Ovarian hyperstimulation syndrome (OHSS) is usually an iatrogenic complication of assisted reproduction technology but can occur spontaneously in rare cases due to the high production of endogenous gonadotropins, beta-hCG level, gonadotropin-like molecules, or due to enhanced sensitivity to endogenous gonadotropins such as mutations follicle-stimulating hormone (FSH) receptor.

‚ÄčAbstract: Ovarian hyperstimulation syndrome (OHSS) is usually an iatrogenic complication of assisted reproduction technology but can occur spontaneously in rare cases due to the high production of endogenous gonadotropins, beta-hCG level, gonadotropin-like molecules, or due to enhanced sensitivity to endogenous gonadotropins such as mutations follicle-stimulating hormone (FSH) receptor.

OHSS is characterized by cystic enlargement of the ovaries and a fluid shift from the intravascular to the third space due to increased capillary permeability and ovarian neoangiogenesis. This reaction is dependent on gonadotropin dosage and human chorionic gonadotrophin (hCG) administration. Vascular endothelial growth factor (VEGF) plays a crucial role in the development of this syndrome.

The OHSS can be classified as mild, moderate, severe, or critical according to symptoms (weight gain, nausea, abdominal pain, dyspnea, ascites, and pleural and pericardial effusion), and ultrasound and laboratory parameters. Moreover, the OHSS can be classified by the timing of onset. It can begin 5 to 7 days after hCG, due to gonadotropin stimulation (early) or at least 9 –12 days after embryo transfer if pregnancy occurs (late).

The ultrasound features are bilateral symmetrically enlarged ovaries containing multiple variable-sized follicles-luteal cysts, free fluid, and ascites. Ultrasound examination also plays an important role in monitoring patients with OHSS and in early recognition of OHSS progression and resolution. Patients with severe or critical forms need intensive care.

Key words: Ovarian hyperstimulation syndrome, OHSS, Assisted Reproductive Technology, Infertility

Authors: Irene Ladisa1,2, Maria Elisabetta Coccia2

  1. Department of Woman and Child Health, Fondazione Policlinico A. Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy.
  2. Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", University of Florence, Florence, Italy.

Reviewers: Karen Fung-Kee-Fung, Francesca Moro

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Definition

Ovarian hyperstimulation syndrome (OHSS) is almost invariably an iatrogenic complication of assisted reproduction technology (ART). The syndrome is characterized by cystic enlargement of the ovaries and a fluid shift from the intravascular to the third space due to increased capillary permeability and ovarian neoangiogenesis. Its occurrence is dependent on the administration of human chorionic gonadotrophin (hCG). OHSS is extremely rare without hCG administration1.

OHSS occurs in women undergoing ART, due to controlled ovarian stimulation (COS) and ovulation induction with gonadotrophins or more rarely, with clomiphene citrate. Infrequently, it can be a spontaneous condition, as a consequence of the high production of endogenous gonadotropins (follicle-stimulating hormone (FSH) or luteinizing hormone (LH)) secreted by pituitary adenomas or ectopic FSH-secreting tumors. It can also be a consequence of high hCG levels in cases of multiple pregnancies, gestational trophoblastic disease, beta-hCG secreting tumor. Other causes are high levels of gonadotropin-like molecules, like thyroid-stimulating hormone (TSH) in hypothyroidism or enhanced sensitivity to endogenous gonadotropins in cases of FSH receptor mutations. Women with FSH receptor mutations typically develop OHSS when they become pregnant due to excessive ovarian stimulation of the FSH receptor by placental hCG 2,3,4,5,6.

OHSS can develop with a wide spectrum of signs and symptoms. It can be classified as mild, moderate, severe, or critical, according to symptoms, ultrasound characteristics and laboratory findings (Table - 1)2,7.

  • Mild OHSS is characterized by enlarged ovaries, abdominal discomfort and gastrointestinal symptoms, but without modification of laboratory parameters.
  • Moderate OHSS, in addition to the profile of mild OHSS, is characterized by enlarged ovaries (8 to 12 cm), ascites and initial hemoconcentration (hematocrit >41%).
  • Severe OHSS, in addition to the profile of moderate OHSS, is characterized by clinical evidence of ascites, severe abdominal pain and pleural effusion in some cases, and shows significant hemoconcentration (hematocrit >55%) and impaired vital organ function.
  • Critical OHSS manifests with worsening of clinical and laboratory parameters seen with severe OHSS and can be a life-threatening disease and may need intensive care.

