1 Bahceci Women Health Care Center and German Hospital in Istanbul and 2 Yeditepe University School of Medicine, Istanbul, Turkey
3 To whom correspondence should be addressed at: Azer Is Merkezi 44/17, Abdi Ipekci Cad, Nisantasi, Istanbul, 80200, Turkey. Email: mbahceci{at}superonline.com
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Key words: ICSI/infertility/miscarriage/pregnancy
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Several studies have assessed miscarriage rates in in-vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) pregnancies as well as the origin of spermatozoa utilized for assisted fertilization is considered in this regard (Coulam et al., 1996; Govaerts et al., 1998
; Orvieto et al., 2000
; Wennerholm et al., 2000
; Schieve et al., 2003
). Miscarriage rates have been also documented in groups of patients with a specific aetiology of infertility, such as polycystic ovarian syndrome (PCOS) or male factor (Mercan et al., 1998
; Wang et al., 2004
). On the other hand, it is of importance to note that miscarriage rates among patients who conceived by assisted reproduction treatment have not been segregated by multiplicity of the gestation.
At present, almost half of fresh embryo transfers result from ICSI (Human Fertilisation and Embryology Authority, 2000) and ICSI has become a routine laboratory service. However, the use of testicular sperm and the micromanipulation of gametes have raised questions about the safety of this procedure. It is therefore necessary to clarify whether ICSI should be used for all in vitro inseminations.
Since chromosomal abnormalities (mostly aneuploidy) have been reported to account for 5075% of miscarriages during the first trimester of gestation (Goddijn and Leschot, 2000; Philipp et al., 2003
), 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 tecnique. However, miscarriage rates have not been extensively assessed in a general infertile population (regardless of male factor) undergoing assisted reproduction treatment with ICSI. It is therefore important to document the survival rate of implanted gestations following ICSI and to compare these rates relative to underlying aetiology 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.
![]() |
Materials and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The remaining gestations were categorized according to the underlying aetiology 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; PCOS was diagnosed by irregular menses, reversed FSH:LH ratio and sonographic appearance of ovaries; and all endometriosis cases were stage II according to the American Fertility Society classification. Infertility was defined as unexplained if comprehensive evaluation failed to reveal any apparent cause.
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 hypo-echoic 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 (Aplio 80, Powervision and Corevision; Toshiba Corp., Japan).
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 10 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 3 weeks (1822 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 i.m., as luteal phase support for 8 weeks after embryo transfer. In our centre, the method for assisted fertilization was ICSI, which was used in all patients regardless of their aetiology of infertility.
All couples were thoroughly informed about the treatment procedures, and written informed consent was obtained from all patients. The treatment protocols were approved by the ethics committee of the German Hospital at Istanbul.
Statistical analyses were performed using the 2-test, Fisher's exact test, analysis of variance with Bonferroni's post hoc test, and multivariate logistic regression analysis, where applicable. P < 0.05 was considered statistically significant.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
During the first trimester, 234 (18.8%) patients experienced pregnancy loss. Miscarriage rate was significantly higher in women aged >40 years than in younger women (42.1 versus 17.6%; OR, 3.1; 95% CI, 2.05.7; P<0.0001).
Multivariate logistic regression analysis demonstrated that miscarriage rates in singleton gestations did not differ according to underlying infertility factor (P>0.05) (Table I). However, when the infertility categories were divided according to age (<35 versus 35 years), older patients with male factor, unexplained factor and tubal factor had significantly increased rates of miscarriage compared with younger patients. In contrast, the survival rates of gestations among the remaining infertility categories were not affected by age (Table II).
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
We 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 (Jozwiak et al., 2004). Furthermore, IVF and ICSI pregnancies that aborted during the first trimester showed no significant differences in the incidence of embryonic anomalies (Causio et al., 2002
).
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, with the latter category consisting of infertility aetiologies depending on women as a single group. Male factor infertility was further subdivided into groups in which ejaculated sperm and non-ejaculated sperm were used.
