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Spontaneous clinical pregnancy following GNRH agonist trigger for final oocyte maturation and freeze-all approach: a case report
Reproductive BioMedicine Online (2016) 32, 233–236
w w w. s c i e n c e d i r e c t . c o m w w w. r b m o n l i n e . c o m
ARTICLE
Spontaneous clinical pregnancy following GNRH agonist trigger for final oocyte maturation and freeze-all approach: a case report Hakan Yarali a,b,*, Gürkan Bozdag b, Mehtap Polat a, Irem Yarali a, Peter Humaidan c a
Anatolia Women’s Health and IVF Center, Ankara, Turkey; b Department of Obstetrics and Gynecology, Faculty of Medicine, Hacettepe University, Ankara, Turkey; c Fertility Clinic, Skive Regional Hospital and Faculty of Health, Aarhus University, Aarhus, Denmark * Corresponding author.
E-mail address: [email protected] (H Yarali). Hakan Yarali, MD, is a professor at Hacettepe University, Ankara, Turkey, in the Department of Obstetrics and Gynecology, and is also founder of Anatolia IVF Centre. Following residency training at Hacettepe University, he did his clinical fellowship at the University of British Columbia, Vancouver between 1991 and 1992. In 1998, the Turkish Scientific Technical and Research Council gave him a promising young scientist award, which is the most prestigious research council in Turkey. He has been the author of over 95 scientific papers. His special interests are polycystic ovary syndrome and assisted reproductive technologies.
We herein describe a 34-year old infertile woman with polycystic ovary syndrome who was underwent follicle stimulation with a gonadotrophin-releasing hormone (GnRH) agonist, and a freeze-all approach, but still conceived spontaneously without any luteal phase support and without development of ovarian hyperstimulation syndrome. The bilateral antral follicle count of the patient was 22. A fixed GnRH antagonist protocol was used. As the number of follicles wider than 11 mm in diameter on the day of stimulation was 28, the final oocyte maturation was triggered by a GnRH agonist and a freeze-all approach was taken. Although no luteal phase support was used after trigger, the patient conceived spontaneously. In conclusion, the endogenous LH level during the luteal phase may be sufficiently high in selected cases to rescue some of the corpora lutea even when a GnRH agonist has been administered for final oocyte maturation. When a freeze-all approach is taken to avoid ovarian hyperstimulation syndrome, couples should be strictly advised to refrain from sexual intercourse after oocyte retrieval.
Abstract
© 2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. KEYWORDS: GnRH agonist triggering, in vitro fertilization, luteal phase support, pregnancy
http://dx.doi.org/10.1016/j.rbmo.2015.11.004 1472-6483/© 2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
234
Introduction The gonadotrophin-releasing hormone (GnRH) antagonist protocol is the protocol of choice in expected or proven hyperovarian responders, as it is associated with a significant reduction in ovarian hyperstimulation syndrome (OHSS) compared with the use of the GnRH agonist protocol, even with HCG administration (Pundir et al., 2012). Moreover, the use of the GnRH antagonist protocol permits the use of GnRH agonist to trigger final oocyte maturation and to proceed either with fresh embryo transfer and a modified luteal phase support (Humaidan et al., 2015) or a freeze-all approach (Griesinger et al., 2011).
