Ovarian Hyperstimulation Syndrome

What is Ovarian Hyperstimulation Syndrome?

Ovarian hyperstimulation syndrome (OHSS) represents a iatrogenic complication of the fertility treatment during the luteal phase or during an early pregnancy. It is caused by medical interventions in the assisted reproduction as a part of infertility programs.

After the gonadotropin therapy, ovarian hyperstimulation syndrome begins upon a few days due to oocyte retrieval or assisted ovulation. It is manifested byovarian enlargement as a consequence of the presence of numerous ovarian cysts. It leads to the acute fluid rearrangemet from the intravascular to the third space.

Ovarian hyperstimulation syndrome is rare after the administration of clomifene citrate or monofollicular ovulation induction with gonadotropin. (1)

In the vast majority of cases, ovarian hyperstimulation syndrome resolves spontaneously. In spite of that fact, it is necessary to provide supportive medical measures and close monitoring.

The most common cause of ovarian hyperstimulation syndrome is the effect of human chorionic gonadotrophin (hCG) or luteinising hormone (FSH) on ovaries. The main causative agents are proinflammatory mediators such as vascular endothelial growth factor (VEGF).

Risk Factors

There are various risk factors associated with ovarian hyperstimulation syndrome such as a previous history of ovarian hyperstimulation syndrome, polycystic ovarian syndrome, increased follicle number (AFC) or elevated anti-Müllerian hormone (AMH).

Additional predisposing factors are an elevated number of resting follicules: ≥ 10 follicules of 4-10 mm in each ovary, Vascular endothelial growth factor (VEGF) of >200 pg ml^-1 , serum oestradiol >3000/4000 pg ml-¹ .a luteinising hormone/follicule-stimulating hormone (LH/FSH) ratio of >2, hyperandrogenism, low body weight and allergies.

Signs & symptoms

Ovarian hyperstimulation syndrome is characterized by lower abdominal discomfort, progressive increase in umbilical region, nausea, vomiting, dyspnoea, diarrhoea, respiratory distress, weight gain, oliguria, anuria. Additional signs are ascites, pleural effusion, thromboembolism and pericardiac effusion.

Characteristic features of ovarian hyperstimulation syndrome are ovarian enlargement, local and systemic effects such as increased vascular permeability and prothrombotic effect. In severe forms,such effects lead to the formation of ascites,hypovolemia, pleural and pericardial effusion.

The acute phase of ovarian hyperstimulation syndrome is characterized by a loss of approximately 20% of total blood volume. Due to hypovolemia,there is a decreased serum osmolality and sodium caused by vasopressin. ⁽²⁾

Classification

Ovarian hyperstimulation syndrome has been classified into a several grades according to its severity.

According to the Leuven University Fertility Center classification system of ovarian hyperstimulation syndrome there are 4 grades of the disorder:

1. Mild ovarian hyperstimulation syndrome that is characterized by abdominal bloating and pain. Ultrasound findings show an ovarian size lower than 8cm2
2. Moderate ovarian hyperstimulation syndrome is characterized by moderate pain while on pain killers tablets, nausea, vomiting, weight gain of maximum 1kg. Ultrasound shows an ovarian size of 8-10 cm

1. Moderate ovarian hyperstimulation syndrome is characterized by the presence of severe abdominal pain, ascites, oliguria, Hct >45%. Ultrasound suggest the presence of ascites and ovarian size of more than 10cm
2. Critical ovarian hyperstimulaiton syndrome is characterized by the presence of tense ascites or hydrothorax, Hct>55%, white blood cell count >25.000/ml, thromboembolism and adult respiratory distress syndrome.

Diagnosis

The diagnosis is based upon clinical criteria. It is suspected in women with severe abdominal pain or pyrexia.

The classical clinical presentation is abdominal distension and discomfort due to induced follicular maturation prior to oocyte retrieval. According to the clinical symptoms, there are two stages of the disorder: acute and late ovarian hyperstimulation syndrome.

Abdominal ultrasound diagnostic procedure

Early stage of ovarian hyperstimulation syndrome presents in the first 7 days of the hCG injection. In most cases it is linked to an overresponsive ovaries.

