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Prolonged Coasting
The single most serious complication that an IVF patient faces, apart from multiple pregnancy, is the risk of becoming seriously ill after being stimulated with injectable fertility medications. This condition is known as Ovarian Hyperstimulation Syndrome (OHSS) and reports suggest that approximately 1% of patients who receive these medications may develop signs of hemoconcentration, weight gain, severe abdominal distension, ovarian enlargement and in severe cases even renal failure. OHSS has also been known to cause maternal death. Previously, the exact cause of this syndrome was incompletely understood, although it is well known that the administration of human Chorionic Gonadotropin (hCG) is the precipitating event which sets in motion the symptoms mentioned above and that OHSS is made worse by pregnancy.
The hCG is used as a surrogate for luteinizing hormone (LH) for oocyte maturation and induction of ovulation. The half-life of hCG is greater than 24 hours versus 60 minutes for LH (Yen et al., 1968) and as a result, hCG causes a prolonged luteotrophic effect resulting in superphysiological levels of estrogen and progesterone.
What causes OHSS?
In order to develop OHSS during assisted reproductive treatment, ovaries need to be present and they need to be stimulated with gonadotropins followed by the administration of hCG as a trigger. It is well known that OHSS subsides if the ovaries are removed or if the trigger shot of hCG is withheld. It is well accepted that hCG possesses no vasoactive activities itself, therefore the development of OHSS must be mediated by one or more of the angiogenic substances released by the ovaries in response to the hCG trigger.
Vascular endothelial growth factor (VEGF) appears to be this substance, and it is the most important mediator of hCG dependent ovarian angiogenesis. It is known that the VEGF is expressed in human ovaries (Yan et al., 1993) and VEGF mRNA levels in granulosa cells increase after hCG administration (Neulen et al., 1995). VEGF not only stimulates new blood vessel development which is important in implantation, but also induces vascular hyperpermeability (McClure et al., 1994) by interacting with VEGF receptor 2 (VEGFR-2).
Experience with an animal model of OHSS, suggests that VEGF is implicated in the cause of OHSS. It is the VEGF that then leads to increase in vascular permeability (VP) which then goes on to cause the rapid accumulation of fluid within the ovary, the peritoneal cavity and other spaces including the plural cavity.
When there are more than 20 follicles developing and the estradiol level rises above 4000 pg/ml then there is a risk of moderate OHSS and with more than 30 follicles and estradiol greater than 6000 pg/ml there would be an 80% chance of developing severe OHSS if the preventive measures discussed in this handout are not instituted. In the past, the only way of avoiding severe OHSS was to withhold the administration of the hCG and cancel the IVF cycle. The patients most likely to develop OHSS are patients with menstrual cycles longer than 30 days or patients with irregular ovulation and menstruation. Age is also a factor, but OHSS can occur in patients over 40 years if more than 20 follicles are produced.
We can therefore predict which patients are most likely to develop OHSS based on menstrual history, the number of follicles/eggs produced in a prior stimulation cycle and we can also estimate the antral follicle count on the third day of natural menstruation and thereby have advanced knowledge of who will produce more than 20 follicles when stimulated. Sometimes, the response to medication is unexpectedly good and if, during the stimulation, it appears as though more than 20 follicles are growing, it is still possible to institute measures to prevent OHSS.
What can we do to prevent and treat OHSS?
Know who is at risk:
The first step in preventing this severe complication is to identify before initiating stimulation, which patients are at risk based on their menstrual history, estimation of the resting follicle count as well as evaluation of any prior stimulation. Having identified a patient as a risk for OHSS, evasive action can be planned including the maneuvers mentioned below.
The agonist or Lupron trigger:
Given that the administration of hCG appears to be the precipitating event for developing OHSS, an alternative to hCG induced ovulation triggering, is the use of a GnRH agonist like Lupron, as the triggering agent. The Lupron trigger induces the release of LH and FSH from the pituitary which then effectively induces oocyte maturation for either retrieval or ovulation induction. This means of triggering was described by Itskovitz et al., in 1988 and 1991 and subsequently by others and suggested as a means of preventing OHSS.