The impact of sperm origin and quality on miscarriage rates was assessed among ICSI pregnancies and compared to those of IVF pregnancies. No differences in miscarriage rates have been reported in patients undergoing ICSI for male factor or IVF for non-male factor (Mercan et al., 1998), and semen origin was found not to affect the miscarriage rate in both sets of patients (Palermo et al., 2000
). We also found that sperm origin did not have any impact on the early survival rate of gestations. In contrast to our findings, the miscarriage rate has been reported to be higher in gestations using surgically retrieved sperm than in those using ejaculated sperm (Anderson et al., 2002
), although others have reported similar results for both groups (Wennerholm et al., 2000
; Goker et al., 2002
).
To our knowledge, our study is the first in which miscarriage rates in a relatively large number of singleton ICSI pregnancies have been segregated according to male and non-male factor infertility. Our results confirm that first trimester survival rates of singleton gestations did not differ when patients with non-male factor infertility underwent ICSI. We also found that the survival rates of gestations achieved by ICSI among non-male factor patients did not differ from those of IVF pregnancies (Winter et al., 2002).
Miscarriage rates among individuals with different causes of infertility have not been assessed thoroughly. Miscarriage rates in a subgroup of patients with infertility factor have been and are being reported in most studies addressing assisted reproduction technology as a part of the outcome. Although individuals with PCOS are prone to have miscarriages (Reindollar, 2000), recent studies have demonstrated that this adverse effect is related not only to the condition itself but to coexisting obesity (Wang et al., 2004
). While we found that the miscarriage rate was highest among PCOS pregnancies, it did not differ significantly from that of the other groups, primarily because of the relatively small size of our PCOS group. We also confirmed that miscarriage rate was not higher in patients with endometriosis than in the general infertile population (Matorras et al., 1998
; Kortelahti et al., 2003
). Similarly, we found that the miscarriage rate in ICSI patients with unexplained infertility did not differ from that in the general infertile population, a result previously observed in patients with unexplained infertility undergoing IVF (Isaksson et al., 2002
).
In agreement with previous studies, we observed an increased risk of miscarriage with increasing maternal age (Fretts et al., 1995; Abdalla et al., 1993
; Andersen et al., 2000
). Indeed, we found that almost half of women aged >40 years aborted prior to the second trimester. Similarly, a 50% miscarriage rate has been reported in women aged >40 years undergoing ICSI (Nikolettos et al., 2000
), and the delivery rate is only 12% in this group of women (Osmanagaoglu et al., 2002
). Therefore, prior to assisted reproduction treatment, the likely pregnancy outcome of these individuals should be considered, and couples should be informed accordingly.
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. We recently demonstrated vanishing embryos in multiple gestations by using the presence of a gestational sac as a landmark (Ulug et al., 2004), 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 (Ulug et al., 2004). In addition, the survival rates of singleton gestations differ from those of multiple gestations during the first trimester (Sebire et al., 1997; Tummers et al., 2003
).
In 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. Our results also demonstrated that ICSI did not pose additional risk for miscarriage when utilized as a regular assisted fertilization method for infertile couples undergoing assisted reproduction treatment.
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Andersen N, Wohlfahrt J, Christens P, Olsen J and Melbye M (2000) Maternal age and fetal loss: population based register linkage study. Br Med J 320, 17081712.
Anderson AR, Wiemer KE, Weikert ML and Kyslinger ML (2002) Fertilization, embryonic development and pregnancy losses with intracytoplasmic sperm injection for surgically-retrieved spermatozoa. Reprod Biomed Online 5, 142147.[Medline]
ASRM/SART Registry (2002) Assisted Reproductive Technology in the United States: 1999. Fertil Steril 78, 918931.[CrossRef][ISI][Medline]
Bonduelle M, Van Assche E, Joris H, Keymolen K, Devroey P, Van Steirteghem A and Liebaers I (2002) Prenatal testing in ICSI pregnancies: incidence of chromosomal anomalies in 1586 karyotypes and relation to sperm parameters. Hum Reprod 17, 26002614.
