaw survival and implantation rates per embryo were 71.8 and 11.7%, respectively. The pregnancy rates in natural cycles (19%) and buserelin/hrt cycles (29%) were not significantly different. Key words: buserelin/cryopreservatjori/embryo/hyperstimulation/ thaw Introduction The use of a gonadotrophinreleasing hormone agonist (GnRHa) for invitro fertilization (IVF) is associated with the abolition of premature luteinizing hormone (LH) surges, harvest of more mature oocytes (Crosignani et al., 1988) and an improvement in the pregnancy rate (Rutherford et al., 1988). However, there is a concomitant increase in the incidence of moderate and severe ovarian hyperstimulation (Golan et al., 1988; SubakSharpe etal, 1988; Wada etai, 1990). The risk of developing ovarian hyperstimulation syndrome (OHS) is increased in women with polycystic ovaries (Dale et al., ), in those with a high oestradiol concentration (Asch et al., 1991) and those developing a large number of follicles (Golan et al., 1988) following the induction of ovulation. The syndrome is exacerbated by additional human chorionic gonadotrophin (HCG), given as luteal supplementation (BelaischAllart et al., 1990), or by a subsequent pregnancy (Herman et al., 1990). In women at risk of OHS, additional HCG (from supplementation or pregnancy) could be avoided by the elective cryopreservation of all the embryos (Amso et al., 1990; Home etal. 1990; Salat Baroux etal., 1990). We have shown previously that this policy does reduce the severity of OHS (IWada etal., in preparation). The outcome of subsequent management and of the frozen thawed embryo replacements are yet to be fully assessed, as reports in the literature concern only isolated cases (Amso et al., 1990; Home et al., 1990). The aims of the present study were the following: (i) to assess the quality of the oocytes and embryos in terms of fertilization, freeze thaw survival and implantation rates; (ii) to compare the pregnancy outcome following embryo replacement using buserelin and hormone replacement therapy (HRT) or natural cycles; and (iii) to determine the factors associated with the development of OHS despite continuation of buserelin treatment in the luteal phase. Materials and methods From 1st June 1989 to 1st May 1991, 78 women with serum oestradiol >5OO pg/ml on the day of ovulatory trigger, following induction of ovulation with buserelin and human menopausal gonadotrophins (HMG) in a long protocol, had all their embryos cryopreserved electively at the pronucleate stage. In addition to the principal causes of infertility (Table I), 5 (45 %) of these women had features of polycystic ovary syndrome (n = 11) or multifollicular (n = 24) ovaries (Adams et al., 1985) at the initial ultrasound examination. Subsequently, 125 embryo replacement cycles were undertaken [ in natural cycles and 9 in buserelin/hormone replacement therapy (HRT) cycles]. Ovarian stimulation Treatment was commenced 7 days before the onset of the next menstrual period, with buserelin (Suprefact; Hoechst, Hounslow, UK) 500 ng s.c. daily, and continued until the ovulatory trigger. On the 12th day of buserelin, pituitary ovarian suppression was confirmed according to the following criteria: serum oestradiol <50 pg/ml, serum LH <2.0 IU/1, no ovarian cysts or follicles > 10 mm in diameter and the onset of menses. Women who did not meet these criteria were assessed weekly thereafter. Once Oxford University Press Downloaded from at Pennsylvania State University on September 17, 201

2 Elective embryo cryopreservatkm for OHS risk pituitary ovarian suppression was confirmed, the injections of HMG (Pergonal; Serono laboratories, Welwyn Garden City, UK or Humegon; Organon laboratories, Oss, The Netherlands) were commenced at a dose of 150 IU (two ampoules) i.m. daily. Treatment was monitored from the 8th day of HMG administration by daily serum oestradiol measurements and vaginal ovarian ultrasonography. Ovulation was triggered with IU HCG when three or more follicles measured >20 mm in diameter. The oocytes were retrieved h later by vaginal ultrasound or laparoscopy. In those women with a serum oestradiol >500 pg/ml, the size of the ovaries was carefully estimated at egg retrieval. All oocytes obtained were inseminated in vitro and all the resulting embryos were frozen at the pronucleate stage (Troup et al., 1990). Treatment with buserelin was continued until the onset of a menstrual