In vitro fertilization for Orthodox Jewish couples: antagonist cycle modifications allowing for mikveh attendance before oocyte retrieval

Transcription

1 In vitro fertilization for Orthodox Jewish couples: antagonist cycle modifications allowing for mikveh attendance before oocyte retrieval David E. Reichman, M.D., Anate Aelion Brauer, M.D., Dan Goldschlag, M.D., Glenn Schattman, M.D., and Zev Rosenwaks, M.D. The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medical Center, New York, New York Objective: To describe a novel method of altering conventional gonadotropin-releasing hormone (GnRH) antagonist in vitro fertilization (IVF) cycles, thereby allowing for the observance of ritual Jewish practices, and to investigate the impact of these cycle modifications on IVF outcomes. Design: Retrospective cohort study. Setting: Academic medical center. Patient(s): Orthodox Jewish couples undergoing GnRH antagonist IVF cycles at The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medical College from January 1, 2007, to November 1, 2011, in whom cycle starts were delayed using GnRH antagonists and estradiol patches. Intervention(s): GnRH antagonist administration on cycle days 2, 3, and 4, as well as estradiol patch application on cycle days 2, 4, and 6. Main Outcome Measure(s): Days of stimulation, total cycle length, implantation, clinical pregnancy, and live-birth rate were compared for 42 Orthodox Jewish couples undergoing a mikveh patching protocol versus 42 control patients matched for age, diagnosis, and IVF cycle characteristics. Result(s): The protocol modifications successfully ensured the ability to visit the mikveh before retrieval by extending total cycle length by 3.85 days on average, with no decrement in implantation (43.2% vs. 39.3%), clinical pregnancy (57.1% vs. 59.5%), or live-birth rates (50.0% vs. 54.8%) as compared with controls. Conclusion(s): GnRH antagonist cycles can be successfully modified to allow for IVF that remains consistent with the observance of Orthodox Jewish practices. (Fertil Steril Ò 2013;99: Ó2013 by American Society for Reproductive Medicine.) Key Words: Infertility, IVF, Jewish, Niddah, mikveh Discuss: You can discuss this article with its authors and with other ASRM members at fertstertforum.com/reichmande-ivf-jewish-mikveh-infertility/ Use your smartphone to scan this QR code and connect to the discussion forum for this article now.* * Download a free QR code scanner by searching for QR scanner in your smartphone s app store or app marketplace. According to Jewish law, Orthodox Jewish couples are prohibited from engaging in sexual intercourse from the start of menstruation until 7 days after the cessation of menses, after which the female must immerse in a ritual purity bath (mikveh) before intercourse can occur. The onset of menses signals the start of the Niddah, a period during which sexual relations are forbidden (1). Such practices often coincide with Received September 6, 2012; revised November 16, 2012; accepted November 26, 2012; published online January 8, D.E.R. has nothing to disclose. A.A.B. has nothing to disclose. D.G. has nothing to disclose. G.S. has nothing to disclose. Z.R. has nothing to disclose. Reprint requests: Zev Rosenwaks, M.D., The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medical Center, 1305 York Avenue, New York, New York ( [email protected]). Fertility and Sterility Vol. 99, No. 5, April /$36.00 Copyright 2013 American Society for Reproductive Medicine, Published by Elsevier Inc. the fertile period of a women's menstrual cycle. Orthodox Jewish men are prohibited from masturbation at any time as well as from sexual intercourse before their partner's immersion in the mikveh, thereby preventing the wasting of seed that is prohibited by Jewish law (Genesis 38:9 10). Occasionally, the need to attend mikveh can in fact be the cause of infertility because the fertile window is missed in women with short menstrual cycles (2). In such patients, treatment with estradiol in the early follicular phase can shorten the duration of menses and suppress 1408 VOL. 99 NO. 5 / APRIL 2013

