Ovarian Hyperstimulation Syndrome

Context

Ovarian hyperstimulation syndrome (OHSS) is a complication of fertility treatment as outlined in the Royal College of Obstetricians and Gynaecologists’ Green-top guideline.1

OHSS is usually mild, self-limiting and does not require emergency department review. However severe or critical OHSS has significant associated morbidity and mortality. 53 cases of severe or critical OHSS were reported in the UK in 2023/4,2 but this is becoming increasingly rare due to changes in fertility treatment protocols (affecting 0.28% of IVF cycles in 2007, reducing to 0.02% in 2021).3 As a result, emergency physicians need to maintain a high index of suspicion to detect OHSS as a rare cause of critical illness in patients undergoing assisted reproductive treatments.

Definition

Ovarian hyperstimulation syndrome is usually an iatrogenic complication of fertility treatment. An affected individual has an unexpectedly excessive response to a treatment course of ovarian stimulation.1

Assisted reproduction cycles usually involve exogenous hormonal stimulation of a patient’s ovaries to produce a maximal amount of oocytes, while simultaneously preventing ovulation until enough follicles mature. Once the desired follicle count is achieved, a ‘trigger’ injection is given to induce the final follicle maturation process.4

In certain patients, exposure of stimulated ovaries to this ‘trigger’ injection leads to the production of proinflammatory mediators, particularly vascular endothelial growth factor (VEGF). This combination of enlarged ovaries, cytokine-mediated vascular permeability and hypercoagulability gives rise to the clinical feature of OHSS.1 OHSS is almost always associated with human chorionic gonadotropin (hCG)-based ‘trigger’ injections; other fertility treatment protocols use gonadotropin-releasing hormone (GnRH) agonists instead of hCG ‘triggers’, dramatically reducing the risk of OHSS.2

VEGF-mediated capillary leakage then causes tissue oedema and fluid loss into the interstitium or ‘third-space’ resulting in ascites. Pleural or pericardial effusions of varying size can also occur.

If severe fluid loss occurs, intravascular fluid depletion and intra-abdominal hypertension from third-spacing lead to impaired organ perfusion, reduced venous drainage and abdominal compartment syndrome. Hepatic injury, paralytic ileus, and acute kidney injury can result. Intravascular fluid depletion also increases the risk of thromboembolic events from haemoconcentration and hypercoagulability.1,5

Learning bites:

• OHSS is usually associated with hCG-based ‘trigger’ injections.
• The main feature of OHSS is VEGF-mediated capillary leakage and intravascular volume depletion.

The diagnosis of OHSS is clinical, but can be challenging as the symptoms are nonspecific and there is no conclusive diagnostic test.1 It should be suspected in all patients undergoing fertility treatment who attend the emergency department, particularly those with risk factors for OHSS. These include5:

• Polycystic ovarian syndrome
• <35 years of age
• Low BMI
• History of OHSS previously
• Those whose ‘trigger’ injection was hCG-based (rather than a GnRH agonist)

Symptoms and signs include:

• Abdominal pain, bloating, nausea and vomiting (due to a combination of uterine and ovarian enlargement, interstitial fluid loss, ascites and ileus)
• Shortness of breath (due to pleural effusions or thrombosis)
• Oliguria (due to hypovolaemia-related renal impairment and/or intra-abdominal hypertension)
• Peripheral oedema
• Drowsiness or altered mental function (from hyponatraemia)
• Findings due to arterial and/or venous thrombosis (including limb swelling, chest pain, limb ischaemia, focal neurological signs or headache)

OHSS-associated thrombosis is infrequent, but typically occurs in the venous system (81% of cases) and unusually may preferentially affect the jugular and subclavian veins ahead of the lower, and then upper, extremities.6 Arterial emboli affecting the cerebral, retinal, coronary and extremity arteries have all been reported with OHSS.5

Patients with OHSS may present critically unwell with any combination of hypovolaemic, obstructive (from massive pulmonary embolism or effusion-related tamponade) and distributive shock (from overwhelming cytokine release or superimposed sepsis).

Importantly, OHSS alone does not commonly cause severe abdominal pain, peritonism or pyrexia. These features should prompt the clinician to exclude ectopic pregnancy, ovarian torsion or cyst rupture, as well as intra-abdominal infection or perforation, as causes. In particular, increased ovarian size due to fertility treatment increases the risk of ovarian torsion.1

Learning bites:

• While OHSS should be suspected in all patients receiving fertility treatment who attend the emergency department, it should not become their default diagnosis without carefully excluding other causes of their symptoms.1
• OHSS does not usually cause severe abdominal pain, peritonism or pyrexia.
• Suspect thromboembolism in patients with OHSS who present to the ED with unusual neurological symptoms or visual disturbance. This applies even if they present several weeks after their OHSS diagnosis with apparent improvement in initial OHSS-related symptoms.

