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PREVENTION OF SEVERE OHSS

16 follicles

12 mature oocytes

14 oocytes

Extras frozen if good

2 to 3 transferred9 fertilize normally

5 divide normally

30-40% of couples

4 stop dividing

& sperm

Typical progression

OHSS is a serious complication of ovulation induction.

In its severest forms, it is complicated by hemoconcentration, venous thrombosis, electrolyte

imbalance and renal and hepatic failure.Shenker and Weinstein, 1978; Navot et al., 1992; Aboulghar et al., 1993

OHSS INCIDENCE Non IVF: mild 8.0 -23%

moderate 0.005 -7%

severe 0.008 -10%

IVF : mild 100%

moderate 21- 44%

severe 1- 10%

estimated mortality 1/45.000-1/500.000

estimated morbidity 0.1-0.5%

PATHOGENESIS OF SEVERE OHSS

Kidney (JGA) rorenin Ovary

ace

PG Angiotensin II A-tensin I A-tensinogen

histamin (liver)

inflam. cytokines ANGIOGENESIS

(IL-1,IL-6,TNF) IL-2 (FF)

Capillary permeability VEGF(ovary)

fluid shift

hCG (LH)

E2

DIAGNOSIS OF SEVERE OHSS

clinic:distended abdomen, diarrhea dyspnea, weight gain, hypotension,

tachycardia

U/S: enlarged ovaries (>12 cm) + ascites X-ray: pleural effusion lab: Hct > 45% total proteins/albumine

trombocytes ureum/creatinine ; creat.clear.

electrolyte imbalance ( K , acidosis)liver enzyms

-hCG

severe critical

ovaries >12 cm > 12 cmascites/hydrothorax massive tensehct >45% >55%WBC >15.000 >25.000oliguria yes extremecreatinin 1.0 - 1.5 >1.6creat. clearence >50 ml/min <50 ml/minrenal failure not yet

yesliver disfunction yes yescomplications nasarca thrombo-emb.

ARDS

How to prevent How to prevent OHSSOHSS??

1. Before Start : Identifying the patients at risk before ovulation induction.

2. Before Start : Metformin & Proper ovulation induction protocol

3. During Cycle : Careful monitoring of ovarian response:• US• E2

4. Before OPU during ovulation induction:• Cancel the cycle• hCG dose and alternatives• Coasting• Antagonist

5. After OPU Cryopreservation of all embryo Dopamine agonist Luteal phase support

Before StartBefore Start

IDENTIFYING THE PATIENTS AT RISK BEFORE OVULATION INDUCTION::

• History of previous OHSS

• PCOD patients.

• AMH > 5

METFORMIN COCHRANE REVIEW, TSO ET AL., 2008

LOW DOSE GONADOTROPİNS

OHSS risk is lower in low dose regimens

Koundouros, 2008

Second: COHSecond: COH

MILD STIMULATION PROTOCOL

KAK

Karimzadah et al., 2010

HOW TO SUSPECT DURING COH

rapidly rising serum E2 levels More than 20 growing follicles

So what to do!!So what to do!!

I. For complete prevention: withholding hCG and continuing GnRHa (Navot et al., 1992)

II. Delaying hCG = Coasting

III. Other alternatives:• Rec hCG• Rec LH• GnRHa

ALTERNATIVES TO HCG

• hCG is similar in action to LH however it is not identical.

• It has a longer half-time and associated with sustained luteotropic effect.

(Itskovitz et al., 1991; Haning et al., 1985)

OTHER ALTERNATIVES TO HCG

1. Rec hCG

250 µg is as effective as 10, 000 IU of hCG in terms of PR and implantation rate, however similar incidence of OHSS.

(The European Rec Human hCG Study Group 2000; Driscoll et al., 2000, Chang et al., 2001)

2. Rec LH

Single rec LH dose significantly reduced OHSS with reduction in PR and implantation rate.

(Al-Inany, et al, 2005)

COCHRANE REVIEW, AL-INANY ET AL., 2011

GNRHAGONIST FOR TRIGGERRING OVULATION YOUSSEF ET AL., 2010

CoastingCoastingIt is withholding gonadotropins for few days before giving hCG

until E2 drops to a safer level.

• Available evidence suggests that such “coasting” does not adversely affect outcome in IVF cycles unless it is prolonged (>2 days)

COCHRANE REVIEW, D’ANGELO E.AL. 2010

Coasting vs. no coasting

CoastingCoasting

CLINICAL AND PRACTICAL ASPECTS

1. When to stop gonadotropins?

• When the leading follicles reach 16mm

2. how many days?

