ICSI and Miscarriage - A Review

Transcription

1 Incidence of First Trimester Miscarriage among Women Undergoing ICSI According to Origin of Sperm for Male Factor and Non-male Factor ALKA GAHLOT*, ML SWARANKAR, RAVIKANT SONI ABSTRACT Prior to the development of intracytoplasmic sperm injection (ICSI), azoospermic and severely oligospermic men had little to no chance of having a biological child. In this study, ICSI outcome in 212 transfers with ejaculated spermatozoa and 44 transfers with surgically retrieved spermatozoa were evaluated. Material and methods: The 68 singleton gestations achieved by ICSI were segregated according to underlying infertility etiology, with 54.41% having male factor and 45.59% having female factor. None of the patients had coexisting infertility factor. Results: The miscarriage rate of all ICSI singleton gestations during the first trimester was 19.12%. There were no significant differences in early pregnancy loss (EPL) rate by infertility factor. Among patients undergoing ICSI because of male factor, there were no significant differences in EPL using ejaculated or nonejaculated sperm. Regardless of etiology, women aged 35 years had significantly higher EPL (36.36%). Conclusion: Our preliminary results demonstrate that first trimester miscarriage rates of ICSI gestations are not affected by underlying infertility etiology but are affected by maternal age. Keywords: Intracytoplasmic sperm injection, infertility, miscarriage, pregnancy Intracytoplasmic sperm injection (ICSI) has gained an increasing popularity due to its consistent fertilization rate and high pregnancy outcome. ICSI has been used largely to treat male factor infertility, with fertilization and pregnancy rates being comparable to those obtained in couples with good semen parameters undergoing standard in vitro insemination. The evident ability of ICSI to achieve high fertilization and pregnancy rates regardless of ejaculated semen parameters has extended its application to azoospermic patients. Injected epididymal and testicular spermatozoa have been used to effect fertilization and pregnancies. Original concerns about ICSI relating to its aggressiveness and arbitrary sperm selection have been eased by reports on the outcome and follow-up of the ICSI newborns. The presence of a significant frequency *Associate Professor Professor Dept. of Obstetrics and Gynecology Senior Demonstrator Dept. of Biochemistry Mahatma Gandhi University of Medical Sciences and Technology, Jaipur, Rajasthan Address for correspondence Dr Alka Gahlot 170, Heera Nagar, DCM, Ajmer Road, Jaipur, Rajasthan dralkagahlot@gmail.com, alkagahlot23@gmail.com of Y chromosome microdeletions and karyotypic anomalies in men with nonobstructive azoospermia has raised concerns about the risks of treatment for these men. The etiology of azoospermia can be divided into obstructive and nonobstructive categories. The former is characterized by normal sperm production and is often caused by congenital mal-development of the vas deferens, a condition known to be associated with cystic fibrosis gene mutations. The treatment for obstructive azoospermia is microsurgical epididymal sperm aspiration (MESA), and when epididymal access is lacking testicular sampling is appropriate. Nonobstructive azoospermia is characterized by a varying degree of spermatogenic failure and at times is associated with an increased number of chromosomal abnormalities. The only method to retrieve spermatozoa from this form of azoospermia is by direct extraction of spermatozoa or germ cells from the testis. Women who are candidates for assisted reproduction technology have characteristics that may predispose them to an increased risk of miscarriage. 1 Several studies have assessed miscarriage rates in in vitro fertilization (IVF) and ICSI pregnancies as well as the origin of spermatozoa utilized for assisted fertilization is considered in this regard. 2 At present, almost half of fresh embryo transfers result from ICSI 3 and Indian Journal of Clinical Practice, Vol. 25, No. 5, October

