Dr. Sharda Jain Dr. Jyoti Agarwal Dr. Jyoti Bhaskar Dr. Abhishek Parihar

OVARIAN HYPERSTIMULATION SYNDROME (OHSS) : Our Experience in 580 IVF Cycles

OHSS in IVF

Incidence PathophysiologyOur experience

PreventionManagement

N- 580 cycles

Really a Unique

Most Serious iatrogenic problem of OI

A Complicated Complication

Associated with increased capillary permeability leading to haemo-

concentration, ASCITES, Pleural / pericardial effusions and ovarian

enlargement

OHSS“Capillary Leakage Syndrome”

Increase B/L Ovarian enlargement + Acute shift in body fluids

Incidence

Mild – 33% Now Omitted in IVF Cycles

Moderate – 3-6%

Severe – 2%

Critical – 0.1 – 0.2%

No Unanimity

CLASSIFICATION OHSS

<10 >10

EARLYEARLY

<10 <10 Correlated to

ovarian response to stimulation.

Acute effect of exogenous hCG administration

1. Occurs within 9 days after oocyte retrieval

LATELATE>10>10

1. Poorly correlated to the ovarian response

1. More correlated to the endogenous hCG produced by the implanting embryos

2. Administration of hCG for LPS

3. After the initial 10 days period after oocyte retrieval

Types of OHSSTypes of OHSS

Pathogenesis is still unclear

3 Treatment Facts that influence OHSS

• HCG Trigger for ovulation creates HAVOC

• Long protocol of Down regulation

With GnRH agonist in IVF is associated

↑ OHSS (No. of days of GT > dose & type )

– Compels IVF experts to use long protocol

Supposedly ↑ PRWith long protocol

We are of the opinion that long protocol parse does not causes OHSS

OHSS does not develop if

HCG is not administered

Dr Razia S

Our Findings also support

HCG

Albert et al. Mol Hum Reprod. 2002;8:409; Chen et al. Hum Reprod. 2000;15:1037; Gómez et al. Endocrinology. 2002;143:4339

Moderate

Moderate abdominal pain

Nausea +/- Vomiting

Ultrasound Evidence of ASCITES

Ovarian size 8-12 cm

Grading (Mild is Deleted in IVF)

Severe

N & V ++, pain ++ , Clinical ascites (rarely hydrothrorax)

Ovarian size > 12 cm, Oliguria

heamoconcentration - HEAMATOCRIT <45%

Critical

Ovarian size > 12 cm

TENSE ASCITES ± HYDROTHORAX

WHITE CELL COUNT > 25 000/ MLPCV > 55 gm %

OLIGURIA / ANURIA

Venous thrombosis ± Thromboembolism

Acute respiratory distress syndrome

Critical OHSSNeeds ICU care

Our Experience with OHSS

A. OHSS does not occur without hcg trigger

B. IF PREGNANCY OCCURS the condition is likely to worsen progressively over a period of three to five weeks requires very close observation including hospitalization in few cases.

C. IF NO PREGNANCY OCCUR the symptoms and sign all disappear spontaneously with in 10 – 12 days of the hcg injection

16Dr Razia SPrediction Can OHSS be accurately Predicted ?

Young patients Lean womenPolycystic Ovarian PCOSPrevious OHSS

• High number of follicle in both ovaries at the quiescent state before Stimulation

(>- 10 follicle of 4-10mm in each ovary)

• Raised AMH

EasilyRecognized

WHO are AT HIGH RISK BEFORE OI – IUI & IVF

Screen Before IVF

PRIMARY RISK FACTORS

SENSITIVE OVARIES Picked up by USD before during after OI

25.0 pmol/l for a high response

( >7 ng/ml

Our Experience of OHSS IVF in 580 IVF cycles

Profile of Early / Late OHSSEarly (N = 6) Late (N = 4)

Incidence 1.03 .68

Age 32 yrs 29 yrs

BMI 22 - 29 26

Basal FSH Mean 7.4 8.3

Basal LH Mean 8.3 4.2

PCOS on USG 52% 25%

E2 on day of HCG Over 4000 Over 2400

Profile of EARLY / LATE OHSS CasesEarly (N = 6) Late (N = 4)

No of Follicle on day of HCG >16 All None

No of Oocyts retrieved 24 - 26 <16

Cancellation of ET 32% (2/6) Nil

No of embryo transfer 3 to 4 3

Positive HCG 50% (2/4) 100%

Abortion / Ectopic 1 (Abortion) 1 (Ectopic)

