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Ovarian Hyperstimulation Syndrome

OHSS

Ovarian hyperstimulation syndrome (OHSS) may occur in women taking medication to increase fertility and promote ovulation. In the majority of cases, the condition is mild but can be severe in a few patients with subsequent serious complications and possibly death.


Presentation

OHSS has a varying number of associated symptoms and significant complications. Patients most commonly complain of abdominal pain, nausea and vomiting. Ascites may result in abdominal enlargement of up to 25 cm with related discomfort.
Ascites is a prominent complication of the disease. It usually results from third spacing due to increased vascular permeability but may also occur after rupture or leakage of fluid from follicles.
Peritonitis can develop because of the presence of ascites. It may be generalized or local and generally follows irritation from ruptured cysts. It is also associated with increased protein concentration in the ascitic fluid as well as important inflammatory mediators.

In some patients OHSS may manifest with acute abdominal pain. Ovarian torsion, intraperitoneal bleeding or cyst rupture are responsible for the pain.

Hypotension and hypovolemia may develop due to fluid shifts and third spacing because of leakage of ovarian blood vessels. They are associated with swelling of the extremities, ascites, and fluid in the thorax and within the pericardium.

Dyspnea most commonly occurs because of mechanical impedance of the diaphragm as a result of the growing collection of ascitic fluid and growth of the ovaries. In rare occasions, dyspnea may develop due to atelectasis, ARDS (acute respiratory distress syndrome), pericardial effusions, pulmonary embolism or pulmonary effusions and edema [11].

OHSS is further characterized by a hypercoagulable state, largely due to hypovolemia and hemoconcentration, which in turn result from fluid shifts and third spacing. There is an associated increased risk of deep vein thrombosis (DVT) and pulmonary embolisms (PE). Both arterial and venous thrombosis can occur, although venous thrombosis is much more common. 83% of all venous thrombi occur in the head, neck and arms. The rest takes place in the lower extremities. The incidence of pulmonary embolism in patients with OHSS ranges from 4 to 12%.
Electrolyte disturbances are prominent in the condition.

Decreased perfusion to the kidneys leads to oliguria and decrease urine sodium excretion. In the distal tubule, there is decreased exchange of potassium and hydrogen ions for sodium, with resultant hyperkalemia and acidosis [12].

Acute renal failure is another potential complication. A hypercoagulable state can lead to the formation of microthrombi and decreased kidney perfusion. This has serious consequences on the function of the kidney.