Case report A 34-year old woman attended Anatolia IVF Center because of problems conceiving. She was diagnosed with polycystic ovary syndrome, having six to eight spontaneous menses annually, mild hirsutism, oily skin and acne. The modified Ferriman–Gallwey score was 7. The body mass index was 24.4 kg/m2 and the waist circumference was 93 cm. The bilateral antral follicle count was 22. The semen analysis was normal. In her past medical history, she had intracranial surgery for a benign tumour, Whipple operation for a pancreatic endocrine tumour and breast surgery for intraductal papilloma. During the consultation, a detailed review of pregnancy rates of natural intercourse, intrauterine insemination and assisted reproduction techniques was provided, and the couple elected to proceed with an intracytoplasmic sperm injection treatment cycle to shorten the time to pregnancy. A fixed GnRH antagonist protocol was assigned and ovarian stimulation commenced with a daily dose of 150 IU recombinent FSH (Gonal-F, Merck, Istanbul, Turkey) from the third day of menses. On the fifth day of stimulation, the oestradiol level was 869 pg/ml, all follicles were 11 mm or less in diameter and GnRH antagonist (Cetrotide; Merck, Istanbul, Turkey) co-treatment started. On the sixth day of stimulation, the oestradiol level increased to 1441 pg/ml, the leading follicles were around 12 mm in diameter, and the daily recombinent FSH dose was reduced to 137.5 IU. On the eighth day of stimulation, the oestradiol was 3234 pg/ml, the leading follicle was 14.5 mm in diameter and the daily recombinent FSH dose was further decreased to 100 IU and then to 75 IU the following day. On the 10th day of stimulation, six follicles exceeded 17 mm in diameter and the oestradiol level was 8921 pg/ml; final oocyte maturation was triggered with 0.2 mg triptorelin acetate (Gonapeptyl; Ferring, Istanbul, Turkey). As the number of follicles greater than 11 mm in diameter on the day of follicle stimulation was 28, a freezeall approach was planned. At oocyte retrieval, 28 oocytes were harvested, 27 were M-2, 21 were normally fertilized and 11 good-quality blastocysts were vitrified. As a freeze-all approach was taken, no luteal phase support was administered. The couple was advised to refrain from sexual intercourse for 5 days after oocyte retrieval. The patient, however, presented with no menses 19 days after the oocyte retrieval and a serum beta-HCG level of 3,131 IU/L. A singleton pregnancy was noted at trans-vaginal ultrasonography 22 days after oocyte retrieval. Although controversial
H Yarali et al. to commence at this stage, daily vaginal progesterone gel (Crinone, Merck, Istanbul, Turkey) was prescribed. A healthy singleton pregnancy with cardiac activity and crown-rump length of 9.6 mm compatible with 7-weeks gestational age was found at transvaginal ultrasonography 38 days after oocyte retrieval, and the luteal phase support was stopped. Embryo dating data supported that the conception occurred after ovulation on the day of, or after, oocyte retrieval. The Non-interventive Human Research Ethics Committee indicated that Institutional Review Board approval was not needed for the publication of this case report.
Discussion The aim of publishing this case is to highlight the following: the occurrence of a spontaneous clinical pregnancy with fetal cardiac activity during the un-supplemented luteal phase after GnRH agonist trigger for final oocyte maturation and freezeall policy; and the absence of any signs of early and lateonset OHSS, although the patient was considered to be at high risk of OHSS development. In the present case, despite a freeze-all approach being taken, a spontaneous pregnancy occurred, most likely through spontaneous ovulation of one of the smaller follicles that had not aspirated. Although the couple was advised to refrain from sexual intercourse after oocyte retrieval, it seems that they breached this advice. Although sperm survival after intercourse may be prolonged in the cervical mucus in ovarian stimulation cycles (Milki et al., 2001; Wilcox et al., 1995), conception resulting from sexual intercourse before oocyte retrieval could not be ruled out. To our knowledge, this is the first case reporting a pregnancy after GnRH agonist triggering for final oocyte maturation and a freeze-all approach. Several cases of conception from intercourse and through embryo transfer during the same HCG triggered cycle, however, have been reported (Cahill et al., 2003; Milki et al., 2001; van der Hoorn et al., 2011). A dizygotic twin pregnancy after transfer of one embryo (van der Hoorn et al., 2011) and quadruplet pregnancy