NEW STRATEGIES FOR OHSS PREVENTION

Ali Rüştü Ergür, M.D., Assoc.Prof.GATA Haydarpaşa Hospital

The 2nd Congress of Current Opinion in Reproductive Medicine and Assisted Reproductive Technologies and1st Congress of the Society of Reproductive Medicine

Çeşme-İzmir, April 20, 2008

THE GOOD

THE BAD

THE UGLY

OHSS (OVARIAN HYPERSTIMULATION SYNDROME)

SHOULD BE ACCEPTED THE MOST

SERIOUS AND DETRIMENTAL

COMPLICATION OF OVARIAN

STIMULATION

OHSS (OVARIAN HYPERSTIMULATION SYNDROME)

WHY THE MOST SERIOUS AND DETRIMENTAL ?

1. Marked extravascular exudate,2. Profound intravascular depletion,3. Hemoconcentration4. Increased blood coagulability

(Rizk and Aboulghar, 2005)

OHSS (OVARIAN HYPERSTIMULATION SYNDROME)

Acute fluid shift out of the intravascular space

AscitesHydrothorax

Generalized edemaMajor electrolyte imbalance

Reduced renal perfusionMarked hemoconcentration

Vascular complications

OHSS (OVARIAN HYPERSTIMULATION SYNDROME)

End-stage complications;

• Liver dysfunction

• Respiratory complications

• Renal complications

• Vascular complications

• Death

OHSS (OVARIAN HYPERSTIMULATION SYNDROME)

HIGH RESPONDERS

PREVENTION OF OHSS

• Level 1 : Patient identification at risk

• Level 2 : Organization of ovarian stimulation for a required but less follicular development

• Level 3 : Proper monitorization

• Level 4 : Decreasing the developing follicles and rapid estradiol increase

• Level 5 : Prevention of pregnancy occurrence

• Level 6 : Medical treatment and hospitalization

PREVENTION OF OHSSLEVEL 1: Patient identification at risk

• Patients with PCOS/Hyperandrogenic chronic anovulation (HCA)

• Previous OHSS history

• Oligomenorrhea or amenorrhea

• High LH/FSH ratio

• Polycystic appearance of ovaries by sonography

• Young age < 35 years old

• Egg donors

PREVENTION OF OHSSLEVEL 2: Ovarian stimulation for a

required but less follicular development

• Low doses of gonadotropins (100-150 IU/day)

• Minimal stimulation protocols (CC/gonadotropin/antagonist)

• Dual suppression with OCP and GnRH-a

• Use of GnRH antagonist vs. agonist

• HCG dose and alternatives

• Metformin

PREVENTION OF OHSSLEVEL 2: Low Dose Gonadotropins

• Low dose gonadotropin therapy, 75-150 IU/day, is effective for the prevention of OHSS whether

gonadotropin is urinary or recombinant

El-Sheikh MM, 2001Golan A, 1988

Homburg R, 2002

VanWely M, 2003 Gorry A, 2006

Low dose gonadotropin therapy (75 IU), Homburg and Howles, 1999

PREVENTION OF OHSSLEVEL 2: Low Dose Gonadotropins

Marci R, 2001

PREVENTION OF OHSSLEVEL 2: Low Dose Gonadotropins

Ragni G, 2006

PREVENTION OF OHSSLEVEL 2: Low Dose Gonadotropins

• OHSS risk is lower in low dose regimens

Koundouros, 2008

PREVENTION OF OHSSLEVEL 2: Minimal Stimulation Protocols

Minimal Stimulation ProtocolCC/Gonadotropins/Antagonist

Advantages1. Reduced cost2. Friendlier IVF3. Acceptable pregnancy rates/transfer4. Less OHSSDisadvantages1. High rate of cancellation and lack of transfer2. Less oocytes3. No excess of embryos for cryopreservation

PREVENTION OF OHSSLEVEL 2: Minimal Stimulation Protocols

Minimal Stimulation ProtocolCC/Gonadotropins/Antagonist

Author Protocol

Weigert (2002) CC 100 mg days 3-7Rec FSH-LH (300 IU) on alternate days

Williams (2002) CC 100 mg days 3-7Gonadotropins (150 IU) starting on day 9

Engel (2002) CC 100 mg days 3-7Gonadotropins (225 IU) starting on day 8Antagonist starting day 8

Hwang (2003) CC 100 mg days 3-7Gonadotropins (150 IU) on alternate daysAntagonist on follicle 14 mm<

