{"paper_id":"b364a4ea-ffdb-4b10-95b6-003ff6e3b371","body_text":"Open Journal of Obstetrics and Gynecology, 2019, 9, 679-690 \nhttp://www.scirp.org/journal/ojog \nISSN Online: 2160-8806 \nISSN Print: 2160-8792 \n \nDOI: 10.4236/ojog.2019.95067  May 22, 2019 679 Open Journal of Obstetrics and Gynecology \n \n \n \n \nFollicular Aspiration Is Superior to Coasting as \nEffective Prophylactic Procedure against \nOvarian Hyperstimulation Syndrome \nWalid Mohamed Elnagar1*, Huda Fathy Ebian2 \n1Obstetrics and Gynecology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt \n2Clinical Pathology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt \n \n \n \nAbstract \nObjectives: Evaluation of outcome follicular aspiration compared to coating \nprocedure for infertile women undergoing ICSI regarding frequency and se-\nverity of ovarian hyperstimulation syndrome (OHSS).  Patients & Methods: \nInfertile PCOS women underwent controlled ovarian stimulation with luteal \nphase GnRH -agonist long down- regulation protocol. Women develo ped se-\nrum E2 level > 4000 pg/ml and/or >20 follicles of ≥10 mm in diameter were \nrandomly divided to receive coasting strategy (Coasting group) or \nTVU-guided aspiration (Aspiration group). When ≥3 follicles were ≥18  mm \nand serum E 2 level was <3000 pg/ml, Gn RH agonist was continued, and \n10,000 IU was administered 36 h before oocyte retrieval , and ICSI was pe r-\nformed 72-hr thereafter and the frequency of moderate -to-severe OHSS was \ndetermined. Results: 82 women developed criteria for categorization and 21 \nwomen (25.6%) developed moderate -to-severe OHSS; 5 women of aspiration \nand 16 of Coasting group ; with significantl y (P = 0.005) lower frequency in \naspiration group. Twenty women developed ascites; 3 women had clinically \ndetectable, while 17 women had US detected ascites with significantly (P = \n0.039) higher frequency among women that had coasting. All other manife-\nstations of OHSS were significantly lower with as piration procedure. Both \ncoasting and aspiration therapy significantly reduced serum E2 and ovarian \ndiameter on day of hCG injection compared to estimates taken at time of c a-\ntegorization. Conclusion: Coasting pr\nocedure prior to hCG injection could \ndecrease incidence of OHSS and lessens its manifestation. Follicular aspir a-\ntion provided more superior results and improved outcome of these women. \nAny of these modalities could be provided to infertile high -risk women ac-\ncording to the availability of experiences and patients’ selection. \nHow to cite this paper: Elnagar, W.M. and \nEbian, H.F. (2019) Follicular Aspiration Is \nSuperior to Coasting as Effective Prophylac-\ntic Procedure against Ovarian Hyperstimula-\ntion Syndrome. Open Journal of Obstetrics \nand Gynecology, 9, 679-690. \nhttps://doi.org/10.4236/ojog.2019.95067 \n \nReceived:  April 23, 2019 \nAccepted: May 19, 2019 \nPublished: May 22, 2019 \n \nCopyright © 2019 by author(s) and  \nScientific Research Publishing Inc. \nThis work is licensed under the Creative \nCommons Attribution International  \nLicense (CC BY 4.0). \nhttp://creativecommons.org/licenses/by/4.0/   \n  \nOpen Access\n\nW. M. Elnagar, H. F. Ebian \n \n \nDOI: 10.4236/ojog.2019.95067 680 Open Journal of Obstetrics and Gynecology \n \nKeywords \nOvarian Hyperstimulation Syndrome, PCOS, Follicular Aspiration, Coasting \nProcedure \n \n1. Introduction \nOvarian stimulation (OS) is c rucial for pregnancy success in assisted reprodu c-\ntive technology treatments  [1]. However, ovarian hyperstimulation syndrome \n(OHSS) in hyper-responders to OS is common despite being self-limited [2]. It is \na severe complication for patients undergoing IVF/ICSI [3]. Vascular endothelial \ngrowth factor (VEGF) plays the most important role in pathogenesis of OHSS \nand is related to concomitant increased capillary permeability and fluid rete n-\ntion [2]. \nPresence of genetic mutations is already known to be involved in OHSS  [4]. \nWomen who had follicle-stimulating hormone receptor variant asparagine/serine in \namino acid 680 are at higher risk for OHSS during IVF  [5]. Also, a potential link \nwas suggested betwe en OHSS and mutations of the FLT4 gene which encodes \nFms-related tyrosine kinase 4  [4]. Production of some pro- inflammatory mole-\ncules such as IL -8, IL -1, IL -6 and TNF -α was incriminated in pathogenesis of \nOHSS [2]. \nTherapeutic options to reduce the incidence and lessen the severity of OHSS \nare variant and with contradictory results [6]. The “freeze-all” strategy provides \nbenefit for high-responder women who were at risk of OHSS, but should not be \noffered universally [7]. Addition of hp-hMG on day of antagonist initiation si g-\nnificantly lowers OHSS rates  [8]. In sequential ovarian stimulation cycles, ind i-\nvidualized doses of follitropin delta decr eased the risk of moderate/severe OHSS  \nthan conventional follitropin alfa regimen [9]. \nMultiple drugs were evaluated for prophylaxis against or treatment of OHSS \n[10]. In rat model of OHSS, administration of myo -inositol and metformin si g-\nnificantly reduced VEGF expression and decreased vascular permeability  [11]. \nProphylactic vitamin D supplemental therapy effectively increased pigment ep i-\nthelium-derived factor which protected against OHSS [12]. Montelukast [13] and \nresveratrol [14] induced reduction of ovarian diameter and VEGF expression. \nCoasting is a well-known strategy to decrease severity of OHSS  [15] and acce-\nleration of coasting in cases of OHSS through treatment with GnRH -ant after \npituitary suppression with GnRH  reduces estradiol (E2) level, and avoids cycle \ncancellation with prevention of OHSS  [16]. Thus, the current study tried evalua-\ntion of outcome follicular aspiration compared to coating procedure for infertile \nwomen undergoing ICSI regarding the frequency and severity of OHSS. \n2. Design \nProspective comparative clinical trial. \n\nW. M. Elnagar, H. F. Ebian \n \n \nDOI: 10.4236/ojog.2019.95067 681 Open Journal of Obstetrics and Gynecology \n \n3. Setting \nDepartment of Obstetrics & Gynecology, and clinical pathology, Faculty of \nMedicine, Zagazig University. \n4. Patients & Methods \nThe study protocol was approved by the Local Ethical Committee. All PCOS i n-\nfertile women assigned to undergo ICSI cycles since June 2016 were eligible for \nevaluation. Inclusion criteria included the presence of at least 20  pre-ovulatory \nfollicles in both ovaries with serum E2 level ≥ 3000 pg/ml in PCOS women. \nPCOS was diagnosed according to Rotterdam criteria depending on the presence \nof at least two of oligomenorrhic and/or anovulatory cycles, clinical and/or bi o-\nchemical s igns of hyperandrogenemia with serum total testosterone level > 0.8 \nng/ml and polycystic ovaries containing > 12 follicles of 2  - 9 mm in diameter \nand/or an ovarian volume > 10 ml per ovary by vaginal ultrasound  [17]. Exclu-\nsion criteria included BMI > 30 kg/m\n2, history of previous development of \nOHSS, endocrinopathies, maintenance on insulin- sensitizing drugs, receiving \nGnRH antagonists.  \nAll women underwent controlled ovarian stimulation (COS) with luteal phase \nGnRH-agonist long down- regulation protocol using subcutaneous injection of \nTriptorelin acetate 0.1 daily (DecapeptylGynTM; Ferring, Kiel, Germany) on 21 st \nday of cycle that precede stimulation. Adequate pituitary  desensitization was es-\ntablished on 2 nd or 3rd day of menses and ovarian stimulation with gonadotr o-\npins was started on 3 rd day of the oncoming cycle by the use of recomb i-\nnant-FSH (r -hFSH, Gonal -F®, 75 UI, Serono, Switzerland) at a daily dose 75  - \n150 IU ac cording to the individual response to treatment for 5  - 7 days. Fo l-\nlow-up consisted of estimation of serum E2 every 2 days and ultrasonographic s-\ncanning by 7  - 10 MHZ probe (Voluson 730 PRO V, GE Healthcare, USA) was \ndone every 3 - 5 days.  \nWomen developed serum E 2 level of >4000 pg/ml and/or sonographic dete c-\ntion of >20 follicles each of ≥10 mm in diameter and at least 20% of follicles \nwere ≥15 mm diameter were included in the trial and were randomly, using \nsealed envelops, divided into two equal groups: Co asting group included women \nunderwent coasting strategy and Aspiration group included women underwent \nfollicular aspiration. For coasting group, serum E\n2 and FSH levels were measured \nfrom the day of coasting until the day of hCG administration. For women o f as-\npiration group, TVU -guided oocyte retrieval was performed under propofol s e-\ndation using single -lumen 17-gauge needle (Cook Ireland, Limerick, Ireland) at \nmaintained pressure of 80 mmHg.  \nWhen at least three follicles reached a mean diameter of ≥18  mm and serum \nE2 level was <3000 pg/ml, GnRH agonist was continued and a single intramu s-\ncular injection of 10,000 IU hCG (Choriomon, IBSA, Switzerland) was admini s-\ntered 36 h before the planned time of oocyte retrieval and then ICSI was per-\nformed, 72 -hr thereaft er, a maximum of two embryos were transferred, as d e-\nscribed previously by Huisman et al. [18]. All embryos were scored according to \n\nW. M. Elnagar, H. F. Ebian \n \n \nDOI: 10.4236/ojog.2019.95067 682 Open Journal of Obstetrics and Gynecology \n \nSteer et al. [19] on day of transfer and embryos in G1 and G2 grade  having 4 \nblastomeres on day 2 or ≥ 8 blastomeres on day 3, less than 20% fragmentation, \nand no multinuclear blastomeres were transferred. Luteal phase support was \nstarted the day after ovum pick up by the vaginal administration of progesterone \n(Cyclogest 2 00 mg suppositories; Actavis UK Limited) twice daily for 16 days \nand was continued for up to 12 weeks if pregnancy occurred.  \n5. Diagnosis and Classification of OHSS \nOHSS was diagnosed acco rding to the criteria of Golan et al. [20] as mild OHSS \non presence of abdominal distension and discomfort (Grade 1) with nausea, \nvomiting and/or diarrhea and ovarian enlargement up to 12 cm (Grade 2). \nModerate OHSS (Grade 3) was diagnosed in patients had clinical presentation of \ngrade 2 OHSS plus ultrasonographic evidence of ascites.  OHSS was considered \nsevere (Grade 4) if there was clinical  evidence of grade 3 OHSS plus clinical ev i-\ndence of ascites and/or hydrothorax, breathing difficulties; and was considered \nas severe OHSS of grade 5 if patient of grade 4 developed increased blood visco s-\nity due to hemoconcentration, as well asdecreasedrenal perfusion [21]. \n6. Evaluated Parameters  \n1) Primary outcome is the frequency of moderate-to-severe OHSS.  \n2) The secondary outcome included the following items: \n- Presence and severity of abdominal pain was graduated using a numerical \npain visual analogue scale (V AS) with 0 means no pain and 10 means severe \nintolerable pain [22]. \n- Nausea and/or vomiting and sense of abdominal distension were scored u s-\ning verbal analogue scale as nil, mild, moderate, and severe symptom.  \n- Hospitalization rate and requirement of paracentesis. \n7. Statistical Analysis \nObtained data were presented as mean ± SD, numbers and percentages. Results \nwere analyzed using One-way ANOVA test, Student t-test and Chi-square test (X2 \ntest). Statistical analysis was conducted using the IBM SPSS (Version 23, 2015) for \nWindows statistical package. P value < 0.05 was considered statistically significant. \n8. Results \nThroughout the duration of the study,  82 women developed criteria for categ o-\nrization (Figure 1 ). There were non -significant differences between women of \nboth groups as regards basal data of enrolled women (Table 1 ).  \nAt time of categorization, serum E2 levels increased significantly in all p a-\ntients compared to their respective basal E2 levels. On day of hCG injection, e s-\ntimated serum E2 levels significantly decreased in patients of both groups in \ncomparison to levels estimated at  time of categorization, but were still signif i-\ncantly higher compared to basal E2 levels. Serum E2 levels estimated at time of \n\nW. M. Elnagar, H. F. Ebian \n \n \nDOI: 10.4236/ojog.2019.95067 683 Open Journal of Obstetrics and Gynecology \n \ncategorization were non- significantly lower in patients who underwent aspir a-\ntion than patients undertook coasting procedure. On t he other hand, serum E2 \nlevels estimated on day of hCG injection were significantly lower in patients of \naspiration group than in patients of coasting group ( Figure 2 ). On day of hCG \ninjection, serum FSH levels were significantly increa sed in all studied patients in \ncomparison to corresponding levels estimated at time of categorization with \nnon-significantly higher levels were estimated in women of aspiration group \nthan women of coasting group (Table 2 ). \nOn day of hCG  injection, ovarian diameter estimated in all studied patients \nwas significantly decreased compared to their respective diameter determined at \ntime of categorization with significantly smaller ovarian diameter in patients of \naspiration group than in patients of coasting group (\nTable 2 , Figure 3 ). \nConsidering the primary outcome; 21 women developed moderate -to-severe \nOHSS for a frequency of 25.6% ( Figure 1 ). Seventeen women developed mo d-\nerate OHSS a nd only four women developed severe OHSS of grade 4 and no \nwomen developed severe OHSS of grade 5. Only five women of aspiration group, \nwhile 16 women of Coasting group developed moderate -to-severe OHSS with \nsignificantly (P = 0.005) lower frequency in asp iration group. The remaining 61 \nwomen developed mild OHSS; 36 and 25 in aspiration and coasting groups, r e-\nspectively (Figure 4 ). \nTwenty women developed ascites; 14 in coasting and 6 in aspiration groups. \nThree women; 2 in coasting and o ne in aspiration groups, had clinically dete c-\ntableascites, while 17 women had US detected ascites clinically received coasting \ntreatment with significantly ( P = 0.039) lower frequency of ascites among wo m-\nen of aspiration group. All women developed abdomina l distension of varied \ngrades, but women received aspiration showed significantly ( P = 0.002) lower \ndistension score than women of coasting group. Nausea and vomiting occurred \nin 73 women and 47 women, respectively with significantly lower scores in \nwomen of aspiration versus coasting group. All women had pain with varied \nscores with significantly lower scores among women of aspiration group (\nTable \n3). Twelve patients (14.6%) required hospitalization; 8 patients in Coasting and \n4 patients in aspiration group with non-significantly (P = 0.211) lower frequency \nof hospitalization in aspiration group, but no patient required paracentesis.  \n \nTable 1 . Data of studied women at time of evaluation. \nGroup Data Coasting (n = 41) Aspiration (n = 41) P value \nAge (years) 27.5 ± 4.3 28.3 ± 3.8 0.522 \nWeight (kg) 82 ± 4.4 80.8 ± 5.6 0.109 \nHeight (cm) 167.1 ± 3.4 166.3 ± 4 0.609 \nBMI (kg/m2) 29.4 ± 1.3 29.2 ± 1.9 0.327 \nDuration of infertility (years) 5.7 ± 1.5 6.2 ± 2 0.287 \nBasal FSH level (IU/L) 7.7 ± 1.4 7.5 ± 1 0.323 \nBasal E2 level (pg/ml) 3162.4 ± 579 3295.5 ± 479 0.219 \nData are presented as mean ± SD; P > 0.05 indicates insignificant difference between both groups. \n\nW. M. Elnagar, H. F. Ebian \n \n \nDOI: 10.4236/ojog.2019.95067 684 Open Journal of Obstetrics and Gynecology \n \nTable 2 . Data of studied women determined on day of hCG injection. \nGroup \nVariable Time \nCoasting  \n(n = 41) \nAspiration  \n(n = 41) P value \nE2 level (pg/ml) \nBasallevel 3162.4 ± 579 3295.5 ± 479 0.219 \nCategorization 7150.5 ± 1016 6602 ± 1495.4 0.056 \nDay of hCG injection 6579.3 ± 1240 5827.2 ± 1498.6 0.015 \nP1 <0.001 <0.001  \nP2 0.025 0.022  \nFSH level (IU/L) \nCategorization 7.7 ± 1.4 7.8 ± 1.6 0.719 \nDay of hCG injection 9 ± 3.4 9.7 ± 3.8 0.386 \nP2 0.027 0.01  \nOvarian  \ndiameter (cm) \nCategorization 14.9 ± 5.8 14.3 ± 5.4 0.461 \nDay