Late stage of ovarian hyperstimulation syndrome starts within 10 or more days following the hCG injection. It is a result of endogenous hCG due to an early pregnancy. ⁽³⁾

In the laboratory findings there is an electrolyte disbalance associated with hyponatriemia and hyperkalemia. Acidosis and hypovolemia are present as well as haemoconcentration, leukocytosis, low creatinine clearance, elevated liver enzymes, hypercoagubility and hypoalbuminaemia.

Medical Treatment

The main goal of ovarian hyperstimulation treatment is an early diagnosis and an adequate choice of the treatment.

In mild forms, ovarian hyperstimulation syndrome usually resolves spontaneously. In case of its worsening, close monitoring, analgesic and antiemetic treatment may be considered. Additional therapy may consist of an adequate oral fluid intake, monitoring of the weight and abdominal circumference, laboratory findings, physical and ultrasound examinations.

Nonsteroidal anti-inflammatory regimens are contraindicated, due to their negative effect on renal function.

Hospital admission is reserved for the most severe cases of ovarian hyperstimulation syndrome. The indications are as follows: severe abdominal pain, oliguria, anuria, dyspnoea, tachypnoea, hypotension, dizziness, syncope, electrolyte disbalance and haemoconcentration.

Individuals with severe forms of ovarian hyperstimulation syndrome are candidates for thromboprophylaxis treatment. In such cases, low molecular weight heparin should be administred (LMWH). ⁽⁴⁾

Paracentesis should be performed in individuals with severe abdominal distension and pain caused by the presence of ascites, oliguria and reduced renal perfusion.

Intravenous colloid therapy is reserved for the individuals with large volumes of fluid removed by paracentesis.

The operative management is indicated if there are complications such as adnexal torsion, ovarian rupture or ectopic pregnancy.

Complications

The most common complications are the accumulation of fluids in the abdominal cavity (ascites), hemoconcentration, hypovolemia and electrolyte impairment.

The most common predisposing factors for the onset of adnexal torsion are ovarian cysts and pregnancy. The presence of ovarian enlargement, unilateral pain, nausea, leucocytosis and anaemia are indicators of adnexal torsion. ⁽⁵⁾

The diagnosis is established by the use of vaginal and abdominal B-mode ultrasound, colour Doppler sonography. Doppler identifies ovarian vascularization. The absence of blood flow is indicative of ovarian torsion. Laparoscopic detorsion is the treatment of choice.

Ovarian haemorrhage is caused by the follicular rupture in case of an acute abdomen linked to the anaemia.

Thromboembolism is associated with ovarian hyperstimulation syndrome.

Prevention

The primary prevention is based upon the appropriate recognition of predisposing factors for ovarian hyperstimulation syndrome. The application of gonadotrophins in ovarian insufficiency is important.

The secondary prevention represents the cancellation of the cycle (GnRH agonists or GnRH antagonists). ⁽⁶⁾

GnRH antagonist protocol is represents a short and simple protocol with good clinical outcome in the prevention measures.

References

1. Delvigne A, Rozenberg S.Review of clinical course and treatment of ovarian hyperstimulation syndrome (OHSS).Hum Reprod Update. 2003 Jan-Feb;9(1):77-96.
2. Evbuomwan IO. Coexistent hemoconcentration and hypoosmolality during superovulation and in severe ovarian hyperstimulation syndrome: a volume homeostasis paradox. Fertil Steril. 2000 Jul;74(1):67-72.
3. Golan A.Ovarian hyperstimulation syndrome: an update review.Obstet Gynecol Surv. 1989 Jun;44(6):430-40.
4. Delvigne A, Rozenberg S.Review of clinical course and treatment of ovarian hyperstimulation syndrome (OHSS).Hum Reprod Update. 2003 Jan-Feb;9(1):77-96.
5. Brinsden PR, Wada I.Diagnosis, prevention and management of ovarian hyperstimulation syndrome.Br J Obstet Gynaecol. 1995 Oct;102(10):767-72.
6. European Society of Human Reproduction (ESHRE). Special Interest Group (SIG) guidelines on ovarian hyperstimulation syndrome (OHSS).