Follicular Aspiration Is Superior to Coasting as Effective Prophylactic Procedure against Ovarian Hyperstimulation Syndrome

Objectives: Evaluation of outcome follicular aspiration compared to coating procedure for infertile women undergoing ICSI regarding frequency and se- verity of ovarian hyperstimulation syndrome (OHSS). Patients & Methods: Infertile PCOS women underwent controlled ovarian stimulation with luteal phase GnRH -agonist long down- regulation protocol. Women develo ped se- rum E2 level > 4000 pg/ml and/or >20 follicles of ≥10 mm in diameter were randomly divided to receive coasting strategy (Coasting group) or TVU-guided aspiration (Aspiration group). When ≥3 follicles were ≥18 mm and serum E 2 level was <3000 pg/ml, Gn RH agonist was continued, and 10,000 IU was administered 36 h before oocyte retrieval , and ICSI was pe r- formed 72-hr thereafter and the frequency of moderate -to-severe OHSS was determined. Results: 82 women developed criteria for categorization and 21 women (25.6%) developed moderate -to-severe OHSS; 5 women of aspiration and 16 of Coasting group ; with significantl y (P = 0.005) lower frequency in aspiration group. Twenty women developed ascites; 3 women had clinically detectable, while 17 women had US detected ascites with significantly (P = 0.039) higher frequency among women that had coasting. All other manife- stations of OHSS were significantly lower with as piration procedure. Both coasting and aspiration therapy significantly reduced serum E2 and ovarian diameter on day of hCG injection compared to estimates taken at time of c a- tegorization. Conclusion: Coasting pr ocedure prior to hCG injection could decrease incidence of OHSS and lessens its manifestation. Follicular aspir a- tion provided more superior results and improved outcome of these women. Any of these modalities could be provided to infertile high -risk women ac- cording to the availability of experiences and patients’ selection. How to cite this paper: Elnagar, W.M. and Ebian, H.F. (2019) Follicular Aspiration Is Superior to Coasting as Effective Prophylac- tic Procedure against Ovarian Hyperstimula- tion Syndrome. Open Journal of Obstetrics and Gynecology, 9, 679-690. https://doi.org/10.4236/ojog.2019.95067 Received: April 23, 2019 Accepted: May 19, 2019 Published: May 22, 2019 Copyright © 2019 by author(s) and Scientific Research Publishing Inc. This work is licensed under the Creative Commons Attribution International License (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/ Open Access W. M. Elnagar, H. F. Ebian DOI: 10.4236/ojog.2019.95067 680 Open Journal of Obstetrics and Gynecology

Ovarian Hyperstimulation Syndrome, PCOS, Follicular Aspiration, Coasting Procedure 1. Introduction Ovarian stimulation (OS) is c rucial for pregnancy success in assisted reprodu c- tive technology treatments [1]. However, ovarian hyperstimulation syndrome (OHSS) in hyper-responders to OS is common despite being self-limited [2]. It is a severe complication for patients undergoing IVF/ICSI [3]. Vascular endothelial growth factor (VEGF) plays the most important role in pathogenesis of OHSS and is related to concomitant increased capillary permeability and fluid rete n- tion [2]. Presence of genetic mutations is already known to be involved in OHSS [4]. Women who had follicle-stimulating hormone receptor variant asparagine/serine in amino acid 680 are at higher risk for OHSS during IVF [5]. Also, a potential link was suggested betwe en OHSS and mutations of the FLT4 gene which encodes Fms-related tyrosine kinase 4 [4]. Production of some pro- inflammatory mole- cules such as IL -8, IL -1, IL -6 and TNF -α was incriminated in pathogenesis of OHSS [2]. Therapeutic options to reduce the incidence and lessen the severity of OHSS are variant and with contradictory results [6]. The “freeze-all” strategy provides benefit for high-responder women who were at risk of OHSS, but should not be offered universally [7]. Addition of hp-hMG on day of antagonist initiation si g- nificantly lowers OHSS rates [8]. In sequential ovarian stimulation cycles, ind i- vidualized doses of follitropin delta decr eased the risk of moderate/severe OHSS than conventional follitropin alfa regimen [9]. Multiple drugs were evaluated for prophylaxis against or treatment of OHSS [10]. In rat model of OHSS, administration of myo -inositol and metformin si g- nificantly reduced VEGF expression and decreased