PREVENTION OF OHSSLEVEL 2: Minimal Stimulation Protocols

Minimal Stimulation Protocol

CC/Gonadotropins/Antagonist

Author Oocytes Preg. Rate/Tr. %

Weigert (2002) 7.7±3.6 43

Williams (2002) 3.9±2.2 38

Engel (2002) 6.4±4.8 26

Hwang (2003) 8.0±3.2 35

PREVENTION OF OHSSLEVEL 2: Minimal Stimulation Protocols

Minimal Stimulation Protocol

CC/Gonadotropins/Antagonist

1. Pregnancy rate per transfer comparable with the long agonist protocol

2. No severe OHSS in all studies

3. This protocol should be considered as an option in patients with OHSS risk

PREVENTION OF OHSSLEVEL 2: Dual suppression with OCP

and GnRH-a

Protocol

1. Low dose OCP (35µg) for 25 days

2. GnRH agonist on day 21 of OCP

3. 150 IU of gonadotropins on the 3rd day of menstrual bleeding with GnRH-a

Damario, 1997

PREVENTION OF OHSSLEVEL 2: Dual suppression with OCP

and GnRH-a

Damario, 1997

PREVENTION OF OHSSLEVEL 2: Dual suppression with OCP

and GnRH-ant

Rombauts, 2006

PREVENTION OF OHSSLEVEL 2: Use of GnRH antagonist vs. agonist

Advantages

1. Lower peak E2 levels

2. Reduced number of oocytes

3. GnRH-a use for ovulation triggering as a substitute for hCG

Disadvantage

1. Lower pregnancy rate compared to long agonist protocol

PREVENTION OF OHSSLEVEL 2: Use of GnRH antagonist vs. agonist

Ludwig, 2001

PREVENTION OF OHSSLEVEL 2: Use of GnRH antagonist vs. agonist

Ragni G, 2005

PREVENTION OF OHSSLEVEL 2: Use of GnRH antagonist vs. agonist

PREVENTION OF OHSSLEVEL 2: Use of GnRH antagonist vs. agonist

GnRH antagonist protocol is a short and simple protocol with good clinical outcome,

but the lower pregnancy rate compared with the GnRH agonist long protocol and the non-significant difference between

both protocols regarding prevention of premature LH surge and prevention of

severe ovarian hyperstimulation syndrome

Al-Inany, 2002

PREVENTION OF OHSSLEVEL 2: Use of GnRH antagonist vs. agonist

Data between the GnRH antagonist group (group I) and the GnRH agonist group (group II)

Group I (Group I (nn=73)=73) Group II (Group II (nn=75)=75)Total recombinant FSH (IU) 2052.1±375.05 2138±407.3Days of stimulation 9.3±1.5 9.6±1.4Days of antagonist 1.86±0.73Estradiol (pg/ml) 1900±562 2140±730Oocytes donated 13.8±3.2 14.3±2.7Fertilization rate (%) 73 79Embryos transferred 2.34±0.77 2.36±0.73Mild hyperstimulation 2 (2.73) 3 (4)Clinical pregnancy/cycle started 29 (39.72) 31 (41.33)Implantation (%) 23.9 25.4Twins 3 (10.34) 4 (12.9)Triplets 1 (3.44) 0 (0)

Prapas N, 2005

PREVENTION OF OHSSLEVEL 2: Use of GnRH antagonist vs. agonist

Effects of GnRH antagonist cotreatment on the incidence of ovarian hyperstimulation syndrome remains uncertain, although a

trend is present in favour of the GnRH antagonists

Tarlatzis, 2006

PREVENTION OF OHSSLEVEL 2: Antagonist in GnRH Analog Cycles

• Retrospective study

• 87 patients with long agonist protocol or microdose flare protocol

• Agonists discontinued and ganirelix acetate started and continued till E2 dropped to less than 3000 pg/ml and appropriate of follicles

Gustofson, 2006

PREVENTION OF OHSSLEVEL 2: Antagonist in GnRH Analog Cycles

Gustofson, 2006

PREVENTION OF OHSSLEVEL 2: HCG Dose and Alternatives

• HCG similar to LH• Longer half-life than LH

SO….

1. Reduce hCG dose2. Recombinant hCG ?3. GnRHa (for gonadotropin only cycles or

antagonist cycles)

PREVENTION OF OHSSLEVEL 2: HCG Dose and Alternatives

Pregnancy outcome in GnRH agonist versus hCG group

Buserelin hCG P

Patients (n) 55 67Rate of ET [n (%)] 48 (87) 57 (85) NSNo. of ET [mean (range)] 1.71 (1–2) 1.64 (1–2) NSPositive hCG per ET [n (%)] 14 (29) 25 (44) >0.10Clinical pregnancy [n (% )] 3 (6) 24 (36) 0.002Implantation rate (n) 3/893 3/97 <0.001Early pregnancy loss [n (%)] 11 (79) 1 (4) 0.005

Humaidan, 2005

PREVENTION OF OHSSLEVEL 2: HCG Dose and Alternatives

Cycle outcome after agonist and HCG triggering of final oocyte maturation Centre 1 Centre 2