period. Patients were kept under outpatient surveillance and seen weekly for clinical assessment and vaginal ultrasound examination. Embryo replacement Embryos were thawed on the day before replacement and were deemed to have survived if cleavage occurred during overnight culture (Troup et al., 1990). The embryos were replaced either after buserelin/hrt or in a natural cycle. Buserelin/HRT cycle Pituitary suppression with buserelin (as described above) was followed by oral oestradiol valerate tablets (Progynova; Schering, UK) 1 mg daily, for the first 5 days; then 1 mg b.d. from days 9 and 2 mg tds from day 10 onwards. Progesterone pessaries (Cyclogest; Hoechst, Hounslow, UK) 400 mg bd were started on day 15 of HRT and the buserelin injections were discontinued. A maximum of three embryos were replaced on day 18 of HRT and a qualitative pregnancy test was performed 17 days later. For those women becoming pregnant, the HRT was continued until 12 completed weeks of gestation (when ultrasound examination at 7 weeks gestation confirmed a vital clinical pregnancy). The dose of oestradiol valerate and progesterone pessaries was gradually reduced in the last 2 weeks of HRT. Natural cycle Serum LH concentrations were measured daily in the periovulatory period and the embryos were replaced 4 days after the onset of the LH surge. luteal phase support was given. The relative benefits of embryo replacement into natural or buserelin/hrt cycles were discussed with each couple and the choice was made by the couples according to their individual circumstances. The relative numbers in each group are shown in Table VI. Diagnosis of OHS Women developing symptoms after treatment were examined and their ovaries assessed by ultrasound. The diagnosis and classification of OHS (moderate or severe) was based on the criteria described originally by Rabau et al. (197) and modified by Schenker and Weinstein (1978). Clinically detectable ascites (rather than small amounts of free fluid within the pelvis seen using ultrasound) was considered a criterion of severe ovarian hyperstimulation. Statistical analysis A twotailed MannWhitney U test was used to compare the details of treatment cycles in women who did or did not develop OHS. Comparisons of various proportions were made by Fisher's exact probability test. Differences were considered significant at fvalues of <0.05. Results The causes of infertility in the 78 couples are shown in Table I. In 4 (58%) couples, the predominant cause was tubal disease, 1 (21 %) couples had idiopathic infertility, nine (12%) had male factor infertility, four (5%) had endometriosis and the remaining three (4%) couples had immunological factors. There were no differences in the aetiology of infertility between women who developed OHS and those who did not. Twentyone women (27%) developed OHS (six severe) following elective embryo cryopreservation, despite the continuation of the buserelin treatment during the luteal phase. There was no difference in the incidence of symptomatic OHS (Table II) whether the indication for elective embryo cryopreservation was only the high serum oestradiol concentration Table I. The aetiology of subfertility in women having all embryos cryopreserved due to a nsk of ovanan hyperstimulation syndrome (OHS) Aetiology Tubal Idiopathic Male Endometnosis Immunological (n = 21) 1 5 (n = 57) 11 4 (n = 78) 4 (58%) 1 (21%) 9(12%) 4(5%) (4%) (100%) Table II. Incidence of symptomatic ovarian hyperstimulation syndrome (OHS) following the elective cryopreservatjon of all embryos in women with serum oestradiol > 500 pg/ml at the time of the ovulatory trigger. cycles moderate OHS severe OHS (OHS) + OR = oocyte retrieval a versus b: not significant (NS) Ovarian diameter of OR + <8 cm 10 2 (20%) 2 (20%)* >8 cm 8 1 (19%) (8.8%) 19 (28%) b (22%) (7%) 21 (27%) Downloaded from at Pennsylvania State University on September 17, 201 9

