Prevention of OHSSDr. Hakan Özörnek

EUROFERTIL IVF Center

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.

OHSS

Mild 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

Classification

Golan et al. 1989

Prevention of 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

Risk factors for OHSS

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

Prevention by PCOS

No metformin (n=159)

Metformin (n=128)

Age 34.8 33BMI 27.2 27.8HMG ampoules 37.1 41.1Oocytes retrieved 23.8 18.8Embryos tranferred 2.8 3Clinical pregnancies 37.6 30.5Moderate and severe OHSS* 20 1

Metformin

Khattab, Reprod Biomed Online, 2006

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)

Metformin

Moll et al. 2007

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

Prevention of OHSS

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

Canceling Cycles

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

Modification of methods to trigger ovulation

5000 vs. 10000 IU uHCG

Tsoumpou I, RBM Online, 2009

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.

GnRHa

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

Folicular aspiration

Because of conflicting reports in the literature there are currently insufficient data to recommend glucocorticoid administration

Glucocorticoid administration

Methylprednisolon (n=50)

Untreated (n=41)

Age 30.5 30.9E2 concentration* pg/ml

4848 3727

Oocytes retrieved* 28.7 24Embryos transferred 3.9 4.0OHSS* 10% 43.9%

Lainas et al., Fertil Steril, 2002

Lutheal phase support with hCG increases the incidence of OHSS.

Progesterone intravaginally or im should be used for the patients at risk of OHSS

Lutheal phase support

Antagonists

Al-Inany HG, RBM Online, 2007

In a Cochrane rewiev the relative odds of hospital admission for OHSS was reduced bye 54 % with antagonists compared with agonists.

Antagonists

Kolibianakis EM, Hum Reprod Update, 2006

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.

Coasting

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 >6,000   >3,000 21 5.4 41   0/51

Benadiva et al 1997 3,803 2 2,206 15   58.8   1/22Tortoriello et al. 1998 4,015 3.05 2,407 15.7 4.9 44.5 16.9 3/44Dhont et al. 1998 3,834 1.9 2,341 19.7 2.3 37.5 20 1/120Lee et al.1998 5,167 2.8 3,667 17.3 3 max 40   4/20Fluker et al. 1999 5,077 2 2,832 10.8 3 36.5 14.3 1/63Egbase et al. 1999 10,055 4.9 1,410 28.3 2.7 33   3/15Waldenstrom et al. 1999 6,292 4.3 1,870 10   51 31 1/65Delvigne et al.2001 8,877 3 1,492 16 2     0/157Al-Shawaf et al. 2001 4,400 3.4 1,368 11 2.1 46.5 25.5 1/50Grochowski et al. 2001 >3,000 3.5 >3,000     32.3 18.1 2/112Isik et al. 2001   4 3,000 18.3 3.2 50.5    Al-Shawaf et al. 2002 4,400 3.6 2,718 13.1 2.1 35.4 24.2 1/89Ulug et al. 2002 4,563 2.9 2,613 17.5 4.2 50.7 19.0 4/207Isaza et al. 2002 6,395 4.2 2,181 19.6 2.6 52.9 22 0/15Chen et al. 2003 3,753 1.5 4,528 21 5 32.1 9.6 3/31Tozer et al. 2004 4,400 4 1,433 12 1.8 33.3 20.3 0/22Moreno et al. 2004 5,769 3.6 2,852 18.1     19 0/132Garcia-Velasco et al. 2004 5,904 3.8 3,312 19.5 2 42.4 24.8 5/159Ulug et al. 2004 5,365 2.7 3,113 19.8 3.5 56.8 28.8 4/233

34/16240.02%

Coasting < 4 days (n=983)

Coasting >4 days (n=240)

Age 30.2 29.9Oocytes retrieved* 16.5 14.9Tranferred embryos 2.99 3.03Clin pregnancy rate* 52.0 35.9Implantation rate* 26.3 18.2

Coasting duration

Mansour, et al., Fertil Steril, 2005

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 (Practical guidelines)

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

Coasting

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.

Cryopreservation of all embryos

D’Angelo et al., Cochrane Library, 2002

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!

Albumin administration

D’Angelo et al., Cochrane Library, 2002

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

HES (Hydroxyethyl starch solution) administration

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.

Dopamine Agonists

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%

Cabergoline

Alvarez et al, 2007

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

Conclusion