Agonist HCG Agonist HCG

Patients 18 24 34 30

Patients OPU 18 24 32 30

Patients ET 15 20 29 28

Positive HCG 16.7% (3/18) 45.8% (11/24) 17.6% (6/34) 20.0% (6/30)

Ongoing preg. Rate 5.6%(1/18) 41.7%(10/24) 2.9%(1/34) 16.7% (5/30)

Early pregnancy loss 66.7% (2/3) 9.1% (1/11) 83.3% (5/6) 16.7% (1/6)

Kolibiniakis, 2005

PREVENTION OF OHSSLEVEL 2: HCG Dose and Alternatives

Acevedo, 2006

PREVENTION OF OHSSLEVEL 2: HCG Dose and Alternatives

• Conclusions– No differences in the number of MII,

fertilization rate and embryo quality– Lower pregnancy and implantation rates– Higher miscarriage rates

For the agonist trigger in IVF patientsFor the agonist trigger in IVF patients

PREVENTION OF OHSSLEVEL 2: Metformin

Comparison of metformin versus placebo or no treatment

in IVF with outcome of OHSS

The risk of OHSS in PCOS women undergoing IVF was reduced with metformin.

Costello, 2006

PREVENTION OF OHSSLEVEL 3: Proper Monitorization

• USG– PCOS patterns– Large number of follicles

• E2• Good predictor to OHSS

Aboulghar, 2003

PREVENTION OF OHSSLEVEL 4: Decreasing the developing follicles

and rapid estradiol increase • Coasting

– Withholding gonadotropin administration for one or more days

– GnRH agonist is continued

– hCG is given when the estradiol levels drop to a safe level (generally <3000 pg/ml)

PREVENTION OF OHSSLEVEL 4: Coasting

Comparison of criteria used for coasting  Reference No. coasted E2 initially (pg/ml) E2 (pg/ml) at hCG Coasting duration

(days)

Sher (1995) 51 >3000 <3000 6.1 (3–11)

Benavida (1997) 22 >3000 <3000 1.9 ± 0.9

Tortoriello(1998) 22 >3000 <3000 2.6 ± 0.3

Dhont (1998) 120 >2500 <2500 1.9 ± 0.8

Lee (1998) 20 >2724 Decreasing 2.8 ± 1.3

Egbase (1999) 15 >6000 <3000 4.9 ± 1.6

Wald. (1999) 65 Variable <2724 4.3 (3–6)

Fluker (1999) 63 >3000 25% decline 3.4 ± 0.1

Al-Shawaf (2001) 50 >3595 <2724 3.4 ± 1.6

Ulug. (2002) 207 >4000 <4000 2.9 ± 0.11

Levinsohn, 2003

PREVENTION OF OHSSLEVEL 4: Coasting

ICSI outcome according to the number of coasting days

Group I <3 days Group II >4 days P

No. of cycles 983 240Age (years) 30.16 ± 4.55 29.89 ± 4.91 NSInfertility period (years) 6.59 ± 4.16 6.56 ± 3.86 NSHMG amp. per cycle 31.76 ± 9.97 30.38 ± 9.03 NSE2 coasting level (pg/ml) 6150 ± 1760 7473 ± 2320 0.0001E2 HCG level (pg/ml)2674 ± 789 2801 ± 930 NSOocytes retrieved 16.45 ± 6.26 14.93 ± 6.01 0.002MII oocytes 12.94 ± 5.58 11.60 ± 5.6 0.0032 PN oocytes 8.16 ± 4.39 7.53 ± 4.59 NSEmbryos per transfer 2.99 ± 0.69 3.03 ± 0.66 NSFertilization rate (%) 62.67 64.92 NSImplantation rate (%) 26.32 18.16 0.0001Clinical pregnancy rate (%)51.96 35.88 0.0002

Mansour, 2005

PREVENTION OF OHSSLEVEL 4: Coasting

ICSI outcome of patients who developed severe OHSS

No. of cycles 16Age (years) 29.06 ± 9.08Infertility (years) 6.23 ± 5.29HMG amp.per cycle 28.94 ± 9.15E2 level-coasting (pg/ml) 6412 ± 3327E2 level-HCG (pg/ml) 4916 ± 2704Oocytes retrieved 20.06 ± 7.91Metaphase II oocytes 15.40 ± 7.16Two-pronuclear oocytes 9.25 ± 4.99Embryos per transfer 3.07 ± 0.47Fertilization rate (%) 42.37Implantation rate (%) 58.87Clinical pregnancy rate (%) 80.00

