Human Reproduction, Vol. 19, No. 2, 360-364,
February 2004
© 2004 European Society of Human Reproduction and Embryology
Survival rates during the first trimester of multiple gestations achieved by ICSI: a report of 1448 consecutive multiples
1 Bahceci Women Health Care Center and German Hospital at Istanbul and 2 Yeditepe University School of Medicine, Istanbul, Turkey
3 To whom correspondence should be addressed at: Azer Is Merkezi 44/17 Kat 6, Abdi Ipekci Cad, Nisantasi, 80200 Istanbul, Turkey. e-mail: mbahceci{at}superonline.com
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Abstract |
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BACKGROUND: The purpose of this study was to determine the rate of spontaneous gestational sac loss during the first trimester in women achieving multiple pregnancies by ICSI. METHODS: A retrospective analysis was performed of 1448 consecutive multiple pregnancies conceived by ICSI. RESULTS: Of the cohort of 1448 pregnancies, twin gestations constituted 59.6% (864), triplets 30.2% (438) and quadruplets 10.0% (146). During the first trimester, 69 (4.7%) patients miscarried, while 179 (12.3%) continued their pregnancies and had fewer gestational sacs at the end of the first trimester than at the beginning. The overall loss rate of any gestational sac during the first trimester in these multiple pregnancies was 10.1%. There was a significant difference in the frequency of spontaneous reduction to twin or singleton pregnancies in the first trimester between women carrying triplets (11.7%) and those carrying quadruplets (3.5%) [P = 0.004; odds ratio (OR) 3.5; 95% confidence interval (CI) 1.3–9.1]. The frequency of gestational sac loss was significantly greater among women >35 years old (20.9%) than in women less than 35 years old (15.9%) (P = 0.03; OR 1.4; 95% CI 1.0–1.9). CONCLUSION: In multiple pregnancies there is a significant risk of spontaneous loss of any embryo during the first trimester. These findings should be considered prior to any decision about selective embryo reduction.
Key words: ART/gestational sac/ICSI/multiple pregnancy/spontaneous reduction
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Introduction |
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IVF and embryo transfer programs are associated with an increased risk of multiple pregnancy and relatively high rates of early pregnancy wastage (Ben-Rafael et al., 1988
; American Fertility Society, 1990). Moreover, these patients are more frequently followed in assisted reproduction treatment (ART) programs than are those who conceive spontaneously, offering a unique opportunity to observe early gestational life ultrasonographically.
Human reproduction is not efficient, and most conceptions are lost very early in gestational life. In this regard, subclinical pregnancy loss can also be higher than expected. The arrest of development and subsequent resorption of an embryo may occur at any point in early gestational life, and with the advent of transvaginal ultrasound it has been observed that vanishing of the embryo is not an infrequent event (Landy et al., 1986). The inverse correlation between the number of gestations and perinatal outcome has been well documented, and elective multifetal pregnancy reduction (MFPR) has been undertaken in order to reduce the risks in high-order pregnancies (Boulot et al., 2000; Yaron et al., 2001). An elapsed period of time following the diagnosis of high-order pregnancy, however, is needed to perform embryo reduction safely (Lipitz et al., 2001). Therefore, the determination of survival rates of multiple gestations during early gestational life is important for health-care providers in order to properly inform their patients. Thus, this data can serve as a basis to delay making a decision regarding MFPR.
There is a scarcity of information about the outcome of multiple pregnancies that spontaneously reduce during the first trimester. Most data available have been derived from multiple gestations with small numbers, primarily from twins conceived spontaneously or by ART (Landy et al., 1986; Manzur et al., 1995; Rodriguez-Gonzales et al., 2002). In this regard, a large cohort of multiple gestations that were followed up by a single centre may more accurately document the fate of implanted embryos in early gestational life. We therefore evaluated spontaneous embryo reductions among multiple gestations following ICSI and embryo transfer during the first 12 weeks of gestation.
