Prevention of OHSS

Shahar Kol, IVF Unit Rambam Health Care Campus, and Macabbi Health Services, Haifa, Israel. February 2012

Content

● Scope of the problem● Preventive strategies● What really works● Physiology of the agonist trigger● Side benefits

Severe OHSS: is it still a problem?

• “In 2003–2005, 4 deaths (of the 12) were due to OHSS”

• ~3 OHSS-related deaths per 100,000 ART cycles

Year

Deaths

95% CI

Number of treatment

cycles Number Rate

1997– 1999 20 19.17 12.41–29.61 104,320

2000–2002 8 7.32 3.71–14.44 109,308

2003–2005 12 10.08 5.76–17.61 119,080

* Source Human Fertilisation and Embryology Authority

Maternal deaths and rates per 100,000 ART procedures, including IVF: United Kingdom: 1997–2005

Three OHSS-related deaths (3:100,000), all had their embryos frozen

Braat DDM, et al. Hum Reprod 2010;25:1782–1786

Incidence and prediction of OHSS in women undergoing GnRH antagonist IVF cycles

● 2524 antagonist-based cycles (1801 patients)● 53 patients (2%) were hospitalized because of OHSS

– Conclusions: clinically significant OHSS is a limitation even in antagonist cycles

“There is more than ever an urgent need for alternative final oocyte maturation – triggering medication”

Papanikolaou EG, et al. Fertil Steril 2006;85:112–120

Preventive strategies: coasting

● There was no evidence to suggest any benefit of withholding gonadotrophins (coasting) after ovulation in IVF for the prevention of OHSS

D’angelo A, et al. Cochrane Database Syst Rev 2011;(6):CD0028110

● There is not enough evidence to show whether using frozen embryos …can reduce OHSS in women who are at high risk

D’angelo A and Amso N. Cochrane Database Syst Rev 2007;(3):CD002806

Preventive strategies: cryopreservation

Youssef MA, et al. Cochrane Database Syst Rev 2011; (2): CD001302

● Intravenous (iv) colloid fluids … at the time of oocyte retrieval may be beneficial for women with a high risk of developing OHSS

● Borderline evidence of benefit with the routine use of human albumin in the prevention of OHSS (1660 patients)

● Good evidence to support the use of hydroxyethyl starch in the prevention of OHSS (487 patients)

Preventive strategies: intravenous albumin

● 1199 patients● IV albumin does not appear to reduce the occurrence of severe OHSS

Venetis CA, et al. Fertil Steril 2011; 95:188–196,196.e1–3

IV albumin for the prevention of severe OHSS: a systemic review and meta-analysis

Preventive strategies: recombinant LH

European Recombinant LH Study Group. J Clin Endocrinol Metab 2001;86:2607–2618

● 15,000 + 10,000 IU gave 20% live birth rate but with a 12% OHSS rate

Treatment arm 5000 IU 15,000 IU 30,000 IU 15,000 + 10,000 IU

p (linearity)Parameters examinedrhLH (n=39)

u-hCG(n=34)

rhLH (n=39)

u-hCG (n=41)

rhLH (n=26)

u-hCG (n=22)

rhLH (n=25)

u-hCG (n=24)

No. of follicles >10 mm 14.03 ± 5.32 16.44 ± 6.9515.17 ± 8.34 15.46 ± 6.75 14.23 ± 5.61 14.00 ± 4.90

a a 0.3007

No. of oocytes retrieved 10.23 ± 4.70 11.74 ± 6.2711.84 ± 7.53 11.78 ± 6.75 12.62 ± 6.22 10.82 ± 5.70

a a 0.1702

Oocytes in metaphase II 85.5% 77.8%90.8% 88.6% 57.6% 84.5%

a a 0.183

No. of oocytes inseminated 9.82 ± 4.74 11.26 ± 5.73 11.63 ± 7.52 11.57 ± 6.57 12.38 ± 6.25 10.55 ± 5.74 a a 0.1687

No. of embryos 5.42 ± 3.33 7.00 ± 4.68 6.65 ± 5.02 6.36 ± 4.68 7.67 ± 4.34 6.33 ± 5.19 a a 0.0983