3 I.Wada el al. (2/10; 20%) or a combination of high serum oestradiol and grossly distended ovaries (19/8; 28%). Women developing OHS had significantly higher (P < 0.05) serum oestradiol levels on the 7th day after oocyte retrieval (Table HI), but there were no differences in age, total dose of HMG, the serum oestradiol concentration and number of follicles (> 10 mm in diameter or > 14 mm in diameter) on the day of ovulatory trigger and the number of eggs retrieved. A total of 1405 oocytes (median 19; range 74 per cycle) were obtained and 88 embryos (median 12; range 1 7 per cycle) were frozen in the 78 treatment cycles (Table IV). The overall fertilization rate was 2.8%. The fertilization rate was significantly lower (P < 0.001) for the oocytes inseminated with oligo/asthenozoospermic semen. difference was seen in the Table 111. Details of the cycles in (OHS) developed after the elective women at risk Parameters: median (range) Age dose of HMG (ampoules). of follicles on day of HCG All > 10 mm > 14 mm. of eggs Serum oestradiol (pg/ml) on day of HCG on day 7 post OR + on day 14 post OR which ovarian hyperstimulation cryopreservation of all embryos (" = 21) 29.5 (242) 22.4 (1104) 0.8 (152) 18.8 (1244) 19. (124) 58 ( ) (25550) (197) syndrome from (n = : 57) 0.4 (2742) 2.8 (220) 29. (145) 18. (1125) 187 (8) 480 (199294) 1802 b (25944) 19 (1982) + OR = oocyte retrieval. a versus b: P < HMG = human menopausal gonadotrophin, HCG = human chorionic gonadotrophin. Table IV. Fertilization rate of oocytes derived from women having all embryos electively cryopreserved due to a risk of ovarian hyperstimulation syndrome (OHS) Semen quality rmozoospermic (9 cycles) Oligo/asthenozoospermic (9 cycles) a versus b. P < / (8%) 19/5 (%) 249/89 (4%) 58/91 (4%) 51/100 (51%) 4/101 (2 4%) 81/1252* (5%) 70/15 b (45.7%) 88/1405 (2.8%) fertilization rate of oocytes from those women who later developed OHS compared to those who did not (Table IV). A total of 427 embryos (Table V) were thawed in 129 cycles (median.4; range 1 per cycle), of which 07 (71.8%) survived (median 2.; range 1 per cycle). There was no difference in the freezethaw survival rate of the embryos from women who developed OHS compared to those who did not. Embryo replacements were undertaken in 125 cycles ( natural and 9 buserelin/hrt, Table VI). Four replacement cycles were cancelled when none of the embryos survived the freeze thaw process. Six of those women who had embryo replacement in buserelin/hrt cycles had originally embarked on monitoring for replacement in natural cycles, but were found to have persistently elevated serum LH levels (> 10 IU/1). There was no significant difference in the implantation rate per embryo (Table VII) in natural cycles (/8; 7.2%) compared to buserelin/hrt cycles (0/22; 1.2%). Thirtythree clinical pregnancies (2.4% per cycle) were achieved. The pregnancy rate per embryo transfer in natural cycles (/; 19%) was similar to that in buserelin/hrt cycles (27/9; 29%). There have been 17 live births (15 singletons and two sets of twins), six early abortions (one in a natural cycle and five in buserelin/hrt cycles) and there are 10 ongoing pregnancies (one set of twins and nine singletons). Discussion Romeu et al. (1987) showed a reduced fertilization rate of oocytes from women showing an exaggerated response to different regimes for induction of ovulation. Pellicer et al. (1989) also Table V. Freezethaw survival of embryos electively cryopreserved from women at risk of ovarian hyperstimulation syndrome (OHS) Embryos. thawed. survived Survival rate (per embryo) a versus b. not significant (NS) %' % b % Table VI. Choice of buserelin/hormone replacement therapy (HRT) or natural cycles for frozen thawed embryo replacement (FER), according to individual circumstances Indication Initial FER Subsequent FER Regular menses Oligomenorrhoea Basal LH = luteinizing hormone.. of cycles Buserelin/HRT LH >10 IU/1 9 Natural Downloaded from at Pennsylvania State University on September 17, 201

4 Elective embryo cryopreservation for OHS risk showed that oocytes obtained in excess of 10 per stimulation cycle were of relatively poor quality. From similar observations, Craft et al. (1988) recommended flexibility in the number of oocytes or embryos replaced in women with an excessive ovarian response, since these women would require more oocytes/embryos per cycle to achieve pregnancy rates comparable with women having a normal ovarian response to stimulation. However, estimation of oocyte quality based solely on the fertilization rate or the morphological appearance of the oocytes or resultant embryos may not be entirely reliable. A further measure of quality is the ability of embryos to withstand the freeze thaw process (Van de Abbeel et al., 1988) and to implant successfully. The results of the present study show that the oocytes/embryos derived in large numbers from women at risk of OHS compare favourably, in