This document discusses prediction and prevention of ovarian hyperstimulation syndrome (OHSS) in non-IVF cycles. It defines OHSS and describes its degrees of severity. Risk factors for OHSS include polycystic ovary syndrome (PCOS) history and high antral follicle count (AFC) or anti-Müllerian hormone (AMH) levels. Prevention strategies discussed include using a low-dose gonadotropin protocol, monitoring estrogen levels and ultrasound findings closely, triggering with a gonadotropin-releasing hormone agonist instead of hCG, and administering hydroxyethyl starch or cabergoline. The document emphasizes that primary prevention through risk assessment and modified stimulation protocols is crucial to avoiding

1. OHSS:
Prediction and prevention in non IVF cycles
Aboubakr Elnashar
Benha university, Egypt

2. TTyyppeess ooff oovvaarriiaann
ssttiimmuullaattiioonn
Induction of
ovulation
Super
ovulation
Controlled
ovarian
stimulation
Patient Anovulatory Anovulatory or ovulatory
Objective One mature
follicle
> 1 >3
Example IUI
Unexp inf
IVF
Method Stimulation Stimulation Down regulation
Stimulation
Prevent premature
LH surge
Aboubakr Elnashar

3. Define
Systemic synd resulting from vasoactive
products released by hyperstimulated
ovaries.
An iatrogenic complication of COS.
Life threatening
Aboubakr Elnashar

4. Degrees: Mathur, 2oo5
Mild Moderate Severe Critical
Cl •Ab bloating
•Mild ab pain
•Mod ab pain
•N± V
• Ascites
•Oliguria
•Tense ascites
•Oligo/anuria
•Thromboembolism
•ARDS
US Ov: ‹8 cm* •Ascites
•Ov: 8–12 cm*
•±hydrothorax
•Ov›12 cm*
•large hydrothorax
Lab •Hct ›45%
•Hypoproteina
emia
•Hct›55%
•WCC›25 000/ml
TT Out pt Out pt,
In pt: unable to
control pain, N
with oral tt,
Difficulties in
monitoring
•In pt •ICU
Aboubakr Elnashar

5. Incidence
Varies:
1.Protocol of ovarian stimulation
2. Patient
3. Classification schemes
An increase in the incidence of
Severe forms of OHSS
Patients hospitalized
(Abramov et al., 1999; Cunha-Filho et al., 2003).
Elenany, 2013:
Non IVF IVF
Mild 8.0-23% 100%
Moderate 0.005-7% 21- 44%
Severe Aboubakr 0.008 Elnashar
-10% 1- 10%

6.  True incidence: unk
Worldwide: Far greater
Underestimated
(Bewley et al 2011)
 Causes
1. ARDS
2. Cerebral infarction
3. Hepatorenal failure
 Mortality from OHSS: unacceptable.
Aboubakr Elnashar

7. Prediction
I.Before stimulation
The most important: PCOS & history of OHSS
1. OHSS in a previous cycle
2. PCOS (Met or LOD)
3. Young patient: ≤30 y
4. BMI: ≤20
5. Basal investigations (NICE, 2013)
Total AFC > 16
AMH>3.5 ng/ml (25.0 pmol/l)
FSH<4 IU/l
Aboubakr Elnashar

8. Aboubakr Elnashar

9. II. During stimulation
1. US :
Number of the immature follicles is more important
than the number of mature follicles in predicting
OHSS.
>4 follicles ≥ 14 mm
(Kamrava et al., 1982; Hugues et al., 2006).
Doppler: low intraovarian vascular resistance
Combination of E2 & US: best chance for prediction
Aboubakr Elnashar

10. 2. E2
 High E2
<1000 pg/ml: No OHSS
1500-2000
risk of OHSS is significant
>2000 pg./ml:
hCG is not given
 Cases with severe OHSS are seen with E2
<1500 pg/ml.
 Slope rise of E2
value is doubled
More accurate
Aboubakr Elnashar

11. Moderate OHSS.
Both ovaries are enlarged and are observed in the posterior cul-de-
sac.
The ovaries are in close contact and displace the uterus
anteriorly.
Both ovaries contain several large Aboubakr Elnashar unruptured follicles.

