Does ICSI affect early serum ß-HCG in pregnancies achieved after IVF?
R.S. Gold,
F. Azem,
I. Yovel,
I. Wagman,
A. Amit and
J.B. Lessing1
The Sara Racine IVF Unit, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, and Sackler Faculty of Medicine, Tel Aviv University, Israel
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Abstract
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This study was conducted to compare early serum human chorionic gonadotrophin (HCG) concentrations in singleton pregnancies achieved after intracytoplasmic sperm injection (ICSI), with those achieved after conventional in-vitro fertilization (IVF). Early serum HCG, 1416 days after embryo transfer, was analysed in 99 IVF pregnancies achieved after ICSI (group A), and compared to 105 conventional IVF pregnancies (group B). All women were treated at the IVF Unit, Lis Maternity Hospital. Records were studied retrospectively. The mean ± SE serum HCG concentration on day 14 after embryo transfer in group A was 190.5 ± 17.4 mIU/ml, compared to 195.7 ± 14.03 mIU/ml in group B. HCG concentration 14 days after embryo transfer in both groups A and B was higher in women with mechanical factor than in couples with male factor infertility or unexplained infertility (246 ± 31.4, 183.3 ± 16.4, 177.98 ± 14.3 mIU/ml respectively). On the 16th day after embryo transfer, the HCG concentration increased, and the difference between the groups was maintained. Only in the subgroup of unexplained infertility did we find a difference in concentrations of HCG between ICSI and conventional IVF: on the 16th day following embryo transfer in this group there was a significant difference in HCG concentrations (395.8 ± 21 and 545.6 ± 45.7 respectively; P = 0.04). HCG concentrations did not differ overall in the conventional IVF pregnancies compared with those achieved by ICSI. However, a statistical difference in early serum HCG concentrations was found in relation to the aetiology of infertility.
Key words:
human chorionic gonadotrophin/intracytoplasmic sperm injection/IVF/pregnancy test
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Introduction
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Sonographic evidence of a viable intrauterine pregnancy can be found initially at approximately the sixth gestational week. Nevertheless, investigators have searched for earlier markers of pregnancy. The higher rate of ectopic pregnancies observed with IVF emphasizes the importance of early pregnancy detection (Center for Disease Control and Prevention, 1995
). Some investigators previously analysed quantitative human chorionic gonadotrophin (HCG) drawn 1116 days after embryo transfer in IVF or in gamete intra-Fallopian transfer (GIFT) pregnancies as a tool for monitoring pregnancy (Dor et al., 1988
; Liu et al., 1988
; Heiner et al., 1992
; Glatstein et al., 1995
). In recent years, the new technique of intracytoplasmic sperm injection (ICSI) has become available, making conception possible for couples with severe male factor infertility. It has been suggested that HCG concentrations in ICSI pregnancies are lower than those in conventional IVF pregnancies because of oocyte micromanipulation, which may delay maturation, or implantation of the embryos (Tulchinsky et al., 1996
; Dietterich et al., 1997
). In this study, we compared early serum HCG 1416 days after embryo transfer in conventional IVF pregnancies, with those achieved after ICSI. We examined the pattern of HCG rise in the two groups, and examined whether pregnancy tests performed at 14 and 16 days after embryo transfer in IVF cycles were also applicable in ICSI cycles.
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Materials and methods
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Patients
Between January 1994 and January 1998 we carried out a retrospective analysis of 204 pregnancies achieved at the Sara Racine IVF Unit, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center in Israel. Data were drawn from hospital files.
Duration of infertility was at least 1 year. All women were checked for endocrine status, mechanical factor was examined by hysterosalpingography, or by laparoscopy and hysteroscopy. Semen analysis was carried out for all the men. Unexplained infertility was defined as infertility of at least 2 years during which tubal, ovulation and male factors were excluded by hysterosalpingography, hysteroscopy, laparoscopy, endocrine profile and semen analysis.
Protocols of ovarian stimulation consisted of human menopausal gonadotrophin (HMG; Pergonal and/or Metrodin, Teva, Petach-Tikva, Israel) combined with gonadotrophin-releasing hormone agonist (GnRHa), followed by administration of 10 000 IU HCG (Chorigon, Teva). Transvaginal oocyte retrieval was performed 3436 h later. Ninety-nine women were treated with ICSI (group A) because of severe male factor, or repeated previous conventional IVF failures. The conventional IVF protocol was applied to 105 women (group B). Embryo transfer was performed 4872 h later. Initial serum pregnancy tests were drawn on the 14th day, and once positive (>10 mIU/ml), were repeated on day 16 after embryo transfer. All HCG tests were undertaken at the same laboratory at our Institute, with the same radioimmunoassay technique.
Exclusion criteria included multiple gestations, first-trimester abortions and incomplete data. Data comprised age, cause of infertility, number of embryo transfer, HCG 14 and 16 days after embryo transfer.
Inclusion criteria for conventional IVF were: failed assisted reproduction of at least six cycles, tubal factor, and male factor. Inclusion criteria for ICSI were: severe male factor, low fertilization rate in previous cycles, or in the same cycle after the first 24 h.
Statistical analysis
Data were analysed using the statistical package SPSS/PC (SPSS Inc., Chicago, IL, USA), and entered into a database (ACESS 5, Microsoft Inc, Seattle, WA, USA). Student's t-test was used for comparison of age, number of embryo transfer, and HCG between the two groups, and
2-test was used for comparing the indication for ICSI. One-way analysis of variance (ANOVA) was used for comparing the results according to the cause of infertility. P < 0.05 was considered as statistically significant.