• Till the E2 drops to < 3000 pg/ml

(Sher et al., 1995; Benavida et al., 1997; Tortoriello et al., 1998;

Egbase et al., 1999; Fluker et al., 2000; Ohata et al., 2000)

3. Dose of hCG?

• 5000 IU is enough

4. Special laboratory aspects?

• Extra time to identify the oocytes from the follicular fluid

GnRH antagonistGnRH antagonist

In a Cochrane review by Al-Inany et al (2011) comparing agonist

and antagonist, significant difference in the incidence of

OHSS was found.

WHY: (AL-INANY ET AL, 2010)

CANCELLATION FOR RISK OF OHSS

So we may say confidently that GnRH antagonist is safer than GnRH agonist in IVF/ ICSI cycles

BUT NOT ALL DOCTORS WOULD GO FOR ANTAGONIST

(GNRH) ANTAGONISTS: OFF LABEL INDICATION

unique Idea Administration during GnRH agonist cycle when follicle reach ~16mm and E2 level >

4000pmol Decrease but Continue hMG (step down

protocol) Monitor by E2 Not more than 3 days

VALUE

allow continued stimulation while rapidly decreasing the E2 level to a range that is clinically acceptable.

OUR RESULTSParameter Coasting (n = 96) Antagonist (n =

94)P-value

Age (years) 30.0 ± 4.9 29.6 ± 4.6 NSDuration of infertility (years) 6.64 ± 4.45 7.07 ± 4.3 NSNo. of HMG injections 30.52 ± 8.9 29.94 ± 8.8 NSDays of stimulation1 9.1 ± 1.5 9.4 ± 1.5 NSPeak oestradiol (pg/ml) 5087 ± 1589 5305 ± 1680 NSOestradiol on day of HCG (pg/ml) 2605 ± 790 2721 ± 699 NSRange of oestradiol on day of HCG (pg/ml)

1110–4136 1223–4093 NS

Day of intervention 2.82 ± 0.97 1.74 ± 0.91 <0.0001

No. of oocytes 14.06 ± 5.20 16.5 ± 7.60 0.02No. of MII oocytes 11.13 ± 4.60 13.14 ± 6.60 NSNo. of fertilized oocytes   7.97 ± 3.80   9.14 ± 4.70 NS

No. of high quality embryos

  2.21 ± 1.10

  2.87 ± 1.20 0.0001

No. of embryos transferred   2.83 ± 0.50   2.79 ± 0.40 NSNo. of cryopreserved embryos   4.50 ± 3.93   5.77 ± 4.87 NSClinical pregnancy (%) 46/96 (47.9) 52/94 (55.3) NSMultiple pregnancy (%) 15/46 (32.6) 17/52 (32.7) NS

Intravenous Albumin to Prevent OHSSIntravenous Albumin to Prevent OHSS

• Cochrane review update (Al-Inany et al., 2011)

7 randomized controlled trials

Clear evidence of beneficial effect

BACKGROUNDAdministration of intravenous fluids such as

human albumin might result in :-

1. A restoration of intravascular volume

2. Inactivation of the vasoactive intermediates

responsible for the pathogenesis of OHSS

5/23

BACKGROUND Hydroxyethyl starch (HES) is a plasma

expander that has gained recent attention as an

alternative to albumin in reducing the incidence

of severe OHSS

HES is a non-biological substance, it avoids any

potential concern about viral transmission that

may be present with albumin

7/23

RESULTS OF SEARCH

10 RCTs (n= 2048)

7 RCTs : HA vs. P

1 RCT : HES vs. P

2 RCTs :HA vs. HES vs. P

9/23

No RCTs compared dextran or haemaccel vs placebo

IV FLUIDS VERSUS PLACEBO, SEVERE OHSS

18/23

AFTER OPU: DOPAMINE AGONIST : YOUSSEF ET AL., 2010

YOUSSEF ET AL., 2010

Postponing the Embryo TransferPostponing the Embryo TransferCryopreservation of all embryosCryopreservation of all embryos

• Several studies showed significant decrease in the incidence of OHSS if the ET was cancelled and all the embryos were cryopreserved.

(Amso et al., 1990; Salat-Baroux et al., 1990; Wada et al., 1993;Tiitinen et al.,1995; Ferraretti et al., 1999)

• Cochrane review (D’Angelo and Amso, 2002)

There is insufficient evidence to support routine cryopreservation.

ConclusionConclusion

OHSSOHSS is a preventable disease is a preventable disease

that should not be allowedthat should not be allowed

to happento happen

CONCLUSIONCONCLUSION Absolute prevention: no hCG or cycle

cancellation Relative prevention: coasting, albumin or

HAES, cryopreservation of all embryos, ovulation trigger by lower hCG dose or GnRHa

Most promising is : GnRHantagonist till E2<4000pmol

THANK YOUDr. Hesham Al-Inany MD, PhDe-mail : hesham@khosoba.com