12. Aboubakr Elnashar

13. Prevention
OHSS must be prevented rather than treated
I. Modified stimulation protocols
1.HMG
a.Lower doses
b. Chronic low dose step up protocol
2. HCG
a.HCG Withholding
b.Decrease HCG dose
c.Replacing
3. Progesterone for LPS not HCG.
Aboubakr Elnashar

14. II. Close Monitoring
1.US
2.E2
III. Modification of technique
Convert to IVF
IV. Adjuvant
1. IV albumin
2. 6% Hydroxyethyl starch
3. Metformin
4. Dopamin agonist
5. Ca gluconate
Aboubakr Elnashar

15. I. Modification of Protocols
1. HMG
I. Step-up:
1. Low dose
2. Chronic low dose
II. Step-down
Aboubakr Elnashar

16. The starting dose of Gnt
Depend on:
1. The intended goal:
unifollicular ovulation or superovulation
2. Age
3. BMI
4. PCOS
5. Ovarian reserve: baseline FSH, ACF, AMH
6. Previous response.
Aboubakr Elnashar

17. low-dose
•Stating dose: 75 IU/d
(White et al., 1996; Hayden et al., 1999; Balasch et al., 2000; Calaf
et al., 2003).
•Duration of starting dose: 5-7 d
-No follicle development: increase the dose by
100%
-Follicle growth: maintain same dose until
follicular selection is achieved.
-Mono-ovulation: 69%
- MP: 5.7%
- OHSS: 0.14%
(Homburg & Howles, 1999. Hum. Reprod. Update 5:493-499).
Aboubakr Elnashar

18. Starting dose:75 IU/d
FSH/hMG/day 75
Day 3 days 5 Day 7
IIff
FFoolllliiccllee >> 1122 mmmm
EE22 >> 440000
CCoonnttiinnuuee
FFSSHH//dd 11
No response ®150 FSH/d
.(for 1 more w (max. 3 amp
EEnnddooccrriinnee RReevv.. 11999977;; 1188:: 7711
Aboubakr Elnashar

19. Chronic low-dose
•Starting dose: 37.5-75 IU
•Duration of starting dose:14 d
•The weekly dose increment: reduced from 100% to 50% or
37.5 IU
(Seibel et al., 1984; Polson et al., 1987; Sagle et al., 1991; Dale et al., 1993).
:Markedly ↓excessive ov stimulation
Marked ↓OHSS.
Aboubakr Elnashar

20. 75 iu
112.5 iu
150 iu
½ Amp.
37.5 iu
0 14 21 28 35
187.5 iu
225 iu
Days
7
One Amp.
42 49
2 Amp.
3 Amp.
White et al. J Clin Endocrinol Metab 1996;81:3821–4
Aboubakr Elnashar

21. 2. Step down protocol in PCOS (2nd line)
• Mimics hormonal pattern in natural cycle.
• Starting dose: once dominant follicle of 12 mm
• Reduce dose by 37.5 IU sequentially
• Not preferred
Aboubakr Elnashar

22. 2. HCG
a. HCG Withholding:
Rationale: hCG is the main triggering cause of
OHSS
Cycle cancellation
financial and emotional implications, frustrates both
patient and physician
Cycle cancellation before administration of HCG is an effective strategy for
the prevention of OHSS, but the emotional and financial burden it imposes
on patients should be considered before the cycle is cancelled. (III-C)
Aboubakr Elnashar

23. b. Decrease HCG dose:
As low as 3300 IU
2000 IU: ineffective, lower successful oocyte recovery
(Kashyab et al, 2010).
 does not prevent OHSS
(Kol, Dor, 2009)
There is no clear evidence that lowering HCG dose
will result in a decrease in the rate of OHSS. (III)
Aboubakr Elnashar

24. d. Replacement of hCG
a.HP HCG (Choriomon): No difference
b.Rec HCG: (Ovitrell) No difference
d. Rec LH (Luveris)
safer than hCG
too expensive
Dosage:15,000–30,000 IU
The use of either LH or HCG for final oocyte
maturation does not influence the incidence of
OHSS. (I)
Aboubakr Elnashar

25. d. GnRHa
No cases of moderate/severe OHSS in 1,152 cycles
Requires use of GnRHan in COS
GnRHa short half-life (3-5 h) eliminates the risk of
OHSS in nonconception cycles.
PR: 17%, with a low rate of multiple pregnancy.
Aboubakr Elnashar

26. 3. Progesterone for LPS not HCG.
Progesterone, rather than HCG, should be used for
LPS. (I-A)
Aboubakr Elnashar

27. II. Monitoring in superovulation
I. US
• Assessing the follicular maturity
• Growth rate: 2- 3 mm/d in a stimulated cycle.
• Follicle 18—20 mm: contain a mature oocyte.
Serial
D5-7 of stimulation. D4: PCOS
Repeat /2-3 d depending on the size of leading follicle,
until it is 18 mm
Aboubakr Elnashar

