Effect of Low-dose Human Chorionic Gonadotropin on the Prevention of Ovarian Hyperstimulation Syndrome and in Vitro Fertilization Outcome

Introduction

Ovarian hyperstimulation syndrome (OHSS) is a life-threatening complication of controlled ovarian stimulation (1). Some rare cases of this syndrome were reported in spontaneous pregnancy, which were related to polycystic ovary syndrome, hypothyroidism, hydatidiform mole, gonadotropin-producing pituitary adenoma, and multiple gestation (2). OHSS occurs 3-7 days after hCG administration in sensitive women and within 12-17 days after hCG administration in the normal papulation (3).

Various prevalence rates have been reported for OHSS in several studies. In the largest cohort study, the mildest type of this disease, which is not clinically important, constituted 20-30% of cases (3), while the moderate to severe types comprised 1-10% of the cases (4), and the life-threatening type consisted of 1-2% of the cases (3, 5). Young and thin women with a history of OHSS, as well as women with polycystic ovary disease (PCOD), hyperprolactinemia, and hypothyroidism are at high risk for OHSS (3, 6).

Although the pathophysiology of OHSS has not been completely described, it seems to be related to ovarian enlargement, increased vascular permeability, and intravascular dehydration that are mediated by vasoactive mediators released by hyperstimulated ovaries under the influence of hCG (7). It has been demonstrated that OHSS is always caused by exogenous or endogenous hCG due to pregnancy (3, 8). Stopping IVF cycles and hCG injection prevent OHSS. However, this is not favorable since physicians are under pressure to achieve a successful outcome from IVF cycles (3). hCG is routinely used for the induction of oocyte maturation (9). hCG dosage and its continuous administration during the luteal phase are the most important risk factors for OHSS (6), and high serum concentrations of hCG may increase the risk of OHSS (9). Thus, it seems that the reduction of hCG dosage is a useful prophylaxis method for OHSS in order to decline the production and effects of vascular endothelial growth factor (VEGF) (10). Nonetheless, the minimum effective hCG dosage has not yet been determined (9).

 Few international studies have been conducted on the reduction of hCG dosage. In this study, we aimed to investigate the effect of reduction of hCG dosage from 5000 units to 1600 units on OHSS incidence rate and IVF outcomes in patients with high risk for OHSS.

Materials and Methods

In a single-blind non-randomized clinical study, 202 infertile women who were candidates for assisted reproductive procedure and aged 18 to 40 years old were enrolled in the study to determine the effect of low-dose hCG on the prevention of OHSS and IVF outcome. The study was carried out from October 2008 through November 2012 in Motahari Hospital, Urmia, Iran.

All the participants underwent controlled ovarian hyperstimulation with gonadotropin/ GnRH agonist long protocol. The women were treated with 0.5 mg subcutaneous buserelin (gonadotropin Releasing Hormone agonist [GnRH], Superfact, Aventis, Germany) daily for 21 days. In case of absence of ovarian cysts in ultrasonography, human menopausal gonado-tropin vial (HMG, Mengon; Ferring GmbH, Germany) or follicle-stimulating hormone (FSH) vial (Gonal-f; Merck Serona, Switzerland) was prescribed for patients, and Superfact was continued with a half-therapeutic dose regimen. After growing follicles to a diameter of 18-20 mm, intramuscular injection of hCG (IVF-C; Pregnil, Iran) was used to induce ovule maturation.

The criteria for high risk OHSS included young age, antral follicle counts of more than 30 in both ovaries, follicle size of larger than 14 mm, poly cystic ovaries on ultrasound and/or polycystic ovarian syndrome (PCOS), serum estradiol of more than 5000 pg/ml, and/or multiple follicular recruitments in both ovaries during ultrasound monitoring in controlled ovarian hyperstimulation on the day of hCG administration. The patients with serum estradiol of less than 5000 pg/ml were excluded. Embryo transference was not performed for those with discomfort in the lower abdomen, bulky ovum, nausea, abdominal distension, or other OHSS symptoms. In these cases, embryos were totally frozen and they were excluded from the study.