with different zygosity after transfer of two embryos have been reported (Cahill et al., 2003; Milki et al., 2001). The present case study, along with previously published cases, clearly emphasize the possibility of a spontaneous pregnancy, although rare, from intercourse in the presence of patent fallopian tube(s) during an in IVF cycle, whether fresh embryo transfer has been carried out or a freeze-all approach has been taken. The threshold for a freeze-all approach has been suggested to be more than 25 follicles wider than 11 mm in diameter on the day of follicle stimulation (Humaidan et al., 2013). This threshold, which has been empirically set, is used in our daily practice; however, in the present case, 28 mature follicles developed, and all embryos were frozen. In early studies, when a fresh embryo transfer is planned after follicle stimluation with GnRH agonist using a standard luteal phase support, disappointingly low pregnancy rates and high biochemical loss rates were reported (Fauser et al., 2002; Humaidan et al., 2005; Kolibianakis et al., 2005). A significantly shorter duration of the LH surge induced by the GnRH agonist trigger compared with the prolonged LH-like activity induced by HCG trigger (Damewood et al., 1989; Yen et al., 1968), coupled with supra-physiological sex steroid levels
Spontaneous pregnancy after freeze-all approach with no luteal phase support (mainly progesterone) resulting from ovarian stimulation (Fatemi, 2009; Fauser and Devroey, 2003; Tavaniotou and Devroey, 2006; Tavaniotou et al., 2001, 2003) contribute to the luteolysis in such cycles. Hence, either a bolus of 1500 IU HCG administered on the day of oocyte retrieval combined with a standard luteal phase support (Humaidan et al., 2010, 2013) or intensive luteal phase support, consisting of progesterone and oestradiol (Engmann et al., 2008) have been recommended as modified luteal phase support strategies to enable fresh embryo transfer, securing reproductive outcomes similar to those of HCG trigger and very low OHSS rates (Humaidan et al., 2015). In the present case, a spontaneous clinical pregnancy with fetal cardiac activity developed despite the fact that no luteal support was administered after the GnRH agonist trigger. The explanation for this remains hypothetical; however, Weissman et al. (1996) previously reported corpus luteum rescue after 7 days of gonadotrophin deprivation in a patient with hypogonadotropic hypogonadism. Therefore, the most plausible explanation for the clinical pregnancy in our case is corpus luteum rescue shortly after implantation. Another contributing factor to the pregnancy could be increased luteal LH levels and decreased sensitivity of the GnRH pulse generator to inhibit ovarian steroids, previously reported in patients with polycystic ovary syndrome (Pastor et al., 1998). Unfortunately, the luteal phase was not monitored in the present case as a freeze-all strategy was used. Interestingly, this high-risk patient with OHSS did not develop any signs of early or late-onset OHSS. This again could be attributed to the long period of low circulating LH levels, down-regulating the function of the multiple corpora lutea to a degree where only a minute fraction was rescued by the implanting embryo, avoiding the development of late-onset OHSS. Although rare, one should bear in mind that, despite a freeze-all approach after GnRH agonist triggering, severe early onset OHSS can still occur. Therefore, to our knowledge, seven such cases have been reported (Fatemi et al., 2014; Gurbuz et al., 2014; Ling et al., 2014; Santos-Ribeiro et al., 2015). In conclusion, we herein report a spontaneous pregnancy that occurred in a freeze-all cycle. To avoid uncontrolled pregnancy, multiple pregnancy and possible development of lateonset OHSS couples should be strictly advised to refrain from sexual intercourse after oocyte retrieval – even in a freezeall cycle. Although, it is a dogma that luteal phase support is mandatory in all stimulated IVF cycles when a fresh transfer is carried out, the endogenous LH during the luteal phase in a small subgroup of patients with polycystic ovary syndrome may sufficiently rescue some corpus luteum function even when GnRH agonist has been administered for final oocyte maturation.
References Cahill, D.J., Jenkins, J.M., Soothill, P.W., Whitelaw, A., Wardle, P.G., 2003. Quadruplet pregnancy following transfer of two embryos: case report. Hum. Reprod. 18, 441–443. Damewood, M.D., Shen, W., Zacur, H.A., Schlaff, W.D., Rock, J.A., Wallach, E.E., 1989. Disappearance of exogenously administered human chorionic gonadotropin. Fertil. Steril. 52, 398– 400.
