Coasting and OHSS Coast ga dO SS

Coasting and OHSSMrs Uma GordonBristol Centre for Reproductive Medicine2011

OHSS• Life threatening iatrogenic complication of ART• 2% of cycles• Safety vs. outcome of IVF(Navot et al. 1992)

Prevention of OHSS• Lower dose of gonadotropins• Agonist /antagonist(Al-Inany et al. 2006)• GnRH-a for ovulation• rLH for ovulation(Kohbianakis et al. 2005)(Al-Inany et al. 2005)• Dose of hCG 5000 iu (Mathur et al. 1995)• Metformin (Costello et al. 2006)

Prevention of OHSS• IV Albumin / HES• Cabergoline• Ovarian diathermy• Cryopreservation of all embryos• Progesterone luteal l support• SET /SBT

Prevention of OHSS• Coasting – most popular pstrategy usedDelvigne & Rozenberg 2002(Systematic review)

Coasting• Withholding gonadotropins• Maintaining pituitary suppression• Daily E2 & if necessary scans• hCG when E2 ‘safe’ level

Coasting - Advantages• Cycle not cancelled• No other medical or surgical interventione t • Fresh embryos are put back• Reduces risk of OHSS while maintainingpregnancy rates

CoastingFSH levels decline• Granulosa cell apoptosis(Tortoriello et al. 1998)• Intermediate and small follicles atretic(Dhont et al. 1998)• Decline in E2 & vasoactive mediators (VEGF)(Garcia-Velasco et al. 2004)

CoastingNo clear cut criteria–When to start coasting ?what follicle size / number / E2 level– Coasting duration ?how long can we coast– What drop of E2 is acceptable ?(Delvigne & Rozenberg 2002)

Coasting challenges- when to start ?

Coasting – start time?At BCRM, E2 done when ≥ 20 follicles on scanIf E2 ≥ 6000pmol/L (minimum) and Folliclediameters ≥ 15mm in diameter- Bristol Centre for Reproductive Medicine

Coasting challenges– what duration ?

Coasting duration – Pregnancy rates• ≤ 3 days vs > 3 52% vs 36%(Mansour et al 2005)n=1223• ≤ 4 days vs > 4 29% vs 16 %(Garcia-Velasco et al 2006)Tortoriello et al 1996, Waldenstrom et al 1999,Ulug et al 2002, Isaza et al 2002

Coasting duration – in contrast• ≤ 3 days vs > 3• ≤ 4 days vs > 4No differenceOwj et al 2007)No difference(Nardo et al 2006)• Fertilisable oocytes upto 6 days(Dhont et al 1998)• Cryopreserved embryos(Arslan et al 2005)

Coasting challenges –-what drop in E2 acceptable ?

Drop in E2 – Pregnancy rates• E2 drop with coasting – no differencevs(Ulug et al 2004)(Kovacs et al 2006)• Cancellation of cycle(Benadiva et al 1997)

Bristol Centre ForReproductive MedicineAim• To look at the effect of coasting durationand E2 Drop / 24 hrs on IVF outcome

Bristol Centre ForReproductive Medicine• 3850 IVF / ICSI cycles - over 7 years• 547 coasted (14%)• Locally developed protocolNurse-managedClinician led

Methodology• GnRH-a long protocol regime• 1 st scan day 8, then 2 to 3 days later• If ≥ 20 follicles, then E2 checked

MethodologyCoasting initiated• If ≥ 20 follicles• With leading 3 follicles ≥ 15 mm &• E2 ≥ 6000 pmol/L

MethodologyCoasting stopped (ie., hCG given)• When E2 falls to ≤ 15000pmol/L• Leading 3 follicles ≥ 17mm in diameter

MethodologyCancellation of cycle• If E2 ≥ 30,000 pmol/L• If E2 Drop > 60% in 24 hours• Coasting > 6 Days

Serum E2 Assay• Competitive immunoassay• Sample dilutions when E2 high or low• Weekend E2 service

Results - 1Coasting Duration• Day 1 to Day 6

Coastingduration(Days)Cycles(n)No. of oocytes(mean)1 145 15.52 126 14.93 81 15.14 45 14.45 18 12.36 11 10.6