of hCG injection 12.4 ± 3.9 10.5 ± 4.7 0.047 \nP2 0.028 0.001  \nData are presented as mean ± SD; P indicates insignificance of difference between both groups; P1: ind i-\ncates significance of difference in E2 serum levels between basal and at categorization levels; P2: indicates \nsignificance of difference between measures estimated at time of categorization and on day of hCG injec-\ntion; P < 0.05: indicates significant difference; P > 0.05: indicates non-significant difference. \n \nTable 3 . OHSS manifestations scoring of women enrolled in both groups. \nManifestations Score \nAbdominal \ndistension \nScore items 1 2 3 4 Total \nGroup \nCoasting 7 (17%) 16 (39%) 17 (41.5) 1 (2.5%) 2.3 ± 0.8 \nAspiration 19 (46.3%) 14 (34.2%) 8 (19.5%) 0 1.7 ± 0.7 \nP value 0.031 0.002 \nNausea \nScore items 0 1 2 3 Total \nGroup \nCoasting 7 (17%) 23 (56.1%) 9 (22.5%) 2 (4.9%) 1.7 ± 0.8 \nAspiration 2 (4.9%) 14 (34.2%) 19 (46.3%) 6 (14.6%) 1.1 ± 0.7 \nP value 0.015 0.0015 \nVomiting \nScore items 0 1 2 3 Total \nGroup \nCoasting 14 (34.2%) 16 (39%) 11 (26.8%) 0 1 ± 0.8 \nAspiration 21 (51.2%) 17 (41.5) 3 (7.3%) 0 0.6 ± 0.6 \nP value 0.049 0.009 \nPain \nScore items 2 3 4 5 Total \nGroup \nCoasting 10 (24.4%) 17 (41.5) 11 (26.8%) 3 (7.3%) 3.2 ± 0.9 \nAspiration 19 (46.3%) 16 (39%) 5 (12.2%) 1 (2.5%) 2.7 ± 0.8 \nP value 0.108 0.007 \nData are presented as numbers & percentages; P indicates insignificance of difference between both groups. \n\nW. M. Elnagar, H. F. Ebian \n \n \nDOI: 10.4236/ojog.2019.95067 685 Open Journal of Obstetrics and Gynecology \n \n \nFigure 1. Consort Flow sheet. \n \n \nFigure 2. Mean serum E2 levels estimated in patients of both groups (  indicates \nsignificant inter-group difference). \n \n \nFigure 3. Mean (±SD) ovarian diameter estimated at time of cate gorization and on day \nof hcG injection in women of both groups  (  significant difference versus at \ncategorization;  significant inter-group difference). \n\n\nW. M. Elnagar, H. F. Ebian \n \n \nDOI: 10.4236/ojog.2019.95067 686 Open Journal of Obstetrics and Gynecology \n \n \nFigure 4. Patients’ distribution according to severity of OHSS  (  \nindicates significant inter-group difference). \n9. Discussion \nThe therapeutic policies provided for patients of both groups did favorably as \nmanifested by the significant reduction of serum E2 and ovarian diameter on \nday of hCG injection in comparison to estimates taken at time of categorization. \nThese results point to a fact that in women at high -risk for development of \nOHSS, certain therapeutic modalities could ameliorate or lessen it s manifest a-\ntions down to acceptable level. In support of this assumption, no patient deve l-\noped severe OHSS of grade 5, only three women developed clinically detectable \nascites, but no patient required paracentesis. Furthermore, about 75% of patients \ndeveloped mild symptoms ranging between grade one and two. \nThe obtained result s concerning patients received coasting procedure are in \nline D’Angelo et al. [23] who reviewed RCT assessed the effect of coasting on \nprevention of OHSS and reported lower rates of OHSS with coasting versus no \ncoasting by rates suggesting that if 45% of women developed moder ate or severe \nOHSS without coasting, only 4%  - 17% would develop it with coasting. Also, \nAbide Yayla \net al. [24] in their retrospective study of women used coasting to \navoid OHSS in 100 high -risk women and documented that all women had \nreached to embryo transfer stage and reported clinical pregnancy rate of 44%. \nAlso, Kailasam et al. [25] prospectively, found coasting for 6 days with subs e-\nquent blastocyst transfer may be an effective strategy for patients at risk of OHSS \nwith no detrimental effects on blastocyst development or live birth outcome \nConcerning comparative study for coasting and follicular aspiration as pr e-\nventive strategy for OHSS, D’Angelo \net al. [25] reviewed literature for RCT  as-\nsessing the efficacy of