No. of embryos transferred 2.39 ± 0.60 2.48 ± 0.85 2.58 ± 0.6 2.52 ± 0.62 2.78 ± 0.8 2.67 ± 0.73 a a 0.4310

Implantation rate 6.0 ± 0.16% 15.0 ± 0.31% 6.0 ± 0.19% 9.0 ± 0.24% 11.0 ± 0.26% 3.0 ± 0.09%19.0 ± 0.33%

17.0 ± 0.33% 0.1373

Pregnancy (total) 15.4% (n=6) 26.5% (n=9) 10.3% (n=4) 24.4% (n=10) 23.1% (n=6) 13.6% (n=3) 32.0% (n=8) 37.5% (n=9) 0.2689

Clinical pregnancy 10.3% (n=4) 23.5% (n=8) 7.7% (n=3) 14.6% (n=6) 15.4% (n=4) 13.6% (n=3) 28.0% (n=7) 25.0% (n=6) 0.1479

Live birth 5.1% (n=2) 17.6% (n=6) 7.7% (n=3) 12.2% (n=5) 15.4% (n=4) 4.5% (n=1) 20.0% (n=5) 16.7% (n=4) 0.0606

Cryopreserved embryos 4.42 ± 2.65 6.81 ± 3.67 7.93 ± 4.18 4.90 ± 3.24 6.27 ± 2.96 4.80 ± 3.19 5.75 ± 2.49 9.89 ± 3.22 0.2645

Cryopreserved embryos transferred

3.42 ± 1.83 5.67 ± 2.65 3.50 ± 1.84 3.27 ± 1.49 3.00 ± 1.41 2.17 ± 0.98 2.50 ± 0.71 4.75 ± 2.43 0.9092

Pregnancy from cryopreserved embryos (total)

16.7% (n=2/12)

0.0% (n=0/9)

50.0% (n=5/10)

27.3% (n=3/11)

62.5% (n=5/8)

33.3% (n=2/6)

0.0% (n=0/2)

0.0% (n=0/8)

b

Clinical pregnancy from cryopreserved embryos

8.3% (n=1/12)

0.0% (n=0/9)

40.0% (n=4/10)

27.3% (n=3/11)

50.0% (n=4/8)

16.7% (n=1/6)

0.0% (n=0/2)

0.0% (n=0/8)

b

Live birth from cryopreserved embryos

8.3% (n=1/12)

0.0% (n=0/9)

30.0% (n=3/10)

18.2% (n=2/11)

12.5% (n=1/8)

0.0% (n=0/6)

0.0% (n=0/2)

0.0% (n=0/8)

b

aThe IVF data of days u-hCG/rhLH 0–4 of patients from group 15,000 + 10,000 IU were pooled with those from group 15,000 IUbBecause the numbers were small, no statistical comparison was performed on these data

European Recombinant LH Study Group. J Clin Endocrinol Metab 2001;86:2607–2618

Preventive strategies: lowering hCG dose

● Reducing the dose of hCG does not eliminate the risk of OHSS in a high-risk group

Schmidt DW, et al. Fertil Steril 2004;82(4):841–846

Youssef MA, et al. Human Reprod Update 2010;16:459–466

Preventive strategies: dopamine agonists

OHSS incidence

OHSS severity

Youssef MA, et al. Human Reprod Update 2010;16:459–466

What really works:

● GnRH agonist versus hCG for oocyte triggering in GnRH antagonist ART cycles

OHSS % (n) nOvulation trigger

Oocyte source

Trial type Reference

0 (0/13)31(4/13)

1513

GnRHahCG

Own RCT, high risk Babayof, et al 2006

0 (0/33)31 (10/32)

3332

GnRHahCG

Own RCT, high risk Engamnn, et al 2008

0 (0/30)17 (5/30)

3030

GnRHahCG

Donors RCT Acevedo, et al 2006

0 (0/1046)1.3 (13/1031)

10461031

GnRHahCG

Donors Retrospective Bodri, et al 2009

0 (0/40) 40GnRHa Own Observational,

High riskGriesinger, et al 2010

0 (0/152)2 (3/150)

152150

GnRHahCG

Own RCT Humaidan, et al 2009

0 (0/23)4 (1/23)