 

 OHSS stage

Clinical features

Biochemical features

Mild

  • Abdominal distention/discomfort

-

 

  • Mild nausea/vomiting

 

 

  • Mild dyspnea

 

 

  • Diarrhea

 

 

  • Enlarged ovaries (ovarian size usually < 8 cm)

 

 

 

 

Moderate

Mild features plus:

  • Hemoconcentration (Hct >41%)

 

  • Ultrasonographic evidence of ascites
  • Elevated WBC (>15,000/microL)

 

   - Ovarian size usually 8–12 cm

  • Hypoproteinemia

 

 

 

Severe

Mild and moderate features plus:

  • Severe hemoconcentration (Hct >55%)

 

  • Clinical evidence of ascites (can be tense ascites)
  • WBC >25,000/microL

 

  • Severe abdominal pain
  • Serum creatinine >1.6 mg/dL

 

  • Intractable nausea and vomiting
  • Creatinine clearance <50 mL/min

 

  • Rapid weight gain (>1 kg in 24 hours)
  • Hyponatremia (Na+ <135 mEq/L)

 

  • Pleural effusion
  • Hyperkalemia (K+ >5 mEq/L)

 

  • Hydrothorax

- Elevated liver enzymes

 

  • Severe dyspnea

 

 

  • Oliguria/anuria

 

 

  • Low blood/central venous pressure

 

 

  • Syncope

 

 

  • Venous thrombosis
  • Ovarian size usually > 12 cm

 

 

 

 

Critical

Presence of severe features plus:

Worsening of biochemical findings seen

 

  • Anuria/acute renal failure

with severe OHSS

 

  • Arrhythmia

 

 

  • Pericardial effusion

 

 

  • Massive hydrothorax

 

 

  • Thromboembolism

 

 

  • Arterial thrombosis

 

 

  • Adult Respiratory distress syndrome

 

 

  • Sepsis

 

 

 

Table 1 – Classification of OHSS features 2,7

Modified from Royal College of Obstetricians and Gynaecologists (Green-top Guideline No. 5 – 2016); Practice Committee of the American Society for Reproductive Medicine Fertil Steril - 2016.

 

ICD code

N98.1

Incidence

The reported incidence of OHSS is highly variable, because of the lack of a generally accepted definition of the syndrome. The reported incidence of mild OHSS is estimated to be 20-33% of the cycles 8,9. The total reported incidence of moderate-severe OHSS in the 21st ESHRE report is 0.20% of the cycles, although it is assumed that the complications of ART remain generally underreported 10.

Pathogenesis

The pathogenesis of OHSS is still unclear but it appears to be a systemic disease resulting from vasoactive products released during COS. Vascular endothelial growth factor (VEGF) seems to play a crucial role, but a variety of cytokines are likely to be involved in the pathogenesis and clinical features of OHSS11.

In a COS cycle, the multiple follicles secrete large quantities of VEGF, which cause a marked increase in capillary permeability resulting in fluid shift from the intravascular to extravascular space. Circulating concentrations of VEGF are positively correlated with the risk of developing OHSS and the severity of the syndrome2,12.

Risk factors

Risk factors to develop the OHSS include the following7,9 :

Pre-treatment:

 

During COS:

  • previous history of OHSS,
  • elevated circulating estradiol (>3500 pg/mL)
  • age <35 years
  • rapidly rising estradiol levels
  • elevated AMH values
  • development of >25 follicles
  • polycystic ovarian syndrome (PCOS), PCO morphology, multi-follicular ovaries
  • use of hCG trigger
  • antral follicle count (AFC) > 24
 
  • oocytes retrieved >15-20
 

Clinical Presentation

As a complication of ovarian stimulation, OHSS can occur during the luteal phase or during early pregnancy. Symptoms are qualified as mild, moderate, severe and critical (Table 1), and as early or late 7,13.

  • “Early" OHSS usually occurs in mild and moderate forms and begins 4 to 7 days after trigger of ovulation, related to excessive response to ovarian stimulation.
  • "Late" OHSS typically starts at least 9 to 12 days after trigger. Consequentially, the rising hCG, due to pregnancy, exacerbates the course of OHSS.

Diagnosis and ultrasound characteristics

The diagnosis of OHSS is based on personal history (ART treatment), and clinical symptoms (e.g. weight gain, nausea, abdominal pain). Transvaginal and transabdominal ultrasound examinations and laboratory parameters verify the severity of the syndrome.

