Intravenous calcium infusion as a novel preventive therapy of ovarian hyperstimulation syndrome for patients with polycystic ovarian syndrome Timur Gurgan, M.D.,a,d Aygul Demirol, M.D.,a Suleyman Guven, M.D.,b Moncef Benkhalifa, M.D.,c Bagdagul Girgin,a and Tin Chiu Li, M.D.e a
Gurgan Clinic Women Health, Infertility and IVF Center, Ankara, Turkey; b Department of Obstetrics and Gynecology, Karadeniz Technical University School of Medicine, Trabzon, Turkey; c ATL R&D Reproductive Biology & Genetics Laboratory, La Verriere, France; d Department of Obstetrics and Gynecology, Hacettepe University, Ankara, Turkey; and e Department of Obstetrics and Gynecology, Sheffield Teaching Hospitals, Sheffield, United Kingdom
Objective: To evaluate the effectiveness of IV calcium infusion on prevention of ovarian hyperstimulation syndrome (OHSS) in patients with polycystic ovary syndrome undergoing assisted reproductive techniques cycles. Design: A retrospective comparative study. Setting: Assisted reproduction techniques centre in Turkey. Patient(s): Four hundred fifty-five women with high risk for OHSS. Intervention(s): The patients in group I (n ¼ 84) were administered IV calcium gluconate for prevention of OHSS, and the patients in group II (n ¼ 371) comprised the control group, with no manipulation for prevention of OHSS and were age- and body mass index–matched with the study group. Main Outcome Measure(s): Ovarian hyperstimulation syndrome rate, clinical pregnancy rate. Result(s): Mean (SD) ages of the women in the calcium infusion group (group I) and the control group (group II) were comparable (30.5 4.3 vs. 31.4 3.9, respectively). Ovarian hyperstimulation syndrome was found in 16.2% (60 patients) in group II, whereas in group I, only 3 patients (3.6%) developed OHSS. Interestingly, all the hyperstimulation cases in group I were mild, and there was no severe effect. Implantation rates were similar in both groups. Furthermore, we obtained clinical pregnancy in nearly 40.5% in group I and 28.8% in group II. The live-birth rate was 38.1% in the calcium infusion group and 24.8% in the control group. Conclusion(s): Intravenous calcium infusion resulted in a significantly lower rate of development of OHSS for patients with polycystic ovary syndrome and high risk of OHSS. This novel therapy may be used for prevention of OHSS effectively. (Fertil Steril 2011;96:53–7. 2011 by American Society for Reproductive Medicine.) Key Words: ART, IV calcium, OHSS, PCOS, prevention
Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies, affecting 5%–10% of women of reproductive age. The principal features of PCOS include androgen excess, ovulatory dysfunction, and/or polycystic ovaries. PCOS is found in approximately 75% of women with anovulatory infertility (1, 2). The treatment of infertile women with PCOS is surrounded by many controversies. On the basis of the currently available evidence and the recommendations of the ThessalonikiEuropean Society of Human Reproduction and Embryology/American Society for Reproductive Medicine (ESHRE/ASRM)-Sponsored PCOS Consensus Workshop Group, the recommended first-line treatment for ovulation induction remains the anti-estrogen clomiphene citrate; second-line intervention can be either treatment with exogenous gonadotropins or laparoscopic ovarian surgery. Recommended third-line treatment is IVF (3). Although favorable IVF outcomes have been reported, uncertainty remains with regard to risk of ovarian hyperstimulation syndrome (OHSS), cycle cancellation rate, oocyte and embryo Received March 30, 2011; revised April 24, 2011; accepted April 26, 2011; published online May 31, 2011. T.G. has nothing to disclose. A.D. has nothing to disclose. S.G. has nothing to disclose. M.B. has nothing to disclose. B.G. has nothing to disclose. T.C.L. has nothing to disclose. Reprint requests: Aygul Demirol, M.D., Gurgan Clinic Women Health, Infertility and IVF Centre, Cankaya Caddesi, no. 20/3, Ankara, Turkey (E-mail:
[email protected]).
0015-0282/$36.00 doi:10.1016/j.fertnstert.2011.04.094
quality, as well as fertilization and pregnancy rates in women with PCOS undergoing IVF (4). Their propensity for an exaggerated response to gonadotropin therapy places them at high risk for developing OHSS. Early OHSS is seen because of their hyperresponsiveness and persistent circulation of the exogenously administered human chorionic gonadotropin. Late OHSS develops following successful implantation and the production of endogenous hCG as pregnancy is established. Indeed, a 10.5% incidence of moderate to severe OHSS has been seen in patients with PCOS, which is greater than the 0.5%–4% observed in the general IVF population (4, 5). The incidence of multiple pregnancies, gestational diabetes mellitus, placental abruption, prematurity, and low birthweight is also higher in cases of pregnancy complicated by severe OHSS (6). The exact etiology of OHSS is not clearly understood. The most well established risk factor for this clinical condition is PCOS. The treatment is currently empirical and the prevention of OHSS is the most important aspect in its management. There are three main strategies for prevention of OHSS: [1] identification of patients at risk (women with a history of OHSS or PCOS); [2] using different ovulation induction strategies before stimulation (metformin, use of in vitro maturation, use of a low-dose FSH protocol, use of a GnRH antagonist protocol); and [3] preventive therapy modalities during stimulation (cycle cancellation, cryopreservation of all embryos for future transfer, coasting, GnRH antagonist administration, IV fluids (albumin, hydroxyethyl starch, 3.5% colloidal intravenous
Fertility and Sterility Vol. 96, No. 1, July 2011 Copyright ª2011 American Society for Reproductive Medicine, Published by Elsevier Inc.