Mansour, 2005

PREVENTION OF OHSSLEVEL 4: Coasting

Uluğ, 2004

PREVENTION OF OHSSLEVEL 4: Coasting

Moreno, 2004

PREVENTION OF OHSSLEVEL 4: Coasting

• Conclusions– Effective for the prevention of OHSS– Start coasting when the leading follicles 14-16

mm and estradiol levels 3000-4000 pg/ml– Less than 4 days– Till E2 drops to < 3000 pg/ml– Prolonged coasting ( > 4 days ) can be

detrimental

PREVENTION OF OHSSLEVEL 5: Prevention of pregnancy

occurrence

• Cryopreservation of all embryos, no ET– Significant decrease in the incidence of OHSS

if the ET cancelled

– Insufficient evidence to support routine cryopreservation

Wada, 1993

Ferraretti, 1999

Amso, 1990

Salat-Baroux, 1990

Cochrane Review, 2002

PREVENTION OF OHSSLEVEL 5: Prevention of pregnancy

occurrence

Aboulghar, 2003

PREVENTION OF OHSSIntravenous Albumin

• Having osmotic and transport functions

• 50 gr. IV at the OPU time

• Osmotic function only lasts < 36 h

• Cochrane Review-2002– Significant reduction in OHSS

PREVENTION OF OHSSIntravenous Albumin

Coasting is as effective as i.v. albumin in preventing OHSS in high-risk patients but yields inferior pregnancy rates

Chen, 2002

PREVENTION OF OHSSIntravenous Albumin

Albumin Placebo P value

No. of cycles 38 37 NAAge 29.3 ± 3.9 29.1 ± 4.1 .87aPCOS 15/38 (39.5%) 8/37 (21.6%) .09bHistory of severe OHSS 4/38 (10.5%) 4/37 (10.8%) .96bNo. of follicles ≥14 mm 20.5 ± 5.2 19.3 ± 3.6 .30aSevere OHSS 8/38 (21.1%) 6/37 (16.2%) .59bEarly severe OHSS 3 (7.9%) 1 (2.7%) .61dLate severe OHSS 2 (5.3%) 2 (5.4%) 1.0dCombined severe OHSS 3 (7.9%) 3 (8.1%) 1.0dClinical pregnancy/embryo transfer 21/38 (55.3%) 23/37 (62.2%) .54bMultiple pregnancy rate 7/21 (33.3%) 7/23 (30.4%) .90bFirst trimester miscarriage rate 1/20 (5%) 4/23 (17.3%) .35dNot effective for OHSS prevention Isikoglu, 2007

PREVENTION OF OHSSHydroxyethyl Starch

• Alternative to albumin

• Increases the oncotic pressure

• 1000 ml of hydroxyethyl starch at the time of OPU

• Cheap and safer alternative to albumin

Graf, 1997

König, 1998

Gokmen, 2001

PREVENTION OF OHSSHydroxyethyl Starch

HES and albumin are effective for OHSS prevention

Gokmen, 2001

PREVENTION OF OHSSCorticosteroids

• Effective» Lainas, 2002

• Not Effective» Tan, 1992

PREVENTION OF OHSSKetoconazole

NOT EFFECTIVE

Parsanezhad, 2003

PREVENTION OF OHSS

Renin-Angiotensin Blockage and Embryo Cryopreservation • Cancellation of ET and dual RAS blockage with an

angiotensin receptor blocker and an angiotensin-converting enzyme inhibitor starting from day 1 after oocyte retrieval. Embryos were cryopreserved and transferred in subsequent cycles.

• Complete elimination of the syndrome is not possible with this treatment.

• Subsequent pregnancy rates with the transfer of frozen-thawed embryos are high.

Ata, 2008

PREVENTION OF OHSSCABERGOLİNE

• Low dose cabergoline

• Reduced VEGFR2

• Reduced OHSS

• 0.5 mg for eight days after the day of OPU• Does not affect ART outcome, prevent OHSS

(In Animals) Gomez, 2006

Alvarez, 2006

PREVENTION OF OHSS

• Bone morphogenetic protein 15 (BMP15) alleles OHSS (Francisco, 2006)

• Elective cryopreservation of all pronuclear oocytes (Griesinger, 2007)

• Coasting vs. GnRH Antagonist (Aboulghar, 2007)

• Low dose hCG (2500 IU) (Nargund, 2007)

PREVENTION OF OHSSCONCLUSIONS

• Patient and risk identification• Avoid flare protocols• Start low doses of gonadotropins• During ovarian stimulation

– Coasting– GnRH antagonist– Low doses of hCG– Agonist as hCG trigger– Dual suppression (OC + Agonist)

PREVENTION OF OHSSCONCLUSIONS

• Stop gonadotropins and continue GnRH agonist or antagonist

• Cryopreservation of all embryos or pronuclear oocytes

• IV albumin or starch

• Corticosteroids

• Cycle cancellation and supportive follicular aspiration

PREVENTION OF OHSSCONCLUSIONS