A mild treatment strategy for in-vitro fertilisation: a randomised non-inferiority trial.
BACKGROUND
Mild in-vitro fertilisation (IVF) treatment might lessen both patients' discomfort and multiple births, with their associated risks. We aimed to test the hypothesis that mild IVF treatment can achieve the same chance of a pregnancy resulting in term livebirth within 1 year compared with standard treatment, and can also reduce patients' discomfort, multiple pregnancies, and costs.


METHODS
We did a randomised, non-inferiority effectiveness trial. 404 patients were randomly assigned to undergo either mild treatment (mild ovarian stimulation with gonadotropin-releasing hormone [GnRH] antagonist co-treatment combined with single embryo transfer) or a standard treatment (stimulation with a GnRH agonist long-protocol and transfer of two embryos). Primary endpoints were proportion of cumulative pregnancies leading to term livebirth within 1 year after randomisation (with a non-inferiority threshold of -12.5%), total costs per couple up to 6 weeks after expected date of delivery, and overall discomfort for patients. Analysis was by intention to treat. This trial is registered as an International Standard Randomised Clinical Trial, number ISRCTN35766970.


RESULTS
The proportions of cumulative pregnancies that resulted in term livebirth after 1 year were 43.4% with mild treatment and 44.7% with standard treatment (absolute number of patients=86 for both groups). The lower limit of the one-sided 95% CI was -9.8%. The proportion of couples with multiple pregnancy outcomes was 0.5% with mild IVF treatment versus 13.1% (p<0.0001) with standard treatment, and mean total costs were 8333 euros and 10745 euros, respectively (difference 2412 euros, 95% CI 703-4131). There were no significant differences between the groups in the anxiety, depression, physical discomfort, or sleep quality of the mother.


CONCLUSIONS
Over 1 year of treatment, cumulative rates of term livebirths and patients' discomfort are much the same for mild ovarian stimulation with single embryos transferred and for standard stimulation with two embryos transferred. However, a mild IVF treatment protocol can substantially reduce multiple pregnancy rates and overall costs.
Heijnen
Esther Mew
EM
Department of Reproductive Medicine and Gynaecology, University Medical Centre, Utrecht, Netherlands; Division of Reproductive Medicine, Erasmus Medical Centre, Rotterdam, Netherlands.
Eijkemans
Marinus Jc
MJ
Department of Reproductive Medicine and Gynaecology, University Medical Centre, Utrecht, Netherlands; Department of Public Health, Erasmus Medical Centre, Rotterdam, Netherlands.
De Klerk
Cora
C
Department of Medical Psychology and Psychotherapy, Erasmus Medical Centre, Rotterdam, Netherlands.
Polinder
Suzanne
S
Department of Medical Psychology and Psychotherapy, Erasmus Medical Centre, Rotterdam, Netherlands; Department of Public Health, Erasmus Medical Centre, Rotterdam, Netherlands.
Beckers
Nicole Gm
NG
Division of Reproductive Medicine, Erasmus Medical Centre, Rotterdam, Netherlands.
Klinkert
Ellen R
ER
Department of Reproductive Medicine and Gynaecology, University Medical Centre, Utrecht, Netherlands.
Broekmans
Frank J
FJ
Department of Reproductive Medicine and Gynaecology, University Medical Centre, Utrecht, Netherlands.
Passchier
Jan
J
Department of Medical Psychology and Psychotherapy, Erasmus Medical Centre, Rotterdam, Netherlands.
Te Velde
Egbert R
ER
Department of Reproductive Medicine and Gynaecology, University Medical Centre, Utrecht, Netherlands.
Macklon
Nick S
NS
Department of Reproductive Medicine and Gynaecology, University Medical Centre, Utrecht, Netherlands; Division of Reproductive Medicine, Erasmus Medical Centre, Rotterdam, Netherlands.
Fauser
Bart Cjm
BC
Department of Reproductive Medicine and Gynaecology, University Medical Centre, Utrecht, Netherlands; Division of Reproductive Medicine, Erasmus Medical Centre, Rotterdam, Netherlands. Electronic address: b.c.fauser@umcutrecht.nl.
D000328:Adult; D003362:Cost-Benefit Analysis; D004624:Embryo Transfer; D005260:Female; D005307:Fertilization in Vitro / Q000191:economics / Q000379:methods*; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists / Q000037:antagonists & inhibitors; D006801:Humans; D007246:Infertility / Q000628:therapy*; D010053:Ovary / Q000187:drug effects; D017060:Patient Satisfaction; D011247:Pregnancy; D011256:Pregnancy Outcome; D011272:Pregnancy, Multiple / Q000706:statistics & numerical data; D016896:Treatment Outcome
D007987:Gonadotropin-Releasing Hormone