Clinical Pregnancy 1/4 3/4

Our Experience of OHSS in 580 IVF cycles

Does PCOS Causes Poor

Egg / Embryo Quality ??IN OUR EXPERIENCE - Women with PCOS undergoing IUI to IVF are commonly found to have poor quality eggs with reduce potential with fertilization

We do not think it is due to intrinsic deficit in egg quality;

it looks related to intra ovarian hormonal changes brought about by OHSS

•Primary

•Secondary

Prevention of OHSS : Better than Cure

“Ten Commandments” Rizk B,1993,ESHRE Symposium

• Avoid hCG trigger in high risk cases (Predicted based on history/ Exam/USG – before & during IVF Cycle)

• Reducing Exposure to large doses Gonadotropins in high risk cases.

• GnRH Antagonist Protocols in high responders

• GnRHa trigger• Avoidance of hCG for LPS• Insulin-Sensitizing Agents

Primary Prevention Strategies

• Cryopreservation of embryos & ET in next cycle (our first Priority)

• Coasting (Second Priority)

• Cycle Cancellation (Last Priority)

• Other Possible Strategies for Preventing OHSS

- Cabergoline - HES

- Antagonist - IV albumin in cases of paracentisis

• Nonrecommended Strategies

Aromatase Inhibitors

Follicular Aspiration

Consider - Low dose HCG on OPU Day (1500 IU) If ET is planed

Secondary Prevention Strategies

GnRH antagonist, instead of a long-protocol Agonist trigger or Reduced Dose of hCG for trigger ????

1.Decrease Gonadotropin dose and duration – 75-112iu start dose – Frequent monitoring

2. GnRH Antagonist Protocols

– Fewer mid-size follicles – Significant reduction in severe OHSS OR 0.43 (0.33-0.57) – Similar Live Birth rates OR 0.86 (0.69-1.08)

Al-Inany et al. Cochrane 2011

How to prevent OHSS in High Risk Cases

Primary Prevention

3. Avoidance of hCG for luteal support

• High E2 and P levels during IVF suppress pituitary LH production • Need exogenous P or hCG/LH • hCG for luteal support doubles

OHSS risk compared

How to Prevent OHSS primary Prevention

4. Metformin* Hyperinsulinaemia in PCOS Co-treatment during IVF Similar Live-Birth rates Significant Reduction in OHSS in PCOS patients

OR 0.27 (0.16-0.47) Tso et al. Cochrane 2009

How to prevent OHSS Primary Prevention

Role of Metformin in OHSS Prevention

• Metformin has also been used for the prevention of OHSS.

• In a meta – analysiss of eight randomized controlled trials of women with PCOS metforming given 2 months before strating COS significantly reduced the risk of severe OHSS (odd ratio(OR))OF 0.21,95% confidence interval (CI)0.11-0.41,p<0.00001)

(costello et al 2006)

Role of Metformin in OHSS Prevention

• The mechanism of action of metformin is not completely clear, but reduction of

Anti – Mullerian Hormone (AMH) values and a reduced insulne dependent VEGE production has been suggested

(Tang et al 2006)

• GnRH antagonist, instead of a long-protocol • Agonist trigger or Reduced Dose of hCG for trigger ????

• Cryopreservation of embryos & ET in next cycle

• Coasting

• Cycle Cancellation

• Other Possible Strategies for Preventing OHSS

- Cabergoline - HES

- Antagonist - IV albumin in cases of paracentisis

• Nonrecommended Strategies

Aromatase Inhibitors

Follicular Aspiration

Consider - Low dose HCG on OPU Day (1500 IU) If ET is planed

Secondary Prevention Strategies

Proposed Protocol of Zero% OHSS at our centre

• The use of the GnRH antagonist protocol for OI instead of long protocol

• Ovulation Triggering with GnRH agonist Instead of HCG trigger

• Cryopreservation of all oocytes and embryos

↓ET in frozen – thawed cycle

3 Steps

STEP - 1

Use of GnRH antagonist

Protocol for OI• Patients friendly

- Fewer injection of OI

- Short duration of stimulation

- Absence of side effects

Uses • ↓↓ OHSS rate• No difference in Term LB Rates

Between antagonist & agonist Al- Inany et al 2006- 20011, Kolibisnskis et al 2006

Devroey et al 2009 2011

STEP - II

Ovulation Triggering - ↓↓↓↓ OHSS Rate- but can’t eliminate it all

together

GOLD STANDARD as ovulation triggering agent because of long half life with levels remaining elevated even after six days of administrations

NO

HCGTRIGGER

Antagonist protocol

GnRH Agonisttrigger

For triggering final Oocyte maturation• Effective in preventing OHSS

(Segal and Casper ,1992

ZERO % OHSS (Severe / Critical)is achieved

• Incidence of Severe OHSS is GnRH antagonist cycles is 0% when triggered with a GnRH agonist.