Weight Gain
  • Most women with the condition have mild symptoms such as: Abdominal bloating Mild pain in the abdomen Weight gain In rare cases, women can have more serious symptoms, including: Rapid weight gain (more than 10 pounds or 4.5 kilograms in 3 to 5 days) Severe[nlm.nih.gov]
  • Mild symptoms include abdominal bloating and feeling of fullness, nausea, diarrhea, and slight weight gain.[en.wikipedia.org]
  • Therefore, women with mild disease should be observed for enlarging abdominal girth, acute weight gain, and abdominal discomfort on an ambulatory basis for at least 2 weeks or until menstrual bleeding occurs.[emedicine.medscape.com]
  • Clinical signs may include any or all of the following: rapid weight gain, ascites, oliguria, hemoconcentration, leukocytosis, along with intravascular hypovolemia, hyponatremia, and hyperkalemia.[ncbi.nlm.nih.gov]
  • RESULTS: Weight gain was highest in the OHSS group. Ovarian weights were lower in the treatment group than OHSS group. Peritoneal fluid VEGF levels were lower for RSV group compared to group 2 and 3.[ncbi.nlm.nih.gov]
Nausea
  • Gestational carriers reported normal nausea and vomiting of pregnancy.[ncbi.nlm.nih.gov]
  • : Abdominal bloating and nausea are common presenting complaints in pregnant women. OHSS is a rare but potentially fatal complication of IVF.[ncbi.nlm.nih.gov]
  • The clinical picture showed abdominal pain, massive ascites, nausea, dyspnea and amenorrhea. After imaging examinations and laboratory tests, the diagnosis was established. The patient was managed expectantly with no complications.[ncbi.nlm.nih.gov]
  • Six days after embryo transfer, the patient presented with complaint of abdominal bloating, nausea, vomiting and shortness of breath. Severe late-onset OHSS, with massive ascites and pleural effusion, was diagnosed.[ncbi.nlm.nih.gov]
Abdominal Pain
  • We present a case of a patient undergoing treatment for infertility who presented to the ED with shortness of breath and abdominal pain.[ncbi.nlm.nih.gov]
  • The patient's condition worsened five days later with sudden onset of sharp abdominal pain, nausea and vomiting, along with impaired laboratory test values.[ncbi.nlm.nih.gov]
  • Long term follow-up is necessary and ovarian torsion should be suspected when accompanied by abdominal pain. Acupuncture plus GnRHa treatment may be an effective way for these cases.[ncbi.nlm.nih.gov]
  • A primigravida presented at 17 1/7 weeks of gestation with abdominal pain because of enlarged ovaries. Multiple fetal abnormalities were seen on pregnancy ultrasound. Fetal trisomy 21 was diagnosed by amniocentesis.[ncbi.nlm.nih.gov]
  • The clinical picture showed abdominal pain, massive ascites, nausea, dyspnea and amenorrhea. After imaging examinations and laboratory tests, the diagnosis was established. The patient was managed expectantly with no complications.[ncbi.nlm.nih.gov]
Abdominal Distension
  • Case 1 and case 2: severe OHSS with abdominal distension, ascites development, and hemoconcentration. Case 1 and case 2: diagnosed by clinical, hematologic, and ultrasound findings. Hospitalization, IV infusion, and peritoneal drainage.[ncbi.nlm.nih.gov]
  • The clinical picture may vary from abdominal distension and discomfort to potentially life-threatening capillary leak with fluid sequestration in a third space, and massive ovarian enlargement.[radiopaedia.org]
  • Clinical and laboratory findings showed third space fluid shift leading to weight gain, generalized tissue edema, ascites, hydrothorax, abdominal distension and pain, chest discomfort, hypovolemia, dehydration, ovaries enlargement, electrolyte disturbances[link.springer.com]
  • Systemic examination revealed decreased air entry in bilateral basal areas of the chest and abdominal distension.[joacc.com]
Neurologic Manifestation
Oliguria
  • Clinical signs may include any or all of the following: rapid weight gain, ascites, oliguria, hemoconcentration, leukocytosis, along with intravascular hypovolemia, hyponatremia, and hyperkalemia.[ncbi.nlm.nih.gov]
  • Severe OHSS was diagnosed in the presence of at least moderate ascites and two or more of the following: maximum ovarian diameter (MOD)   100 mm, hematocrit (Ht)  45%, white blood cell count (WBC)  15 000/mm 3 , hydrothorax, dyspnea and oliguria.[ncbi.nlm.nih.gov]
  • Indeed, patients classified as having severe OHSS have rapid weight gain, tense ascites, hemodynamic instability, respiratory difficulty, progressive oliguria, and laboratory abnormalities.[moh-it.pure.elsevier.com]
  • 2.1 Staff & equipment Mild Abdominal pain, bloating Nausea Ovarian vol Normal Moderate Moderate abdominal pain Vomiting Ovarian vol 8-12 cm3 Ascites May be normal Severe Dehydration Oliguria Ovarian vol 12 cm3 Ascites Haematocrit 45% Electrolyte imbalance[icid.salisbury.nhs.uk]
  • Criteria for severe OHSS include enlarged ovary, ascites, hematocrit 45%, WBC 15,000, oliguria, creatinine 1.0-1.5 mg/dl, creatinine clearance 50 ml/min, liver dysfunction, and anasarca.[en.wikipedia.org]
Clitoromegaly
  • Our case is an infant born at 23 weeks gestational age who at 30 weeks postconceptional age (PCA) developed elevated 17-hydroxyprogesterone on her newborn screen with associated clitoromegaly and a ventral groove on the inferior aspect of the erectile[ncbi.nlm.nih.gov]
Vulvar Edema
  • Modest vulvar edema is frequently seen in a severe form of OHSS; however, cases of massive bilateral vulvar edema are rare and pathogenesis is uncertain.[ncbi.nlm.nih.gov]

Workup

Ultrasound monitoring is very important in the workup of OHSS. It allows the measurement of the rate of growth of the ovaries. In case growth is excessive, stimulation can be toned down or withheld.