vascular permeability [11]. Prophylactic vitamin D supplemental therapy effectively increased pigment ep i- thelium-derived factor which protected against OHSS [12]. Montelukast [13] and resveratrol [14] induced reduction of ovarian diameter and VEGF expression. Coasting is a well-known strategy to decrease severity of OHSS [15] and acce- leration of coasting in cases of OHSS through treatment with GnRH -ant after pituitary suppression with GnRH reduces estradiol (E2) level, and avoids cycle cancellation with prevention of OHSS [16]. Thus, the current study tried evalua- tion of outcome follicular aspiration compared to coating procedure for infertile women undergoing ICSI regarding the frequency and severity of OHSS. 2. Design Prospective comparative clinical trial. W. M. Elnagar, H. F. Ebian DOI: 10.4236/ojog.2019.95067 681 Open Journal of Obstetrics and Gynecology 3. Setting Department of Obstetrics & Gynecology, and clinical pathology, Faculty of Medicine, Zagazig University. 4. Patients & Methods The study protocol was approved by the Local Ethical Committee. All PCOS i n- fertile women assigned to undergo ICSI cycles since June 2016 were eligible for evaluation. Inclusion criteria included the presence of at least 20 pre-ovulatory follicles in both ovaries with serum E2 level ≥ 3000 pg/ml in PCOS women. PCOS was diagnosed according to Rotterdam criteria depending on the presence of at least two of oligomenorrhic and/or anovulatory cycles, clinical and/or bi o- chemical s igns of hyperandrogenemia with serum total testosterone level > 0.8 ng/ml and polycystic ovaries containing > 12 follicles of 2 - 9 mm in diameter and/or an ovarian volume > 10 ml per ovary by vaginal ultrasound [17]. Exclu- sion criteria included BMI > 30 kg/m 2, history of previous development of OHSS, endocrinopathies, maintenance on insulin- sensitizing drugs, receiving GnRH antagonists. All women underwent controlled ovarian stimulation (COS) with luteal phase GnRH-agonist long down- regulation protocol using subcutaneous injection of Triptorelin acetate 0.1 daily (DecapeptylGynTM; Ferring, Kiel, Germany) on 21 st day of cycle that precede stimulation. Adequate pituitary desensitization was es- tablished on 2 nd or 3rd day of menses and ovarian stimulation with gonadotr o- pins was started on 3 rd day of the oncoming cycle by the use of recomb i- nant-FSH (r -hFSH, Gonal -F®, 75 UI, Serono, Switzerland) at a daily dose 75 - 150 IU ac cording to the individual response to treatment for 5 - 7 days. Fo l- low-up consisted of estimation of serum E2 every 2 days and ultrasonographic s- canning by 7 - 10 MHZ probe (Voluson 730 PRO V, GE Healthcare, USA) was done every 3 - 5 days. Women developed serum E 2 level of >4000 pg/ml and/or sonographic dete c- tion of >20 follicles each of ≥10 mm in diameter and at least 20% of follicles were ≥15 mm diameter were included in the trial and were randomly, using sealed envelops, divided into two equal groups: Co asting group included women underwent coasting strategy and Aspiration group included women underwent follicular aspiration. For coasting group, serum E 2 and FSH levels were measured from the day of coasting until the day of hCG administration. For women o f as- piration group, TVU -guided oocyte retrieval was performed under propofol s e- dation using single -lumen 17-gauge needle (Cook Ireland, Limerick, Ireland) at maintained pressure of 80 mmHg. When at least three follicles reached a mean diameter of ≥18 mm and serum E2 level was <3000 pg/ml, GnRH agonist was continued and a single intramu s- cular injection of 10,000 IU hCG (Choriomon, IBSA, Switzerland) was admini s- tered 36 h before the planned time of oocyte retrieval and then ICSI was per- formed, 72 -hr thereaft er, a maximum of two embryos were transferred, as d e- scribed previously by Huisman et al. [18]. All embryos were scored according to W. M. Elnagar, H. F. Ebian DOI: 10.4236/ojog.2019.95067 682 Open Journal of Obstetrics and Gynecology Steer et al. [19] on day of transfer and embryos in G1 and G2 grade having 4 blastomeres on day 2 or ≥ 8 blastomeres on day 3, less than 20% fragmentation, and no multinuclear blastomeres were transferred. Luteal phase support was started the day after ovum pick up by the vaginal administration of progesterone (Cyclogest 2 00 mg suppositories; Actavis UK Limited) twice daily for 16 days and was continued for up to 12 weeks if pregnancy occurred. 