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Engmann, L., DiLuigi, A., Schmidt, D., Nulsen, J., Maier, D., Benadiva, C., 2008. The use of gonadotropin-releasing hormone (GnRH) agonist to induce oocyte maturation after cotreatment with GnRH antagonist in high-risk patients undergoing in vitro fertilization prevents the risk of ovarian hyperstimulation syndrome: a prospective randomized controlled study. Fertil. Steril. 89, 84– 91. Fatemi, H.M., 2009. The luteal phase after 3 decades of IVF: what do we know? Reprod. Biomed. Online 19 (Suppl. 4), 4331. Fatemi, H.M., Popovic-Todorovic, B., Humaidan, P., Kol, S., Banker, M., Devroey, P., Garcia-Velasco, J.A., 2014. Severe ovarian hyperstimulation syndrome after gonadotropin-releasing hormone (GnRH) agonist trigger and “freeze-all” approach in GnRH antagonist protocol. Fertil. Steril. 101, 1008–1011. Fauser, B.C., Devroey, P., 2003. Reproductive biology and IVF: ovarian stimulation and luteal phase consequences. Trends Endocrinol. Metab. 14, 236–242. Fauser, B.C., de Jong, D., Olivennes, F., Wramsby, H., Tay, C., Itskovitz-Eldor, J., van Hooren, H.G., 2002. Endocrine profiles after triggering of final oocyte maturation with GnRH agonist after cotreatment with the GnRH antagonist ganirelix during ovarian hyperstimulation for in vitro fertilization. J. Clin. Endocrinol. Metab. 87, 709–715. Griesinger, G., Schultz, L., Bauer, T., Broessner, A., Frambach, T., Kissler, S., 2011. Ovarian hyperstimulation syndrome prevention by gonadotropin-releasing hormone agonist triggering of final oocyte maturation in a gonadotropin-releasing hormone antagonist protocol in combination with a “freeze-all” strategy: a prospective multicentric study. Fertil. Steril. 95, 2029–2033, 2033 e1. Gurbuz, A.S., Gode, F., Ozcimen, N., Isik, A.Z., 2014. Gonadotrophinreleasing hormone agonist trigger and freeze-all strategy does not prevent severe ovarian hyperstimulation syndrome: a report of three cases. Reprod. Biomed. Online 29, 541–544. Humaidan, P., Bredkjaer, H.E., Bungum, L., Bungum, M., Grondahl, M.L., Westergaard, L., Andersen, C.Y., 2005. GnRH agonist (buserelin) or hCG for ovulation induction in GnRH antagonist IVF/ ICSI cycles: a prospective randomized study. Hum. Reprod. 20, 1213–1220. Humaidan, P., Ejdrup Bredkjaer, H., Westergaard, L.G., Yding Andersen, C., 2010. 1,500 IU human chorionic gonadotropin administered at oocyte retrieval rescues the luteal phase when gonadotropin-releasing hormone agonist is used for ovulation induction: a prospective, randomized, controlled study. Fertil. Steril. 93, 847–854. Humaidan, P., Polyzos, N.P., Alsbjerg, B., Erb, K., Mikkelsen, A.L., Elbaek, H.O., Papanikolaou, E.G., Andersen, C.Y., 2013. GnRHa trigger and individualized luteal phase hCG support according to ovarian response to stimulation: two prospective randomized controlled multi-centre studies in IVF patients. Hum. Reprod. 28, 2511– 2521. Humaidan, P., Engmann, L., Benadiva, C., 2015. Luteal phase supplementation after gonadotropin-releasing hormone agonist trigger in fresh embryo transfer: the American versus European approaches. Fertil. Steril. 103, 879–885. Kolibianakis, E.M., Schultze-Mosgau, A., Schroer, A., van Steirteghem, A., Devroey, P., Diedrich, K., Griesinger, G., 2005. A lower ongoing pregnancy rate can be expected when GnRH agonist is used for triggering final oocyte maturation instead of HCG in patients undergoing IVF with GnRH antagonists. Hum. Reprod. 20, 2887– 2892. Ling, L.P., Phoon, J.W., Lau, M.S., Chan, J.K., Viardot-Foucault, V., Tan, T.Y., Nadarajah, S., Tan, H.H., 2014. GnRH agonist trigger and ovarian hyperstimulation syndrome: relook at “freeze-all strategy”. Reprod. Biomed. Online 29, 392–394. Milki, A.A., Hinckley, M.D., Grumet, F.C., Chitkara, U., 2001. Concurrent IVF and spontaneous conception resulting in a quadruplet pregnancy. Hum. Reprod. 16, 2324–2326.