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Results
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The mean ± SD age of 204 women was 32.6 ± 5.2 years (range 2244). The mean age was 31.5 ± 5.1 years in the ICSI group (A) and 33.5 ± 5.1 years in the non-ICSI group (B) (P = 0.07). Overall indications for IVF were male factor (49%), unexplained infertility (31.4%), and tubal factor (19.1%). A further 0.5% were classified as `rescue' IVF, i.e. women who had over-reacted to conventional ovulation induction with HMG and produced multiple follicles and were therefore shifted to IVF in order to avoid hyperstimulation on the one hand, or cancellation of the cycle on the other. In group A, women were treated for: male factor (65.7%), unexplained infertility (17.2%), tubal factor (16.2%), and rescue cycle IVF (1%) (Table I
). Because of low fertilization rate after 24 h in the rescue cycle IVF, the woman was treated by ICSI and not by conventional IVF. In group B, women were treated for: unexplained infertility (44.8%), male factor (33.3%), and tubal factor (21.9%) (P = 0.0001 for comparisons of aetiologies between groups). The number of embryos transferred (Table II
) in group A was smaller than in group B, but not significantly different (3.9 versus 3.7; P = 0.7).
The mean ± SE serum HCG on the 14th day after embryo transfer in group A was 190.5 ± 17.4 versus 195.7 ± 14.03 mIU/ml in group B (not significant). The mean ± SE serum HCG on the 16th day after embryo transfer was also greater in group B, compared to group A, but not statistically significant (577.6 ± 66.12 versus 599.3 ± 46.7). Delta HCG (difference between day 16 HCG and day 14 HCG) in group A was 387.1 ± 54.3, compared to 403.6 ± 43.1 in group B (not significant). In both groups, the HCG concentration on the 16th day after embryo transfer was significantly greater than that of day 14 post-embryo transfer (P < 0.0001). Table III
summarizes the data according to the cause for infertility.
The mean ± SD age according to cause of infertility was almost the same in the tubal and unexplained groups (33.97 ± 5.9 and 33.92 ± 56 respectively), and it was statistically different from the mean age in the male factor infertility group (31.16 ± 4.6; P < 0.005). This trend was also maintained in the number of embryos transferred in each group, i.e. 4.2 ± 1.5 and 4.01 ± 1.2 respectively, compared with 3.6 ± 1.03 in the male factor group (P < 0.005). HCG concentrations human chorionic gonadotropin levels on days 14 and 16 were significantly higher in the tubal group than in the male factor and unexplained infertility groups (P < 0.005; Table III
). When we compared the rise in HCG according to cause of infertility and treatment (ICSI versus IVF) (Tables IV, V and VI

) we found no statistically significant difference in HCG on days 14 and 16, or in
HCG in the subgroups of tubal and male infertility (Tables IV and V
). However, there was a significant statistical difference in HCG concentrations on day 16 and
HCG in the patients with unexplained infertility (Tables IV
), between ICSI and IVF groups.
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Discussion
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Early detection of pregnancy is important for both patient and medical team. Confirmation of pregnancy may relieve anxiety, but at the same time can alert health care providers to high-risk conditions, such as early pregnancy loss, ectopic pregnancy and multiple gestations. Effective clinical management requires a method to detect and monitor pregnancy as soon as possible (Levy et al., 1991
; Center for Disease Control and Prevention, 1995
).
The standard policy of many IVF programmes is to monitor early pregnancies with serial HCG testing. These tests usually begin around the 11th to the 16th day after embryo transfer. This protocol was established before the era of ICSI. A previous study indicated that gestational sac size in twin pregnancies after IVF was smaller than that of spontaneous twin pregnancies (Dietterich et al., 1997
). Tulchinsky et al. (1996) reported that serum HCG concentrations of patients who became pregnant after IVF treatments lagged 1.5 days behind those who conceived spontaneously. The authors suggested that GnRHa caused a delay in embryo implantation because of reduced uterine receptivity. Recently, it was reported (Lam et al., 1999
) that lower concentrations of HCG occurred in ICSI compared with IVF gestations of 1520 weeks; however, this difference was not statistically significant. These reports raised the question whether ICSI further decreases or delays the rise in HCG due to changes in oocyte maturation, or implantation of the embryo.
The results of our study showed that, in patients who conceived after ICSI, only in the subgroup of patients with unexplained infertility were early serum HCG concentrations statistically significantly lower than in patients who conceived with conventional IVF. In all other infertility subgroups (male and tubal infertility) no such difference was found. Conversely, we found a statistically significant difference between early serum concentrations of HCG according to the cause of infertility. Patients with tubal factor had higher concentrations of HCG than those with male factor or unexplained cause of infertility. These two findings may be due to hormonal changes occurring due to sperm or oocyte factors in the male factor and unexplained infertility groups, in contrast to the tubal infertility group that theoretically has neither hormonal nor male factor problems. In the unexplained infertility group, the HCG on day 16 was lower in the ICSI-treated couples, perhaps due to an egg factor. These findings cannot be explained because of a difference in age, or in number of embryos that were transferred, since there were no statistical differences in these attributes between the IVF and ICSI patients in the unexplained infertility groups. It seemed to us that HCG concentrations were related to the cause of infertility but since this was a retrospective study with no randomization, a prospective, randomized study is required to arrive at a definite conclusion.
From our data, it appears that the protocol of initial serum HCG obtained 14 to 16 days after embryo transfer should not be changed, whether or not ICSI is used.
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Notes
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1 To whom correspondence should be addressed at: The Sara Racine IVF Unit, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, 6 Weizman Street, Tel Aviv 64239, Israel.E-mail: lessing{at}tasmc.health.gov.il 
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Submitted on June 28, 1999;
accepted on February 28, 2000.