5. Diagnosis and Classification of OHSS OHSS was diagnosed acco rding to the criteria of Golan et al. [20] as mild OHSS on presence of abdominal distension and discomfort (Grade 1) with nausea, vomiting and/or diarrhea and ovarian enlargement up to 12 cm (Grade 2). Moderate OHSS (Grade 3) was diagnosed in patients had clinical presentation of grade 2 OHSS plus ultrasonographic evidence of ascites. OHSS was considered severe (Grade 4) if there was clinical evidence of grade 3 OHSS plus clinical ev i- dence of ascites and/or hydrothorax, breathing difficulties; and was considered as severe OHSS of grade 5 if patient of grade 4 developed increased blood visco s- ity due to hemoconcentration, as well asdecreasedrenal perfusion [21]. 6. Evaluated Parameters 1) Primary outcome is the frequency of moderate-to-severe OHSS. 2) The secondary outcome included the following items: - Presence and severity of abdominal pain was graduated using a numerical pain visual analogue scale (V AS) with 0 means no pain and 10 means severe intolerable pain [22]. - Nausea and/or vomiting and sense of abdominal distension were scored u s- ing verbal analogue scale as nil, mild, moderate, and severe symptom. - Hospitalization rate and requirement of paracentesis. 7. Statistical Analysis Obtained data were presented as mean ± SD, numbers and percentages. Results were analyzed using One-way ANOVA test, Student t-test and Chi-square test (X2 test). Statistical analysis was conducted using the IBM SPSS (Version 23, 2015) for Windows statistical package. P value < 0.05 was considered statistically significant. 8. Results Throughout the duration of the study, 82 women developed criteria for categ o- rization (Figure 1 ). There were non -significant differences between women of both groups as regards basal data of enrolled women (Table 1 ). At time of categorization, serum E2 levels increased significantly in all p a- tients compared to their respective basal E2 levels. On day of hCG injection, e s- timated serum E2 levels significantly decreased in patients of both groups in comparison to levels estimated at time of categorization, but were still signif i- cantly higher compared to basal E2 levels. Serum E2 levels estimated at time of W. M. Elnagar, H. F. Ebian DOI: 10.4236/ojog.2019.95067 683 Open Journal of Obstetrics and Gynecology categorization were non- significantly lower in patients who underwent aspir a- tion than patients undertook coasting procedure. On t he other hand, serum E2 levels estimated on day of hCG injection were significantly lower in patients of aspiration group than in patients of coasting group ( Figure 2 ). On day of hCG injection, serum FSH levels were significantly increa sed in all studied patients in comparison to corresponding levels estimated at time of categorization with non-significantly higher levels were estimated in women of aspiration group than women of coasting group (Table 2 ). On day of hCG injection, ovarian diameter estimated in all studied patients was significantly decreased compared to their respective diameter determined at time of categorization with significantly smaller ovarian diameter in patients of aspiration group than in patients of coasting group ( Table 2 , Figure 3 ). Considering the primary outcome; 21 women developed moderate -to-severe OHSS for a frequency of 25.6% ( Figure 1 ). Seventeen women developed mo d- erate OHSS a nd only four women developed severe OHSS of grade 4 and no women developed severe OHSS of grade 5. Only five women of aspiration group, while 16 women of Coasting group developed moderate -to-severe OHSS with significantly (P = 0.005) lower frequency in asp iration group. The remaining 61 women developed mild OHSS; 36 and 25 in aspiration and coasting groups, r e- spectively (Figure 4 ). Twenty women developed ascites; 14 in coasting and 6 in aspiration groups. Three women; 2 in coasting and o ne in aspiration groups, had clinically dete c- tableascites, while 17 women had US detected ascites clinically received coasting treatment with significantly ( P = 0.039) lower frequency of ascites among wo m- en of aspiration group. All women developed abdomina l distension of varied grades, but women received aspiration showed significantly ( P = 0.002) lower distension score than women of coasting group. Nausea and vomiting occurred in 73 women and 47 women, respectively with significantly lower scores in women of aspiration versus