Citation for published version (APA): Youssef, M. A. F. M. (2016). Ovarian stimulation in IVF in relation to ovarian response

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1 UvA-DARE (Digital Academic Repository) Ovarian stimulation in IVF in relation to ovarian response Youssef, Mohamed Link to publication Citation for published version (APA): Youssef, M. A. F. M. (2016). Ovarian stimulation in IVF in relation to ovarian response General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam ( Download date: 07 Jul 2018

2 Chapter 3 Can dopamine agonist at a low dose reduce ovarian hyperstimulation syndrome in women at risk undergoing ICSI treatment cycles? A randomized controlled study. Shaltout A, Shohyab A, Youssef MA. Eur J Obstet Gynecol Reprod Biol. 2012; 165(2):

3 Abstract Objective: Dopamine agonists were proposed as a preventive strategy for severe ovarian. The aim of this randomized controlled study is to evaluate the role of dopamine agonist at lower doses (0.25 mg) as a preventive strategy of severe hyperstimulation syndrome (OHSS) in women at high risk in IVF/ICSI treatment cycles. Study design: Two hundred women at risk to develop OHSS undergoing IVF/ICSI treatment cycle were included; the study group received 0.25 mg of cabergoline for 8 days from the day of HCG administration versus no treatment for the prevention of OHSS. Reduction of the incidence OHSS was the primary outcome. Results: The overall incidence of OHSS was significantly reduced, almost 50%, in cabergoline group in comparison with control group (RR: 0.5, 95% CI: ), with absolute risk reduction following cabergoline administration 11% (ARR: 0.11, 95% CI: ). The corresponding number needed to treat (NNT) was 9. Conclusion: Prophylactic treatment with the dopamine agonist, cabergoline, at lower doses (0.25 mg) reduces the incidence of OHSS in women at high risk undergoing IVF/ICSI treatment. 64

4 Introduction Ovarian hyperstimulation syndrome (OHSS) is a potential complication of ovarian induction therapy affecting 1 14% of all IVF/ICSI cycles [Garcia-Velasco and Pellicer 2003]. As the pathophysiology of this syndrome is not clearly understood [Aboulghar 2009; Garcia-Velasco 2009; Alper et al., 2009; Go mez et al., 2010; Nastri et al., 2010], different strategies have been tried to prevent OHSS, such as cycle cancellation, coasting [Garcia-Velasco 2006], intravenous fluid administration around the time of oocyte retrieval [Youssef et al., 2011], GnRH agonist for final oocyte maturation triggering in GnRH antagonist cycles [Youssef et al., 2011], natural-cycle IVF or in vitro oocyte maturation [Edwards 2007], recombinant HCG instead of urinary HCG [Youssef et al., 2011], metformin [Khattab et al., 2006], elective cryopreservation of all embryos and embryo transfer in future cycles [Vyjayanthi et al., 2006], and, recently, GnRH antagonist for pituitary desensitization instead of long GnRH agonist [Al- Inany et al., 2011]. Unfortunately, none of the strategies currently employed completely prevents severe OHSS after HCG administration. Capillary permeability is the end step of the cascade of the pathophysiology of OHSS and is associated with third space fluid accumulation and fluid shift. Vascular endothelial growth factor (VEGF) is a vasoactive mediator which increases capillary permeability and is expressed at a higher level in the granulosa cells [Rizk et al., 1997]. The administration of a dopamine agonist in immature rats at low doses simultaneously with HCG prevented an increase in vascular permeability and did not affect angiogenesis [Ata et al., 2009]; the effect was due to the availability of dopamine type 2 receptors [Soares et al., 2008]. Dopamine agonists prevent the phosphorylation of VEGF receptor 2 and reduce the in vitro and in vivo release of vasoactive angiogenic agents. As a result, vascular permeability is also reduced [Gomez et al., 2006; Rollene et al., 2009; Busco et al., 2010]. Consequently, dopamine agonist at a daily dose of 0.5 mg has been supposed to be a potential new strategy to prevent OHSS and reduce its severity [Alvarez et al., 2007; Spitzer et al., 2011]. Cabergoline, an ergot derivative, is a potent dopamine receptor agonist on D2 receptors. It is frequently used as a first-line agent in the management of prolactinomas due to higher affinity for D2 receptor sites, less severe side effects, and more convenient dosing schedule than the older treatment, bromocriptine. Many studies have evaluated cabergoline as a preventive strategy to reduce the incidence of OHSS using varying doses and regimens. Concerns arose about the risk of cabergoline dose and duration of treatment in terms of endometrial angiogenesis, implantation, pregnancy and congenital anomalies. We assumed that 0.25 mg of cabergoline could safely and effectively reduce the incidence of OHSS in women undergoing ICSI treatment without harming treated women or their babies. 65