2323

GnRHahCG

Own Retrospective, case-controlled, high risk

Engmann, et al 2006

0 (0/42) 42GnRHahCG - cancelled

Own Retrospective case-control, high risk

Manzanares, et al 2009

0 (0/254)6 (10/175)

254175

GnRHahCG

Donors Retrospective Hernandez, et al 2009

0 (0/82)7 (5/69)

8269

GnRHahCG

Own Retrospective, high risk

Orvieto, et al 2006

0 (0/32)1 (1/42)

3242

GnRHahCG

Donors Retrospective, high risk: agonist arm only

Shapiro, et al 2007

0 (0/44)7 (3/44)

4444

GnRHahCG

Donors RCT Sismanoglu, et al 2009

8 (1/12) 12GnRH, luteal rescue with hCG 1500IU

Own Observational, high risk

Humaidan, et al 2009

0 (0/106)8 (9/106)

106106

GnRHahCG

Donors RCT Galindo, et al 2009

0 (0/50)16(8/50)

5050

GnRHahCG

Donors RCT Melo, et al 2009

0 (0/45)15 (33)

445

GnRHahCG

Own RCT, high risk Shahrokh, et al 2010

• 16 publications

• Agonist: 2005 patients, not a single case of OHSS!

• hCG: 92 cases in 1810 patients, 5.1%

OHSS prevention by GnRH agonist triggering of final oocyte maturation in a GnRH antagonist protocol in combination with freeze-all strategy: a prospective multicenter study

● Conclusions: “…a single case of a severe early onset OHSS occurred”

– E2 trigger day=47,877 pmol/L

– 13 oocytes– “drastic decrease of hemoglobin levels to 4.9 mmol/L” (8 grams/dL)

patient received blood transfusion 2 days post OPU– Hematocrit: 41 trigger day, 37 OPU day, ‘,<35’ post blood transfusion– 3–4 days post trigger 3.9 litres of “blood-stained ascites which was

indicative of a subacute intraperitoneal hemorrhage”

Griesinger G, et al. Fertil Steril 2011;95:2029–2033

Failures?

The physiology of agonist trigger

1. Humaidan P, et al. Reprod Biomed Online 2011; (Epub ahead of print);2. Gonen Y, et al. J Clin Endocrinol Metab 1990;71:918–922

LH surge1 FSH surge2

What happens after agonist trigger? Complete luteolysis!

Luteal phase

Natural cycle Day 7–9 = 75 pg/mL vs 18

Natural cycle Day 7–9 = 750 pg/mL vs 84

Nevo O, et al. Fertil Steril 2003;79:1123–1128

How to secure good clinical outcome post agonist trigger?

● High risk fresh transfer: intensive E2+P luteal support

● High risk: ‘freeze-all’● Low risk: luteal rescue based on LH activity

Luteal phase: intensive E+POHSS high-risk patients

Study group Control group Odds ratio (95%CI) p value

Primary end points

OHSS (ITT)

Total, n (%) 0/33 (0) 10/32 (31.3) 0 (0–0.26)a <0.01

Moderate/severe, n (%) 0/33 (0) 5/32 (15.6) 0 (0–0.74)a 0.02

OHSS (PP)

Total, n (%) 0/30 (0) 10/2 (34.5) 0 (0–0.26)a <0.01

Moderate/severe, n (%) 0/30 (0) 5/29 (17.2) 0 (0–0.73)a 0.02

Secondary end point (PP)

Implantation rate, n (%) 22/61 (36) 20/64 (31) 1.18 (0.52–2.65) 0.69

Other end points (PP)

Positive pregnancy, n (%) 19/30 (63.3) 18/29 (62.1) 1.06 (0.37–3.0) 0.92

Clinical pregnancy rate, n (%) 17/30 (56.7) 15/29 (51.7) 1.22 (0.4–3.4) 0.45

Ongoing pregnancy rate, n (%) 16/30 (53.3) 14/29 (48.3) 1.22 (0.4–3.4) 0.45

aThe estimates of these odds ratios are zero, because no patient developed OHSS in the study group; ITT=intention to treat; PP=per protocol

Engmann L, et al. Fertil Steril 2008;89:84–91

Modified luteal support post agonist trigger

1500 IU hCG administered at oocyte retrieval rescues the luteal phase when GnRH agonist is used for ovulation induction: a prospective, randomized, controlled study

