dr. hakan Özörnek eurofertil ivf center. ohss is an iatrogenic complication of ovulation...
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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 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
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 30.9
E2 concentration* pg/ml
4848 3727
Oocytes retrieved* 28.7 24
Embryos transferred 3.9 4.0
OHSS* 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 1/22
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 2,832 10.8 3 36.5 14.3 1/63
Egbase et al. 1999 10,055 4.9 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 3 1,492 16 2 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
>3,000 3.5 >3,000 32.3 18.1 2/112
Isik 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 1/89
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 4.2 2,181 19.6 2.6 52.9 22 0/15
Chen et al. 2003 3,753 1.5 4,528 21 5 32.1 9.6 3/31
Tozer et al. 2004 4,400 4 1,433 12 1.8 33.3 20.3 0/22
Moreno et al. 2004 5,769 3.6 2,852 18.1 19 0/132
Garcia-Velasco et al. 2004
5,904 3.8 3,312 19.5 2 42.4 24.8 5/159
Ulug 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 29.9
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
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