5 The aim of this randomized controlled study was to evaluate the efficacy and safety of a low dose (0.25 mg) of the dopamine agonist, cabergoline, in the prevention of OHSS in women at risk of developing OHSS when undergoing ICSI treatment cycles. Materials and Methods Two hundred infertile couples undergoing ICSI at a private IVF/ICSI center (Samir Abbass, Jeddah, SA) and at risk of developing OHSS were included between January 2007 and October The risk of developing OHSS was defined as follows: E2 level on day of HCG > 3500 pg/ml, and with 20 follicles > 12 mm. Patients with E pg/ml were excluded from the study. The protocol was approved by the Internal Ethical Research Committee and patients were included after signing a written consent form. A long mid-luteal GnRH agonist protocol, 0.1 mg triptorelin SC (Decapeptyl; Ferring, Germany) was used for pituitary downregulation in both groups. Once pituitary downregulation had been confirmed, controlled ovarian hyperstimulation (COH) was started using fixed dose of HMG, IU (Menogon 75 IU, IM injections, Ferring, Germany), for 5 days; the dose was then adjusted according to response. When three leading follicles reached 18 mm, final oocyte maturation was triggered with a single dose of 5000 IU of HCG, which is the policy of our center. On the day of HCG administration, couples were allocated by a series of computer generated random numbers into two groups: the cabergoline group (Group I; n = 100), received 0.25 mg daily for 8 days and the non-cabergoline group (Group II; n = 100), did not receive cabergoline. Transvaginal guided oocyte retrieval was performed h later. All the patients received 500 ml of hydroxyethyl starch (HES) over 30 min as a routine strategy in our center on the day of ovum pickup. Ultrasound guided transfer (ET) of 2 3 embryos was performed 72 h later. The luteal phase was supported with 400 mg progesterone vaginal pessaries (Cyclogest; Cox Pharmaceuticals, Whiddon Valley, UK), twice daily up to the day of pregnancy test. Hemoconcentration, the presence of ascites, measuring the perpendicular diameter of free fluid in the pouch of Douglas, and the ovarian volume were reported in both groups on the day of ET and one week later. The primary outcome measure was reduction of the overall incidence of OHSS according to Golan s classification [Golan et al., 1989] and secondary outcome measures included severe and mild to moderate OHSS, early (<7 9 days) and late OHSS ( 10 days), number of retrieved oocytes, number of mature oocytes, hospitalization rate due to severe OHSS, fertilization rate, clinical pregnancy rate (defined as presence of fetal heart pulsation 2 weeks after a positive b-hcg test), live birth rate, and incidence of congenital anomalies. 66

6 Statistical analysis was performed using SPSS (Version 17, SPSS Inc., Chicago, IL, USA). Dichotomous outcomes were expressed as percentages and relative ratios (RR) with 95% CI. Continuous outcomes were expressed as mean ± SD. Chi-square test and Student s t tests were performed to evaluate the statistical differences between the variables. A P value of 0.05 was considered statistically significant. All outcomes were calculated according to intention to treat analysis. Results A total of 250 patients were assessed for eligibility, and 50 patients were not included. Two hundred patients were randomized: 100 women to the cabergoline group and 100 women to the control group. Embryo transfer was cancelled due to failure to recover oocytes during oocyte retrieval in 2 cases and 3 cases, and failure of fertilization in 2 cases and 1 case, in the cabergoline and non-cabergoline groups, respectively. One woman discontinued cabergoline because she experienced severe nausea and vomiting (Fig. 1). There was no evidence of a statistically significant difference between both groups as regards their age, BMI and cause of infertility (Table 1). The actual incidence of OHSS was 10% in the cabergoline group and 21% in the control group. Thus the incidence of OHSS was significantly reduced, by almost 50%, in the cabergoline group in comparison with the control group (RR: 0.5, 95% CI: ), with an absolute risk reduction following cabergoline administration of 11% (ARR: 0.11, 95% CI: ). The corresponding number needed to treat (NNT) was 9. OHSS was stratified into mild, moderate and severe according to Golan s classification [23]. Although the incidence of both severe and moderate OHSS was almost 30% lower in the cabergoline group, this difference was not statistically significant (RR: 0.33, 95% CI: and 0.34, 95% CI: ). As regards the onset of OHSS, we could stratify the OHSS cases into an early ( 7 9 days from day of HCG administration) and a late (10 days) onset. While cabergoline markedly reduced early onset OHSS, there was no statistical evidence of a reduction of late onset OHSS in comparison with the control group. There was evidence of a statistically significant increase in the signs of OHSS on the day of ET in the form of hemoconcentration (RR: 0.44, 95% CI: ), ascitic fluid collection and ovarian volume in the control group in comparison with the cabergoline group. Consequently, the hospitalization rate was lower in the cabergoline group in comparison with the control group, but this difference was not statistically significant (RR: 0.42, 95% CI: ) (Table 2). There was no evidence of a statistically significant difference between the groups as regards the number of oocytes retrieved (23.4 ± 2.7 vs. 24 ± 2.6), number of MII oocytes (16.4 ± 2.8 vs ± 2.7), or fertilization rate (72% vs. 74%). 67