Causio F, Fischetto R, Sarcina E, Geusa S and Tartagni M (2002) Chromosome analysis of spontaneous abortions after in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Eur J Obstet Gynecol Reprod Biol 105, 4448.[CrossRef][ISI][Medline]
Coulam CB, Opsahl MS, Sherins RJ, Thorsell LP, Dorfmann A, Krysa L, Fugger E and Schulman JD (1996) Comparisons of pregnancy loss patterns after intracytoplasmic sperm injection and other assisted reproductive technologies. Fertil Steril 65, 11571162.[ISI][Medline]
Ezra Y and Schenker JG (1995) Abortion rate in assisted reproductiontrue increase? Early Pregnancy 1, 171175.[Medline]
Fretts RC, Schmittdiel JMA, McLean FH, Usher RH and Goldman MB (1995) Increased maternal age and the risk of fetal death. New Engl J Med 333, 953957.
Goddijn M and Leschot NJ (2000) Genetic aspects of miscarriage. Baillières Best Pract Res Clin Obstet Gynaecol 14, 855865.[CrossRef][ISI][Medline]
Goker EN, Sendag F, Levi R, Sendag H and Tavmergen E (2002) Comparison of the ICSI outcome of ejaculated sperm with normal, abnormal parameters and testicular sperm. Eur J Obstet Gynecol Reprod Biol 104, 129136.[CrossRef][ISI][Medline]
Govaerts I, Devreker F, Koenig I, Place I, Van den Bergh M and Englert Y (1998) Comparison of pregnancy outcome after intracytoplasmic sperm injection and in-vitro fertilization. Hum Reprod 13, 15141518.[Abstract]
Human Fertilisation and Embryology Authority (2000) For Patients; Information and Guide. URL: http://wwwhfeagovuk.
Jozwiak EA, Ulug U, Mesut A, Erden HF and Bahceci M (2004) Prenatal karyotypes of fetuses conceived by intracytoplasmic sperm injection. Fertil Steril 82, 628633.[CrossRef][ISI][Medline]
Kortelahti M, Anttila MA, Hippelainen MI and Heinonen ST (2003) Obstetric outcome in women with endometriosisa matched casecontrol study. Gynecol Obstet Invest 56, 207212.[CrossRef][ISI][Medline]
Kozinszky Z, Zadori J, Orvos H, Katona M, Pal A and Kovacs L (2003) Obstetric and neonatal risk of pregnancies after assisted reproductive technology: a matched control study. Acta Obstet Gynecol Scand 82, 850856.[CrossRef][ISI][Medline]
Isaksson R, Gissler M and Tiitinen A (2002) Obstetric outcome among women with unexplained infertility after IVF: a matched casecontrol study. Hum Reprod 17, 17551761.
Macklon NS, Geraedts JP and Fauser BC (2002) Conception to ongoing pregnancy: the black box of early pregnancy loss. Hum Reprod Update 8, 333343.
Matorras R, Rodriguez F, Gutierrez de Teran G, Pijoan JI, Ramon O and Rodriguez-Escudero FJ (1998) Endometriosis and spontaneous abortion rate: a cohort study in infertile women. Eur J Obstet Gynecol Reprod Biol 77, 101105.[CrossRef][ISI][Medline]
Mercan R, Lanzendorf SE, Mayer J Jr, Nassar A, Muasher SJ and Oehninger S (1998) The outcome of clinical pregnancies following intracytoplasmic sperm injection is not affected by semen quality. Andrologia 30, 9195.
