Dr. Hakan Özörnek EUROFERTIL IVF Center Prevention of OHSS Dr. Hakan Özörnek EUROFERTIL IVF Center

OHSS OHSS is an iatrogenic complication of ovulation induction. The syndrom can result in serious life treatening complications The syndrom charecterized by leakage of fluid from the intravascular compartment, with accumulation in the peritoneal and pleural cavities, resulting in hypotension and a decrease in renal blood flow and volume of urine.

Classification Mild OHSS Moderate OHSS Severe OHSS Grade 1 Abdominal distention and discomfort Grade 2 + nausea, vomiting and/or diarrhoea Moderate OHSS Grade 3 + ultrasonic evidence of ascites Severe OHSS Grade 4 + clinical evidence of ascites and/or hydrothorax or dyspnoea Grade 5 + haemoconcentration, coagulation abnormalities, diminished renal perfusion Golan et al. 1989

Prevention of OHSS

Risk factors for OHSS PCOS High number of antral follicles at day3 (>10/ovary) Enlarged ovarian volume LH/FSH > 2 Hyperandrogenism Young age < 35 Low body weight Previous ocurrence of OHSS

Prevention by PCOS Diet – weight lose Metformin Ovarian drilling Nonstimulated – natural cycle IVM Oral ovulation induction Low dose gonadotropin

Metformin No metformin (n=159) Metformin (n=128) Age 34.8 33 BMI 27.2 27.8 HMG ampoules 37.1 41.1 Oocytes retrieved 23.8 18.8 Embryos tranferred 2.8 3 Clinical pregnancies 37.6 30.5 Moderate and severe OHSS* 20 1 Khattab, Reprod Biomed Online, 2006

Metformin In a systematic review for IVF, it was found that metformin led to fewer cases of OHSS (RR 0.33;95% CI 0.13-0.80) Moll et al. 2007

Prevention of OHSS Withholding hCG ‘cancelling’ Delaying hCG ‘coasting’ Modification of methods to trigger ovulation Early unilateral follicular aspiration Progesterone for luteal phase support Cryopreservation of all embryos Gradual and slow hMG protocol in PCOS Albumin administration at time of retrieval Glucocorticoid administration

Canceling Cycles hCG triggers the development of OHSS Withholding hCG is the only method that totally avoids the risk of OHSS Serum E2 level upper limit 4000 pg/ml After stopping the gonadotrophin treatment the GnRH agonist or antagonist should be continiued until the ovaries recover to normal size

Modification of methods to trigger ovulation Decrease in hCG dose 10.000 IU vs. 5.000 IU or 3.000 IU no difference GnRHa Used in antagonist cycle, as effective as hCG, decreased insidence of OHSS rLH PRT multicenter hCG vs rLH significantly fewer moderate and severe cases of OHSS rhCG

5000 vs. 10000 IU uHCG Tsoumpou I, RBM Online, 2009

GnRHa The quick reversibility of the antagonist induced pituitary suppression can be of advantage by allowing the use of GnRHa for the purpose of ovulation triggering. A GnRH agonist trigger effectively prevents OHSS.

Folicular aspiration Folicular aspiration at the time of oocyte retrieval had no protective effect of OHSS Unilateral folicular aspiration prior to HCG also does not reduce the incidence of severe OHSS

Glucocorticoid administration Methylprednisolon (n=50) Untreated (n=41) Age 30.5 30.9 E2 concentration* pg/ml 4848 3727 Oocytes retrieved* 28.7 24 Embryos transferred 3.9 4.0 OHSS* 10% 43.9% Because of conflicting reports in the literature there are currently insufficient data to recommend glucocorticoid administration Lainas et al., Fertil Steril, 2002

Lutheal phase support Lutheal phase support with hCG increases the incidence of OHSS. Progesterone intravaginally or im should be used for the patients at risk of OHSS

Antagonists Al-Inany HG, RBM Online, 2007

Antagonists In a Cochrane rewiev the relative odds of hospital admission for OHSS was reduced bye 54 % with antagonists compared with agonists. Kolibianakis EM, Hum Reprod Update, 2006

Coasting First described and applied by Sher et al in 1993 hCG administration postponed until the patients serum E2 level decreases to a safer zone. Significantly higher percentage of granulosa lutein cells become apoptotic after coasting. E2 levels usually to rise rapidly in the 48 h following initiation of the coasting period, then plateaued and began to fall 96-168 h after the gonadotropins were stopped.