7 Enrollment Assessed for eligibility (n= 250) Excluded (n= 50) Declined to participate (n= 50 ) Randomized (n= 200) Allocated to Cabergoline (n= 100) Received allocated intervention (n= 100 ) Did not receive allocated intervention (give reasons) (n= 0) Allocation Allocated to control (n= 100) Received allocated intervention (n=100 ) Did not receive allocated intervention (give reasons) (n=0) Lost to follow-up (give reasons) (n= 0) Discontinued intervention (n=1) due to nausea & vomiting Follow-Up Lost to follow-up (give reasons) (n=0) Discontinued intervention (n= 0) Analysed (n= 100) Excluded from analysis (n=0) Analysis Analysed (n=100) Excluded from analysis (n=0) Figure.1. Flow diagram shows patients enrollment in the study. 68

8 Table I: Demographic criteria of included women in both groups Cabergoline group (Group I) (n=100) mean± SD Control group (Group II) (n=100) mean± SD P- value * Age (years) 27.6± ±3.8 NS BMI (Kg/m 2 ) 24.56±2.7 25±3.3 NS Cause of Infertility (n ;%) Male factor 42 (44.2%) 45 (46.8%) NS Anovulation 22 (23% ) 20 (20.8%) NS Unexplained infertility 16 (16.8) 13 (13.5%) NS Tubal factor 15 (15.7%) 18 (18.7%) NS No. women with PCOS (n ;%) 47 (49.5%) 50 (52%) NS E2 on day of hcg ± ± 377 NS * P value of 0.05 was considered statistically significant Table II: Clinical outcomes in cabergoline and control groups Cabergoline (Group I) Control (Group II) RR (95% CI) p-value mean± SD mean± SD Severe OHSS (n ;%) 1(10%) 3 (14%) 0.7 ( ) NS Moderate OHSS (n ;%) 4(40%) 11(52%) 0.76 ( ) NS Mild OHSS (n ;%) 5 (50%) 7 (33%) 1.50( 0.63 to 3.57) NS Early onset OHSS (n ;%) 0 8 (38%) 0.12 ( ) NS Late onset OHSS (n ;%) 10 (100%) 13 (61%) 1.56 ( ) 0.01 ovarian volume (ml) 129.3± ±56.6 < Ascitic fluid (cm) 4.6± ±1.7 < OHSS incidence (n ;%) 10 (10 %) 21 (21 % ) 0.5 ( ) Haemoconcentration (n; %) (8/100) (8.4%) ( 18/100) (18.75% ) 0.44 ( ) 0.03 Hospitalization (n; %) 1(10%) 5 (23%) 0.42 ( ) NS * P value of 0.05 was considered statistically significant 69