2 ICSI has become a routine laboratory service. Since, chromosomal abnormalities (mostly aneuploidy) have been reported to account for 50-75% of miscarriages during the first trimester of gestation, 4 one measurable outcome to evaluate the safety of ICSI can be the rate of miscarriage among ICSI pregnancies. Conceivably, an increased rate of pregnancy loss may indicate an abnormal outcome related to ICSI as a technique. It is therefore important to document the survival rate of implanted gestations following ICSI and to compare these rates relative to underlying etiology of infertility. In this study, we report the first trimester survival rates of singleton gestations achieved by ICSI from patients with different types of infertility. MATERIAL AND METHODS The study was conducted prospectively from January 2012 to December 2012 at Jaipur Fertility Center, ART Division of Mahatma Gandhi University of Medical Sciences and Technology, Jaipur. Among the 256 patients who underwent ICSI, 68 (26.56%) were diagnosed as singleton gestations following embryo transfer. We excluded from this study all patients who had multiple gestation, monochorionic or heterotopic pregnancies or Frozen-Thawed embryo transfer. Couples having coexisting infertility factors or women with a history of recurrent pregnancy loss were also excluded from the study, as were couples known to have structural or numerical chromosomal aberrations. The remaining gestations were categorized according to the underlying etiology of infertility. Male factor cases were diagnosed according to the standards of the World Health Organization; tubal factor cases were diagnosed by either hysterosalpingogram or laparoscopy; polycystic ovarian syndrome (PCOS) was diagnosed by irregular menses, reversed folliclestimulating hormone (FSH): Luteinizing hormone (LH) ratio and sonographic appearance of ovaries; and all endometriosis cases were II according to the American Fertility Society classification. Pregnancy was diagnosed as the presence of an intrauterine implanted embryo, defined as a gestational sac as determined by transvaginal ultrasonogram following ICSI and embryo transfer. A gestational sac was defined by the presence of an intrauterine hypoechoic area of 8 mm and covered by a double echogenic rim with a visible yolk sac (diameter 2 mm), as identified by a 6 MHz vaginal probe (Toshiba color Doppler N-10-30). A miscarriage was defined as the cessation or lack of detection of cardiac activity in the gestational sac or the inability to detect a previously defined gestational sac after vaginal bleeding during the 12 weeks following embryo transfer. Gestations with trophoblast regression but without sonographic evidence of pregnancy were not considered as miscarriages. All patients underwent scanning by transvaginal ultrasonogram 4 weeks (28-30 days) after embryo transfer. None of the gestations evaluated started as a multiple type followed by subsequent vanishing of embryos. All patients continued to receive progesterone, 100 mg IM once or 200 mg vaginally 8-hourly daily as luteal phase support for 12 weeks after embryo transfer. All couples were thoroughly informed about the treatment procedures, and written informed consent was obtained from all patients. Statistical analyses were performed using the χ 2 test, p < 0.05 was considered statistically significant. RESULTS When we diagnosed infertility factors among the recruited couples with positive pregnancy, we found that 37 (54.41%) were due to male factor and 31 (45.59%) were due to female factors including tubal factor, endometriosis, PCOS, other factors such as hyperprolactinemia, hypogonadotropic, hypogonadism, myoma uteri, uterine dysconfiguration, genital tuberculosis or secondary infertility. The mean age of the women was years, and the mean age of their spouses was years. The miscarriage rates in singleton gestations did not significantly differ according to underlying infertility factor, 21.62% versus 16.13% in male and female infertility, respectively (p > 0.05). During the first trimester overall 13 (19.12%) patients experienced pregnancy loss (Table 1). Miscarriage rate was significantly higher in women aged 35 years than in younger women (36.36% versus 10.86%, p < 0.05). However, when the infertility categories were divided according to age (<35 vs 35 years), older patient with male factor, had increased rates of miscarriage compared with younger patients, which is not statistically significant (Table 2). Among patients with male factor infertility, there was no significant difference in miscarriage rates when surgically retrieved sperm 25% or ejaculated sperm 20% were used for ICSI. Miscarriage rates also did not differ significantly in patients undergoing assisted reproduction treatment with ICSI because of female factor 16.13% (p > 0.05) (Table 3). Table 1. Miscarriage Rates of Gestations by Infertility Factor No. of pregnancies (%) No. of miscarriage (%) Male factor 37/68 = /37 = Female factor 31/68 = /31 = Total 68 13/68 = Indian Journal of Clinical Practice, Vol. 25, No. 5, October 2014

