Ovarian Hyperstimulation: Diagnosis, Prevention, and Management

Paolo Emanuele Levi-Setti; Noemi Di Segni; Clara Gargasole; Camilla Ronchetti; Federico Cirillo

doi:10.1055/s-0041-1736492

Seminars in Reproductive Medicine, Inhaltsverzeichnis

Semin Reprod Med 2021; 39(05/06): 170-179
DOI: 10.1055/s-0041-1736492

Review Article

Ovarian Hyperstimulation: Diagnosis, Prevention, and Management

Paolo Emanuele Levi-Setti

¹IRCCS Humanitas Research Hospital, Department of Gynecology, Division of Gynecology and Reproductive Medicine, Fertility Center, Milan, Italy

,

Noemi Di Segni

¹IRCCS Humanitas Research Hospital, Department of Gynecology, Division of Gynecology and Reproductive Medicine, Fertility Center, Milan, Italy

²Humanitas University, Department of Biomedical Sciences, Milan, Italy

,

Clara Gargasole

¹IRCCS Humanitas Research Hospital, Department of Gynecology, Division of Gynecology and Reproductive Medicine, Fertility Center, Milan, Italy

²Humanitas University, Department of Biomedical Sciences, Milan, Italy

,

Camilla Ronchetti

¹IRCCS Humanitas Research Hospital, Department of Gynecology, Division of Gynecology and Reproductive Medicine, Fertility Center, Milan, Italy

²Humanitas University, Department of Biomedical Sciences, Milan, Italy

,

Federico Cirillo

¹IRCCS Humanitas Research Hospital, Department of Gynecology, Division of Gynecology and Reproductive Medicine, Fertility Center, Milan, Italy

› Institutsangaben

Abstract

Ovarian hyperstimulation syndrome (OHSS) is a severe complication of controlled ovarian stimulation (COS). Pathogenesis of the disease is based on massive transudation of protein-rich fluid from the vascular compartment into the peritoneal, pleural and pericardial spaces, with a variable picture of clinical manifestations depending on its severity. Nowadays OHSS can easily be avoided by several prevention methods, ranging from identification of high-risk patients, choice of a correct protocol stimulation, trigger with gonadotropin-releasing hormone (GnRH) agonists or, finally, the freeze-all strategy. When OHSS occurs, it can usually be managed as outpatient care. Only if severe/critical cases are diagnosed hospitalization is necessary for appropriate rehydration, monitoring of fluid balance and eventual drainage of ascitic fluid. One of the most dangerous complications of OHSS is venous thromboembolism (VTE). Thromboprophylaxis has shown to be cost effective and widely used, while there are controversies regarding the usage of low dose aspirin (LDA) as a preventive measure.

Keywords

ovarian hyperstimulation syndrome - assisted reproduction technologies - diagnosis - prevention - management