28. a. Follicles:
number & size
Documentation of all follicles >10 mm {predict the
risk of multiple pregnancies}.
1 or 2 follicles 18-20 mm: HCG
>4 follicles ≥ 14 mm: stop HCG
(Kamrava et al., 1982; Hugues et al., 2006).
Aboubakr Elnashar

29. II. E2
• Correlates closely with the stage of development
of the dominant follicle
• D8 stimulation E2 >200 pg / ml indicates adequate
dose of Gnt (Speroff et al, 2006).
E2 on day of HCG
<200
500-1500 1500-2000 >2000
pg./ml
pregnancies
are rare
optimal risk of
OHSS is
significant
HCG is not
given
Cycle is
cancelled
Aboubakr Elnashar

30. III. Modification of technique
Rescue IVF
If we convert to IVF + freeze all embryos and then ET in next cycle (as
cases with very high E2 levels are not only at high risk for OHSS but also
lead to “out of phase endometrium” with lower implantation rates).
Aboubakr Elnashar

31. IV. Adjuvant
1 - IV albumin:
Immediately on the day of hCG
Effectiveness:
IV albumin does not reduce severe OHSS.
(Youssef, Al-Inany et al, Cochrane Database Syst Rev 2011; Venetis : a
systematic review and metaanalysis.2011)
Albumin or other plasma expanders at the time of egg retrieval are not
recommended for the prevention of OHSS. (I-E)
Aboubakr Elnashar

32. 2. 6% HES
 slow infusion of 500 mL of 6% HES on day of
HCG
 significantly reduced the incidence of moderate-severe
OHSS
 HAES Sterile= HES (6%) in isotonic saline or
 Voluven= 500 ml (68 EP)
Aboubakr Elnashar

33. HES Vs Albumin
Much cheaper
More effective
No anaphylactic reaction
(Abramov et al,2001; Chen et al, 2003)
 HES markedly decreases the incidence of severe
OHSS.
(Youssef, Al-Inany et al, Cochrane Database SR 2011; Venetis :
SR and MA. 2011)
Aboubakr Elnashar

34. 3. Dopamin agonist (cabergoline)
0.5 mg daily for 8 days from day of hCG
(Seow et al, 2013)
Type 2 receptors for VEGF are believed to be
involved in the pathophysiology of OHSS
Effective for the prevention of OHSS. without
sacrificing PR
(Esinler et al, 2013).
Reduces the incidence, but not severity of OHSS,
without compromising pregnancy outcomes.
(Yousef et al, 2010, SR and MA)
Aboubakr Elnashar

35. less effective for tt of OHSS.
(S R and MA., Baumgarten et al, 2013)
Cabergolin VS IV albumin
more effective and less costly
(Tehraninezad et al, 2012)
Cabergoline starting from the day of HCG
reduces the incidence of OHSS in patients at
higher risk and does not appear to lower PR. (II-
2)
Aboubakr Elnashar

36. 4. Metformin in PCOS
Mechanism
: reduction of intraovarian androgen by reducing hyperinsulinism:
reduction in E2 and favours orderly follicular growth in response to
exogenous GnT
reduction of AMH and a reduced insulne dependent VEGE (Tang et al
2006)
reduces the risk of OHSS
no effect on CPR or LBR
improves the rates of miscarriage and implantation
(Palomba et al, 2013).
The addition of metformin should be considered in
patients with PCOS because it may reduce the
incidence of OHSS. (I-A)
given 2 months before starting stimulation (Castello et
al 2006)
Aboubakr Elnashar

37. 5. Calcium gluconate
10 ml of 10% solution in 200 ml NS within 40 min of
OR and continued on day 1, day 2 and day 3.
prevent severe OHSS and decreases OHSS
occurrence rates
Ca gluconate Vs Cb2
 comparable success rates
(Naredi et al, 2013).
Aboubakr Elnashar

38. Key Take home Messages
(Rizk B., 2010)
Primary prevention
1. Prediction of OHSS from history, exam, and US
2. LOD in PCOS
3. Metformin in PCOS
5. Close monitoring during stimulation
6. Low-dose gonadotropins
6. Chronic low dose protocol
Aboubakr Elnashar

39. 2ndry prevention
1. Withholding hCG if S/S of mild OHSS or E2: 1500
2. Rescue IVF
3. GnRHa or Rec LH to trigger ovulation
4. Progesterone for LPS
5. Dopamine agonist
6. HES 6%
Aboubakr Elnashar

40. Thank you
Facebook
https://www.facebook.com/groups/2277
44884091351/
Aboubakr Elnashar