Women with mild OHSS typically present with abdominal pain, bloating, mild nausea, and occasionally vomiting. Women with moderate and severe forms present with rapid weight gain, abdominal tension, dyspnea and tachypnea, oliguria/anuria, orthostatic hypotension. Critical OHSS presents worsening renal function, pleural and/or pericardial effusion and thromboembolic events 2,7,14.

The typical ultrasound feature of patients with OHSS is bilateral symmetrically enlarged ovaries containing multiple variable-sized follicles-luteal cysts with “wheel spoke” appearance15 (peripheral location of the follicles surrounding a central core of ovarian stroma, with thin septa separating the cysts)15,16. The cysts generally present with anechoic content but can also have hemorrhagic content in cases of hemorrhagic events. Other ultrasound features are free fluid in the pelvis and ascites. The relevance of ascites and the involvement of other areas correlates to the most severe cases that require hospitalization and more intensive care. Ultrasound evaluation also plays a role in monitoring patients with OHSS and in early recognition of its progression and resolution.

Laboratory parameters reveal hemoconcentration, electrolyte imbalance, and alteration in renal and hepatic function17 (Table - 1).  

Differential diagnosis

The differential diagnosis includes ovarian torsion, pelvic inflammatory disease, intra-abdominal hemorrhage due to corpus luteum, ectopic pregnancy, appendicitis, and ovarian cancer.

Prevention

Prevention of OHSS is the best strategy to be applied and different approaches could be used:

  • A tailored COS is mandatory to avoid high response, and subsequent treatment modulation.18 Lower doses of FSH are recommended to reduce OHSS.19
  • The risk of developing OHSS is more likely in patients with PCOS. Metformin treatment before and during an ART cycle reduces the incidence of OHSS20.  Protocol of ovarian stimulation with FSH/FSHr plus gonadotrophin releasing hormone (GnRH) antagonist are also recommended to avoid a premature LH surge. A GnRH agonist is required to trigger ovulation instead of using hCG by stimulating the pituitary to release endogenous LH in cases of high estradiol level (>2500-3000 pg/mL) and multiple follicles in the ovaries (> 20 follicles), 21,22. According to ESHRE guidelines 2020, a GnRH agonist trigger is recommended for final oocyte maturation in women at risk of OHSS18.
  • Another option to prevent OHSS in high-risk patients, is to retrieve oocytes, and then freeze all of them.
  • In high-risk cases (patients with symptoms and ultrasound characteristics indicating OHSS), the embryo transfer is cancelled. The “freeze all embryos” strategy reduces the risk of severe and late onset OHSS (strong strength, moderate quality of evidence), but mild or moderate early onset OHSS may still occur 18,23.
  • Dopamine agonist administration starting at the time of hCG trigger, in high risk patients with “freeze all”, reduce the incidence of OHSS7.
  • When during COS estradiol exceeds some predetermined threshold, as predictor for excessive ovarian production of VEGF following luteinization, a possible preventive approach is to reduce gonadotrophin dosage, or more effective to stop, “coasting”, for one-two days (more than three days may reduce oocyte quality and pregnancy rates). When circulating estradiol reaches a lower level, a luteinizing stimulus is administered, and the cycle proceeds. A major advantage of coasting (withholding of gonadotrophins) is that the treatment cycle is not suspended24,25.
  • Cycle cancellation can be one of the last ratios, in high-risk patients.
  • Consider prophylaxis with LMWH for outpatients with two to three risk factors in addition to OHSS (age >35 years, obesity, immobility, elevated hematocrit, personal or family history of thrombosis, thrombophilia, and pregnancy)26.

Management and treatment

In most cases, OHSS is self-limiting. Women with mild or moderate OHSS can be managed as outpatients2. Clinical monitoring with daily recording of weight, abdominal circumference, and urinary output are mandatory.

Women with severe OHSS require increased vigilance to manage the symptoms and reduce the risk of further complications. Hospitalization should be considered for women who are unable to achieve satisfactory pain control or to attend for regular outpatient follow-up. Likewise, inability to maintain adequate fluid intake due to nausea or worsening symptoms after outpatient monitoring would be candidates for hospitalization 2. Increasing abdominal pain, oliguria, weight gain, increased abdominal circumference, and shortness of breath suggest worsening OHSS.