Volltext

Referenzen

References
1 Humaidan P, Nelson SM, Devroey P. et al. Ovarian hyperstimulation syndrome: review and new classification criteria for reporting in clinical trials. Hum Reprod 2016; 31 (09) 1997-2004
2 Agrawal NR, Gupta G, Verma K, Varyani N. Spontaneous ovarian hyperstimulation syndrome in a triplet pregnancy. Case Rep Crit Care 2012; 2012: 189705
3 Topdagi Yilmaz EP, Yapca OE, Topdagi YE, Kaya Topdagi S, Kumtepe Y. Spontaneous Ovarian Hyperstimulation Syndrome with FSH Receptor Gene Mutation: Two Rare Case Reports. Case Rep Obstet Gynecol 2018; 2018: 9294650
4 Di Carlo C, Savoia F, Gargano V, Sparice S, Bifulco G, Nappi C. Successful pregnancy complicated by spontaneous, familial, recurrent ovarian hyperstimulation syndrome: report of two cases. Gynecol Endocrinol 2013; 29 (10) 897-900
5 Timmons D, Montrief T, Koyfman A, Long B. Ovarian hyperstimulation syndrome: A review for emergency clinicians. Am J Emerg Med 2019; 37 (08) 1577-1584
6 Nelson SM. Prevention and management of ovarian hyperstimulation syndrome. Thromb Res 2017; 151 (Suppl. 01) S61-S64
7 Blumenfeld Z. The Ovarian Hyperstimulation Syndrome. Vitam Horm 2018; 107: 423-451
8 Courbiere B, Oborski V, Braunstein D, Desparoir A, Noizet A, Gamerre M. Obstetric outcome of women with in vitro fertilization pregnancies hospitalized for ovarian hyperstimulation syndrome: a case-control study. Fertil Steril 2011; 95 (05) 1629-1632
9 Nastri CO, Teixeira DM, Moroni RM, Leitão VM, Martins WP. Ovarian hyperstimulation syndrome: pathophysiology, staging, prediction and prevention. Ultrasound Obstet Gynecol 2015; 45 (04) 377-393
10 Golan A, Ron-el R, Herman A, Soffer Y, Weinraub Z, Caspi E. Ovarian hyperstimulation syndrome: an update review. Obstet Gynecol Surv 1989; 44 (06) 430-440
11 Navot D, Bergh PA, Laufer N. Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment. Fertil Steril 1992; 58 (02) 249-261
12 Humaidan P, Quartarolo J, Papanikolaou EG. Preventing ovarian hyperstimulation syndrome: guidance for the clinician. Fertil Steril 2010; 94 (02) 389-400
13 Royal College of Obstetricians and Gynaecologists. The Management of Ovarian hyperstimulation syndrome. London: RCOG; 2016. . Accessed October 5, 2021 at: https://www.rcog.org.uk/globalassets/documents/guidelines/green-top-guidelines/gtg_5_ohss
14 Practice Committee of the American Society for Reproductive Medicine. Electronic address: ASRM@asrm.org, Practice Committee of the American Society for Reproductive Medicine. Prevention and treatment of moderate and severe ovarian hyperstimulation syndrome: a guideline. Fertil Steril 2016; 106 (07) 1634-1647
15 Korhonen KV, Savolainen-Peltonen HM, Mikkola TS, Tiitinen AE, Unkila-Kallio LS. C-reactive protein response is higher in early than in late ovarian hyperstimulation syndrome. Eur J Obstet Gynecol Reprod Biol 2016; 207: 162-168
16 Lainas GT, Lainas TG, Venetis CA. et al. Ultrasound and hematological changes during early luteal phase in women at high risk for developing ovarian hyperstimulation syndrome. Ultrasound Obstet Gynecol 2018; 51 (01) 126-133
17 Lainas GT, Kolibianakis EM, Sfontouris IA. et al. Outpatient management of severe early OHSS by administration of GnRH antagonist in the luteal phase: an observational cohort study. Reprod Biol Endocrinol 2012; 10: 69
18 Abramov Y, Elchalal U, Schenker JG. Pulmonary manifestations of severe ovarian hyperstimulation syndrome: a multicenter study. Fertil Steril 1999; 71 (04) 645-651
19 Devroey P, Adriaensen P. OHSS Free Clinic. Facts Views Vis ObGyn 2011; 3 (01) 43-45