236 Pastor, C.L., Griffin-Korf, M.L., Aloi, J.A., Evans, W.S., Marshall, J.C., 1998. Polycystic ovary syndrome: evidence for reduced sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone. J. Clin. Endocrinol. Metab. 83, 582–590. Pundir, J., Sunkara, S.K., El-Toukhy, T., Khalaf, Y., 2012. Metaanalysis of GnRH antagonist protocols: do they reduce the risk of OHSS in PCOS? Reprod. Biomed. Online 24, 6–22. Santos-Ribeiro, S., Polyzos, N.P., Stouffs, K., De Vos, M., Seneca, S., Tournaye, H., Blockeel, C., 2015. Ovarian hyperstimulation syndrome after gonadotropin-releasing hormone agonist triggering and “freeze-all”: in-depth analysis of genetic predisposition. J. Assist. Reprod. Genet. 32, 1063–1068. Tavaniotou, A., Devroey, P., 2006. Luteal hormonal profile of oocyte donors stimulated with a GnRH antagonist compared with natural cycles. Reprod. Biomed. Online 13, 326–330. Tavaniotou, A., Albano, C., Smitz, J., Devroey, P., 2001. Comparison of LH concentrations in the early and mid-luteal phase in IVF cycles after treatment with HMG alone or in association with the GnRH antagonist Cetrorelix. Hum. Reprod. 16, 663– 667. Tavaniotou, A., Bourgain, C., Albano, C., Platteau, P., Smitz, J., Devroey, P., 2003. Endometrial integrin expression in the early
H Yarali et al. luteal phase in natural and stimulated cycles for in vitro fertilization. Eur. J. Obstet. Gynecol. Reprod. Biol. 108, 67–71. van der Hoorn, M.L., Helmerhorst, F., Claas, F., Scherjon, S., 2011. Dizygotic twin pregnancy after transfer of one embryo. Fertil. Steril. 95, 805e1–805e3. Weissman, A., Loumaye, E., Shoham, Z., 1996. Recovery of corpus luteum function after prolonged deprivation from gonadotrophin stimulation. Hum. Reprod. 11, 943–949. Wilcox, A.J., Weinberg, C.R., Baird, D.D., 1995. Timing of sexual intercourse in relation to ovulation. Effects on the probability of conception, survival of the pregnancy, and sex of the baby. N. Engl. J. Med. 333, 1517–1521. Yen, S.S., Llerena, O., Little, B., Pearson, O.H., 1968. Disappearance rates of endogenous luteinizing hormone and chorionic gonadotropin in man. J. Clin. Endocrinol. Metab. 28, 1763–1767.
Declaration: The authors report no commercial or financial conflicts of interest.
