Ovarian Hyperstimulation Syndrome (OHSS) - causes, diagnosis and management of this condition. How to minimize its risk and what are the related practice guidelines?

1. MINIMIZE RISK OF OHSS
Practice guidelines
When it happens

2. OHSS
 One of the most dreaded
complications of ovarian
stimulation
 Can be serious & life – threatening

4. OHSS
 Iatrogenic
 Incidence increasing with increase in
no. of IVF cycles
 Best treatment – ‘ Prevention ’
 Primum non nocere –
‘ first – do no harm ’

5. OHSS
‘ Loss of control over COH ’
 Only after overstimulated ovaries
‘ exposed to hCG inj ’
C U L P R I T
HMG HCG

6. OHSS - PATHOGENESIS
LH
Macrophages and granuiosa cells
HCG
IL-2 VEGF TNF
IL 6, IL 1 ETC
Microthrombi Inc. vascular permeability
OHSS
Secondary
mediators

7. PATHOPHYSIOLOGY
Hallmark – sudden of vascular permeability
Massive extravascular exudate
Accumulates in preritoneal cavity loss of fluid into 3rd space
Protein rich ascites profound fall in intravascular vol.
Fall in plasma oncotic pressure Haemo Suppression of
concentration urine formation
Further loss of Intravascular fluid
 Secondary Hyperaldosteronism salt retention
peripheral
edema

8. CLASSIFICATION OF OHSS
I - Depending on time of onset
Early & late OHSS
 Correlated to ov.
response to stimulation
 Is an ac. Effect of
‘exogenous hCG’
administration
 Usually occurs with
in 9 days after oocyte
retrieval
 Poorly correlated to the
ov. Response
 Caused by endogenous
hCG produced by an
implanting embryo or
administration of
hCG for luteal phase
 Occurs after initial
10 – days period

9. CLASSIFICATION OF OHSS
mild - 20-33%
II – severity classification moderate - 3-6%
severe - 0.1-2%
 Relating symptoms &
 Incorporating vaginal U /S & lab. Parameters
 Distinguished by the extent of fluid shift into body
cavities
 Signs & symptoms vary in individual cases &
cannot be assigned to a particular grade of
OHSS

10. SEVERITY CLASSIFICATION
MILD
 relatively common
 Symptoms
* lower abd.pain
& discomfort
* mild wt. gain
* nausea, vomit-
ing
* Diarrhoea
 Ovarian enlargement
on U/S
MODERATE
 Presence of ascites
on U/S
 Involves fluid shift of
< 500 ml
 Moderate haemo
conc. & elevated
lencocytes
 Symptoms include
* Rapid wt. gain
> 1 kg. / d
* Abd. distension
nausea & vomiting
SEVERE
 in symptoms
 Tense ascites
Hydrothorax
 Haemoconcentration
 Hypovolemia
 Oliguria
 Hepatorenal failure

11. MILD OHSS
Very common
Managed expectantly
 Monitor symptoms
 Encourage to
 Weigh (herself daily)
 Take abundant fluids & electrolyte
supplemented drinks
 Maintain light physical activity
IMPORTANCE OF MILD OHSS
 Should alert both patient & physician
 Need for Hospitalization

12. Gr 2 / MODERATE
HYPERSTIMULATION
 Need reassurance, explanation &
Hospitalisation
 More intensive patient monitoring of
 Daily wt, urine output
 Abd. Girth charting
 Lab. Evaluation
• For e/o haemoconcentration
• Serum electrolytes
 Encourage oral fluids
 IV rehydration
 IV albumin

13.  Adequate analgesia
 Paracetamol
 Pethidine
 Avoid NSAID
 Antiemetics
 Metoclopromide or
 stemetil
 Paracentesis
 Full length TED stockings &
Anticoagulants
 Heparin 5,000 u S.C. bd
 Clexane 20 / 40 mg. S.C. od

14. Gr 3 / SEVERE
HYPERSTIMULATION
‘ LIFE – THREATENING SITUATION ’
RECOGNIZED BY –
 Development of clinically detectable &
painful ascites with
Deterioration in
 Respiration
 Circulation
 Renal function
 Striking / Leucocytosis – 40,000 / cm²
 Haematocrit
 > 45 % ‘ Serious warning sign ‘
 > 55 % ‘ Life-threatening ‘
 In most cases, admission to ICU

15. PARACENTESIS

16.  Paracentesis of Ascitic fluid
 Abdominal U/S guided
 Transvaginal U/S guided
Indications – of paracentesis
 Symptomatic releif of tense ascites
 Oliguria
 Rising serum creatinine, falling creatinine
clearance
 haemoconcentration
 Paracentesis of Hydrothorax
 For relief of Dyspnoea
 Cardiac tamponade from pericardial effusion –
fatal if not relieved rapidly
 Careful cardiological assessment & cardiac U/S

17. BEWARE OF ACCUMULATION
OF FLUID IN CAVITIES

18.  Diuretics
 contraindicated
 Anticoagulation
 Patient is not ambulatory
 e/o thromboembolism or
 Deterioration coagulation profile

19. SURGERY
 ‘Should be avoided’
 Unless
 e/o ovarian torsion
 Marked haemorrhage or
 Rupture of one of the
ovarian cysts