20 Nardo LG, Gelbaya TA, Wilkinson H. et al. Circulating basal anti-Müllerian hormone levels as predictor of ovarian response in women undergoing ovarian stimulation for in vitro fertilization. Fertil Steril 2009; 92 (05) 1586-1593
21 Aflatoonian A, Oskouian H, Ahmadi S, Oskouian L. Prediction of high ovarian response to controlled ovarian hyperstimulation: anti-Müllerian hormone versus small antral follicle count (2-6 mm). J Assist Reprod Genet 2009; 26 (06) 319-325
22 Vembu R, Reddy NS. Serum AMH Level to Predict the Hyper Response in Women with PCOS and Non-PCOS Undergoing Controlled Ovarian Stimulation in ART. J Hum Reprod Sci 2017; 10 (02) 91-94
23 Jayaprakasan K, Chan Y, Islam R. et al. Prediction of in vitro fertilization outcome at different antral follicle count thresholds in a prospective cohort of 1,012 women. Fertil Steril 2012; 98 (03) 657-663
24 Al-Inany HG, Youssef MA, Ayeleke RO, Brown J, Lam WS, Broekmans FJ. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database Syst Rev 2016; 4: CD001750
25 Toftager M, Bogstad J, Bryndorf T. et al. Risk of severe ovarian hyperstimulation syndrome in GnRH antagonist versus GnRH agonist protocol: RCT including 1050 first IVF/ICSI cycles. Hum Reprod 2016; 31 (06) 1253-1264
26 Lambalk CB, Banga FR, Huirne JA. et al. GnRH antagonist versus long agonist protocols in IVF: a systematic review and meta-analysis accounting for patient type. Hum Reprod Update 2017; 23 (05) 560-579
27 Toftager M, Bogstad J, Løssl K. et al. Cumulative live birth rates after one ART cycle including all subsequent frozen-thaw cycles in 1050 women: secondary outcome of an RCT comparing GnRH-antagonist and GnRH-agonist protocols. Hum Reprod 2017; 32 (03) 556-567
28 Bosch E, Broer S, Griesinger G. et al; ESHRE Guideline Group on Ovarian Stimulation. Erratum: ESHRE guideline: ovarian stimulation for IVF/ICSI. Hum Reprod Open 2020; 2020 (04) a067
29 Teede HJ, Misso ML, Costello MF. et al; International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril 2018; 110 (03) 364-379
30 Humaidan P, Papanikolaou EG, Kyrou D. et al. The luteal phase after GnRH-agonist triggering of ovulation: present and future perspectives. Reprod Biomed Online 2012; 24 (02) 134-141
31 Martínez F, Mancini F, Solé M. et al. Antagonist rescue of agonist IVF cycle at risk of OHSS: a case series. Gynecol Endocrinol 2014; 30 (02) 145-148
32 van Tilborg TC, Oudshoorn SC, Eijkemans MJC. et al; OPTIMIST study group. Individualized FSH dosing based on ovarian reserve testing in women starting IVF/ICSI: a multicentre trial and cost-effectiveness analysis. Hum Reprod 2017; 32 (12) 2485-2495
33 Namavar Jahromi B, Parsanezhad ME, Shomali Z. et al. Ovarian Hyperstimulation Syndrome: A Narrative Review of Its Pathophysiology, Risk Factors, Prevention, Classification, and Management. Iran J Med Sci 2018; 43 (03) 248-260
34 Aboulghar M. Agonist and antagonist coast. Fertil Steril 2012; 97 (03) 523-526
35 D'Angelo A, Amso NN, Hassan R. Coasting (withholding gonadotrophins) for preventing ovarian hyperstimulation syndrome. Cochrane Database Syst Rev 2017; 5: CD002811
36 Cerrillo M, Pacheco A, Rodríguez S. et al. Effect of GnRH agonist and hCG treatment on VEGF, angiopoietin-2, and VE-cadherin: trying to explain the link to ovarian hyperstimulation syndrome. Fertil Steril 2011; 95 (08) 2517-2519
37 Casper RF. Reducing the Risk of OHSS by GnRH Agonist Triggering. J Clin Endocrinol Metab 2015; 100 (12) 4396-4398
38 Hernández ER, Gómez-Palomares JL, Ricciarelli E. No room for cancellation, coasting, or ovarian hyperstimulation syndrome in oocyte donation cycles. Fertil Steril 2009; 91 (4, Suppl) 1358-1361