coasting versus unilateral follicular aspiration and doc u-\nmented that data were not pooled due to heterogeneity. Moreover, review of r e-\ncently published articles detected only one study compared the effect of coasting \nversus aspiration on incidence of OHSS; however, that study reported no diffe r-\nence between follicular reduction prior to HCG and coasting, in terms of OHSS \n\n\nW. M. Elnagar, H. F. Ebian \n \n \nDOI: 10.4236/ojog.2019.95067 687 Open Journal of Obstetrics and Gynecology \n \nreduction as a primary endpoint [26], these results are contradictory to the result \nof the current study and this difference could be attributed to multiple imita-\ntions of Bushaqer’s study [26], firstly, the sample size is small; 39 women were \ndivided into two study groups and 8 women developed OHSS; 6 versus 2 women \nin each group, respectively but these numbers could not reach the appropriate \nlimit for statistical analysis to be significant or non- significant. Secondly, B u-\nshaqer’s study [26] did not comment  on the frequencies of OHSS severity m a-\nnifestations, which are more important than the sole frequency of OHSS.  \nOn the other hand, the current study reported significantly reduced OHSS \nmanifestations, both as frequency and severity, with follicular aspiration than \nwith coasting, so the current study approved the efficacy and safety of follicular \naspiration i n comparison to coasting despite of proved efficacy of coasting.  In \nsupport of these findings, an early study conducted by Zhu \net al. [27] had docu-\nmented that follicular aspiration during the selection phase can prevent severe \nOHSS and reduce OHSS prevalence in patients with PCOS undergoing COH. \nMore recently, Haydardedeoglu et al. [28] documented that in poor responders \nboth follicular aspiration and flushing has similar results, but follicular flushing \nis time consuming. \nThe reported clinical effectiveness of coasting could be attributed to affecting \nfollicles, especially immature follicles, through apoptosis with significant d e-\ncrease in VEGF expression and secretion [29]  [30]. Thus, coasting acts through \ninhibition of VEGF protein transcription and translation which is a \ntime-consuming process and is unpredictable to be absolute inhibition. On the \nother hand, follicular aspiration allows removal of the already formed VEGF \nthus rapidly eliminating its effect and giving no chance by oocyte removal for \nre-synthesis of growth fa ctors [31] [32]. Additionally, aspiration removes other \ncytokines that may have a role in induction of OHSS as IL -2 which increased l e-\nvels induce vascular dilat ation syndrome [33]. IL-17 [34] melatonin and melato-\nnin receptor 2 [3] that were reported to be correlated with incidence and severity \nof OHSS. These data could explain the reported superior clinical effect of aspir a-\ntion in comparison to coasting procedure. \n10. Conclusion \nCoasting procedure prior to hCG injection could decrease the incidence of \nOHSS and lessens its manifestation. However, follicular aspiration provided \nmore superior results and improved outcome of these women. Any of these \nmodalities could be provided to in fertile high -risk women according to the \navailability of experiences and patients’ selection. Wider scale studies are man-\ndatory to establish the results and to evaluate underlying mechanisms for the \nreported clinical effectiveness of these procedures. \nConflicts of Interest \nThe authors declare no conflicts of interest regarding the publication of this p a-\nper. \n\nW. M. Elnagar, H. F. 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(2019) Association of IL -17 and IL -23 Follicular Fluid Concentra-\ntions and Gene Expression Profile in Cumulus Cells from Infertile Women at Risk \nfor Ovarian Hyperstimulation Syndrome. \nHuman Fertility  (Cambridge, England), \n1-7. https://doi.org/10.1080/14647273.2019.1566648","source_license":"CC0","license_restricted":false}