Severe OHSS generally requires the performance of several imaging and laboratory tests. Ultrasound of the abdomen and the ovaries are recommended, in particular because they can detect associated medical emergencies such as ovarian torsion. Worrisome findings on a complete blood count include a hematocrit above 45% and a high white blood cell count. Renal function should be assessed with measurements of serum urea and creatinine. Other recommended tests include a screen for coagulation factors, liver function tests, a chest x-ray to detect any pleural effusions and a daily measurement of abdominal girth.

Treatment

Treatment is mostly supportive and is directed at the complications of the disease. Risk can be assessed with an ultrasound or measurements of blood estrogen levels. One Cochrane review, nonetheless, suggests that ultrasound scans alone may be sufficient. In case imaging or blood tests predict a high risk of OHSS, withholding hCG is recommended.

Freezing embryos is advisable when insemination has occurred. It is important not to transfer fresh embryos. Frozen embryos may be transferred in the coming cycles. However, routine freezing in place of routine transfer of fresh embryos should not take place. A 2011 Cochrane review found no evidence for 'coasting': a process in which hCG stimulation is stopped but agonist suppression is continued. Other studies, however, report weak evidence that coasting can reduce the incidence of severe OHSS.

Management of OHSS depends on whether the condition is severe or mild to moderate. Mild to moderate OHSS generally requires paracetamol or opiates for analgesia. It is recommended to avoid Non-steroidal anti-inflammatory drugs. Nausea may be treated with anti-emetics that are deemed safe in the early periods of pregnancy. Monitoring should occur every 1 to 2 days, and physicians should explain to patients the possible symptoms that may need urgent assessment and treatment. Women should be additionally advised to increase their intake of oral fluids.

Severe cases, on the other hand, require a more radical approach. Patients can be admitted to the intensive care unit (ICU) where fluid balance is closely followed. In cases where oral hydration is not possible, intravenous fluids will have to be administered. If hypovolemia persists despite IV fluids, an albumin colloid may be given through the IV route. Hyponatremia is common among patients with OHSS and electrolytes in general need to be carefully monitored. In addition, guidelines recommend the avoidance of diuretics. Women complaining from severe symptoms can be treated by aspiration of the ascites or the pleural fluid. Severe complications such as an acute kidney injury, pericardial effusions or acute respiratory distress syndrome can develop in case the patient is not intensely monitored and treated accordingly.

Prognosis

Ovarian hyperstimulation syndrome has an excellent prognosis in cases that are mild to moderate. Nonetheless, morbidity can be significant in severe conditions and fatalities sometimes take place. However, with prompt and adequate treatment, OHSS can have a good prognosis even in severe cases.

Death in OHSS occurs in about 1 case for every 400,000 to 500,000 stimulated cycles. Responsible causative mechanisms include shock due to hypovolemia, bleeding, hypercoagulability and formation of thromboemboli and bleeding.

Etiology

The etiological mechanisms underlying ovarian hyperstimulation syndrome (OHSS) remain unknown, but increased vascular perfusion of the ovaries is thought to be critical in the disease process [3]. Several hormones have been also involved and they include estradiol, prolactin, prostaglandins, histamine, estrogen and its analogs. Substances that specifically act on blood vessels and increase permeability play a prominent role. Among them are endothelin-1, tumor necrosis factor alpha (TNF-alpha), interleukins and VEGF. The latter is secreted by the ovaries [4] [5].