39 Youssef MA, Van der Veen F, Al-Inany HG. et al. Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist-assisted reproductive technology. Cochrane Database Syst Rev 2014; (10) CD008046
40 Erb TM, Vitek W, Wakim AN. Gonadotropin-releasing hormone agonist or human chorionic gonadotropin for final oocyte maturation in an oocyte donor program. Fertil Steril 2010; 93 (02) 374-378
41 Leth-Moller K, Hammer Jagd S, Humaidan P. The Luteal Phase after GnRHa Trigger-Understanding An Enigma. Int J Fertil Steril 2014; 8 (03) 227-234
42 Youssef MA, Abou-Setta AM, Lam WS. Recombinant versus urinary human chorionic gonadotrophin for final oocyte maturation triggering in IVF and ICSI cycles. Cochrane Database Syst Rev 2016; 4: CD003719
43 Zhai J, Liu J, Zhao S. et al. Kisspeptin-10 inhibits OHSS by suppressing VEGF secretion. Reproduction 2017; 154 (04) 355-362
44 Jayasena CN, Abbara A, Comninos AN. et al. Kisspeptin-54 triggers egg maturation in women undergoing in vitro fertilization. J Clin Invest 2014; 124 (08) 3667-3677
45 Abbara A, Jayasena CN, Christopoulos G. et al. Efficacy of Kisspeptin-54 to Trigger Oocyte Maturation in Women at High Risk of Ovarian Hyperstimulation Syndrome (OHSS) During In Vitro Fertilization (IVF) Therapy. J Clin Endocrinol Metab 2015; 100 (09) 3322-3331
46 Abbara A, Clarke S, Islam R. et al. A second dose of kisspeptin-54 improves oocyte maturation in women at high risk of ovarian hyperstimulation syndrome: a Phase 2 randomized controlled trial. Hum Reprod 2017; 32 (09) 1915-1924
47 Abbara A, Islam R, Clarke SA. et al. Clinical parameters of ovarian hyperstimulation syndrome following different hormonal triggers of oocyte maturation in IVF treatment. Clin Endocrinol (Oxf) 2018; 88 (06) 920-927
48 Abbara A, Clarke SA, Dhillo WS. Novel Concepts for Inducing Final Oocyte Maturation in In Vitro Fertilization Treatment. Endocr Rev 2018; 39 (05) 593-628
49 Thomsen L, Humaidan P. Ovarian hyperstimulation syndrome in the 21st century: the role of gonadotropin-releasing hormone agonist trigger and kisspeptin. Curr Opin Obstet Gynecol 2015; 27 (03) 210-214
50 Devroey P, Polyzos NP, Blockeel C. An OHSS-Free Clinic by segmentation of IVF treatment. Hum Reprod 2011; 26 (10) 2593-2597
51 Wong KM, van Wely M, Mol F, Repping S, Mastenbroek S. Fresh versus frozen embryo transfers in assisted reproduction. Cochrane Database Syst Rev 2017; 3: CD011184
52 Shi Y, Sun Y, Hao C. et al. Transfer of Fresh versus Frozen Embryos in Ovulatory Women. N Engl J Med 2018; 378 (02) 126-136
53 Borges Jr E, Braga DP, Setti AS, Vingris LS, Figueira RC, Iaconelli Jr A. Strategies for the management of OHSS: Results from freezing-all cycles. JBRA Assist Reprod 2016; 20 (01) 8-12
54 Garcia-Velasco JA. Agonist trigger: what is the best approach? Agonist trigger with vitrification of oocytes or embryos. Fertil Steril 2012; 97 (03) 527-528
55 Fatemi HM, Popovic-Todorovic B, Humaidan P. et al. Severe ovarian hyperstimulation syndrome after gonadotropin-releasing hormone (GnRH) agonist trigger and “freeze-all” approach in GnRH antagonist protocol. Fertil Steril 2014; 101 (04) 1008-1011
56 Griesinger G, Schultz L, Bauer T, Broessner A, Frambach T, Kissler S. Ovarian hyperstimulation syndrome prevention by gonadotropin-releasing hormone agonist triggering of final oocyte maturation in a gonadotropin-releasing hormone antagonist protocol in combination with a “freeze-all” strategy: a prospective multicentric study. Fertil Steril 2011; 95 (06) 2029-2033 , 2033.e1
57 Gurbuz AS, Gode F, Ozcimen N, Isik AZ. Gonadotrophin-releasing hormone agonist trigger and freeze-all strategy does not prevent severe ovarian hyperstimulation syndrome: a report of three cases. Reprod Biomed Online 2014; 29 (05) 541-544