2 Fertility and Sterility endogenous follicle-stimulating hormone (FSH) levels, allowing for extension of the follicular phase until mikveh has been visited (2 4). Attending mikveh can be more problematic for Orthodox couples who require in vitro fertilization (IVF) to conceive. At a minimum, mikveh requires at least 12 days from the start of menstruation to the initiation of sexual activity, as menses according to Jewish law is defined as at least 5 days from the start of bleeding, even for those women who bleed for only 3 or 4 days (5). Although gonadotropin-releasing hormone (GnRH) agonists can be used to delay cycle start until the cessation of menstruation, GnRH-antagonist cycles are more convenient and well tolerated by patients, potentially advantageous for poor responders, and allow for the administration of a GnRH-agonist trigger to decrease the risk of ovarian hyperstimulation syndrome (OHSS) (6, 7). For the last several years, we have modified our conventional GnRH antagonist stimulation protocols for Orthodox Jewish couples to allow for IVF cycles that are consistent with their religious beliefs and practices while still maximizing cycle outcomes. In the following study, we analyzed the efficacy of such cycle modifications aimed at extending IVF cycle length, both in terms of whether patients were able to attend mikveh before retrieval, and whether these modifications affected pregnancy rates with respect to controls. MATERIALS AND METHODS Cycle Inclusion Criteria This study was approved by the Weill Cornell Medical College institutional review board. The cycles selected for inclusion were identified after review of all GnRH-antagonist IVF cycles performed at The Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine from January 1, 2007, to November 1, Inclusion criteria were Orthodox Jewish patients whose IVF cycle starts were delayed with a GnRH antagonist and whose menstrual bleeding was curtailed via estrogen patching. For patients with more than one such cycle, only the first cycle was included for analysis to avoid repeated-measures bias. Because of the small possibility that sperm might be found in the ejaculate before testicular sperm extraction (TESE), patients intended for TESE were asked to produce a specimen on the morning of their procedure; such patients were thus included in the study. Couples requiring TESE in whom cycles were canceled due to failure to retrieve sperm were excluded from analysis (four cases). A total of 9,167 GnRH antagonist IVF cycles occurred over the above study period and were analyzed to determine suitability for inclusion. Clinical Protocols Orthodox Jewish couples identified for inclusion were treated with one of four GnRH-antagonist stimulation protocols, either without hormonal suppression in the preceding cycle or with oral contraceptive pills (OCP), estradiol (E 2 ) patches, or a combination of E 2 patches and GnRH antagonist injections in the luteal phase before stimulation. All patients presented for serum hormonal analysis and baseline ultrasound on cycle day 2 after the initiation of menses. For those patients meeting cycle start criteria (FSH <12 miu/ml, negative b-human chorionic gonadotropin [b-hcg], absence of large ovarian cysts), a GnRH antagonist (ganirelix acetate, 0.25 mg; Organon; or Cetrotide, 0.25 mg; EMD-Serono) was administered on cycle days 2, 3, and 4 to delay the initiation of injectable medications if attendance at mikveh was intended. Moreover, a single 0.1 mg estradiol patch (Climara; Bayer Healthcare Pharmaceuticals) was applied on cycle day 2, and exchanged for a new patch on cycle days 4 and 6 to allow for more rapid cessation of menses and provide additional early hormonal suppression (see Fig. 1). Controlled ovarian hyperstimulation with injectable gonadotropins (Follistim, Merck; Gonal-F, EMD-Serono; and/ or Menopur, Ferring) was in all cases started on cycle day 5 for patients intending to attend mikveh. Conversely, control patients started gonadotropin on cycle day 2 in the typical fashion. After stimulation had begun, patients were started on a GnRH antagonist (ganirelix acetate, 0.25 mg, Organon; or Cetrotide, 0.25 mg, EMD-Serono) to prevent ovulation according to a flexible dosing protocol, in general when either the lead follicle measured R13 mm or serum E 2 exceeded 300 pg/ml, whichever occurred first (8, 9). For all patients, ovarian stimulation was performed per our normal protocols, seeking to maximize follicular recruitment while minimizing risks of OHSS; gonadotropin doses were, in general, adjusted in a step-down fashion depending on ovarian response. Human chorionic gonadotropin (Profasi, EMD-Serono; Novarel, Ferring Pharmaceuticals; or Pregnyl, Schering-Plough) was administered when at least two follicles had attained a mean diameter of 17 mm, according to a flexible hcg-dosing regimen previously described elsewhere (10). Alternatively, in patients with E 2 >3,000 pg/ml, a 2 mg subcutaneous GnRH-agonist trigger was administered. Retrieval was performed 35 to 37 hours after the hcg trigger under transvaginal ultrasound guidance. Luteal progesterone support with intramuscular progesterone was begun the day after retrieval. In cases of GnRH-agonist trigger, aggressive luteal estradiol support was administered in addition to progesterone (11). Control patients were identified so as to compare cycle length and clinical outcomes against the study population. Controls were matched for age, number of prior IVF attempts, FIGURE 1 Schematic for in vitro fertilization cycle protocol modification. *Boxes composed of dashed-lines represent optional luteal pretreatment. VOL. 99 NO. 5 / APRIL