• This was tested in OOCYTE DONORS (Melo et al ,2009)

Major Disadvantages in self cycles ↑ Luteal phase defect &

significant ↓ Pregnancy Rate

It is EASIER Said Than Doneto cancel a cycle !!

↓

GnRH AGONIST as a triggering agent

Luteal phase defect - ↓ PRNegative effect on corpus luteum function

Negative effect on function of endometrium

BY GIVING HCG 1500 units on O.P.U.

day – P.R. ↑ (NORMALISED)

↑

Cryo Preservation

↑

Step III

CRYO PRESERVATION of oocytes & embryoA valuable modality…But Skill - is the key

Oocyte / embryo vitrification –

↑ P.R. (40% - 80%)

↓ Severe OHSS to 0% Results better than COASTING

Ethical Issue of freezing embryo

• Prevents OHSS as No endogenous hCG• An additional benefit of postponing ET * Avoiding embryo exposure to extremely elevated

steroid concentrations.

* Supraphysiological hormone levels -detrimental

to endometrial receptivity, as well as embryotoxic

Valbuena D, Martin J et alFertilSteril2001;76:962–8

Shapiro B et al .FertilSteril2011;96:344–8

ShapiroB, DaneshmandS,GarnerF et alFertilSteril2011;96:516–8

Crypreservation of Embryo & Postponing ET

CDC Report 2008

Pregnancy Rate same

in FRESH / FROZEN – thawed cycles

• Withholding Gonadotropins for few days before giving hCG until E2 drops to a safer level (below 3000)

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

Coasting

Coasting diminishes the granulosa cell cohort

• Follicular growth will continue with the same rate.• E2 will continue to rise then will plateau and then decline.

1. When to stop gonadotropins?

• When the leading follicles reach 16mm

2. how many days?

• Till the E2 drops to < 3000 pg/ml

Ragaa Mansour et al Human Reproduction Vol.20, 2005

Raziel a et al HumanReproduction,Vol .18 ,2003

3. How ever Pregnancy rates appear to decrease while

coasting during prolonged gonadotropin-free periods

Practical TipsPractical Tips

(Ulug  et al, 2004)

duration cycle IR % PR %

1 or 2 100 (48.2%) 41.0 55.73 days 49 (23.6%) 18.4 27.94 days 58 (28.2%) 10.5 26.7

IR : implantation rate; PR pregnancy rateFR was unaffected

Ulug et.al. HumReprod 2002

Our impression on coasting

At present clinicians should employ strategies which appear to result in a lower incidence of severe OHSS rather than coasting until further evidence has accumulated. cochrane 2011

• Coasting is a useful protocol for prevention of OHSS based on multiple retrospective studies and one randomized controlled trial.

We are slowly giving up in Favour of Embryo freezing & ET next cycle

• In our Experience OHSS does not develop if hCG is not administered.

• Even if hCG dose is decrease OHSS is really possible.

• OHSS is more frequent when hCG is used for

luteal support rather than progesterone.

• OHSS is more frequent and severe in

conception cycles and particularly multiple pregnancies

trigger

• IVF outcome unaffected

• No significant difference in the incidence of OHSS

Big alert is flagged • If >20 growing follicles(>/=12mm);• Serum E2 >3,000pg/mL the day of

hCG admin - istration• Be obsessed for Presence of incipient

Ascitis on OPU day • Previous OHSS even with less evident

signs of a strong ovarian response

Practical Tips to avoid OHSS

Most Important Tips

Is important to know that symptoms and signs of OHSS are severely aggravated by rising hcg levels.

Thus women with OHSS - should not receive additional; hcg injection as luteal phase support

6.6. Non recommended strategies:Non recommended strategies:* Follicular Aspiration* Aromatase Inhibitors

o * Glucocorticoids - Does not eliminate the risk of OHSS

We do not give Further studies are needed

Management of OHSS

* Treatment for women with mild OHSS and many with moderate OHSS can be managed on an Outpatient basis.

* Conventional management of OHSS is focused on Supportive Care until the spontaneous resolution of the condition

• Pain relief -paracetamol /oral or parenteral opiates.