58 Ling LP, Phoon JW, Lau MS. et al. GnRH agonist trigger and ovarian hyperstimulation syndrome: relook at 'freeze-all strategy'. Reprod Biomed Online 2014; 29 (03) 392-394
59 Santos-Ribeiro S, Polyzos NP, Stouffs K. et al. Ovarian hyperstimulation syndrome after gonadotropin-releasing hormone agonist triggering and “freeze-all”: in-depth analysis of genetic predisposition. J Assist Reprod Genet 2015; 32 (07) 1063-1068
60 Basu S, Nagy JA, Pal S. et al. The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor. Nat Med 2001; 7 (05) 569-574
61 Tang H, Mourad S, Zhai SD, Hart RJ. Dopamine agonists for preventing ovarian hyperstimulation syndrome. Cochrane Database Syst Rev 2016; 11: CD008605
62 Kamat BR, Brown LF, Manseau EJ, Senger DR, Dvorak HF. Expression of vascular permeability factor/vascular endothelial growth factor by human granulosa and theca lutein cells. Role in corpus luteum development. Am J Pathol 1995; 146 (01) 157-165
63 Gaafar S, El-Gezary D, El Maghraby HA. Early onset of cabergoline therapy for prophylaxis from ovarian hyperstimulation syndrome (OHSS): A potentially safer and more effective protocol. Reprod Biol 2019; 19 (02) 145-148
64 Motta T, de Vincentiis S, Marchini M, Colombo N, D'Alberton A. Vaginal cabergoline in the treatment of hyperprolactinemic patients intolerant to oral dopaminergics. Fertil Steril 1996; 65 (02) 440-442
65 Agarwal N, Ghosh S, Bathwal S, Chakravarty B. Large-Volume Paracentesis, up to 27 L, With Adjuvant Vaginal Cabergoline in the Case of Severe Ovarian Hyperstimulation Syndrome with Successful Pregnancy Outcome: A Case Report. J Hum Reprod Sci 2017; 10 (03) 235-237
66 Namavar Jahromi B, Zolghadri J, Rahmani E. et al. Effect of low-dose aspirin on the development of ovarian hyperstimulation syndrome and outcomes of assisted reproductive techniques in the women with PCOS, a randomized double-blinded clinical trial. Taiwan J Obstet Gynecol 2019; 58 (02) 255-260
67 Dahan MH, Tannus S, Seyhan A, Tan SL, Ata B. Combined modalities for the prevention of ovarian hyperstimulation syndrome following an excessive response to stimulation. Gynecol Endocrinol 2018; 34 (03) 252-255
68 Prapas Y, Ravanos K, Petousis S. et al. GnRH antagonist administered twice the day before hCG trigger combined with a step-down protocol may prevent OHSS in IVF/ICSI antagonist cycles at risk for OHSS without affecting the reproductive outcomes: a prospective randomized control trial. J Assist Reprod Genet 2017; 34 (11) 1537-1545
69 Deng L, Li XL, Ye DS. et al. A Second Dose of GnRHa in Combination with Luteal GnRH Antagonist May Eliminate Ovarian Hyperstimulation Syndrome in Women with ≥30 Follicles Measuring ≥11 mm in Diameter on Trigger Day and/or Pre-trigger Peak Estradiol Exceeding 10 000 pg/mL. Curr Med Sci 2019; 39 (02) 278-284
70 Shrem G, Steiner N, Balayla J. et al. Use of cabergoline and post-collection GnRH antagonist administration for prevention of ovarian hyperstimulation syndrome. Reprod Biomed Online 2019; 39 (03) 433-438
71 Tso LO, Costello MF, Albuquerque LE, Andriolo RB, Marjoribanks J, Macedo CR. Metformin treatment before and during in vitro fertilization or intracytoplasmic sperm injection in women with polycystic ovary syndrome: summary of a Cochrane review. Fertil Steril 2015; 104 (03) 542-544
72 Tso LO, Costello MF, Albuquerque LE, Andriolo RB, Macedo CR. Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome. Cochrane Database Syst Rev 2014; (11) CD006105
