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

4. 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.

5. 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

6. Prevention of OHSS

7. 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

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

9. 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

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

11. 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

12. 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

13. Modification of methods to trigger ovulation
Decrease in hCG dose
IU vs IU or 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

14. 5000 vs IU uHCG
Tsoumpou I, RBM Online, 2009

15. 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.

16. 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

17. 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

18. 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

19. Antagonists
Al-Inany HG, RBM Online, 2007

20. 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

21. 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 h after the gonadotropins were stopped.

22. 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

23. 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%

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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.

32. 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

33. 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.

34. 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

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