Coasting Cochrane review identified 13 studies of which only one trial met the inclusion criteria. There was no difference in the incidence of moderate and severe OHSS and in the clinical pregnancy rate between the groups. D’Angelo et al., Cochrane Library, 2002

Coasting studies (Garcia-Velasco, F&S, 2006) Study E2 1st day coasting (pg/mL) No.of days coasting E2 day Hcg (pg/ml) No.of oocytes Embryos transferred PR (%) IR (%) Severe OHSS(n) Sher et al.1993 >6,000   >3,000 35.2 0/17 Sher et al.1995 21 5.4 41 0/51 Benadiva et al 1997 3,803 2 2,206 15 58.8 1/22 Tortoriello et al. 1998 4,015 3.05 2,407 15.7 4.9 44.5 16.9 3/44 Dhont et al. 1998 3,834 1.9 2,341 19.7 2.3 37.5 20 1/120 Lee et al.1998 5,167 2.8 3,667 17.3 3 max 40 4/20 Fluker et al. 1999 5,077 2,832 10.8 3 36.5 14.3 1/63 Egbase et al. 1999 10,055 1,410 28.3 2.7 33 3/15 Waldenstrom et al. 1999 6,292 4.3 1,870 10 51 31 1/65 Delvigne et al.2001 8,877 1,492 16 0/157 Al-Shawaf et al. 2001 4,400 3.4 1,368 11 2.1 46.5 25.5 1/50 Grochowski et al. 2001 3.5 32.3 18.1 2/112 Isik et al. 2001 4 3,000 18.3 3.2 50.5 Al-Shawaf et al. 2002 3.6 2,718 13.1 35.4 24.2 1/89 Ulug et al. 2002 4,563 2.9 2,613 17.5 4.2 50.7 19.0 4/207 Isaza et al. 2002 6,395 2,181 19.6 2.6 52.9 22 0/15 Chen et al. 2003 3,753 1.5 4,528 5 32.1 9.6 3/31 Tozer et al. 2004 1,433 12 1.8 33.3 20.3 0/22 Moreno et al. 2004 5,769 2,852 19 0/132 Garcia-Velasco et al. 2004 5,904 3.8 3,312 19.5 42.4 24.8 5/159 Ulug et al. 2004 5,365 3,113 19.8 56.8 28.8 4/233 34/1624 0.02%

Coasting < 4 days (n=983) Coasting >4 days (n=240) Coasting duration Coasting < 4 days (n=983) Coasting >4 days (n=240) Age 30.2 29.9 Oocytes retrieved* 16.5 14.9 Tranferred embryos 2.99 3.03 Clin pregnancy rate* 52.0 35.9 Implantation rate* 26.3 18.2 Mansour, et al., Fertil Steril, 2005

Coasting (Practical guidelines) Start at Serum E2>4500 pg/ml > 15 and < 30 mature follicles Measure E2 on a daily basis, do not skip any day to avoid sudden unexpected drops Give hCG when E2 level falls to < 3500 pg/ml Abandone if E2 level rises to >6500 pg/ml > 30 mature follicles Coasting takes > 4 days

Coasting Coasting is a good alternative that can avoid cycle cancellation in high responders, who have high risk of developing severe OHSS Even if OHSS develops after coasting both its incidence and severity will be diminished

Cryopreservation of all embryos Insted of canceling the cycle after the administration of hCG retrieve the oocytes and than cryopreserve all embryos Cochrane review identified 17 studies, two of which met the inclusion criteria. When elective cryopreservation was compared with fresh embryo transfer no difference was found between the two groups in the incidence of OHSS. There is insufficient evidence to support routine cryopreservation. D’Angelo et al., Cochrane Library, 2002

Albumin administration Albumin is prevent the development of OHSS by increasing plasma oncotic pressure and binding of OHSS mediators of ovarian origin The cochrane review shows a clear benefit from administration of iv albumin at te time of oocyte retrieval in prevention of severe OHSS in high risk cases. For every 18 women at risk of severe OHSS albumin infusion will save one more case Albumin is a human product! D’Angelo et al., Cochrane Library, 2002

HES (Hydroxyethyl starch solution) administration Synthetic macromolecules used to prevent OHSS and avoid the potential risks from using human products such as albumin HES is effective volume expander. It is as effective as albumin It is cheaper and safer

Dopamine agonists VEGF is directly involved in the clinical manifestations of OHSS by increasing vascular permeability. Dopamine agonists have been shown to significantly reduce vascular permeability. The administration of dopamine agonists at doses that are routinely used to treat hyperprolactinaemic patients, can reduce vascular permeability decreasing the risk and severity of OHSS

Dopamine Agonists Dopamine agonists have a positive effect on OHSS symptoms such as ascites, abdominal distension and discomfort. Fertilization, implantation and ongoing pregnancy rates are not affected by the use of dopamine agonists during assisted reproduction treatments.

Cabergoline First RCT showed that cabergoline significantly lowered haematocrit, haemoglobin and ascites on day 4 and day 6 after treatment, as compared with placebo. 35 high risk OHSS patients 0.5 mg Cabergolin start on HCG day administer for 8 days No OHSS, pregnancy rate 41% Alvarez et al, 2007

Conclusion OHSS is a serious complication of ovarian stimulation The identification of high risk patients and in particular PCOS patients and the use of low dose protocols of ovarian stimulation have an important role in the prevention of OHSS To date no methods are available to completly prevent this complication except for withholding hCG.

Conclusion Coasting for at least as long as 3 days can be successfully used in the prevention of OHSS It appears that iv albumin administered at the time of oocyte retrieval may help the prevention of OHSS The effect of combining methods which act at two different levels (eq. coasting and HES administration) helps for a better prevention

Conclusion Cryopreservation of oocytes, use of GnRH antagonist and Dopamine derivates were used successfully. There is a clear need for large randomised studies