Received 28 June 2015; refereed 16 September 2015; accepted 5 November 2015.
w w w. s c i e n c e d i r e c t . c o m w w w. r b m o n l i n e . c o m
ARTICLE
Spontaneous clinical pregnancy following GNRH agonist trigger for final oocyte maturation and freeze-all approach: a case report Hakan Yarali a,b,*, Gürkan Bozdag b, Mehtap Polat a, Irem Yarali a, Peter Humaidan c a
Anatolia Women’s Health and IVF Center, Ankara, Turkey; b Department of Obstetrics and Gynecology, Faculty of Medicine, Hacettepe University, Ankara, Turkey; c Fertility Clinic, Skive Regional Hospital and Faculty of Health, Aarhus University, Aarhus, Denmark * Corresponding author.
E-mail address: [email protected] (H Yarali). Hakan Yarali, MD, is a professor at Hacettepe University, Ankara, Turkey, in the Department of Obstetrics and Gynecology, and is also founder of Anatolia IVF Centre. Following residency training at Hacettepe University, he did his clinical fellowship at the University of British Columbia, Vancouver between 1991 and 1992. In 1998, the Turkish Scientific Technical and Research Council gave him a promising young scientist award, which is the most prestigious research council in Turkey. He has been the author of over 95 scientific papers. His special interests are polycystic ovary syndrome and assisted reproductive technologies.
We herein describe a 34-year old infertile woman with polycystic ovary syndrome who was underwent follicle stimulation with a gonadotrophin-releasing hormone (GnRH) agonist, and a freeze-all approach, but still conceived spontaneously without any luteal phase support and without development of ovarian hyperstimulation syndrome. The bilateral antral follicle count of the patient was 22. A fixed GnRH antagonist protocol was used. As the number of follicles wider than 11 mm in diameter on the day of stimulation was 28, the final oocyte maturation was triggered by a GnRH agonist and a freeze-all approach was taken. Although no luteal phase support was used after trigger, the patient conceived spontaneously. In conclusion, the endogenous LH level during the luteal phase may be sufficiently high in selected cases to rescue some of the corpora lutea even when a GnRH agonist has been administered for final oocyte maturation. When a freeze-all approach is taken to avoid ovarian hyperstimulation syndrome, couples should be strictly advised to refrain from sexual intercourse after oocyte retrieval.
Abstract
© 2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. KEYWORDS: GnRH agonist triggering, in vitro fertilization, luteal phase support, pregnancy
http://dx.doi.org/10.1016/j.rbmo.2015.11.004 1472-6483/© 2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
234
Introduction The gonadotrophin-releasing hormone (GnRH) antagonist protocol is the protocol of choice in expected or proven hyperovarian responders, as it is associated with a significant reduction in ovarian hyperstimulation syndrome (OHSS) compared with the use of the GnRH agonist protocol, even with HCG administration (Pundir et al., 2012). Moreover, the use of the GnRH antagonist protocol permits the use of GnRH agonist to trigger final oocyte maturation and to proceed either with fresh embryo transfer and a modified luteal phase support (Humaidan et al., 2015) or a freeze-all approach (Griesinger et al., 2011).