Based on timing

Some patients present with ‘early’ OHSS, within seven days of the ‘trigger’ injection due to an excessive ovarian response. Patients with ‘late’ OHSS present ten or more days after the ‘trigger’ injection, usually from endogenous hCG due to an implanting pregnancy. This form of OHSS is usually more severe and prolonged.8

Based on symptoms and investigation findings

The Royal College of Obstetricians and Gynaecologists (RCOG) have proposed the following severity classification.1

Learning bites

• Clinically apparent ascites is estimated to be present in 99% of cases of severe OHSS and may be helpful in discriminating OHSS from other conditions.5
• Ovarian size alone (based on ultrasound) is not a reliable indicator of OHSS severity since follicles may have been aspirated as part of fertility treatment prior to onset of symptoms.

Treatment of OHSS is supportive with most non-pregnancy associated cases resolving in 10-14 days.

Mild (the vast majority of cases) and most moderate OHSS will be managed on an outpatient basis by the fertility treatment centre with oral analgesia, advice about monitoring fluid intake and urine output, regular reviews and contact details for advice. There is considerable variation in practice between specialists as to the threshold for admission. Selected cases of severe OHSS may also be suitable for similar outpatient management on specialist advice, with thromboprophylaxis added due to the risk of VTE.

If a patient attends the ED with OHSS, consultation with obstetric colleagues is important to help guide management. Indications for hospital admission include:

• Inability to achieve adequate pain control;
• Inability to take maintain hydration;
• Worsening symptoms (such as weight gain, breathlessness or reduced urine output) while being managed as an outpatient;
• Social circumstances which prevent regular face to face follow up;
• Critical OHSS

In the emergency department, fluid resuscitation to restore intravascular volume is the treatment priority. Analgesia, antiemetics and electrolyte correction may also be required, in addition to oxygenation and ventilatory support as necessary. If associated infection is suspected, start empiric antimicrobial therapy.

Patients with significantly increased intraabdominal pressure and ileus from large volume ascites may benefit from nasogastric decompression and paracentesis. Specialist consultation and intensive care level support is often required.

Patients admitted with OHSS should all receive thromboprophylaxis unless there is a contraindication.

Surgery is only indicated for other issues such as ovarian torsion, rupture or ectopic pregnancy.

The fertility treatment centre (rather than the treating emergency medicine clinician) must also report all cases of severe or critical OHSS to the Human Fertility and Embryology Authority in the UK. Similar reporting requirements apply in most other countries.

Learning bite:

• Consult obstetric colleagues to guide management of patients who present with suspected or confirmed OHSS.
• Restoring intravascular volume, analgesia, antiemetics and electrolyte correction are the treatment priorities in the emergency department.
• Inpatient management may include gastric decompression, paracentesis and critical care if required.

• Assuming that OHSS only occurs within a week of a ‘trigger’ injection. Late onset OHSS can present several weeks after a ‘trigger’ injection.
• Attributing severe pain, peritonism or pyrexia to OHSS. These symptoms are far more likely to be caused by other intra-abdominal pathologies such as ovarian torsion, ectopic pregnancy or infection.
• Relying on ultrasound determination of ovarian size to classify OHSS severity. If the patient has had follicle aspiration for oocyte collection, quantifying ovarian size will be unreliable.

1. Mathur R, Drakeley A, Raine-Fenning N, et al. The management of ovarian hyperstimulation syndrome. Green-top guideline no. 5. London, UK: Royal College of Obstetricians and Gynaecologists, 2016.
2. Human Fertilisation and Embryology Authority. State of the fertility sector 2023/24. London, UK. 2024. [accessed 09 December 2024].
3. Sokteang S, Pirtea P, Toner JP, et al. Ovarian hyperstimulation syndrome should be dead, we are just waiting on the obituary. Fertil Steril 2024;122(2):230-32. doi: 10.1016/j.fertnstert.2024.02.040
4. Alyasin A, Mehdinejadiani S, Ghasemi M. GnRH agonist trigger versus hCG trigger in GnRH antagonist in IVF/ICSI cycles: A review article. Int J Reprod Biomed 2016;14(9):557-66.
5. Timmons D, Montrief T, Koyfman A, et al. Ovarian hyperstimulation syndrome: A review for emergency clinicians. The American journal of emergency medicine 2019;37(8):1577-84. doi: 10.1016/j.ajem.2019.05.018
6. Mor YS, Schenker JG. Ovarian hyperstimulation syndrome and thrombotic events. Am J Reprod Immunol 2014;72(6):541-8. doi: 10.1111/aji.12310
7. Evbuomwan I. The role of osmoregulation in the pathophysiology and management of severe ovarian hyperstimulation syndrome. Hum Fertil (Camb) 2013;16(3):162-7. doi: 10.3109/14647273.2013.831996
8. Mathur RS, Akande AV, Keay SD, et al. Distinction between early and late ovarian hyperstimulation syndrome. Fertil Steril 2000;73(5):901-7. doi: 10.1016/s0015-0282(00)00492-1