● 305 patients● No significant differences were seen regarding:

– Positive hCG/ET rate (48 and 48%) – Ongoing pregnancy rate (26 and 33%) – Delivery rate (24 and 31%) – Rate of early pregnancy loss (21 and 17%)– Between the GnRHa and 10,000 intrauterine hCG groups,

respectively

Humaidan P, et al. Fertil Steril 2010;93:847–854

Tailored luteal phase support

GnRHa/hCG hCG

Patients, n 125 141

Rate of transfer, n (%) 110/125 (88) 116/141 (82)

Embryos transferred, mean 1.3 1.3

IR 49/158 (36) 43/145 (30)

Pos hCG per ET, n (%) 47/110 (43) 41/116 (35)

Clinical pregnancy per patient, n (%) 43/125 (34) 40/141 (28)

Ongoing pregnancy per patient, n (%) 37/125 (30) 36/141 (26)

Humaidan P, et al. personal communication

Patients with ≤14 follicles ≥12 mm on day of trigger GnRHa + 1500 IU hCG x 2, versus 5000 IU hCG, both groups E2+P luteal support.

Side benefits

● Agonist trigger: more MII oocytes compared with hCG trigger1-4

● Potential benefit of FSH surge:5-9 – Promotes LH receptor formation in luteinizing granulosa cells– Promotes nuclear maturation (i.e. resumption of meiosis) – Promotes cumulus expansion

1. Humaidan P, et al. Reprod Biomed Online 2005;11:679–6842. Humaidan P, et al. Human Reprod 2009;24:2389–23943. Imoedemhe DA, et al. Fertil Steril 1991;55:328–3324. Oktay K, et al. Reprod Biomed Online 2010;20:783–788 5. Eppig JJ. Nature 1979;281:483–4846. Strickland and Beers. J Biol Chem 1976;251:5694–57027. Yding Andersen C. Reprod Biomed Online 2002;5:232–2398. Yding Andersen C, et al. Mol Hum Reprod 1999;5:726–7319. Zelinski-Wooten MB, et al. Human Reprod 1995;10:1658–1666

The advantage for the ‘normal responder’

Kol S, et al. Human Reprod 2011;26:2874–2877

FSH/hMG

Antagonist

Agonist trigger

36 hours

OPU

1500 IU hCG

4 days

1500 IU hCG

ET

Stimulation characteristics and embryology data

Stimulation (days) 9.3 ± 2.0

GnRH antagonist (days) 3.8 ± 0.9

FSH (units) 2443 ± 925

E2 day of trigger (pmol/L) 3764 ± 1227

P day of trigger (nmol/L) 2.4 ± 1.65

LH day of trigger (IU/L) 1.9 ± 1.3

Oocytes retrieved 6.7 ± 2.5

Embryos obtained 3.6 ± 1.7

Embryos transferred 2.9 ± 0.9

Embryos frozen 0.8 ± 1.5

Beta hCG (IU/L) 152 ± 86

E2 (day of pregnancy test, pmol/L) 6607 ± 3789

P (day of pregnancy test, nmol/L) 182 ± 50

Values are mean ± SD

Reproductive outcomes

Positive hCG/cycle, n (%) 11/15 (73)

Clinical ongoing pregnancy, n (%) 7/15 (47)

Early pregnancy loss, n (%) 4/11 (36)

Kol S, et al. Human Reprod 2011;26:2874–2877

“The concept of an OHSS-Free Clinic has become a reality. This approach should include pituitary down-regulation using a GnRH antagonist, ovulation triggering with a GnRH agonist and vitrification of oocytes or embryos”

“…luteal phase supplementation with low-dose hCG has to be fine tuned.”

Devroey P, et al. Human Reprod 2011; 26: 2593–2597

Crystal ball: where are we heading?

Thank you

Out In‘Long agonist’ protocols Antagonist-based protocols

hCG trigger Agonist trigger

Progesterone-based luteal support LH activity-based luteal support

1–2% severe OHSS Total OHSS elimination

OHSS-related death rate: 3:100,000 Total OHSS elimination

Painful P injections or leaky, messy vaginal P

Patient-friendly luteal phase