3 ORIGINAL ARTICLE: INFERTILITY type of antagonist protocol, diagnosis, starting dose of medication, peak estradiol level, number of oocytes retrieved, number of embryos transferred, type of trigger (hcg vs. GnRH agonist) and day of embryo transfer (day 3 vs. day 5). Where possible, an attempt was made to control for male factor infertility cases requiring testicular sperm extraction (TESE), as a sizeable minority of patients (33%) in the study group required this intervention. The researchers were blinded to cycle length, total gonadotropins administered, and clinical outcomes when selecting controls based on these variables. Variables Assessed Demographic characteristics of the two groups, including age, gravity, parity, body mass index (BMI), number of previous IVF attempts, day-3 FSH, and diagnosis were assessed. IVF cycle characteristics were compared between the two groups. Number of days of stimulation, amount of gonadotropins administered, total cycle length, implantation, clinical pregnancy rate per retrieval, and live-birth per retrieval were assessed as the main study outcomes. Fertilization rate was defined as the number of two pronuclear (2PN) zygotes divided by the total number of mature oocytes inseminated. Implantation rate was defined as the number of sacs detected by ultrasound at 5 to 6 weeks divided by the total number of embryos transferred. Clinical pregnancy rate was defined as the number of cycles with at least one viable fetus (as evidenced by fetal cardiac activity by ultrasound at 7 weeks) per retrieval. Live-birth was defined as the number of cycles resulting in at least one live-born child delivered at >28 weeks' gestation out of all retrievals performed. Statistical Analysis STATA Statistical Software v.11 (StataCorp LP) was used to perform data analyses. Continuous variables between the study and control groups were analyzed via the Mann- Whitney U-test. Categorical variables were analyzed via chi-square. In all cases, P<.05 was considered to be statistically significant. RESULTS Forty-two cycles met the inclusion criteria for the study and were selected for analysis. The demographic characteristics of the index and control groups are shown in Table 1. Patients in the mikveh group had higher parity and higher BMI with respect to controls. There were otherwise no differences between the two groups with respect to age, gravity, day-3 FSH, or prior IVF attempts. For both groups, male factor infertility represented the most common diagnosis (76.2%), followed by idiopathic (9.5%), polycystic ovary syndrome (PCOS) (7.1%), tubal factor (4.8%), and diminished ovarian reserve (2.4%) Of Orthodox couples presenting with male factor infertility, 33.3% required TESE versus only 21.4% of couples in the control group. Antagonist cycles with OCP pretreatment represented the majority of stimulation protocols (64.3%). The remainder of patients either received no hormonal pretreatment (21.4%), luteal estradiol in combination TABLE 1 Demographic characteristics of study population versus controls. Number Age a Gravidity Parity Day-3 FSH (miu/ml) BMI Prior IVF a Note: Values ¼ mean standard deviation. BMI ¼ body mass index; FSH ¼ folliclestimulating hormone. a Variable used in construction of matched control group. with GnRH antagonist before menses (7.1%) or luteal E 2 alone (7.1%). Distribution of diagnoses as well as stimulation protocols were identical between the two groups based on the matching criteria set forth in the study. IVF cycle characteristics as well as intermediate cycle outcomes are shown in Table 2. As would be predicted based on the variables used for selection of controls, IVF cycle characteristics were similar between the two groups. No differences were observed between the mikveh patients and controls in terms of starting dose of medications or E 2 level at hcg trigger. Three patients in each group were triggered with a GnRH agonist. Endometrial thickness was increased in the mikveh group (12.2 mm vs mm, P¼.03). No differences were observed in terms of number of oocytes retrieved, oocyte maturity, number of zygotes, fertilization rate, or number of embryos transferred. In both groups, day-5 transfer occurred in 28.6% of patients, while the remainder underwent transfer on day 3. The main study outcomes are shown in Table 3. Patients undergoing cycle modifications to allow for mikveh attendance required, on average, 1 day of additional stimulation before trigger as compared with controls. Study patients received, on average, approximately 474 IU of additional gonadotropins over the course of their cycles (P¼.05). Total cycle length, as defined by the first day of menstrual bleeding up to and including the day before retrieval, was on average TABLE 2 Characteristics of IVF cycle of study population versus controls. Start dose (IU) a E 2 at hcg (pg/ml) a 1, , Endometrial stripe(mm) No. of oocytes a No. of MII No. of 2PN Fertilization rate 72.7% 71.8%.7735 No. transferred a No. frozen Note: Values ¼ mean standard deviation or percentage. E2 ¼ estradiol; hcg ¼ human chorionic gonadotropin; MII ¼ metaphase 2; PN ¼ pronuclei. a Variable used in construction of matched control group VOL. 99 NO. 5 / APRIL 2013