Coastingduration(Days)Cycles(n)Normal fertilization rate1 145 1218 / 1875 (65.0%)2 126 1042 / 1592 (65.5%)5%)3 81 696 / 1030 (67.6%)4 45 371 / 545 (68.1%)5 18 137 / 195 (70.3%)6 11 73 / 91 (80.2%)P value 0.025

Coastingduration(Days)Cycles (n)Ongoing pregnancy/livebirth rate1 145 45 / 145 (31%)2 126 43 / 126 (34%)3 81 24 / 81 (29%)4 45 15 / 45 (33%)5 18 6 / 18 (33%)6 11 5 / 11 (45%)P value 0.92

Results - 2E2 Drop: HCG-1 to day of HCG• No drop• 1-15%15%• 16-30%• 31-45%• 46-60% 60%

Change inE2 levels l (HCG -1to day of HCG)Cycles(n)No. of oocytes(mean)No Drop in E2 252 12.8E2 Drop 1-15% 15% 42 11.7E2 Drop 16-30%59 12.3E2 Drop 31-45%56 12.3E2 Drop 46-60% 60% 17 10.8P value 0.19

Change inE2 levels l (HCG -1to day of HCG)Cycles(n)Normal fertilizationrateNo Drop in E2 252 2123 /3236 (65.6%)E2 Drop 1-15% 15% 42 319 / 492 (64.8%)E2 Drop 16-30%59 491 / 727 (67.5%)E2 Drop 31-45%56 471 / 690 (68.3%)E2 Drop 46-60% 60% 17 133 / 183 (72.7%)P value 0.19

Change in E2 levelsCycles(%) (n)Ongoingpregnancy/Live birthrateNo Drop in E2 252 78 / 252 (31%)E2 Drop 1-15% 15% 42 14 / 42 (33%)E2 Drop 16-30%59 22 / 59 (37%)E2 Drop 31-45%56 19 / 56 (33%)E2 Drop 46-60%60% 17 5 / 17 (29%)P value 0.91

Results - 3OHSS Cases• Moderate to severe• Requiring hospitalisation

Results 3• 6.1% OHSS in coasted cycles• Moderate 4.7%Severe 14%1.4%• Overall 0.67% in all treated cycles

Conclusions - 1• There is a reduction in egg numbers withincreased duration of coasting• IVF/ICSI outcome was not compromised- up to 6 days of coasting- with E2 drop of up to 60% over24 hours prior to HCG

Conclusions - 2• Coasting results in a low incidence ofOHSS in high risk patients

OHSS• Defining the “acceptable” level of OHSS• This study - 6.7% moderate and severe OHSS inhigh risk patients (0.67% in all cycles)• Aim should be : 0 % moderate and severe OHSS

OHSS – morbidity and mortality• CEMACH report 2007Four maternal deaths directlylinked to OHSS over 3 years

Coasting audit• At BCRM, hCG given when E2 ≤ 15000pmol/L• Literature ‘Safe’ value for hCGadministration 11000 pmol/L

Coasting AuditBCRM – Change of practise in 2010• hCG when E2 ≤ 12,000 pmol/L (rather than15,000 pmol/L)• Appears to have halved the moderate tosevere OHSS cases per year

1068 Coasted cycles• Retrospective analysis of 13 years data• No difference in live birth rates with 8 days ofcoasting (28.6%)• No difference with E2 level on day of hCG or E2dropAbdalla & Nicopoullos 2010

Cochrane review• Coasting vs EUFA• Coasting vs GnRH-a• Coasting vs no coastingD’Angelo et al 2011

Cochrane review• The four trials reported on outcomes for273 women• Two of the trials were conferenceabstracts – Aflatoonian 2006 (EUFA) andKamthane, 2007 (no coasting)• Only one of the trials reported on theoutcome of live birth (abstract)t)D’Angelo et al 2011

Coasting versus EUFA: OHSS

Coasting vs GNRH-a: Clinical pregnancy

Coasting versus GnRHa: No. of oocytes

Coasting vs no coasting: OHSS

Cochrane review• A significant benefit of coasting over nocoasting for a reduction in moderate tosevere OHSSD’Angelo et al 2011

Short Coasting• Stopped gonadotropins and GnRH-a• Rapid drop in E2• Egg numbers 17• Pregnancy rate 40%Moon et al. 2008

No room for over response or OHSSin any assisted reproduction cycle