This document discusses the authors' experience with ovarian hyperstimulation syndrome (OHSS) in 580 in vitro fertilization (IVF) cycles. It provides information on: - The incidence of mild, moderate, and severe OHSS in their IVF cycles. - The pathophysiology of OHSS and how it is classified as early or late depending on timing. - Their findings that OHSS does not occur without hCG trigger and symptoms resolve within 10-12 days without pregnancy. - Strategies for preventing OHSS including GnRH antagonist protocols, GnRH agonist trigger, cryopreservation of embryos, and use of metformin in PCOS patients. - Their proposed "

1. Dr. Sharda Jain
Dr. Jyoti Agarwal
Dr. Jyoti Bhaskar
Dr. Abhishek Parihar
OVARIAN
HYPERSTIMULATION
SYNDROME (OHSS)
: Our Experience in 580 IVF Cycles

2. OHSS in IVF
Incidence
Pathophysiology
Our experience
Prevention
Management
N- 580 cycles

3. Really a Unique
Most Serious iatrogenic problem of OI
A Complicated Complication

4. 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

5. Incidence
Mild – 33% Now Omitted in IVF Cycles
Moderate – 3-6%
Severe – 2%
Critical – 0.1 – 0.2%

6. No Unanimity
CLASSIFICATION
OHSS

7. <10 >10

8. 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

9. Pathogenesis is still unclear

10. 3 Treatment Facts that
influence OHSS
• HCG Triggerfor 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 ↑ PR
With long protocol
We are of the opinion that long protocol parse
does not causes OHSS

11. OHSS does not develop if
HCG
is not administered
Dr Razia S
Our Findings also support

12. 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

13. 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%

14. Critical
Ovarian size > 12 cm
TENSE ASCITES ± HYDROTHORAX
WHITE CELL COUNT > 25 000/ ML
PCV > 55 gm %
OLIGURIA / ANURIA
Venous thrombosis ± Thromboembolism
Acute respiratory distress syndrome
Critical OHSS
Needs ICU care

15. 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

16. 16Dr Razia SPrediction Can OHSS be accurately Predicted ?

17. Young patients
Lean women
Polycystic Ovarian
PCOS
Previous OHSS
• High number of follicle in both ovaries at the
quiescent state before Stimulation
(>- 10 follicle of 4-10mm in each ovary)
• Raised AMH
Easily
Recognized
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

18. Our Experience of OHSS IVF
in 580 IVF cycles
Profile of Early / Late OHSS
Early (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

19. Profile of EARLY / LATE OHSS Cases
Early (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

20. 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

21. •Primary
•Secondary
Prevention of OHSS : Better
than Cure
“Ten Commandments” Rizk B,1993,ESHRE Symposium

22. • 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

23. • 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 ????

24. 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

25. 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

26. 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

27. 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)

28. 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)

29. • 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

30. 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

31. 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

32. 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
HCG
TRIGGER
Antagonist
protocol
GnRH
Agonist
trigger
For triggering final Oocyte maturation
• Effective in preventing OHSS
(Segal and Casper ,1992

33. 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

34. It is EASIER Said Than Done
to cancel a cycle !!
↓
GnRH AGONIST
as a triggering agent
Luteal phase defect - ↓ PR
Negative effect on corpus luteum function
Negative effect on function of endometrium
BY GIVING HCG1500 units on O.P.U.
day – P.R. ↑ (NORMALISED)
↑
Cryo
Preservation
↑

35. Step III
CRYO PRESERVATION
of oocytes & embryo
A 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

36. • 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

37. CDC Report 2008
Pregnancy Rate same
in FRESH / FROZEN – thawed
cycles

38. • 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

39. 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.

40. 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)

41. duration cycle IR % PR %
1 or 2 100 (48.2%) 41.0 55.7
3 days 49 (23.6%) 18.4 27.9
4 days 58 (28.2%) 10.5 26.7
IR : implantation rate; PR pregnancy rate
FR was unaffected
Ulug et.al. HumReprod 2002

42. 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

43. • 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

44. • IVF outcome unaffected
• No significant difference in the
incidence of OHSS

45. 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

46. 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

47. 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

48. Management of OHSS

49. * 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

50. • Pain relief -paracetamol /oral or
parenteral opiates.
NSAID should not be given
• Antiemetic drugs - those appropriate
for the possibility of early pregnancy

51. • 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

52. • Hospital admission should be
recommended to women with severe
OHSS.
• Multidisciplinary care
• If Features of critical OHSS – ICU Care.

53. • 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

54. Inpatient monitoring of patients with OHSS

55. • 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.

56. • 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

57. 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)

58. 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

59. • Successful management of severe
early OHSS by reinitiating GnRH
antagonist 3 days after oocyte
retrieval incombination with embryo
cryopreservation
LainasTG et al ReprodBiomedOnline2007

60. Consider
A. Hydroxyethyl starch on OPU Day
Nonbiological
Potentially safer , cheaper and more effective .
B. IV Albumin if paracentesis is needed

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

62. • Need for symptomatic pain
relief/resp difficulty
• Tense ascites
• Oliguria with impaired renal
function
• Hemoconcentration unresponsive
to medical treatment

63. Our Experience
Consider 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

65. 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

66. 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

68. Key : Take Home Messages
• SAFETY OF PATIENT in IVF is public
& doctors TOP PRIORITY
Concept has to be accepted sooner than
later by FOGSI / ICMR
Strict guidelines to follow
OHSS FREE IVF CLINIC Can be reality ?
Yes ofcourse Hospitalization / ICU care can be prevented!!

69. 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

70. 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

71. 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

72. IS A REALITY

73. Thank You