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Materials and methods |
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The records of patients who conceived by ICSI at the German Hospital at Istanbul between 1997 and 2002 were retrospectively evaluated. Records of pregnancies demonstrating multiple gestational sacs at their first ultrasound examination after embryo transfer were retrieved and segregated according to the initial number of gestational sacs. The number of surviving embryos by the end of the first trimester, as detected by demonstration of heartbeats on ultrasonogram 70–77 days after embryo transfer, was recorded. All patients underwent scanning by transvaginal ultrasound 3 weeks (18–22 days) after embryo transfer. Patients who subsequently were followed up outside the hospital, had monochorionic pregnancies or who had frozen embryo transfer were excluded from the study. Quintuplets (three cases) were also excluded. Elective embryo reduction procedure was not performed on any of these pregnancies during the assessment period.
An intrauterine implanted embryo, defined as a gestational sac as determined by transvaginal ultrasonogram following ICSI and embryo transfer, was considered as a pregnancy. An intrauterine hypoechoeic area of at least 8 mm covered by a double echogenic rim with yolk sac (diameter 
2 mm), which was identified by a 6 MHz vaginal probe (Aplio 80; Powervision and Corevision, Toshiba Corporation, Japan), was considered a gestational sac (Rowling et al., 1999). A multiple gestation was defined as a pregnancy having more than one gestational sac. Resorption of a gestational sac and cessation or lack of detection of cardiac activity in a gestational sac during the 10 weeks following embryo transfer were regarded as gestational sac loss, and were indicative of spontaneous embryo reduction in a multiple pregnancy.
During the assisted conception treatment program, embryo transfers were performed between 14 and 19 days after the beginning of the last menstrual period and 3 days following oocyte retrieval. All patients continued to receive progesterone, 100 mg i.m., as luteal phase support for 8 weeks after embryo transfer. The method for assisted fertilization was ICSI in our centre, which has been universally used in all patients regardless of infertility aetiology. All procedures were approved by the Institutional Review Board of the German Hospital at Istanbul.
Statistical analyses were carried out by using the 
2-test, Fisher’s exact test and analysis of variance with Bonferroni’s post hoc test where applicable. A P-value <0.05 was considered statistically significant.
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Results |
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The characteristics of our ART program during the 7-year period are depicted in Table I. Among the multiple gestations conceived by ICSI during the assessed period, 1448 (68.5%) met our inclusion criteria and were enrolled in this study. The mean maternal age of patients with multiple gestations was 30.09 ± 4.4 years. Of the multiple gestations, twins constituted 59.6% (864), triplets 30.2% (438) and quadruplets 10.0% (146) of the cohort. During the first trimester, 69 (4.7%) patients miscarried. With respect to miscarriage rate, there was no statistical difference between women <35 years old (4.7%) and women >35 years old [4.9%; odds ratio (OR) 0.9; 95% confidence interval (CI) 0.5–1.6].
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The outcome of multiple gestations according to the initial gestational sac count at the end of first trimester following embryo transfer is depicted in Table II. There was no statistical correlation between maternal age distribution and initial gestational sac number. Of the patients who continued their pregnancies, 179 (12.3%) had fewer gestational sacs by the end of the first trimester than initially detected. During the first trimester, 10.1% (366/3626) of the gestational sacs initially present in multiple pregnancies were lost. Of patients having two initial gestational sacs, at least one was lost by the 12th week of gestational age in 158 (18.2%). Of patients with three initial gestational sacs, at least one was lost at 12 weeks in 69 (15.7%); and of patients having four initial gestational sacs, at least one was lost at 12 weeks in 21 (14.3%). The mean maternal age of patients experiencing reduction of gestational number did not differ when they were grouped according to the initial sac count (31.0 ± 5.1 years for two sacs; 29.7 ± 4.4 years for three sacs; and 31.0 ± 3.5 years for four sacs).
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When the possibility of a multiple pregnancy losing any gestational sac in the first trimester was calculated according to the number of gestational sacs, no significant difference was found between multiple pregnancy groups. We found, however, that the frequency of spontaneous reduction to twin or singleton pregnancy in the first trimester was significantly higher for those women initially having three sacs (11.7%) than for those having four (3.5%) (P = 0.004; OR 3.5; 95% CI 1.3–9.1).