Case report A 34-year old woman attended Anatolia IVF Center because of problems conceiving. She was diagnosed with polycystic ovary syndrome, having six to eight spontaneous menses annually, mild hirsutism, oily skin and acne. The modified Ferriman–Gallwey score was 7. The body mass index was 24.4 kg/m2 and the waist circumference was 93 cm. The bilateral antral follicle count was 22. The semen analysis was normal. In her past medical history, she had intracranial surgery for a benign tumour, Whipple operation for a pancreatic endocrine tumour and breast surgery for intraductal papilloma. During the consultation, a detailed review of pregnancy rates of natural intercourse, intrauterine insemination and assisted reproduction techniques was provided, and the couple elected to proceed with an intracytoplasmic sperm injection treatment cycle to shorten the time to pregnancy. A fixed GnRH antagonist protocol was assigned and ovarian stimulation commenced with a daily dose of 150 IU recombinent FSH (Gonal-F, Merck, Istanbul, Turkey) from the third day of menses. On the fifth day of stimulation, the oestradiol level was 869 pg/ml, all follicles were 11 mm or less in diameter and GnRH antagonist (Cetrotide; Merck, Istanbul, Turkey) co-treatment started. On the sixth day of stimulation, the oestradiol level increased to 1441 pg/ml, the leading follicles were around 12 mm in diameter, and the daily recombinent FSH dose was reduced to 137.5 IU. On the eighth day of stimulation, the oestradiol was 3234 pg/ml, the leading follicle was 14.5 mm in diameter and the daily recombinent FSH dose was further decreased to 100 IU and then to 75 IU the following day. On the 10th day of stimulation, six follicles exceeded 17 mm in diameter and the oestradiol level was 8921 pg/ml; final oocyte maturation was triggered with 0.2 mg triptorelin acetate (Gonapeptyl; Ferring, Istanbul, Turkey). As the number of follicles greater than 11 mm in diameter on the day of follicle stimulation was 28, a freezeall approach was planned. At oocyte retrieval, 28 oocytes were harvested, 27 were M-2, 21 were normally fertilized and 11 good-quality blastocysts were vitrified. As a freeze-all approach was taken, no luteal phase support was administered. The couple was advised to refrain from sexual intercourse for 5 days after oocyte retrieval. The patient, however, presented with no menses 19 days after the oocyte retrieval and a serum beta-HCG level of 3,131 IU/L. A singleton pregnancy was noted at trans-vaginal ultrasonography 22 days after oocyte retrieval. Although controversial
H Yarali et al. to commence at this stage, daily vaginal progesterone gel (Crinone, Merck, Istanbul, Turkey) was prescribed. A healthy singleton pregnancy with cardiac activity and crown-rump length of 9.6 mm compatible with 7-weeks gestational age was found at transvaginal ultrasonography 38 days after oocyte retrieval, and the luteal phase support was stopped. Embryo dating data supported that the conception occurred after ovulation on the day of, or after, oocyte retrieval. The Non-interventive Human Research Ethics Committee indicated that Institutional Review Board approval was not needed for the publication of this case report.
Discussion The aim of publishing this case is to highlight the following: the occurrence of a spontaneous clinical pregnancy with fetal cardiac activity during the un-supplemented luteal phase after GnRH agonist trigger for final oocyte maturation and freezeall policy; and the absence of any signs of early and lateonset OHSS, although the patient was considered to be at high risk of OHSS development. In the present case, despite a freeze-all approach being taken, a spontaneous pregnancy occurred, most likely through spontaneous ovulation of one of the smaller follicles that had not aspirated. Although the couple was advised to refrain from sexual intercourse after oocyte retrieval, it seems that they breached this advice. Although sperm survival after intercourse may be prolonged in the cervical mucus in ovarian stimulation cycles (Milki et al., 2001; Wilcox et al., 1995), conception resulting from sexual intercourse before oocyte retrieval could not be ruled out. To our knowledge, this is the first case reporting a pregnancy after GnRH agonist triggering for final oocyte maturation and a freeze-all approach. Several cases of conception from intercourse and through embryo transfer during the same HCG triggered cycle, however, have been reported (Cahill et al., 2003; Milki et al., 2001; van der Hoorn et al., 2011). A dizygotic twin pregnancy after transfer of one embryo (van der Hoorn et al., 2011) and quadruplet pregnancy with different zygosity after transfer of two embryos have been reported (Cahill et al., 2003; Milki et