4 Fertility and Sterility TABLE 3 Total cycle length and clinical outcomes for study population versus controls. Total gonadotropins (IU) 2, , , Days of stimulation Total cycle length (min max) (14 22) (10 16) <.0001 % of cycles with retrieval at <13 d 0 50% <.0001 Implantation rate 43.2% 39.3%.8290 Clinical pregnancy rate 57.1% 59.5%.8292 Live-birth rate 50.0% 54.8%.6699 Note: Values ¼ mean standard deviation or percentage days longer in the patients delayed for mikveh. The shortest total cycle length for mikveh patients was 14 days, as opposed to 10 days in the control group. In the control group, 50% of patients had retrieval before cycle day 13, which would by definition have precluded the ability to observe Orthodox Jewish practices had they been intended in these cycles (given that, according to Jewish law, cycle day 12 is the earliest that a woman may visit the mikveh). While duration of menstrual bleeding was not specifically analyzed in this study, chart review revealed that all patients in the study group were successfully delayed long enough to allow for their religious observances. No differences were observed between the two groups in terms of clinical outcomes, as evidenced by similar rates of implantation, clinical pregnancy, and live-birth for the index and control populations. DISCUSSION In the present study, we set out to examine the efficacy of cycle modifications aimed at allowing Orthodox Jewish couples sufficient time after cessation of menses to visit the mikveh before oocyte retrieval. By treatment with a GnRH antagonist on cycles day 2, 3, and 4 to delay stimulation, while additionally treating with E 2 patches on cycles day 2, 4, and 6 to curtail menstrual bleeding and provide further early suppression, all patients were afforded the additional time required by Jewish law to observe religious practices before retrieval. No detriment to these cycles was observed as evidenced by implantation, clinical pregnancy, and livebirth rates as compared with controls who had similar demographic and IVF cycle characteristics. Clinical pregnancy rates were commensurate with controls despite a significant number of patients requiring TESE in the study group. As with any subpopulation of patients, fertility specialists will benefit their patients by gaining familiarity with the religious restrictions of this population as they relate to reproduction and assisted reproductive techniques. For instance, while fewer and fewer reproductive endocrinologists perform postcoital tests as a screening measure for male factor infertility, most Orthodox Jewish men are not permitted to undergo semen analysis until a postcoital test has demonstrated a significant need for further evaluation (12). It should be noted that there is heterogeneity of opinion among rabbinical authorities with regard to method of sperm procurement. Most commonly, couples are instructed by their rabbi to use nonspermicidal condoms with a pinpoint perforation during intercourse, as ejaculation should be vaginally contained. Other rabbinical interpretations include aspiration of the ejaculate from the vagina after intercourse without a condom (a technique that poses the risk of specimen contamination) versus allowing for masturbation (particularly during the period when sexual relations are forbidden). Although the reproductive practices of religious Jews have been well described both in the religious and medical literature, the specific adaptations to IVF cycles to accommodate Jewish religious beliefs have not been heretofore described in the published literature. To our knowledge, this is the first published study to describe cycle modifications of Orthodox Jewish couples undergoing IVF cycles. Hormonal manipulations to accommodate the religious beliefs of this patient population, however, are not a new concept, and have been previously described for patients undergoing ovulation induction or timed intercourse (2 4). Speroff et al. (13) have advocated the use of clomiphene citrate starting on cycle days 7 or 8 to delay ovulation, but in our experience this practice is less effective than treatment with estrogen alone early in the cycle and is altogether not feasible in IVF cycles. For