9 Table III: ovarian stimulation & pregnancy outcomes in cabergoline and control groups Cabergoline Group (n=100) Mean ± SD Control Group (n=100) Mean ± SD RR (95% CI) p-value No. oocytes retrieved per woman randomized 23.4±2.7 24±2.6 NS No. MII oocytes per woman randomized 16.4± ±2.7 NS Fertilization rate (%) 72 % 74% NS Clinical pregnancy rate per woman randomized Early miscarriage rate per woman randomized Ongoing pregnancy rate per woman randomized 42 (42%) 41(41%) 1.02 ( ) NS 5 (5%) 5 (5%) 1.0 ( ) NS 37(37%) 36(36%) 0.90 ( ) NS Live birth rate per woman randomized 37(37%) (0.68 to 2.35) NS * P value of 0.05 was considered statistically significant As regards pregnancy outcomes there was no evidence of a statistically significant difference between the groups in the clinical pregnancy rate (42% vs. 41%); early miscarriage rate (5% vs. 5%), ongoing pregnancy rate (37% vs. 36%) and live birth rate (37% vs. 36%). There was no report of any fetal congenital anomalies in either the cabergoline group or the control group (Table 3). Comments This prospective randomized controlled trial has demonstrated that the use of a small dose of cabergoline (0.25 mg) in high-risk women reduces the risk of OHSS development. Cabergoline is a dopamine agonist that prevents phosphorylation of the D2 receptor. We assumed that 0.25 mg of cabergoline could be safely and effectively reduce the incidence of OHSS in women undergoing ICSI treatment without harming treated women or their babies. Although this study has some limitations, owing to the lack of sample size calculation, that need to be taken into account when considering its generalizability, our data show a favorable effect of cabergoline in reducing the incidence of OHSS with an absolute risk reduction of 11%, which means that eleven women out of 100 will not experience OHSS 70

10 under cabergoline administration that they would have as controls. The corresponding number needed to treat was 9, which mean nine women must be treated with 0.25 mg cabergoline for 8 days to prevent one extra OHSS that would have happened without treatment. As severe OHSS, the clinically most relevant outcome, is rare, the data do not suggest that cabergoline could reduce the risk of both moderate and severe OHSS. Our study findings also suggest that the use of cabergoline may not impair implantation and pregnancy rates, which means that cabergoline might not alter the endometrial angiogenesis [Alvarez et al., 2007; Salah Edeen et al., 2009], but our study was not powered to detect such a statistical difference between the groups. Different studies have evaluated the use of cabergoline as a preventive strategy for OHSS with a varying dose from 0.5 mg up to 1.0 mg [Ata et al., 2009]. Recently, a systematic review and meta-analysis of four randomized controlled studies (n = 570 women), including the present study, comparing cabergoline versus placebo or no treatment for the prevention of severe OHSS was published. The studies used different regimens, 0.5 mg of cabergoline for 3 weeks beginning on the day after oocyte retrieval [Alvarez et al., 2007]; 0.5 mg tablet of cabergoline daily for 8 days [Alvarez et al., 2007]; and 0.5 mg, one tablet on two successive days, repeated 1 week later, starting from day of HCG injection [Salah Edeen et al., 2009]. There was evidence of a statistically significant reduction in the incidence of OHSS in the cabergoline group (OR: 0.41, 95% CI: ) with an absolute risk reduction of 12% (95% CI: %), but there was no statistically significant evidence of a reduction in severe OHSS (OR: 0.50, 95% CI ) which agrees with our results [Youssef et al., 2010] As regards the effect of cabergoline on endometrial angiogenesis, there was no evidence of statistically significant differences in live birth rate, ongoing pregnancy rate, clinical pregnancy rate and miscarriage rate between the groups. In addition, there was no report of congenital anomalies either in cabergoline group or control group. Recently, concern was raised about the potential risks of new onset of cardiac valvulopathy with the use of dopamine agonists, especially cabergoline and pergolide, in patients with Parkinson s disease and requiring high doses for long duration [Schade et al., 2007]. Most studies of dopamine agonist use in prolactinoma, however, where dopamine agonist doses are 10-fold lower than those employed in Parkinson s disease, have not observed valvular abnormalities [Herring et al., 2009; Vallette et al., 2009]. On the other hand, a case of severe tricuspid regurgitation has been reported in a woman with acromegaly who had been taking low-dose (0.5 mg/day) cabergoline for one year, and the morphology of the tricuspid valve was typical of cabergoline related valvulopathy. Thus, it is concluded that cabergoline may 71

11 not be totally safe even at lower doses, and close echocardiography monitoring is recommended in patients receiving cabergoline treatment, regardless of the dose level employed [Izgi et al., 2010; Tan et al., 2010]. For OHSS, however, lower doses are used over a much shorter duration and that might reduce the risk of cardiac valve disease. In conclusion, the dopamine agonist, cabergoline, at a low dose (0.25 mg) as a prophylactic strategy leads to a significantly lower overall OHSS incidence in high-risk patients without jeopardizing the pregnancy outcomes. Funding None. Acknowledgement None. 72

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