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infusion solution, and dextran), triggering ovulation by low-dose hCG and dopamine agonist therapy) (7, 8). The novel strategy for prevention of OHSS is use of IV calcium infusion, but there are limited data in the literature on the effectiveness of this treatment modality (9). The effect of such therapy on prevention of OHSS in a significantly large number of patients with PCOS has not been reported previously. In the present study, we aimed to evaluate the effectiveness of IV calcium infusion on prevention of OHSS in patients with PCOS undergoing assisted reproduction technique cycles.
MATERIALS AND METHODS Patients and Study Design A total of 455 patients with PCOS diagnosed to be at risk of OHSS and treated in our infertility and IVF Center during the period extending from January 2001 to February 2010 were evaluated for this retrospective study. The patients were divided into two cohorts. The patients in group I (n ¼ 84) were administered IV calcium gluconate for prevention of OHSS; the patients in group II (n ¼ 371) were the control group, receiving no intervention for prevention of OHSS and age- and body mass index–matched with the study group. All patients were retrospectively evaluated for symptoms and signs of OHSS as a primary outcome measure. Main inclusion criteria were development of more than 14 leading follicles larger than 10 mm and a serum estradiol level higher than 3,000 pg/mL at the end of ovulation induction with oral contraceptive pills þ luteal long down-regulation protocol. Exclusion criteria were as follows: [1] having endocrinopathies (including diabetes mellitus, hyperprolactinemia, Cushing’s disease, and congenital adrenal hyperplasia), a systemic disease (e.g., asthma), a collagen disorder, hypercholesterolemia, sickle cell anemia, a history of neoplasm; [2] patients need coasting for high risk of OHSS; [3] using any medication (e.g., insulin-sensitizing drugs and GnRH antagonists); [4] patients need cycle cancellation; and [5] severe male infertility requiring testicular sperm extraction. Polycystic ovary syndrome was diagnosed according to the criteria of the Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group (10). The hypothesis is that in patients with PCOS, those who had IV calcium infusion will have lower OHSS rates in intracytoplasmic sperm injection cycles than that in the control group.
Ovarian Stimulation and Patients Procedures All patients were stimulated with oral contraceptive pills þ luteal long down regulationprotocol. All patients were treated earlier with oral contraceptive pills (Desolett tablet; 0.15 mg desogestrel and, 0.03 mg estradiol [Etinil; Organon]) for the cycle preceding ovulation induction. Leuprolide acetate (Lucrin; Abbott Cedex) was started at the luteal phase (on 15th day of oral contraceptive pill treatment). A daily dose of leuprolide acetate 1 mg SC was started and decreased to 0.5 mg/d following confirmation of downregulation, which was verified by serum estradiol levels lower than 60 pg/mL. Recombinant-FSH (Puregon; Organon) was administered in a step-down protocol starting with a 150 IU/d after down-regulation confirmation, and after 5 days the dose was adjusted according to the ovarian response. Human chorionic gonadotropin (10,000 IU IM, Pregnyl; Organon) was administered when at least two or three follicles reached a mean diameter of 17 mm. Transvaginal oocyte retrieval was scheduled 36 hours after hCG injection. Intracytoplasmic sperm injection was performed for all metaphase II oocytes and ETs were performed on day 3 for all patients under ultrasound guidance. Luteal phase was supported by daily vaginal P suppositories (Crinone; Serono) starting one day after oocyte pick-up. Embryos were graded on day 3 according to a 1–4 scoring system (with 1 being the best), which was based on fragmentation, cell symmetry, and blastomere number. The embryos with even blastomeres and no fragmentation were classified as grade 1, those with even blastomeres and 45%). In the presence of severe OHSS, the following objective (fluid in pouch of Douglas, fluid around uterus [pelvis], fluid around intestinal loops, hematocrit >45%, white blood cells >15,000/mm3, and low urine output [2), which suggests that LH dominance leads to disturbed androgen–oestrogen conversion and to a higher propensity for OHSS (20). The hallmark of OHSS is an increase in capillary permeability resulting in a fluid shift from the intravascular space to third space compartments (12). The possible contributing factors in the pathophysiology of OHSS are increased secretion or exudation of protein-rich fluid from enlarged ovaries or peritoneal surfaces, increased follicular fluid levels of prorenin and renin (21), increased angiotensin-mediated changes in capillary permeability (22), and finally increased vascular endothelial growth factor, which is an angiogenic cytokine known to be a potent stimulator of the vascular endothelium (23). Furthermore, vascular endothelial growth factor (VEGF) appears to play an integral role in follicular growth, corpus luteum function, and ovarian angiogenesis (12, 23). In a recent study, the effectiveness and safety of dual renin–angiotensin system blockage for prevention of OHSS in overstimulated patients undergoing IVF was evaluated. This novel strategy for use in patients at high risk for OHSS did not completely eliminate
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TABLE 2 Comparison of embryologic characteristics and cycle outcome in calcium gluconate–administered group (group I) and control group (group II).
Parameter Mean no. of oocytes retrieved Mean no. of metaphase II oocytes retrieved Fertilization rate (%) Mean no. of available embryos Grade 1 Grade 2 Grade 3 Mean no. of embryos transferred Grade 1 Grade 2 Implantation rate (%) Clinical pregnancy rate (%) Pregnancy outcome (%) Biochemical pregnancy Missed abortion (