73 Huang X, Wang P, Tal R, Lv F, Li Y, Zhang X. A systematic review and meta-analysis of metformin among patients with polycystic ovary syndrome undergoing assisted reproductive technology procedures. Int J Gynaecol Obstet 2015; 131 (02) 111-116
74 Palomba S, Falbo A, La Sala GB. Effects of metformin in women with polycystic ovary syndrome treated with gonadotrophins for in vitro fertilisation and intracytoplasmic sperm injection cycles: a systematic review and meta-analysis of randomised controlled trials. BJOG 2013; 120 (03) 267-276
75 Jacob SL, Brewer C, Tang T, Picton HM, Barth JH, Balen AH. A short course of metformin does not reduce OHSS in a GnRH antagonist cycle for women with PCOS undergoing IVF: a randomised placebo-controlled trial. Hum Reprod 2016; 31 (12) 2756-2764
76 Swanton A, Lighten A, Granne I. et al. Do women with ovaries of polycystic morphology without any other features of PCOS benefit from short-term metformin co-treatment during IVF? A double-blind, placebo-controlled, randomized trial. Hum Reprod 2011; 26 (08) 2178-2184
77 Shrivastav P, Nadkarni P, Craft I. Day care management of severe ovarian hyperstimulation syndrome avoids hospitalization and morbidity. Hum Reprod 1994; 9 (05) 812-814
78 Olchowy A, Olchowy C, Łasecki M. et al. Ovarian Hyperstimulation Syndrome as a Growing Diagnostic Problem in Emergency Department Settings: A Case Report. J Emerg Med 2019; 56 (02) 217-221
79 Chen CD, Wu MY, Chao KH, Lien YR, Chen SU, Yang YS. Update on management of ovarian hyperstimulation syndrome. Taiwan J Obstet Gynecol 2011; 50 (01) 2-10
80 Minami T, Mph, Yamana H. et al. Artificial colloids versus human albumin for the treatment of ovarian hyperstimulation syndrome: A retrospective cohort study. Int J Reprod Biomed (Yazd) 2019; 17 (10) 709-716
81 Mor YS, Schenker JG. Ovarian hyperstimulation syndrome and thrombotic events. Am J Reprod Immunol 2014; 72 (06) 541-548
82 Rova K, Passmark H, Lindqvist PG. Venous thromboembolism in relation to in vitro fertilization: an approach to determining the incidence and increase in risk in successful cycles. Fertil Steril 2012; 97 (01) 95-100
83 Spyropoulos AC, Lin J. Direct medical costs of venous thromboembolism and subsequent hospital readmission rates: an administrative claims analysis from 30 managed care organizations. J Manag Care Pharm 2007; 13 (06) 475-486
84 Kearon C, Akl EA, Comerota AJ. et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2 Suppl): e419S-e496S
85 Wormer KC, Jangda AA, El Sayed FA, Stewart KI, Mumford SL, Segars JH. Is thromboprophylaxis cost effective in ovarian hyperstimulation syndrome: A systematic review and cost analysis. Eur J Obstet Gynecol Reprod Biol 2018; 224: 117-124
86 Jacobson B, Rambiritch V, Paek D. et al. Safety and Efficacy of Enoxaparin in Pregnancy: A Systematic Review and Meta-Analysis. Adv Ther 2020; 37 (01) 27-40
87 Mauermann E, Vökt C, Tsakiris DA, Tobler D, Girard T. Heparin-induced thrombocytopenia in pregnancy: an interdisciplinary challenge-a case report and literature review. Int J Obstet Anesth 2016; 26: 79-82
88 Malbrain ML, Cheatham ML, Kirkpatrick A. et al. Results from the International Conference of Experts on Intra-abdominal Hypertension and Abdominal Compartment Syndrome. I. Definitions. Intensive Care Med 2006; 32 (11) 1722-1732
89 Gebril A, Hamoda H, Mathur R. Outpatient management of severe ovarian hyperstimulation syndrome: a systematic review and a review of existing guidelines. Hum Fertil (Camb) 2018; 21 (02) 98-105
90 Kanayama S, Kaniwa H, Tomimoto M, Zhang B, Nishioka K, Oi H. Laparoscopic detorsion of the ovary in ovarian hyperstimulation syndrome during the sixth week of gestation: A case report and review. Int J Surg Case Rep 2019; 59: 50-53