The major limitation on the use of GnRH agonist (Lupron) to trigger oocyte maturation is the fact that the Lupron trigger may be ineffective in women with a low gonadotropin reserve or after pituitary down-regulation with a GnRH agonist like Lupron as used in the long protocol.. In these situations the pituitary is unresponsive for the induction of an endogenous LH surge. Since the traditional method for stimulation for high responders in most IVF programs was a long protocol using suppression with birth control pills as well as a GnRH agonist like Lupron, the application of GnRH agonist (Lupron trigger) for induction of ovulation has been limited in the past.
The introduction of GnRH antagonist protocols (Albano et al., 1997; Itskovitz-Eldor et al., 1998) offered the option of using a GnRH agonist like Lupron, to trigger ovulation thereby preventing OHSS. It was found that the pituitary gland is capable of producing an LH surge sufficient for maturation of follicles in response to this Lupron trigger as long as premature ovulation was being prevented by the use of an antagonist like Ganerelix.
Dopamine agonist, Cabergoline (Dostinex):
Some patients are not suitable for the antagonist protocol or in some instances patients were not suspected of being high responders and they then present with a larger than expected number of follicles already on a long Lupron protocol, where the only method of triggering remains hCG. Knowing that the unavoidable administration of hCG results in the release of the vascular endothelial growth factor, VEGF, and also the VEGF receptor 2, which appears to be the cause of the vascular permeability (VP) which causes the OHSS, researchers looked for methods to block the effects of the VGEFR-2. Through the work of Alverez et al., 2007, it was demonstrated that the dopamine agonist, cabergoline (Cb2) also known as Dostinex, could block the negative effects of the VEGF-2, while preserving the beneficial angiogenic effects of the VEGF which is required for implantation.
A prospective, randomized, placebo-controlled study was carried out with oocyte donors receiving 0.5 mg/day of Cb2 for 8 days, starting on the day of hCG administration (Alvarez et al., 2007) They demonstrated that Cb2 reduced the amount of ascites accumulating in the pelvis, and both hemoconcentration and the incidence of moderateŠsevere OHSS were seen to diminish. Moreover, by employing magnetic resonance and evaluating several pharmacokinetic parameters, they showed that VP in human ovaries subjected to COH increased after hCG administration, and that this effect was prevented by Cb2.
Alvarez et al., concluded that Cb2 may provide a new, specific and non-toxic approach to the treatment of OHSS, by which the increased VP, which is mediated by the VEGF/VEGR2 pathway, is blocked without altering angiogenesis. This could be of great clinical interest to the field of ART. The protocol would include 0.5 mg of cabergoline daily for eight days beginning on the day of hCG.
Coasting and Fluid restriction:
Regardless of the protocol used for stimulation, the symptoms of abdominal distention and discomfort, that go with OHSS. can be dramatically lessened by applying fluid restriction of 1 L per day of an electrolyte containing solution. The solutions recommended are Gatorade or Propel, the latter having less sugar but the same electrolyte combination. It is best to start the fluid restriction before administration of the hCG and to continue until menstruation or in the case of pregnancy until the symptoms of OHSS subside. It is also important to prevent constipation that can be the consequence of fluid restriction by using a stool softener and when necessary a Fleet enema. Fluid restriction along with prolonged coasting was described by Sher et al., in 1992 and fluid restriction should be applied whenever there are more than 20 follicles and regardless of the protocol that has been chosen.
Due to the hemoconcentration that results from the OHSS as well as the fluid restriction, it is advisable to add aspirin 81 mg daily after the egg retrieval and in certain cases it may be appropriate to add anticoagulant prophylaxis in the form of Lovenox 40 mg daily, until menses occur or in the case of pregnancy when the symptoms of distention and discomfort have passed.
©2012, Zouves Fertility Center
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