Conditions that may require intensive unit care include adult respiratory distress syndrome, renal failure, or thromboembolism. Thromboprophylaxis should be initiated early, with compression stockings and prophylactic LMWH for all hospitalized patients with OHSS, because of hemoconcentration. The presence of hemoconcentration requires maintenance of intravascular blood volume and perfusion and electrolyte balance. Crystalloid and colloid infusion are recommended, as well as intravenous albumin supplementation in cases of ascites. All supportive strategies to improve hemodynamics and urinary output (at least 50 ml/h) should be considered.

Paracentesis is only recommended in cases of severe ascites, severe oliguria/anuria and dyspnea to reduce intra-abdominal pressure and increase urine output 2. Antibiotic prophylaxis can be evaluated to avoid infections.

Cabergoline is a treatment option and  appears to have a beneficial effect on women with OHSS (0.5 mg/day orally for 8 days minimum)27,28. Finally, a high protein diet is indicated.

Prognosis

The pathophysiological process of OHSS is self-limiting and increased vascular permeability regresses spontaneously with menstruation in cases of early OHSS. If pregnancy occurs, resolution may take longer and needs modulation of therapy related to sign, symptoms and clinical and laboratory parameters.

Pregnancy Outcome

Some studies suggest that IVF pregnancies complicated by moderate or severe OHSS have an increased risk of spontaneous abortion, venous thrombosis, gestational diabetes, pregnancy-induced hypertension, placental abruption, premature delivery, and low birthweight compared to IVF pregnancy not associated with OHSS. These pregnancies should be considered high-risk and should be monitored closely 29,30.

References

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2.      Royal College of Obstetricians and Gynaecologists RCOG. The Management of Ovarian Hyperstimulation Syndrome (Green-top Guideline No. 5). Published 2016. https://www.rcog.org.uk/guidance/browse-all-guidance/green-top-guidelines/the-management-of-ovarian-hyperstimulation-syndrome-green-top-guideline-no-5/

3.      Mittal K, Koticha R, Dey AK, et al. Radiological Illustration of Spontaneous Ovarian Hyperstimulation Syndrome. Pol J Radiol. 2015;80:217-227. doi:10.12659/PJR.893536

4.      Borna S, Nasery A. Spontaneous ovarian hyperstimulation in a pregnant woman with hypothyroidism. Fertil Steril. 2007;88(3):705.e1-3. doi:10.1016/j.fertnstert.2006.12.003

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7.      Practice Committee of the American Society for Reproductive Medicine. Electronic address: [email protected], 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(7):1634-1647. doi:10.1016/j.fertnstert.2016.08.048

8.      Delvigne A. Symposium: Update on prediction and management of OHSS. Epidemiology of OHSS. Reprod Biomed Online. 2009;19(1):8-13. doi:10.1016/s1472-6483(10)60040-5

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10.    The European IVF-Monitoring Consortium (EIM) for the European Society of Human Reproduction and Embryology (ESHRE), Wyns C, De Geyter C, et al. ART in Europe, 2017: results generated from European registries by ESHRE†. Hum Reprod Open. 2021;2021(3):hoab026. doi:10.1093/hropen/hoab026

11.    Braat DDM, Schutte JM, Bernardus RE, Mooij TM, van Leeuwen FE. Maternal death related to IVF in the Netherlands 1984-2008. Hum Reprod Oxf Engl. 2010;25(7):1782-1786. doi:10.1093/humrep/deq080

12.    Abramov Y, Barak V, Nisman B, Schenker JG. Vascular endothelial growth factor plasma levels correlate to the clinical picture in severe ovarian hyperstimulation syndrome. Fertil Steril. 1997;67(2):261-265. doi:10.1016/S0015-0282(97)81908-5

13.    Mathur RS, Akande AV, Keay SD, Hunt LP, Jenkins JM. Distinction between early and late ovarian hyperstimulation syndrome. Fertil Steril. 2000;73(5):901-907. doi:10.1016/s0015-0282(00)00492-1

14.    Barbieri RL. Ovarian Hyperstimulation Syndrome (OHSS). In: Loriaux L, ed. Endocrine Emergencies: Recognition and Treatment. Contemporary Endocrinology. Humana Press; 2014:213-226. doi:10.1007/978-1-62703-697-9_18

15.    Jung BG, Kim H. Severe spontaneous ovarian hyperstimulation syndrome with MR findings. J Comput Assist Tomogr. 2001;25(2):215-217. doi:10.1097/00004728-200103000-00009