3 Table 2. Outcome of Gestations by Infertility Factor and Maternal Age <35 years 35 years P value No. of pregnancy (%) No. of miscarriage (%) No. of pregnancy (%) No. of miscarriage (%) Male factor 25/46 = /25 = 12 12/22 = /12 = NS Female factor 21/46 = /21 = /22 = /10 = NS Total 46 5/46 = /22 = S Table 3. Miscarriage Rates among Women Undergoing ICSI According to Origin of Sperm for Male Factor and Non-male Factor No. of pregnancy No. of miscarriage (%) Surgically retrieved spermatozoa 12 3/12 = 25 Ejaculated spermatozoa (male factor) 25 5/25 = 20 Ejaculated spermatozoa (non-male factor) 31 5/31 = Total 68 13/68 = DISCUSSION Human reproduction is not efficient; with the majority of conceptions being lost very early in gestational life. 5 Implanted embryos may undergo developmental arrest at any point during early gestational life. Pregnancies achieved by the use of assisted reproduction technologies; however, are easier to follow than those conceived spontaneously, offering the opportunity to observe early gestational life ultrasonographically. Miscarriage significantly reduces the initial success and efficacy of assisted reproduction treatment, as well as increasing the psychological burden on patients. Couples who are planning assisted reproduction pregnancies should be informed of the potential hazards of these methods, enabling them to be aware of any potential risk factors that may cause miscarriage. Several studies have reported miscarriage rates in ICSI pregnancies, and have compared rates in IVF and spontaneous pregnancies. Whereas most have found no significant differences in early miscarriage rates, one study found that the early pregnancy loss rate was significantly lower in ICSI (11%) than in IVF (24%) pregnancies. 6 Although, there are no randomized data on miscarriage rates following ICSI and IVF, 7 early pregnancy and perinatal outcomes of ICSI gestations appear not to be different from those of IVF gestations. 8 In addition, no clinical effects of ICSI severe enough to cause a miscarriage during the first trimester have been reported. 9 It has been suggested that offspring from ICSI carry an increased rate of chromosomal aberrations. 10 Those abnormalities; however, seem to be related to the underlying parental risk of abnormality and not to the ICSI procedure itself. Although patients undergoing assisted reproduction treatment have a higher rate of miscarriage than do fertile patients, these differences in loss rates are not completely understood and may originate from predisposing factors that are more prevalent in patients suffering from infertility. 1 Some studies recently reported that prenatal karyotypes of fetuses in pregnancies achieved by ICSI for male factor infertility did not differ from fetal karyotypes in pregnancies achieved by ICSI for non-male factor infertility. 11 Furthermore, IVF and ICSI pregnancies that aborted during the first trimester showed no significant differences in the incidence of embryonic anomalies. 12 In the majority of reports, ICSI procedures have been performed in cases of male factor infertility, which may eventually pose a risk to the offspring. Therefore, we studied segregated gestations according to male and female factor infertility. Male factor infertility was further subdivided into groups in which ejaculated sperm and nonejaculated sperm were used. The impact of sperm origin and quality on miscarriage rates was assessed among ICSI pregnancies. No differences in miscarriage rates have been reported in patients undergoing ICSI for male factor or IVF for non-male factor, and semen origin was found not to affect the miscarriage rate in both sets of patients. 13 In support to our findings, the miscarriage rate has been reported to be higher in gestations using surgically retrieved sperm than in those using ejaculated sperm, 14 although others have reported similar results for both groups. 15 Our results confirm that first trimester survival rates of singleton gestations did not differ when patients with non-male factor infertility underwent ICSI. In agreement with previous studies, we observed an Indian Journal of Clinical Practice, Vol. 25, No. 5, October

4 increased risk of miscarriage with increasing maternal age. 16 The current study differs in two ways from similar studies evaluating miscarriage rates in ICSI pregnancies. The earlier studies used the demonstration of a fetal heartbeat to define pregnancy. This method; however, may miss a significant number of implanted embryos following transfer, which would have been detected by the presence of a gestational sac, even in the absence of cardiac motion. In other words, this method may underestimate the lifespan of earliest stage implanted embryos, which would have been detected by ultrasonographic visualization. A study recently demonstrated vanishing embryos in multiple gestations by using the presence of a gestational sac as a landmark 17 indicating that this approach would better evaluate the intrauterine fate of implanted ICSI embryos. In contrast to most other studies evaluating miscarriage rates in ICSI pregnancies, we evaluated miscarriage rates only in singleton gestations. Most of the earlier studies assessing early pregnancy loss in ICSI pregnancies did not account for multiple fetuses and defined abortion as the total miscarriage of the pregnancy. During early gestational life, a significant number of multiple gestations can have spontaneous reductions, which should be considered in calculations of abortion rates. 