Vasoactive Substances

OHSS is the result of amplification of normal ovulatory physiology. IVF stimulation protocols commonly result in maturation of upwards of 10 to 20 follicles of varying size on each ovary. OHSS is triggered by release of vasoactive substances in response to hCG or LH. These vasoactive substances cause increased capillary permeability, leading to third spacing of fluid, hemoconcentration, and reduced vascular volume.

Possible participants in the pathogenesis of OHSS include vascular endothelial growth factor (VEGF), prostaglandins, other members of the cytokine family, and nitric oxide, as well as components of the renin and the angiotensin system, especially angiotensin II.^9–13 All of these are recognized participants in the normal physiology of folliculogenesis and luteogenesis.^14,15

The primary mediator of increased vascular permeability associated with OHSS appears to be the cytokine VEGF.^9,10 VEGF is secreted by granulosa and theca cells in the late follicular phase. Neoangiogenesis, essential to folliculogenesis and especially to luteogenesis, is induced largely by VEGF.^11–13

Ovarian hyperstimulation syndrome is most commonly thought to be the result of vascular hyperpermeability caused by excessive VEGF-induced changes associated with extreme neoangiogenesis. The expression of VEGF by granulosa cells has been shown to be up-regulated by hCG, and unbound levels of VEGF correlate with the severity of OHSS.^16,17 Inhibition of VEGF is associated with improvement in vascular permeability.^18,19 Evidence indicates that supernumerary follicles are the predominant source of superphysiologic quantities of VEGF in patients who develop OHSS.²⁰ VEGF acting directly or indirectly in concert with other factors may diffuse into the peritoneal cavity, resulting in increased permeability of diffuse mesothelial vessels. Removal of these substances by paracentesis may facilitate reduction of capillary hyperpermeability, resulting in the observed improvement in the clinical sequelae.²¹

Fluid Homeostasis

The primary dysfunction in OHSS is movement of protein-rich fluid out of the vascular space into the abdominal cavity and occasionally the pleural or pericardial spaces, leading to varying degrees of hemoconcentration and hypovolemia.

The hemoconcentration associated with OHSS leads to hypercoagulability and increased risk of thromboembolism, especially if it occurs in combination with thrombophilias or other coagulopathies.^22,23 There is also evidence that OHSS may induce a primary hypercoagulable state independent of hemoconcentration.²⁴

The hypovolemia resulting from OHSS can lead to low blood pressure and decreased central venous pressure, followed by decreased renal perfusion. Decreased renal perfusion results in increased sodium and water reabsorption in the proximal tubule and reduced exchange of hydrogen and potassium for sodium in the distal tubule, potentially leading to oliguria with prerenal azotemia, hyponatremia, and hyperkalemic acidosis.²⁵ Medical complications secondary to OHSS include renal insufficiency, adult respiratory distress syndrome, hepatocellular damage, hypovolemic shock, disseminated intravascular coagulation, and thromboembolism.⁵

Classification

OHSS is best thought of as a broad continuum of signs and symptoms.^27,28 However, for management and reporting purposes, OHSS is generally classified as mild, moderate, or severe (Table 40-2). Mild OHSS is a self-limited and clinically benign condition characterized by ovarian enlargement (generally less than 5 cm), abdominal bloating, and discomfort. Moderate OHSS indicates progressively greater ovarian enlargement and significant symptoms that are difficult to manage outside a hospital environment. Severe OHSS involves massive cystic ovarian enlargement in excess of 10 cm and tense abdominal ascites with or without pleural effusion.²⁷

Table 40-2 Classification of Ovarian Hyperstimulation Syndrome

Onset of Symptoms

The LH surge or ovulatory hCG level is followed by formation of multiple corpus luteum cysts and unusually large, cystic ovaries. OHSS presents as early as several days after ovulation or egg retrieval or may not emerge until the last week of the cycle in response to the rising hCG resulting from embryo implantation.