16.    Jung SE, Byun JY, Lee JM, et al. MR imaging of maternal diseases in pregnancy. AJR Am J Roentgenol. 2001;177(6):1293-1300. doi:10.2214/ajr.177.6.1771293

17.    Smith LP. Ultrasound and Ovarian Hyperstimulation Syndrome. In: Stadtmauer LA, Tur-Kaspa I, eds. Ultrasound Imaging in Reproductive Medicine: Advances in Infertility Work-up, Treatment and ART. Springer International Publishing; 2019:321-333. doi:10.1007/978-3-030-16699-1_19

18.    The Eshre Guideline Group On Ovarian Stimulation, Broer S, Griesinger G, et al. ESHRE guideline: ovarian stimulation for IVF/ICSI. Hum Reprod Open. 2020;2020(2). doi:10.1093/hropen/hoaa009

19.    Olivennes F, Howies CM, Borini A, et al. Individualizing FSH dose for assisted reproduction using a novel algorithm: the CONSORT study. Reprod Biomed Online. 2011;22 Suppl 1:S73-82. doi:10.1016/S1472-6483(11)60012-6

20.    Tso LO, Costello MF, Albuquerque LET, 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. doi:10.1002/14651858.CD006105.pub3

21.    Al-Inany HG, Youssef MA, Aboulghar M, et al. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database Syst Rev. 2011;(5):CD001750. doi:10.1002/14651858.CD001750.pub3

22.    Humaidan P, Kol S, Papanikolaou EG, Copenhagen GnRH Agonist Triggering Workshop Group. GnRH agonist for triggering of final oocyte maturation: time for a change of practice? Hum Reprod Update. 2011;17(4):510-524. doi:10.1093/humupd/dmr008

23.    Griesinger G, Berndt H, Schultz L, Depenbusch M, Schultze-Mosgau A. Cumulative live birth rates after GnRH-agonist triggering of final oocyte maturation in patients at risk of OHSS: a prospective, clinical cohort study. Eur J Obstet Gynecol Reprod Biol. 2010;149(2):190-194. doi:10.1016/j.ejogrb.2009.12.030

24.    Delvigne A, Rozenberg S. Preventive attitude of physicians to avoid OHSS in IVF patients. Hum Reprod Oxf Engl. 2001;16(12):2491-2495. doi:10.1093/humrep/16.12.2491

25.    D’Angelo A, Brown J, Amso NN. Coasting (withholding gonadotrophins) for preventing ovarian hyperstimulation syndrome. Cochrane Database Syst Rev. 2011;(6):CD002811. doi:10.1002/14651858.CD002811.pub3

26.    Management of ovarian hyperstimulation syndrome - UpToDate. Accessed May 28, 2022. https://www.uptodate.com/contents/management-of-ovarian-hyperstimulation-syndrome?search=ohss&source=search_result&selectedTitle=2~81&usage_type=default&display_rank=2

27.    Ferrero H, García-Pascual CM, Gómez R, et al. Dopamine receptor 2 activation inhibits ovarian vascular endothelial growth factor secretion in vitro: implications for treatment of ovarian hyperstimulation syndrome with dopamine receptor 2 agonists. Fertil Steril. 2014;101(5):1411-1418. doi:10.1016/j.fertnstert.2014.01.031

28.    Tang H, Mourad S, Zhai SD, Hart RJ. Dopamine agonists for preventing ovarian hyperstimulation syndrome. Cochrane Database Syst Rev. 2016;11:CD008605. doi:10.1002/14651858.CD008605.pub3

29.    Mathur RS, Jenkins JM. Is ovarian hyperstimulation syndrome associated with a poor obstetric outcome? BJOG Int J Obstet Gynaecol. 2000;107(8):943-946. doi:10.1111/j.1471-0528.2000.tb10393.x

30.    Wiser A, Levron J, Kreizer D, et al. Outcome of pregnancies complicated by severe ovarian hyperstimulation syndrome (OHSS): a follow-up beyond the second trimester. Hum Reprod Oxf Engl. 2005;20(4):910-914. doi:10.1093/humrep/deh713

This article should be cited as: Ladisa I., Coccia M.E.: Ovarian hyperstimulation syndrome, Visual Encyclopedia of Ultrasound in Obstetrics and Gynecology, www.isuog.org, September 2022.


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