20. EARLY DISCONTINUATION OF
PREGNANCY
 May be considered in selected
patients
 To prevent progression of OHSS

21. PREVENTION
STRATEGIES

22. IDENTIFYING AT – RISK
PATIENT
 Changes in ovarian stimulation
regimens
 To take preventative measures
PREDICTIVE FACTORS
 Primary risk factors-
 Which increases risk of OHSS
 Secondary risk factors-
 Become apparent during stimulation

23. PRIMARY RISK FACTORS
 Young age
 H/o excessive response to
Gonadotrophins
 Previous H/o OHSS
 PCOS

24. PREDICTIVE FACTORS FOR
PRIMARY RISK
 AMH
 More accurate predictor
 Increased risk of OHSS with
AMH > 7ng/ml
 U/s- ovary with ≥ 12 antral follicles

25. SECONDARY RISK FACTORS
 Ovarian response parameters-
 Levels & rate of increase of serum E2
 Follicular size & No.
 No. of oocytes collected
 Increased inhibin-B production

26. PREVENTING OHSS
 Primary measures
 High responders – low stimulation
regimens
 Secondary measures
 In situations of excessive response
 Withdrawal
 Delay or
 Modifications to avert OHSS

27. PRIMARY PREVENTION
1. REDUCING EXPOSURE TO GONADOTROPHINS
1. Reducing dose – IUI cycles
 Chronic low-dose step up protocols
• Higher rate of monofollicular development
• Lower risk of OHSS & multiple preg.
 Or step-down protocols
2. Reducing duration – IVF cycles

28. 3. Mild stimulation protocols
 Administration of FSH delayed until mid to
late follicular phase
 Introduction of GnRH antagonists for late-
cycle suppression
 Significant cost reduction

29. 2. GnRH-ANTAGONIST PROTOCOLS
 GnRH agonist cycles – increased incidence of
OHSS
 Incidence of severe OHSS
Lower in Antagonist protocols as per cochrane
review & meta-analysis

30. 3. AVOIDANCE OF hCG FOR LPS
 Luteal phase support required
 hCG support is known to risk of
OHSS
 Use of progesterone halves the risk

31.  In PCOS &
 In Normo-ovulatory at high risk
of OHSS
 Clinicl outcomes improved in
recent years
4. IN-VITRO MATURATION

32. SECONDARY PREVENTION
STRATEGIES
1. COASTING
 When E2 levels > 2,500 pg/ml & > 30 small
developing follicles
 Withholding further stimulation
 Delaying hCG until E2 levels plateau
or decrease
 Incidence of OHSS appears to be low but
oocyte quality & endometrial
receptivity low

33. 2. REDUCED DOSE OF HCG
 hCG ‘ Risk factor ’ for OHSS
 Standard dose – 10,000u. Inj.
 Cornell low dose hCG protocol
 Sliding scale-
E2 – 2,000-3,000 pg/ml – 5,000-3,300IU
hCG
> 3,000pg/ml – coasting until E2 falls
< 3,000 pg/ml
 Does not eliminate risk of OHSS

34. 3. CRYOPRESERVATION OF ALL EMBRYOS
 Progression of IVF OPU
 Cryopreservation of embryos
 Thaw & ET later cycle
 Early OHSS
may still occur
 Late OHSS
can be avoided
 Success rates generally lower
 Vitrification reduces damage
 An adjunct intervention - not a
stand alone option

35. 4. CYCLE CANCELLATION
WITHHOLDING HCG
‘ ONLY GUARANTEED METHOD ’
For prevention of early OHSS
 In OI with out GnRH-a use-
 A natural LH surge & ovulation
 Possibility of late OHSS
 Suitable contraception
 Significant financial burden of treatment
& psychological distress

36. 5. ALTERNATIVE AGENTS FOR
TRIGGER
 hCG successful trigger
 Long half life
 Inc. risk of OHSS
 GnRH-a
 In antagonist cycles
 Recombinant Lh
 Shorter half life

37. 6. OTHER POSSIBLE STRATEGIES
 GnRH antagonist salvage in patients
with elevated serum E2
 Iv albumin & HES
 Glucocorticoids
 Insulin sensitizing agents

38. 7. DOPAMINE AGONISTS
 Cabergoline
 Pretreatment before OI
• Reduces ov. Response to FSH
 Acts at VEGF receptor
 Effective in reducing severity
 Does not eliminate
 Does not appear to affect
ART outcome

39. 8. NON-RECOMMENDED STRATEGIES
 Follicular aspiration
 aspiration of granulosa cells from
one ovary
 Aromatase inhibitors

40. IMPACT OF OHSS - PREGNANCY
 Severity of OHSS
 Clinical pregnancy rate higher in severe OHSS
 Higher frequency of miscarriages
(Raziel et al - 02)
 Higher likelihood of multiple pregnancy &
adverse pregnancy outcome
(Luke et al - 94)

41. IMPACT OF OHSS –
IF NO CONCEPTION
 Symptoms of OHSS
 Ovarian cyst may persist
 Consider
 IVM
 Ovarian drilling before next
stimulation
 Needs counselling

42. CONCLUSION
 Preventable condition
 Implementation of evidence
based strategies
 To significantly reduce its
occurrence
Should be taken seriously because
of physical & emotional distress

43. FUTURE
 ‘ Mild ’ stimulation for IVF
 Single embryo transfer
 In-Vitro maturation of oocytes
 Artificial ovary
 Need for further randomized controlled
trials to design individualized
treatment protocols to produce optimal
ovarian response & minimize
occurrence of OHSS