The role of hCG is evidenced by the decrease in OHSS when hCG is withheld. hCG is thought to act by increasing vascular permeability and triggering angiogenesis. This eventually leads to third spacing and ultimately in OHSS. Several conditions can exacerbate vascular permeability and lead to OHSS, in particular gonadotrophic adenomas, molar pregnancy and pregnancy itself.

Normally, luteinizing hormone acts through a similar process but the conditions mentioned above exaggerate its effects. This is because hCG has a long half life and direct stimulation effects on the ovaries. These changes can persist even after ovulation, particularly in regards to the vasculature surrounding the ovaries. It is worth pointing out that recombinant exogenous hCG has stronger effects than the endogenously produced hormone. These effects may be worsened when the hormones are not given in the correct time or when induction is initiated during a hyperestrogenic state.

Several risk factors are associated with OHSS. They include high levels of estradiol, prior history of PCOS (polycystic ovarian syndrome), hCG administration, endogenous hCG caused by indirect induction treatments and a large number of follicles. Martin et al. attempted to quantify the risk. They found that the rate of OHSS can reach 80% if the level of estradiol surpasses 6000 mcg before the initiation of hCG treatment and if the number of follicles present is greater than 30.

Epidemiology

The incidence of OHSS is dependent on the severity of the condition. Mild forms of OHSS in 8 to 23% of patients, moderate forms in 1% to 7% and severe forms in 0.25% to 5% [6]. Frequency of OHSS is especially elevated when elevated blood estradiol levels are present as shown by the increased number of follicles on ultrasound. It is also increased when GnRH agonists are used in combination with gonadotropins [7]. It should be noted that only women of childbearing age are prone to OHSS.

Sex distribution
Age distribution

Pathophysiology

The pathophysiological mechanisms underlying OHSS remain poorly understood. Estradiol (E2) has been extensively implicated in the disease but its degree of involvement and mechanisms of action are controversial. There is in general an increase in E2 concentrations although decreased E2 serum levels have been also described in congenital adrenal hyperplasia and hypogonadotropic hypogonadism. Furthermore, in the absence of hCG, levels of serum E2 do not have any effects on the presence or severity of OHSS. No vasoactive effects have been attributed for E2, but the levels found in the serum are predictive for the development of the condition regardless of the exact mediating mechanism. Furthermore, scientists have shown a link between the cystic fibrosis transmembrane conductance regulator (CFTR) and E2 mediated mechanisms. E2 tends to upregulate CFTR, which in turn leads to an increase in the activity of channels in a number of exocrine glands as well as in the peritoneum. This leads to shift of fluid and accumulation, and may underlie a potential mechanism for the role of E2 in OHSS [8].

On the other hand, a number of cytokine and growth factors have been implicated in the disease. They include IL-2, IL-6, IL-9, IL-10, IL-18, in addition to vascular endothelial growth factor (VEGF). VEGF, in particular, has been found in peritoneal fluid and was strongly linked to critical pathophysiological mechanisms underlying the disease. Other substances that play a prominent role are prolactin, prostaglandins, histamine and renin-angiotensin [9].

VEGF acts by increasing vascular permeability and its effects can be counteracted by an injection of antiserum rhVEGF. Gonadotrophic stimulation also leads to an increase in VEGF concentration as well as VEGF mRNA. It may also result in increased expression of VEGFR-2 mRNA. Studies on human subjects sound that hCG administration lead to VEGF secretion in granulosa-lutein cells. Furthermore, levels of VEGF can predict the occurrence of OHSS and the degree of its severity [10].

Prevention

Several techniques have been devised in an attempt to reduce the incidence of OHSS. GnRH agonists can be used instead of hCG during the stimulation phase, although this has resulted in reduced live birth rates. Furthermore, freezing embryos and implanting them in a following cycle may completely eliminate OHSS when this is done in combination with the use of GnRH. Women with PCOS can also significantly reduce their risk of developing the condition if they take metformin, but there is no improvement in live birth rates. Dopamine antagonists such as cabergoline can additionally decrease risk by reducing vascular permeability and is especially helpful in high risk women with moderate OHSS. Plasma can be expanded and consequently hypovolemia reduced through the administration hydroxyethyl starch infusions (HES).