coasting group. All women had pain with varied scores with significantly lower scores among women of aspiration group ( Table 3). Twelve patients (14.6%) required hospitalization; 8 patients in Coasting and 4 patients in aspiration group with non-significantly (P = 0.211) lower frequency of hospitalization in aspiration group, but no patient required paracentesis. Table 1 . Data of studied women at time of evaluation. Group Data Coasting (n = 41) Aspiration (n = 41) P value Age (years) 27.5 ± 4.3 28.3 ± 3.8 0.522 Weight (kg) 82 ± 4.4 80.8 ± 5.6 0.109 Height (cm) 167.1 ± 3.4 166.3 ± 4 0.609 BMI (kg/m2) 29.4 ± 1.3 29.2 ± 1.9 0.327 Duration of infertility (years) 5.7 ± 1.5 6.2 ± 2 0.287 Basal FSH level (IU/L) 7.7 ± 1.4 7.5 ± 1 0.323 Basal E2 level (pg/ml) 3162.4 ± 579 3295.5 ± 479 0.219 Data are presented as mean ± SD; P > 0.05 indicates insignificant difference between both groups. W. M. Elnagar, H. F. Ebian DOI: 10.4236/ojog.2019.95067 684 Open Journal of Obstetrics and Gynecology Table 2 . Data of studied women determined on day of hCG injection. Group Variable Time Coasting (n = 41) Aspiration (n = 41) P value E2 level (pg/ml) Basallevel 3162.4 ± 579 3295.5 ± 479 0.219 Categorization 7150.5 ± 1016 6602 ± 1495.4 0.056 Day of hCG injection 6579.3 ± 1240 5827.2 ± 1498.6 0.015 P1 <0.001 <0.001 P2 0.025 0.022 FSH level (IU/L) Categorization 7.7 ± 1.4 7.8 ± 1.6 0.719 Day of hCG injection 9 ± 3.4 9.7 ± 3.8 0.386 P2 0.027 0.01 Ovarian diameter (cm) Categorization 14.9 ± 5.8 14.3 ± 5.4 0.461 Day of hCG injection 12.4 ± 3.9 10.5 ± 4.7 0.047 P2 0.028 0.001 Data are presented as mean ± SD; P indicates insignificance of difference between both groups; P1: ind i- cates significance of difference in E2 serum levels between basal and at categorization levels; P2: indicates significance of difference between measures estimated at time of categorization and on day of hCG injec- tion; P 0.05: indicates non-significant difference. Table 3 . OHSS manifestations scoring of women enrolled in both groups. Manifestations Score Abdominal distension Score items 1 2 3 4 Total Group Coasting 7 (17%) 16 (39%) 17 (41.5) 1 (2.5%) 2.3 ± 0.8 Aspiration 19 (46.3%) 14 (34.2%) 8 (19.5%) 0 1.7 ± 0.7 P value 0.031 0.002 Nausea Score items 0 1 2 3 Total Group Coasting 7 (17%) 23 (56.1%) 9 (22.5%) 2 (4.9%) 1.7 ± 0.8 Aspiration 2 (4.9%) 14 (34.2%) 19 (46.3%) 6 (14.6%) 1.1 ± 0.7 P value 0.015 0.0015 Vomiting Score items 0 1 2 3 Total Group Coasting 14 (34.2%) 16 (39%) 11 (26.8%) 0 1 ± 0.8 Aspiration 21 (51.2%) 17 (41.5) 3 (7.3%) 0 0.6 ± 0.6 P value 0.049 0.009 Pain Score items 2 3 4 5 Total Group Coasting 10 (24.4%) 17 (41.5) 11 (26.8%) 3 (7.3%) 3.2 ± 0.9 Aspiration 19 (46.3%) 16 (39%) 5 (12.2%) 1 (2.5%) 2.7 ± 0.8 P value 0.108 0.007 Data are presented as numbers & percentages; P indicates insignificance of difference between both groups. W. M. Elnagar, H. F. Ebian DOI: 10.4236/ojog.2019.95067 685 Open Journal of Obstetrics and Gynecology Figure 1. Consort Flow sheet. Figure 2. Mean serum E2 levels estimated in patients of both groups ( indicates significant inter-group difference). Figure 3. Mean (±SD) ovarian diameter estimated at time of cate gorization and on day of hcG injection in women of both groups ( significant difference versus at categorization; significant inter-group difference). W. M. Elnagar, H. F. Ebian DOI: 10.4236/ojog.2019.95067 686 Open Journal of Obstetrics and Gynecology Figure 4. Patients’ distribution according to severity of OHSS ( indicates significant inter-group difference). 9. Discussion The therapeutic policies provided for patients of both groups did favorably as manifested by the significant reduction of serum E2 and ovarian diameter on day of hCG injection in comparison to estimates taken at time of categorization. These results point to a fact that in women at high -risk for development of OHSS, certain therapeutic modalities could ameliorate or lessen it s manifest a- tions down to acceptable level. In support of this assumption, no patient deve l- oped severe OHSS of grade 5, only three women developed clinically detectable ascites, but no patient required paracentesis. Furthermore, about 75% of patients developed mild symptoms ranging between grade one and two. The obtained result s concerning patients received coasting procedure are in line D’Angelo et al. [23] who reviewed RCT assessed the effect of coasting on prevention of OHSS and reported lower rates of OHSS with coasting