17 In addition, the survival rates of singleton gestations differ from those of multiple gestations during the first trimester. 18 Data support the idea that performing ICSI in all cases of assisted reproduction is not advantageous, and probably it is only more expensive and time consuming. 19 CONCLUSION We have shown that first trimester miscarriage rates in singleton gestations achieved by ICSI were not affected by the underlying infertility factor, but were affected by maternal age. REFERENCES 1. Ezra Y, Schenker JG. Abortion rate in assisted reproductiontrue increase? Early Pregnancy 1995;1(3): Schieve LA, Tatham L, Peterson HB, Toner J, Jeng G. Spontaneous abortion among pregnancies conceived using assisted reproductive technology in the United States. Obstet Gynecol 2003;101(5 Pt 1): Human Fertilisation and Embryology Authority. For Patients; Information and Guide. URL: wwwhfeagovuk Philipp T, Philipp K, Reiner A, Beer F, Kalousek DK. Embryoscopic and cytogenetic analysis of 233 missed abortions: factors involved in the pathogenesis of developmental defects of early failed pregnancies. Hum Reprod 2003;18(8): Macklon NS, Geraedts JP, Fauser BC. Conception to ongoing pregnancy: the black box of early pregnancy loss. Hum Reprod Update 2002;8(4): Orvieto R, Ben-Rafael Z, Ashkenazi J, Yoeli R, Messing B, Perri T, et al. Outcome of pregnancies derived from assisted reproductive technologies: IVF versus ICSI. J Assist Reprod Genet 2000;17(7): van Rumste MM, Evers JL, Farquhar CM. ICSI versus conventional techniques for oocyte insemination during IVF in patients with non-male factor subfertility: a Cochrane review. Hum Reprod 2004;19(2): Kozinszky Z, Zádori J, Orvos H, Katona M, Pál A, Kovács L. Obstetric and neonatal risk of pregnancies after assisted reproductive technology: a matched control study. Acta Obstet Gynecol Scand 2003;82(9): American Society for Reproductive Medicine; Society for Assisted Reproductive Technology Registry. Assisted reproductive technology in the United States: 1999 results generated from the American Society for Reproductive Medicine/Society for Assisted Reproductive Technology Registry. Fertil Steril 2002;78(5): Bonduelle M, Van Assche E, Joris H, et al. Prenatal testing in ICSI pregnancies: incidence of chromosomal anomalies in 1586 karyotypes and relation to sperm parameters. Hum Reprod 2002;17(10): Jozwiak EA, Ulug U, Mesut A, Erden HF, Bahçeci M. Prenatal karyotypes of fetuses conceived by intracytoplasmic sperm injection. Fertil Steril 2004;82(3): Causio F, Fischetto R, Sarcina E, Geusa S, Tartagni M. Chromosome analysis of spontaneous abortions after in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Eur J Obstet Gynecol Reprod Biol 2002;105(1): Palermo GD, Neri QV, Hariprashad JJ, et al. ICSI and its outcome. Semin Reprod Med 2000;18(2): Anderson AR, Wiemer KE, Weikert ML, Kyslinger ML. Fertilization, embryonic development and pregnancy losses with intracytoplasmic sperm injection for surgically-retrieved spermatozoa. Reprod Biomed Online 2002;5(2): Göker EN, Sendag F, Levi R, Sendag H, Tavmergen E. Comparison of the ICSI outcome of ejaculated sperm with normal, abnormal parameters and testicular sperm. Eur J Obstet Gynecol Reprod Biol 2002;104(2): Nybo Andersen AM, Wohlfahrt J, Christens P, Olsen J, Melbye M. Maternal age and fetal loss: population based register linkage study. BMJ 2000;320(7251): Ulug U, Jozwiak EA, Mesut A, et al. Survival rates during the first trimester of multiple gestations achieved by ICSI: a report of 1448 consecutive multiples. Hum Reprod. 2004;19(2): Tummers P, De Sutter P, Dhont M. Risk of spontaneous abortion in singleton and twin pregnancies after IVF/ICSI. Hum Reprod 2003;18(8): Borini A, Gambardella A, Bonu MA, et al. Comparison of IVF and ICSI when only few oocytes are available for insemination. Reprod Biomed Online 2009;19(2): Indian Journal of Clinical Practice, Vol. 25, No. 5, October 2014

5 Diabetes Patients have a significant risk of developing Severe Constipation Occupied ~,', Each 61 conta1n's 9m (2 /eve/ s lsap Poon ti 901 H 11/)!JSk Haritak; s 4g varnapatr; r::.~ soo rng '-Jt.Cfact rng Get, Set and GO LAXative., DIABETIX ADMslonof FRANCO INDIAN PHARllACl:UTICAU PVT. Ln>.