IUI with gonadotrophins

P DevroeyP DevroeyCentre for Reproductive Medicine

Dutch - speaking Brussels Free University

Laarbeeklaan 101

1090 Brussels Belgium

• Debate is an intellectual game between friends

• Stimulation of ovulatory women• Is IUI not an intellectual blunder ?

Intellectual blunder ? Of miskleun ?

• Ovulation induction in anovulatory

women

• Ovarian (superovulation) in IVF

• Ovarian stimulation in ovulatory women

(ovarian enhancement)

Primary endpoint

• Singleton life birth

• (Significant) reduction of multiple

pregnancies

• At present ~ 35 children / 100 are

members of a multiple pregnancy~

Ovulation enhancement in ovulatory women (IUI)

Clomiphene citrate Gonadotrophins

Cheep drug Expensive drug

Limited monitoring Extensive monitoring

Limited multiple pregnancy rate

Substantial multiple pregnancy rate

(3x higher)

Aanbevelingen voor ovulatie inductie

• Monitoring van clomifeen stimulatie– Echografische monitoring met hormonale screening op dag 10

is nuttig

– Zuiver echografische screening zonder hormonale screening kan een alternatief zijn

• Monitoring tijdens stimulatie met gonadotrophines– Is essentieel om multiple zwangerschappen te voorkomen

– Hormonale bepalingen dag 5 van de cyclus

– Hormonale follow-up om de 2/3 dagen of frequenter

– Echografische follow-up

Werkgroep Reproductieve Geneeskunde VVOG

Ovulation enhancement in ovulatory women (IUI) (continued)

Clomiphene citrate Gonadotrophins

Reduced need for selective follicular aspiration

Substantial need for selective follicular aspiration

Reduced need for cancellation

Substantial need for cancellation

Reduced need for conversion to IVF

Substantial need for conversion to IVF

9

1211

9

78

54 4 4

0

5

10

15

28 30 32 34 36

GonadotrophinsClomid

Dickey FS 2001

% multiple pregnancies

age

Strategies to prevent (high order) multiple pregnancies (IUI)

• Selective follicular aspiration of

supernumerary follicles

– Might be useful in experienced hands

– Needs further investigation in large RCT

– Applicability in non - IVF centers needs

further investigationCohlen 2004

Strategies to prevent (high order) multiple pregnancies (IUI)

• Conversion to IVF

– Suddenly surprise

– Non - informed couples

– Treatment more expensive

– Treatment more invasive

• Conversion to IVF / ET should be discouraged

Cohlen 2004

IUI versus IVF - cost effectiveness

• Goverde

• Karande

• IUI is more cost effective but no costs

for multiple pregnancies !!

Clomiphene citrate versus gonadotrophins

Small RCT !

Balasch HR 1994 FSH is superior

Matorras HR 2002 FSH is superior

Echocard FS 2000 FSH is not superior

Hughes HR 1997 CC seems less effective

Cohlen Data Base Syst Rev 2002 CC seems less effective

Clomiphene citrate versus gonadotrophins

“ However large RCTs with sufficient power to detect clinical relevant

differences in cost effectiveness between CC and gonadotrophins in IUI cycles

are still lacking”

Cohlen 2004

Current best evidence for advanced treatment of unexplained subfertility

• There is a call for a large international factorial study

– No treatment

– CC IUI

– FSH IUI

– IVFCollins HR 2003

Current best evidence for advanced treatment of unexplained subfertility

(continued)

• While such a study might cost millions of dollars, if it is not done many more millions could be wasted on treatments that are not as effective as they now seem

Collins HR 2003

Published data IUI and gonadotrophines

• Male factor infertility (1998 - 2000)– Pregnancy rate 14 %– Multiple 12.3 %

• Unexplained infertility (1998 - 2000)– Pregnancy rate 22 %– Multiple 20 %

D’Hooghe TG 2002

Published data IUI and gonadotrophines

• Male factor infertility (1994 - 2000)– Pregnancy rate 12.7 %– Multiple 15.6 %

• Normospermic group (1994 - 2000)– Pregnancy rate 21.3 %– Multiple 15.6 %

Spiessens FS 2003

“ Ovarian stimulation for IUI was performed either with clomiphene citrate

(CC 50 or 100 mg / d) from day 3 to day 7 of the menstrual cycle (n : 271) or with

hMG (75 or 150 IU / d) from day 2 of the cycle (n : 601) “

Spiessens D’Hooghe page 1186 FS 2003

“ When women had two or more mature follicles (> 14 mm) at the time of hCG

injection, selective follicle aspiration was offered and usually one or two follicles

were kept intact after this procedure“

Spiessens D’Hooghe page 1186 FS 2003

IUI donorPeriode n Zwanger %

UZ Antwerpen 1999 - 2000 351 59 17.0

UZ Gent 1991 - 2003 1275 199 15.6

UZ KUL 1996 - 2002 486 91 18.7

LIFE 1989 - 2000 1821 346 19.0

GIFT GENK 1989 - 2002 398 73 18.7

AZ - VUB 1996 - 2000 442 112 25.4

Clasen (Werkgroep)

Multiple pregnancies - cost

Twins

AZ - VUB 6 926 - 51 348 Euro

USA 51 715 US dollar

Singleton 9 000 US dollar

Infertility therapy - associated multiple pregnancies : an ongoing epidemic RBM OnLine 2003

Comparison between clomiphene citrate and gonadotrophins

• Subject of several small RCTs

• Regret fully, the conclusions are

contradictory

Cohlen

Conclusions

IUI is an effective option (10 % pregnancy rate) If 1 000 000 sperm cells after sperm

preparationBut lowe dose step-up protocols (50 U)

not withstanding close monitoringStill strict cancellation criteria to prevent

multiple pregnanciesProbably in experienced hands selective aspiration

may be an effective alternative

Coda

IUI associated with gonadotrophins treatment• Invasive

– Follicular aspiration

– Cancellation

– IVF

• Enhance ovulation• Results in 30 % of children, member of a

multiple pregnancy