versus no coasting by rates suggesting that if 45% of women developed moder ate or severe OHSS without coasting, only 4% - 17% would develop it with coasting. Also, Abide Yayla et al. [24] in their retrospective study of women used coasting to avoid OHSS in 100 high -risk women and documented that all women had reached to embryo transfer stage and reported clinical pregnancy rate of 44%. Also, Kailasam et al. [25] prospectively, found coasting for 6 days with subs e- quent blastocyst transfer may be an effective strategy for patients at risk of OHSS with no detrimental effects on blastocyst development or live birth outcome Concerning comparative study for coasting and follicular aspiration as pr e- ventive strategy for OHSS, D’Angelo et al. [25] reviewed literature for RCT as- sessing the efficacy of coasting versus unilateral follicular aspiration and doc u- mented that data were not pooled due to heterogeneity. Moreover, review of r e- cently published articles detected only one study compared the effect of coasting versus aspiration on incidence of OHSS; however, that study reported no diffe r- ence between follicular reduction prior to HCG and coasting, in terms of OHSS W. M. Elnagar, H. F. Ebian DOI: 10.4236/ojog.2019.95067 687 Open Journal of Obstetrics and Gynecology reduction as a primary endpoint [26], these results are contradictory to the result of the current study and this difference could be attributed to multiple imita- tions of Bushaqer’s study [26], firstly, the sample size is small; 39 women were divided into two study groups and 8 women developed OHSS; 6 versus 2 women in each group, respectively but these numbers could not reach the appropriate limit for statistical analysis to be significant or non- significant. Secondly, B u- shaqer’s study [26] did not comment on the frequencies of OHSS severity m a- nifestations, which are more important than the sole frequency of OHSS. On the other hand, the current study reported significantly reduced OHSS manifestations, both as frequency and severity, with follicular aspiration than with coasting, so the current study approved the efficacy and safety of follicular aspiration i n comparison to coasting despite of proved efficacy of coasting. In support of these findings, an early study conducted by Zhu et al. [27] had docu- mented that follicular aspiration during the selection phase can prevent severe OHSS and reduce OHSS prevalence in patients with PCOS undergoing COH. More recently, Haydardedeoglu et al. [28] documented that in poor responders both follicular aspiration and flushing has similar results, but follicular flushing is time consuming. The reported clinical effectiveness of coasting could be attributed to affecting follicles, especially immature follicles, through apoptosis with significant d e- crease in VEGF expression and secretion [29] [30]. Thus, coasting acts through inhibition of VEGF protein transcription and translation which is a time-consuming process and is unpredictable to be absolute inhibition. On the other hand, follicular aspiration allows removal of the already formed VEGF thus rapidly eliminating its effect and giving no chance by oocyte removal for re-synthesis of growth fa ctors [31] [32]. Additionally, aspiration removes other cytokines that may have a role in induction of OHSS as IL -2 which increased l e- vels induce vascular dilat ation syndrome [33]. IL-17 [34] melatonin and melato- nin receptor 2 [3] that were reported to be correlated with incidence and severity of OHSS. These data could explain the reported superior clinical effect of aspir a- tion in comparison to coasting procedure. 10. Conclusion Coasting procedure prior to hCG injection could decrease the incidence of OHSS and lessens its manifestation. However, follicular aspiration provided more superior results and improved outcome of these women. Any of these modalities could be provided to in fertile high -risk women according to the availability of experiences and patients’ selection. Wider scale studies are man- datory to establish the results and to evaluate underlying mechanisms for the reported clinical effectiveness of these procedures. Conflicts of Interest The authors declare no conflicts of interest regarding the publication of this p a- per. W. M. Elnagar, H. F. Ebian DOI: 10.4236/ojog.2019.95067 688 Open Journal of Obstetrics and Gynecology

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