Table III shows the outcome of multiple pregnancy groups according to maternal age. While only 15.9% of women <35 years old experienced loss of any gestational sac, this rate rose to 20.9% among women >35 years old (P = 0.03; OR 1.4; 95% CI 1.0–1.9). Older women initially carrying twins had an increased frequency of spontaneously reducing to singleton pregnancies than younger women (P = 0.003; OR 1.5; 95% CI 1–2.1). In women initially carrying triplets and quadruplets, however, there was no significant difference in frequency of gestational sac loss between younger and older women. The percentage of multiple pregnancies retaining the same number of gestational sacs at the end of the first trimester as a function of maternal age is shown in Figure 1.
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Discussion |
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The spontaneous loss of twin conceptii in very early pregnancy can be high, and it has been assumed that for every live-born twin pair, 10–12 initial twin pregnancies end up as singletons (Boklage, 1995
). In this regard, post-partum evaluation of placentas from multiple pregnancies has also revealed morphological evidence of vanished embryos (Jauniaux et al., 1988). Furthermore, the vanishing of an embryo has been suggested as explaining the discordance between chorionic villus karyotype and fetal phenotype (Reddy et al., 1991). On the other hand, the diagnosis of multiple gestations in their early stages cannot be totally accurate, and it was reported recently that the diagnosis of at least 40% of twin pregnancies was delayed until 13 weeks of gestation, a factor that can make the calculation of true post-conceptional loss among multiple gestations difficult (Glinianaia et al., 2002). The results of our report allow an estimation of the probability that a multiple pregnancy will continue to the end of the first trimester with the same number of gestational sacs as identified at 5–6 weeks.
Embryonic wastage after natural conception is greatest during the first 12 weeks of gestation, and this loss in the general population has been estimated at 20–25% (Asch et al., 1998). Although they are beyond the scope of this study, factors that can be involved in the aetiology for the demise of gestations during the first trimester can be aneuploidy, congenital abnormalities and maternal factors.
Previously, early pregnancy loss was expected to be higher in women undergoing assisted conception treatment than in fertile women (Ezra and Schenker, 1995; Simon et al., 1999). However, it has recently been demonstrated that infertile women who conceive after ART are not at increased risk for early pregnancy loss compared with women who conceive naturally (Pezeshki et al., 2000; Queisser-Luft et al., 2002). Furthermore, it has been proposed that spontaneously conceived twins are more likely to undergo reduction to singleton pregnancies than are twins resulting from infertility treatment (Santema et al., 1995; Dickey et al., 2002).
Our ART program uses ICSI exclusively as the method of fertilization in patients undergoing ART. The two major reasons for using ICSI in our practice as the method of fertilization are the relatively large proportion of couples with male factor infertility, and in order to optimize fertilization rates, particularly in women with poor ovarian response.
The difference in spontaneous early pregnancy loss between IVF and ICSI pregnancies was also evaluated. In a review of 1293 pregnancies after ICSI, early pregnancy loss rate was found to be 21.4%, not very different from the reported rate of spontaneous abortions after IVF (Wennerholm et al., 2000). Thus, the incidence of chromosomal abnormalities in spontaneously aborted embryos did not differ significantly when IVF and ICSI pregnancies were compared (Causio et al., 2002).