terms of their fertilization, freeze thaw survival and implantation rates, with supernumerary gamete intrafallopian transfer (GIFT) oocytes and embryos from our units (CritchJow et al., 1990) and with the fertilization rate of oocytes obtained in our IVF programme (Ibrahim et al., 1990). Troup et al. (1990) showed that the stage of embryo development at the time of cryopreservation influences the freezethaw survival and implantation rates and that pronucleate embryos achieved better results than early cleavage or expanded blastocysts. This observation encouraged us to freeze the embryos in the present study at the pronucleate stage and the satisfactory results we have obtained support the findings of Troup et al. (1990). SalatBaroux et al. (1990) observed that the policy of elective embryo cryopreservation does not eliminate the occurrence of symptomatic hyperstimulation. We have shown that the policy ameliorates the severity of the disorder (Wada et al., 1992). The major advantage derived from avoiding the additional HCG (from luteal supplementation or pregnancy) is that complicated (Rabau grade ) ovarian hyperstimulation (Rabau et al., 197; Schenker and Weinstein, 1978) with cerebrovascular accidents (Rizk et al., 1990), deep vein thrombosis (Kaaja etai, 1989) or liver abnormality (Ryley et al., 1990), is most unlikely to occur. The present study has shown that those women who developed OHS had higher serum oestradiol concentrations 7 days after the ovulatory trigger compared to those who did not. This probably TaWe VII. Pregnancy outcome following embryo replacement buserelin/hormone replacement therapy (HRT) cycles Embryos. replaced. implanted Implantation rate (per embryo) Pregnancies. pregnant Pregnancy rate (per cycle) Cycles Natural (n = ) 8 (7.2%)' (19%) c Three sets of twins a versus b: NS (not significant). c versus d: NS Buserelin/HRT (n = 9) 22 0 (1.2%) b 21* (29%) d in natural or (n = 125) 07 (11.7%) (2%) reflects the contribution from a cohort of smaller follicles which may have undergone further development during the luteal phase. Nevertheless, there are no reliable means of predicting which women are more likely to develop symptomatic hyperstimulation. The present study and that by Delvigne et al. (1991), did not identify differences in age, total dose of HMG or number of oocytes retrieved, comparing those women who did with those who did not develop OHS, despite having high serum oestradiol concentrations on the day of the ovulatory trigger. We have reported previously that in our general population of IVF patients, the main risk factors associated with the development of ovarian hyperstimulation are the serum oestradiol concentration, the number of follicles > 14 mm in diameter, whether gametes/embryos are replaced and luteal support given, the occurrence of pregnancy and the presence of polycystic ovaries (Wada et al., 1992). significant difference was seen in the pregnancy outcome following embryo replacements in natural or buserelin/hrt cycles in this study. For the choice of a replacement cycle, consideration should be given to the relative advantages of the buserelin/hrt cycle (which has a fixed schedule and entails fewer visits to the unit) for those women who reside some distance from the IVF unit, those with oligomenorrhoea or menstrual irregularity and women with elevated serum LH levels. High basal LH levels are associated with increased pregnancy loss (Regan et al., 1990). Women with regular menstrual cycles, those who wish to avoid drug therapy or who may not comply strictly with the HRT protocol, should consider the natural cycle a suitable option for embryo replacements. In conclusion, the oocytes and embryos obtained from women at risk of OHS are of good quality in terms of fertilization, freeze thaw survival and implantation rates. A most satisfactory pregnancy rate has been achieved with embryo replacements in both natural and buserelin/hrt cycles. Acknowledgements We thank all the laboratory, nursing and secretarial staff of the two units for their help with this study, in particular Diane Critchlow, Maureen Newman, Greg Home, Helen Izzard, John Prior, Jean Bent, Anne Ratcliffe, Marilyn Wallace, Anne Marie Smith, Vikki Doney, Lynnsey McHugh and Helen Fagan. References Adams,J., Poison,D.W., Abdulwahid.N., Morris,D.V., Franks,S., Mason.H.D., Tucker,M. and PriceJ. 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