Nikolettos N, Kupker W, Al-Hasani S, Demirel LC, Schopper B, Sturm R and Diedrich K (2000) ICSI outcome in patients of 40 years age and over: a retrospective analysis. Eur J Obstet Gynecol Reprod Biol 91, 177182.[CrossRef][ISI][Medline]
Osmanagaoglu K, Tournaye H, Kolibianakis E, Camus M, Van Steirteghem A and Devroey P (2002) Cumulative delivery rates after ICSI in women aged >37 years. Hum Reprod 17, 940944.
Orvieto R, Ben-Rafael Z, Ashkenazi J, Yoeli R, Messing B, Perri T, Shalev Y and Bar-Hava I (2000) Outcome of pregnancies derived from assisted reproductive technologies: IVF versus ICSI. J Assist Reprod Genet 17, 385387.[CrossRef][ISI][Medline]
Palermo GD, Neri QV, Hariprashad JJ, Davis OK, Veeck LL and Rosenwaks Z (2000) ICSI and its outcome. Semin Reprod Med 18, 161169.[CrossRef][ISI][Medline]
Philipp T, Philipp K, Reiner A, Beer F and Kalousek DK (2003) Embryoscopic and cytogenetic analysis of 233 missed abortions: factors involved in the pathogenesis of developmental defects of early failed pregnancies. Hum Reprod 18, 17241732.
Reindollar RH (2000) Contemporary issues for spontaneous abortion. Does recurrent abortion exist? Obstet Gynecol Clin North Am 27, 541554.[ISI][Medline]
Revised Classification of Endometriosis. American Society for Reproductive Medicine (1997) Fertil Steril 67, 817821.
Schieve LA, Tatham L, Peterson HB, Toner J and Jeng G (2003) Spontaneous abortion among pregnancies conceived using assisted reproductive technology in the United States. Obstet Gynecol 101, 959967.
Sebire NJ, Thornton S, Hughes K, Snijders RJ, Nicolaides KH (1997) The prevalence and consequences of missed obortion in twin pregnancies at 10 to 14 weeks of gestation. B J Obstet Gynaecol 104, 847848.
Tummers P, De Sutter P and Dhont M (2003) Risk of spontaneous abortion in singleton and twin pregnancies after IVF/ICSI. Hum Reprod 18, 17201723.
Ulug U, Jozwiak EA, Mesut A, Berksoy MM and Bahceci M (2004) Survival rates during the first trimester of multiple gestations achieved by ICSI: a report of 1448 consecutive multiples. Hum Reprod 19, 360364.
van Rumste MM, Evers JL and Farquhar CM (2004) ICSI versus conventional techniques for oocyte insemination during IVF in patients with non-male factor subfertility: a Cochrane review. Hum Reprod 19, 223227.
Wang JX, Norman RJ and Wilcox AJ (2004) Incidence of spontaneous abortion among pregnancies produced by assisted reproductive technology. Hum Reprod 19, 272277.
Wennerholm UB, Bergh C, Hamberger L, Westlander G, Wikland M and Wood M (2000) Obstetric outcome of pregnancies following ICSI, classified according to sperm origin and quality. Hum Reprod 15, 11891194.
World Health Organisation Laboratory Manual for the Examination of Human Semen and sperm-cervical mucus interaction. 4th edn, Cambridge University, 1999.
Winter E, Wang J, Davies MJ and Norman R (2002) Early pregnancy loss following assisted reproductive technology treatment. Hum Reprod 17, 32203223.
Wisanto A, Magnus M, Bonduelle M, Liu J, Camus M, Tournaye H, Liebaers I, Van Steirteghem AC and Devroey P (1995) Obstetric outcome of 424 pregnancies after intracytoplasmic sperm injection. Hum Reprod 10, 27132718.[Abstract]
Tarlatzis BC and Bili H (2000) Intracytoplasmic sperm injection. Survey of world results. Ann NY Acad Sci 900, 336344.
Submitted on October 13, 2004; resubmitted on November 1, 2004; accepted on November 22, 2004.
|