Spontaneous embryo reduction, defined as the vanishing of embryos during early gestational life, has long been an area of interest, and various rates ranging from 5 to 52.6% have been reported (Table IV). In the majority of these studies, a significant rate of spontaneous embryo reduction among multiple gestations in the first trimester was reported. Nevertheless, little information has been published about early pregnancy loss in high-order pregnancies (sac number more than three). Moreover, a wide range of spontaneous reduction rates between studies exist. In one study, 
50% of 38 triplet pregnancy achieved by ART experienced at least one embryo reduction (Manzur et al., 1995), and a recent study of 155 pregnancies with three or more gestational sacs showed that >50% of these patients had spontaneous reductions prior to 12 weeks of gestational age (Dickey et al., 2002). Thus, in the latter study there was also a trend towards increasing loss of gestational sacs relative to the multiplicity of the pregnancy, with spontaneous losses observed in 36% of women originally carrying twins, 53% in those carrying triplets and 65% in those carrying quadruplets (Dickey et al., 2002). In contrast, Skrablin et al. (2000) reported the spontaneous loss rates as 11.5 and 16.6% for triplet and quadruplet and quintuplet pregnancies, respectively, among 64 multiple gestations. The different figures between studies can derive from: (i) differences in the definition of pregnancy, such as presence of sac or cardiac activity; (ii) different ultrasound equipment used; (iii) calculations being based on per patient or per gestational sac; (iv) different population characteristics, such as spontaneously conceived or by ART; and (v) small population numbers being assessed. On the other hand, despite high rates of pregnancy loss in early gestational life, intrauterine loss of a twin after the first trimester was found to be as low as 3.5% (Sonneveld and Corey, 1992).
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Current evidence has shown that the spontaneous abortion rate increases relative to maternal age (Keenan et al., 1998
). In contrast, our results, derived from a cohort of over 1400 multiple pregnancies conceived by ART, showed no greater risk for total miscarriage among women >35 years than among women <35 years old. On the other hand, spontaneous embryo loss has been observed more frequently in older women who had ongoing pregnancies beyond the first trimester. This finding may be due to the relatively large proportion of twin pregnancies among our cohort, because the risk was marked in older women having twin gestations.
This study was designed to examine the life span of implanted embryos at the earliest stage possible permitting visualization by ultrasonography. Determination of a yolk sac inside the gestational sacs enabled us to accurately visualize multiple gestational sacs, and thus to assess the fate of embryos regardless of embryonic cardiac activity. Gestational sacs can be visualized by transvaginal ultrasound 35.5 days after last menstrual peiod, whereas fetal cardiac activity cannot be visualized until 44.5 days (Steinkampf et al., 1997). When only one gestational sac developed, however, subsequent loss of viability in the first trimester was found to occur in 8.5% of 232 singleton pregnancies (Goldstein, 1994). Using fetal cardiac activity as an indicator, several studies have demonstrated that the spontaneous abortion rate varies from 6 to 22.7% during the first trimester (Frates et al., 1993; Molo et al., 1993; Laufer et al., 1994; Falco et al., 1996). Furthermore, using fetal cardiac activity in multiple gestations, the rate of spontaneous fetal demise for a specific embryo in early pregnancy was found to be 5% (Kol et al., 1993). If we were to change our reference point to detection of cardiac activity, then in twin gestations, 3.7% demonstrated two cardiac activities, but decreased to an ongoing singleton by 12 weeks of gestation. In triplet gestations, 3.5% demonstrated three cardiac activities, but decreased to ongoing singleton or twin pregnancies by 12 weeks of gestation. In quadruplet gestations, 2.1% demonstrated four cardiac activities, but decreased to ongoing twin or triplet pregnancies by 12 weeks of gestation. None of the patients originally carrying four embryos spontaneously reduced to an ongoing singleton pregnancy.
Perinatal as well as maternal mortality and morbidity are increased in multiple pregnancies; therefore, the most efficient method for preventing high-order pregnancies is to decrease the number of transferred embryos. In this regard, our practices have changed during recent years, as have those at other infertility centres around the world, and we have been started to limit the number of embryos transferred. On the other hand we believe that each ART program must determine in an individual fashion the point at which pregnancy rates do not improve with additional embryos transferred.
Our results conclude that there is significant risk of early pregnancy loss in the form of vanishing embryos in the first trimester among multiple pregnancies achieved by ICSI. However, this risk does not appear to be increased by the method of conception. Thus, we have shown here that at least 11% of initially diagnosed triplets will spontaneously reduce to twins or a singleton pregnancy by the end of first trimester. For quadruplet pregnancies, however, the reduction rate is significantly lower. In addition, our findings suggest that the decision regarding whether to perform MFPR should be left until the end of the first trimester in a high-order pregnancy.
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Submitted on June 23, 2003; resubmitted on October 2, 2003; accepted on October 24, 2003.
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