Most commonly, patients present with complaints of abdominal bloating, shortness of breath, nausea, unusual weight gain, and decreased urine output. Patients with severe OHSS appear ill, with marked abdominal distension secondary to ascites. They frequently become significantly short of breath in the supine position, again secondary to abdominal ascites. Laboratory findings include elevated hematocrit, leukocytosis, hyponatremia, hyperkalemia, elevated blood urea nitrogen (BUN)-to-creatinine ratio, and occasionally mildly elevated results on liver function tests. On ultrasound, ovaries will be large and cystic with variable amounts of free peritoneal fluid filling the abdominal space. Occasional patients will present with a pleural effusion, most commonly right sided, with or without abdominal ascites.²⁹

Clinical Course

OHSS is self-limited. In the absence of pregnancy, it will resolve spontaneously with the onset of luteolysis at the end of the cycle. Resolution of OHSS is heralded by progressive resolution of ascites and rapid diuresis. If the patient becomes pregnant, however, signs and symptoms will continue or even exacerbate during the second week after ovulation due to rising endogenous hCG levels. Continued observation and medical intervention is often necessary beyond the missed menstrual period. Despite continued rising hCG levels, however, the vast majority of cases will stabilize and begin to improve gradually before the 6-week ultrasound.

Avoidance of Excessive Stimulation

Although it is not possible to prevent all cases of hyperstimulation syndrome, recognition of high-risk patients followed by judicious management of gonadotropin therapy to avoid excessive stimulation can reduce the incidence of OHSS. Menotropin doses should be carefully considered for each patient based on her clinical characteristics. Lower doses and more frequent monitoring should be considered for those patients who are most likely to respond aggressively, especially young patients and those with PCOS. Frequent, sometimes daily, surveillance of serum estradiol levels and follicular growth can facilitate modulation of gonadotropin doses, limiting the rate of estrogen rise without a detrimental effect on follicular growth.

If rapidly rising estrogen levels reach or threaten to become unacceptably high, withholding the daily dose of gonadotropin can reduce the incidence and severity of OHSS. This approach, coasting, can in some cases result in arrest and atresia of all or most of the follicles; however, in many cases hCG administration can be delayed until the estradiol level returns to a more acceptable level without a detrimental effect on the subsequent oocyte and embryo quality or pregnancy rate.^33–36 Coasting has been shown to be associated with reduced concentrations of follicular VEGF and a significantly lower incidence of severe OHSS.³⁷ Coasting is most successful when the serum estradiol has exceeded 3000 pg/mL and the lead follicle has reached a diameter larger than 14 mm. If growth of the lead follicles continues, administration of hCG can be withheld for up to 4 days until the serum estradiol reaches an acceptable level. Prolonged coasting beyond 4 days is associated with a decrease in implantation and pregnancy rates.³⁸

Withholding hCG

Because the clinical signs and symptoms of hyperstimulation will not develop until final follicular maturation and luteinization occur in response to hCG or LH, it is most prudent to withhold the ovulatory dose of hCG in patients who are clearly overstimulated based on follicular number, size, and estrogen level.^31,33 Although the decision to drop a cycle ultimately becomes a matter of clinical judgment, in general it is our practice to withhold hCG in the presence of a large number of small follicles and a peak estradiol level in excess of 4000 pg/mL.

Intravenous Albumin

Intravenous administration of an osmotically active “colloid” agent at the time of retrieval appears to reduce the risk and severity of OHSS in high-risk patients. Administration of intravenous albumin (25 g) during and immediately after the egg retrieval has been recommended for women with a peak estradiol level of 3000 pg/mL or a large number of small and intermediate-sized follicles.³⁹ Based on a meta-analysis using the Cochrane standard, it is estimated that for every 18 women treated with albumin, 1 case of OHSS will be avoided.⁴⁰ However, prophylactic administration of albumin to high-risk patients remains controversial because of conflicting data regarding its efficacy as well as concerns regarding the expense and safety.⁴¹