Summary

Ovarian hyperstimulation syndrome (OHSS) is relatively common condition that can take place in women undergoing treatment to enhance fertility and ovulation [1]. Most cases are mild or moderate with no serious complications but severe conditions do occur and necessitate urgent intervention [2] [3]. Pathophysiological mechanisms remain uncertain but it is though that exogenous hormone administration leads to significantly increased vascular permeability in the ovaries, leading to fluid leak with subsequent ascites, hypovolemia, electrolyte abnormalities and coagulopathy. Treatment is supportive and targeted at the frequent complications of the disease and may require admission to the intensive care unit when the condition is severe. Prognosis is excellent in mild to moderate forms. Morbidity may be significant in severe cases, but adequate and urgent treatment yields excellent outcomes.

Patient Information

Ovarian hyperstimulation syndrome (OHSS) is a medical condition that occurs in women taking exogenous hormones to enhance their fertility and ovulation. Most cases are mild to moderate with no significant complications, but severe cases necessitate urgent treatment. It results from increased permeability of the blood vessels supplying the ovaries, leading to fluid leaks and subsequent events that target a number of systems in the body. Patients usually present with increase in the abdominal size with associated discomfort, nausea and vomiting. Treatment is supportive and is directed at the varying complications. Outcomes are excellent when the condition is mild or moderate but patients may fall significantly ill in the severe form of OHSS. Nonetheless, prompt and adequate treatment still yields excellent results.

References

Article

  1. Myrianthefs P, Ladakis C, Lappas V, et al. Ovarian hyperstimulation syndrome (OHSS): diagnosis and management. Intensive Care Med. 2000 May; 26(5):631-4. 
  2. Golan A, Ron-el R, Herman A, et al. Ovarian hyperstimulation syndrome: an update review. Obstet Gynecol Surv. 1989 Jun; 44(6):430-40.
  3. Morris RS, Paulson RJ. Ovarian derived prorenin-angiotensin cascade in human reproduction. Fertil Steril. 1994 Dec; 62(6):1105-14. 
  4. Elchalal U, Schenker JG. The pathophysiology of ovarian hyperstimulation syndrome--views and ideas. Hum Reprod. 1997 Jun; 12(6):1129-37. 
  5. Levin ER, Rosen GF, Cassidenti DL, et al. Role of vascular endothelial cell growth factor in Ovarian Hyperstimulation Syndrome. J Clin Invest. 1998 Dec 1; 102(11):1978-85.
  6. Brinsden PR, Wada I, Tan SL, et al. Diagnosis, prevention and management of ovarian hyperstimulation syndrome. Br J Obstet Gynaecol. 1995 Oct; 102(10):767-72.
  7. Haning RV, Jr, Austin CW, Carlson IH, Kuzma DL, Shapiro SS, Zweibel WJ. Plasma estradiol is superior to ultrasound and urinary estriol glucuronide as a predictor of ovarian hyperstimulation during induction of ovulation with menotropins. Fertil Steril. 1983;40:31–6.
  8. Ajonuma LC, Tsang LL, Zhang GH, et al. Estrogen-induced abnormally high cystic fibrosis transmembrane conductance regulator expression results in ovarian hyperstimulation syndrome. Mol Endocrinol. 2005;19:3038–44.
  9. Rizk B, Aboulghar M, Smitz J, Ron-El R. The role of vascular endothelial growth factor and interleukins in the pathogenesis of severe ovarian hyperstimulation syndrome. Hum Reprod Update. 1997;3:255–66.
  10. 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;67:261–5.
  11. Abramov Y, Elchalal U, Schenker JG. Pulmonary manifestations of severe ovarian hyperstimulation syndrome: A multicenter study. Fertil Steril. 1999;71:645–51.
  12. Polishuk WZ, Schenker JG. Ovarian overstimulation syndrome. Fertil Steril. 1969;20:443–50.

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Last updated: 2019-07-11 20:03