patients frequently separated from their partners at the time of ovulation, or for religious patients with short cycles who resume sexual activity only after ovulation has occurred, administration of exogenous estrogen in the early follicular phase, either in the form of oral or transdermal preparations, has been demonstrated to be effective in delaying ovulation (2, 3). Although estrogen alone in the early follicular phase typically suppresses endogenous FSH, the addition of a GnRH antagonist during the period of delay further insures prevention of an early dominant follicle during an IVF cycle. The modifications described in this study were effective in allowing all Orthodox Jewish patients the time needed to attend mikveh, but they were associated with slightly increased costs, as three additional GnRH antagonist injections as well as more gonadotropins were required during stimulation as compared with controls. Two days of GnRH antagonist injections rather than 3 days may have been sufficient to extend the cycle length in combination with estrogen treatment, as the shortest cycle length in the study population was 14 days. Increased endometrial thickness was observed in the mikveh group; while statistically significant, this finding is VOL. 99 NO. 5 / APRIL

5 ORIGINAL ARTICLE: INFERTILITY of questionable clinical significance given the minor difference in measurement between groups (14). Our study was not without limitations. We did not specifically compare the number of days of menstrual bleeding in the study population versus controls, as this data was retrospectively collected; based on our experience, however, early follicular phase estrogen treatment is quickly effective in curtailing menses. The small sample size of the study should be noted. Additionally, it should be noted that GnRH downregulation with delay of gonadotropin start is an alternative approach for such patients. In our own experience, however, the ability to use a GnRH agonist trigger to help prevent ovarian hyperstimulation syndrome makes the protocol described herein the more ideal approach. Even contemporary fertility treatments can remain consistent with ancient traditions and religious beliefs with only minimal adaptations to conventional practice. Nearly every religion is associated with its own unique views regarding reproduction; as physicians, we greatly benefit our patients by not only treating our patients' illnesses but also making that treatment consistent with their individual system of beliefs. We hope that the present study may assist infertility specialists and counselors in understanding and addressing the particular concerns that may be experienced by devout Jewish couples presenting for infertility treatment. REFERENCES 1. Haimov-Kochman R, Rosenak D, Orvieto R, Hurwitz A. Infertility counseling for Orthodox Jewish couples. Fertil Steril 2010;93: Yairi-Oron Y, Rabinson J, Orvieto R. A simplified approach to religious infertility. Fertil Steril 2006;86: Dahan MH, Goldstein J, Ratts V, Odem R. Programming ovulation using estrogens for patients to time intercourse. Obstet Gynecol 2005;105: Rabinson J, Katan C. Endometriosis: halakhic aspects as indications for treatment. Isr Med Assoc J 2005;7: Hirsh AV. Infertility in Jewish couples, biblical and rabbinic law. Hum Fertil (Camb) 1998;1: Lainas TG, Sfontouris IA, Papanikolaou EG, Zorzovilis JZ, Petsas GK, Lainas GT, et al. Flexible GnRH antagonist versus flare-up GnRH agonist protocol in poor responders treated by IVF: a randomized controlled trial. Hum Reprod 2008;23: Al-Inany HG, Youssef MA, Aboulghar M, Broekmans F, Sterrenburg M, Smit J, et al. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database Syst Rev 2011:CD Al-Inany H, Aboulghar MA, Mansour RT, Serour GI. Optimizing GnRH antagonist administration: meta-analysis of fixed versus flexible protocol. Reprod Biomed Online 2005;10: Mochtar MH. The effect of an individualized GnRH antagonist protocol on folliculogenesis in IVF/ICSI. Hum Reprod 2004;19: Kashyap S, Parker K, Cedars MI, Rosenwaks Z. Ovarian hyperstimulation syndrome prevention strategies: reducing the human chorionic gonadotropin trigger dose. Semin Reprod Med 2010;28: Engmann L, Benadiva C. Agonist trigger: what is the best approach? Agonist trigger with aggressive luteal support. Fertil Steril 2012;97: Ribner DS. Ejaculatory restrictions as a factor in the treatment of Haredi (Ultraorthodox) Jewish couples. Arch Sex Behav 2004;33: Speroff L, Glass RH, Kase NG. Clinical gynecologic endocrinology and infertility. 6th ed. Philadelphia: Lippincott Williams & Wilkins; Noyes N, Liu HC, Sultan K, Schattman G, Rosenwaks Z. Endometrial thickness appears to be a significant factor in embryo implantation in in-vitro fertilization. Hum Reprod 1995;10: VOL. 99 NO. 5 / APRIL 2013