The mechanism of action for intravenous albumin is not clear. It was initially hypothesized that albumin exerts it effect by increasing intravascular osmotic pressure. However, because of its small molecular weight, albumin is cleared from the circulation within a short time of the retrieval. Other possible mechanisms include increased plasma binding of a factor or factors involved in the pathogenesis of OHSS. Other osmotic agents have also been used with some success, including 5% hydroxyethylstarch and 3.5% degraded gelatin polypeptides (Haemaccel).^42–44

Follicular Aspiration

Clinical experience suggests that follicular aspiration offers partial protection against hyperstimulation syndrome. Every effort should be made to empty as many follicles as possible at the time of retrieval.

Luteal Phase Support

OHSS is promoted by luteogenesis and inhibited by luteolysis. Strategies to limit the severity and longevity of OHSS are based on limiting luteogenesis or promoting luteolysis. Luteal support with hCG should not be used in patients with a peak estradiol level greater than 3000 pg/mL because hCG increases the duration and severity of OHSS by promoting luteogenesis. Progesterone with or without additional estrogen is the safer alternative.

Introduction of a GnRH antagonist early in the luteal phase will lead to early luteolysis.⁴⁵ Because OHSS resolves with involution of the corpora lutea, the clinical course of severe OHSS can be abbreviated or even eliminated by this approach. If the stimulation protocol did not include down-regulation with a GnRH agonist, the gonadotropin flare secondary to initiation of a GnRH agonist can be used to induce oocyte maturation and ovulation followed almost immediately by irreversible luteolysis.^18,46–51

Pituitary response to initiation of a GnRH agonist is preserved following a GnRH antagonist/gonadotropin stimulation protocol. If embryos are transferred in a cycle in which premature luteolysis is induced, exogenous hormone replacement is required to support endometrial maturation and implantation.⁵² Alternatively, the embryos can be cryopreserved for transfer at a later time.⁵³

Diagnosis

Proactive management of patients with early signs and symptoms of OHSS can ameliorate the severity of OHSS.⁵⁴ Patients generally present with complaints of abdominal bloating, shortness of breath, and nausea. Symptomatic patients should be seen and evaluated promptly. Clinical parameters should include a physical examination, including a chest and abdominal examination (but not a bimanual pelvic examination) as well as a pelvic or abdominal ultrasound for ovarian enlargement or ascitic fluid and to rule out torsion.

Laboratory studies should include complete blood count, electrolytes, BUN, and creatinine. Hemoconcentration (hematocrit >45%) heralds the development of ascites, marginal renal perfusion, and decreasing urine output and increases the risk of thromboembolic events.⁵⁵

Most patients with OHSS will have some degree of ascites (Table 40-3). Less commonly, patients will develop pleural effusion, which can occur unilaterally (usually on the right) and in the absence of significant abdominal ascites. A high index of suspicion and careful evaluation are important to differentiate this condition from pulmonary embolism.³²

Table 40-3 Complications Associated with OHSS

Ascites

Pulmonary Hydrothorax Adult respiratory distress syndrome Pulmonary embolism Pulmonary edema Atelectasis Hemorrhage

Thrombosis Venous (majority) Upper limb, head and neck veins Arterial Intracerebral Only gold members can continue reading. Log In or Register to continue Share this: Click to share on Twitter (Opens in new window) Click to share on Facebook (Opens in new window) Related posts: Lactation and Galactorrhea Artificial Insemination Modern Concepts in Intrauterine Devices Laparoscopic Management of Adnexal Masses Gynecologic Laparoscopy Hysterosalpingography Stay updated, free articles. Join our Telegram channel Join Tags: Clinical Reproductive Medicine and Surgery Aug 27, 2016 | Posted by admin in UROLOGY | Comments Off on Complications of Assisted Reproductive Technologies Full access? Get Clinical Tree Get Clinical Tree app for offline access Get Clinical Tree app for offline access