NSAID should not be given

• Antiemetic drugs - those appropriate for the possibility of early pregnancy

• Women should be encouraged to drink to thirst, rather than to excess.this is the most physiological approach to replace fluids.

• STRENUOUS EXERCISE and SEXUAL INTERCOURSE should be avoided for fear of injury or torsion of hyper-stimulated ovaries.

• Women should continue progesterone luteal support but hCG luteal support is inappropriate & not to be given

• Hospital admission should be recommended to women with severe OHSS.

• Multidisciplinary care

• If Features of critical OHSS – ICU Care.

• Women admitted to hospital with OHSS should be assessed at least daily, with more frequent assessment of those with critical OHSS.

Standard care involves

• Monitoring of appropriate clinical parameters• Fluid balance management• Thromboprophylaxis and• Ascites treatment

Inpatient monitoring of patients with OHSS

• Routine screening for thrombophilia in all women undergoing assisted conception is not warranted.

• Thromboprophylaxis should be provided for all women admitted to ICU with OHSS.

• Dopamine agonists and GnRH antagonists , when given together at the time of diagnosis of OHSS, appear to work rapidly and effectively to diminish the clinical symptoms of the disease

Rollene et al ,Fertil Steril 2009

Role of Cabergoline in OHSS prevention

• Cabergoline appears to reduce that risk of OHSS in high – risk women especially in moderate OHSS.

• But there is no evidence that it reduces the chances of severe OHSS.

• The use of cabergoline does not affect the pregnancy outcome risk of adverse. Events

(Chocrane reviews 2012)

Role of Cabergoline in OHSS Prevention

• Cabergoline 0.5 mg tablet daily starting on the day of hcg (just before) injection and continued for total of 8 days have been shown to reduce the risk of OHSS

• Successful management of severe early OHSS by reinitiating GnRH antagonist 3 days after oocyte retrieval incombination with embryo cryopreservation

LainasTG et al ReprodBiomedOnline2007

Consider

A. Hydroxyethyl starch on OPU Day

Nonbiological Potentially safer , cheaper and more

effective .

B. IV Albumin if paracentesis is needed

• Recently, there has been a trend toward the use of outpatient management with early paracentesis for moderate to severeOHSS.

• Need for symptomatic pain relief/resp difficulty

• Tense ascites• Oliguria with impaired renal

function• Hemoconcentration

unresponsive to medical treatment

Our ExperienceConsider Early paracentesis

If raising headend does not help patients & patients symptoms become severe & lot of fluid is there in abdominal cavity --- can be safely drained by trans abdominal of trans vaginal route by sterile needle aspiration once or twice.

The problem usually correct itself within 10 to 12 days of the hcg

shot if pregnancy does not occure, or by the eighth week of pregnancy

SPECIAL TIPS

for Donor stimulation

• Always use GnRH ANTAGONIST PROTOCOL

• Give GnRH AGONIST TRIGGER for ovulation

• If Suspicious of Moderate OHSS

* Give cabergoline before trigger * After OPU give antagonist inj. for 2-3 days * Give progesterone withdrawl inj MPA Before discharge or Tablets. * Follow - up is must

Women should be reassured that pregnancy

may continue normally despite OHSS, and there is no

evidence of an increased risk of congenital abnormalities.

Mathur RS,Jenkins JM et al BJOG 2000 Raziel A et al Hum Reprod 2002 Wiser A et al Hum Reprod 2005

Key : Take Home Messages

• SAFETY OF PATIENT in IVF is public

& doctors TOP PRIORITY

Concept has to be accepted sooner than later by FOGSI / ICMRStrict guidelines to follow

OHSS FREE IVF CLINIC Can be reality ?

Yes ofcourse Hospitalization / ICU care can be prevented!!

Slowly Replace Long protocol of GnRH agonist with short antagonist protocol

+ Agonist ovulation trigger

+ Oocyte & embryo freezing

+ET in

Natural cycle Or Artificially prepared Endometrium

Key Take Home Messages

OHSS : an IATROGENIC problem must never hold you back if you face it.

Instead - these problems can help you shine brighter in the next take off –

of your PROFESSIONAL MATURITY & support OHSS Free Clinic

Future Strategy for Safe IVF Practice

• 100% antagonist cycle

• 100 % Agonist trirger for ovulation

• 100% freezing of embryos

• 100% frozen-thawed IVF cycles

Zero % OHSS Free Clinic

IS A REALITY

Thank You