The patients were divided into two groups. The women with serum estradiol of 5000 to 8000 pg/ml received 5000 units of hCG and those with serum estradiol of higher than 8000 pg/ml (high risk for OHSS) received 1600 units (one third of vial 5000 units) of hCG.

After 34-36 hours of hCG injection, the ova were punctured under vaginal ultrasonography guide. The ova were fertilized by the intracytoplasmic sperm injection (ICSI) technique and embryos were transferred into the uterine cavity through cervix 48-72 hours later.

Progesterone (100 mg/daily) was prescribed as the luteal phase support following embryo transference. Beta hCG (βhCG) was measured two weeks later, and if it was positive, vaginal ultrasonography was conducted to confirm pregnancy after two weeks, also the control ultrasound test was repeated to observe embryo’s heartbeat at the 8^th week of pregnancy. The patients were followed up until the 14th week of pregnancy. Quantity and quality of oocytes, and quantity and quality of the embryos, rate of pregnancy, frequency of abortion, and incidence rate of OHSS were investigated and compared between the groups.

The study followed the tenets of the Declaration of Helsinki; informed consent was obtained from all the participants, and the study was approved by the Ethics Committee of Urmia University of Medical Sciences.

To analyze the data, descriptive statistics including frequency, percentage, mean, and standard deviation and inferential statistics consisting of independent t-test and Chi-square test were employed in SPSS, version 16. P-value less than 0.05 was considered significant.

Results

A total of 202 women were enrolled, 87 of whom had serum estradiol of 5000-8000 pg/ml and received hCG at a dose of 5000 units and 115 with a serum estradiol of higher than 8000 pg/ml received 1600 units of hCG. The maximum serum estradiol level was 13750 pg/ml.

The mean age of the patients in the 1600 and 5000-unit groups were 28.35±3.98 years and 29.44±5.28 years, respectively (P=0.09). Ova and embryos of the patients were investigated . The total ova and embryos of the 5000-unit group were 804 and 480, respectively, and those in the 1600-unit group were 1321 and 854, respectively (Table 1).

Considering the ratio of total embryos to total ova, fertilization rates were 64.64% in the 1600-unit group and 59.70% in the 5000-unit group. There was a significant difference between the two groups regarding fertilization rate (P=0.001).

Embryos were not transferred in 17 out of 115 participants in the 1600-unit group due to OHSS symptoms (13 cases), non-formation of ovum (2 cases), and non-formation of embryo (2 cases). The rate of pregnancy in the 1600-unit group was 56.12%, of whom two cases had ectopic pregnancy and eight cases had abortion (15.09%).

 The embryo was not transferred for 7 out of 87 participants in the 5000-unit group  due to OHSS symptoms (4 cases), non-formation of ovum (2 cases), and non-formation of embryo (1 case). The rate of pregnancy in this group was 45%; 1 (2.77%) case was EP and 10 cases had abortion (28.57%). There was no significant difference between the two groups in terms of pregnancy rate (P=0.092) and frequency of abortion (P=0.171).

OHSS symptoms were observed in 13 (11.30%) women in the 1600-unit group and in 4 (4.59%) women in the 5000-unit group. Therefore, transfer of embryo was cancelled in these women and their embryos were frozen. No significant difference was observed between the two groups regarding OHSS rate and rate of IVF cycle cancellation (P=0.089). Only one case
from the 1600-unit group had severe OHSS symptoms, and other cases only experienced mild symptoms.

          Table 1. Frequency distribution of IVF cycles characteristics according to the hCG dosage

                           ^** Metaphase 1, vacuolated or GV

                           ^* Metaphase 2

                           ²Independent t-test

                           ¹Chi-square test

Discussion