al., 2001). The present case study, along with previously published cases, clearly emphasize the possibility of a spontaneous pregnancy, although rare, from intercourse in the presence of patent fallopian tube(s) during an in IVF cycle, whether fresh embryo transfer has been carried out or a freeze-all approach has been taken. The threshold for a freeze-all approach has been suggested to be more than 25 follicles wider than 11 mm in diameter on the day of follicle stimulation (Humaidan et al., 2013). This threshold, which has been empirically set, is used in our daily practice; however, in the present case, 28 mature follicles developed, and all embryos were frozen. In early studies, when a fresh embryo transfer is planned after follicle stimluation with GnRH agonist using a standard luteal phase support, disappointingly low pregnancy rates and high biochemical loss rates were reported (Fauser et al., 2002; Humaidan et al., 2005; Kolibianakis et al., 2005). A significantly shorter duration of the LH surge induced by the GnRH agonist trigger compared with the prolonged LH-like activity induced by HCG trigger (Damewood et al., 1989; Yen et al., 1968), coupled with supra-physiological sex steroid levels
Spontaneous pregnancy after freeze-all approach with no luteal phase support (mainly progesterone) resulting from ovarian stimulation (Fatemi, 2009; Fauser and Devroey, 2003; Tavaniotou and Devroey, 2006; Tavaniotou et al., 2001, 2003) contribute to the luteolysis in such cycles. Hence, either a bolus of 1500 IU HCG administered on the day of oocyte retrieval combined with a standard luteal phase support (Humaidan et al., 2010, 2013) or intensive luteal phase support, consisting of progesterone and oestradiol (Engmann et al., 2008) have been recommended as modified luteal phase support strategies to enable fresh embryo transfer, securing reproductive outcomes similar to those of HCG trigger and very low OHSS rates (Humaidan et al., 2015). In the present case, a spontaneous clinical pregnancy with fetal cardiac activity developed despite the fact that no luteal support was administered after the GnRH agonist trigger. The explanation for this remains hypothetical; however, Weissman et al. (1996) previously reported corpus luteum rescue after 7 days of gonadotrophin deprivation in a patient with hypogonadotropic hypogonadism. Therefore, the most plausible explanation for the clinical pregnancy in our case is corpus luteum rescue shortly after implantation. Another contributing factor to the pregnancy could be increased luteal LH levels and decreased sensitivity of the GnRH pulse generator to inhibit ovarian steroids, previously reported in patients with polycystic ovary syndrome (Pastor et al., 1998). Unfortunately, the luteal phase was not monitored in the present case as a freeze-all strategy was used. Interestingly, this high-risk patient with OHSS did not develop any signs of early or late-onset OHSS. This again could be attributed to the long period of low circulating LH levels, down-regulating the function of the multiple corpora lutea to a degree where only a minute fraction was rescued by the implanting embryo, avoiding the development of late-onset OHSS. Although rare, one should bear in mind that, despite a freeze-all approach after GnRH agonist triggering, severe early onset OHSS can still occur. Therefore, to our knowledge, seven such cases have been reported (Fatemi et al., 2014; Gurbuz et al., 2014; Ling et al., 2014; Santos-Ribeiro et al., 2015). In conclusion, we herein report a spontaneous pregnancy that occurred in a freeze-all cycle. To avoid uncontrolled pregnancy, multiple pregnancy and possible development of lateonset OHSS couples should be strictly advised to refrain from sexual intercourse after oocyte retrieval – even in a freezeall cycle. Although, it is a dogma that luteal phase support is mandatory in all stimulated IVF cycles when a fresh transfer is carried out, the endogenous LH during the luteal phase in a small subgroup of patients with polycystic ovary syndrome may sufficiently rescue some corpus luteum function even when GnRH agonist has been administered for final oocyte maturation.
References Cahill, D.J., Jenkins, J.M., Soothill, P.W., Whitelaw, A., Wardle, P.G., 2003. Quadruplet pregnancy following transfer of two embryos: case report. Hum. Reprod. 18, 441–443. Damewood, M.D., Shen, W., Zacur, H.A., Schlaff, W.D., Rock, J.A., Wallach, E.E., 1989. Disappearance of exogenously administered human chorionic gonadotropin. Fertil. Steril. 52, 398– 400.
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Declaration: The authors report no commercial or financial conflicts of interest.
Received 28 June 2015; refereed 16 September 2015; accepted 5 November 2015.