title: Prevention of multiple pregnancies in couples with unexplained or mild male subfertility: randomised controlled trial of in vitro fertilisation with single embryo transfer or in vitro fertilisation in modified natural cycle compared with intrauterine insemination with controlled ovarian hyperstimulation.
abstract: OBJECTIVE
  To compare the effectiveness of in vitro fertilisation with single embryo transfer or in vitro fertilisation in a modified natural cycle with that of intrauterine insemination with controlled ovarian hyperstimulation in terms of a healthy child.
  
  
  METHODS
  Multicentre, open label, three arm, parallel group, randomised controlled non-inferiority trial.
  
  
  METHODS
  17 centres in the Netherlands.
  
  
  METHODS
  Couples seeking fertility treatment after at least 12 months of unprotected intercourse, with the female partner aged between 18 and 38 years, an unfavourable prognosis for natural conception, and a diagnosis of unexplained or mild male subfertility.
  
  
  METHODS
  Three cycles of in vitro fertilisation with single embryo transfer (plus subsequent cryocycles), six cycles of in vitro fertilisation in a modified natural cycle, or six cycles of intrauterine insemination with ovarian hyperstimulation within 12 months after randomisation.
  
  
  METHODS
  The primary outcome was birth of a healthy child resulting from a singleton pregnancy conceived within 12 months after randomisation. Secondary outcomes were live birth, clinical pregnancy, ongoing pregnancy, multiple pregnancy, time to pregnancy, complications of pregnancy, and neonatal morbidity and mortality
  
  
  RESULTS
  602 couples were randomly assigned between January 2009 and February 2012; 201 were allocated to in vitro fertilisation with single embryo transfer, 194 to in vitro fertilisation in a modified natural cycle, and 207 to intrauterine insemination with controlled ovarian hyperstimulation. Birth of a healthy child occurred in 104 (52%) couples in the in vitro fertilisation with single embryo transfer group, 83 (43%) in the in vitro fertilisation in a modified natural cycle group, and 97 (47%) in the intrauterine insemination with controlled ovarian hyperstimulation group. This corresponds to a risk, relative to intrauterine insemination with ovarian hyperstimulation, of 1.10 (95% confidence interval 0.91 to 1.34) for in vitro fertilisation with single embryo transfer and 0.91 (0.73 to 1.14) for in vitro fertilisation in a modified natural cycle. These 95% confidence intervals do not extend below the predefined threshold of 0.69 for inferiority. Multiple pregnancy rates per ongoing pregnancy were 6% (7/121) after in vitro fertilisation with single embryo transfer, 5% (5/102) after in vitro fertilisation in a modified natural cycle, and 7% (8/119) after intrauterine insemination with ovarian hyperstimulation (one sided P=0.52 for in vitro fertilisation with single embryo transfer compared with intrauterine insemination with ovarian hyperstimulation; one sided P=0.33 for in vitro fertilisation in a modified natural cycle compared with intrauterine insemination with controlled ovarian hyperstimulation).
  
  
  CONCLUSIONS
  In vitro fertilisation with single embryo transfer and in vitro fertilisation in a modified natural cycle were non-inferior to intrauterine insemination with controlled ovarian hyperstimulation in terms of the birth of a healthy child and showed comparable, low multiple pregnancy rates.Trial registration Current Controlled Trials ISRCTN52843371; Nederlands Trial Register NTR939.
authors.affiliation: Centre for Reproductive Medicine, Academic Medical Centre, University of Amsterdam, 1100 DD Amsterdam, Netherlands.
authors.forename: A J
authors.initials: AJ
authors.lastname: Bensdorp
authors.affiliation: Centre for Reproductive Medicine, Academic Medical Centre, University of Amsterdam, 1100 DD Amsterdam, Netherlands.
authors.forename: R I
authors.initials: RI
authors.lastname: Tjon-Kon-Fat
authors.affiliation: Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Centre, University of Amsterdam.
authors.forename: P M M
authors.initials: PM
authors.lastname: Bossuyt
authors.affiliation: Máxima Medical Centre, Department of Obstetrics and Gynaecology, Veldhoven, Netherlands.
authors.forename: C A M
authors.initials: CA
authors.lastname: Koks
authors.affiliation: St Antonius Hospital, Department of Obstetrics and Gynaecology, Nieuwegein, Netherlands.
authors.forename: G J E
authors.initials: GJ
authors.lastname: Oosterhuis
authors.affiliation: University Medical Centre Groningen, University of Groningen, Department of Obstetrics and Gynaecology, Groningen, Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Hoek
authors.affiliation: Vrije Universiteit Medical Centre, Centre for Reproductive Medicine, Amsterdam.
authors.forename: P G A
authors.initials: PG
authors.lastname: Hompes
authors.affiliation: University Medical Centre Utrecht, Department for Reproductive Medicine, Utrecht, Netherlands.
authors.forename: F J M
authors.initials: FJ
authors.lastname: Broekmans
authors.affiliation: Onze Lieve Vrouwe Gasthuis, Department of Obstetrics and Gynaecology, Amsterdam, Netherlands.
authors.forename: H R
authors.initials: HR
authors.lastname: Verhoeve
authors.affiliation: Jeroen Bosch Hospital, Department of Obstetrics and Gynaecology, 's Hertogenbosch, Netherlands.
authors.forename: J P
authors.initials: JP
authors.lastname: de Bruin
authors.affiliation: University Medical Centre Maastricht, Department of Obstetrics and Gynaecology, Maastricht, Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: van Golde
authors.affiliation: Centre for Reproductive Medicine, Academic Medical Centre, University of Amsterdam, 1100 DD Amsterdam, Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Repping
authors.affiliation: Isala Clinics, Department of Obstetrics and Gynaecology, Zwolle, Netherlands.
authors.forename: B J
authors.initials: BJ
authors.lastname: Cohlen
authors.affiliation: Albert Schweitzer Hospital, Department of Obstetrics and Gynaecology, Dordrecht, Netherlands.
authors.forename: M D A
authors.initials: MD
authors.lastname: Lambers
authors.affiliation: Amphia Hospital, Department of Obstetrics and Gynaecology, Breda, Netherlands.
authors.forename: P F
authors.initials: PF
authors.lastname: van Bommel
authors.affiliation: Catharina Hospital, Department of Obstetrics and Gynaecology, Eindhoven, Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Slappendel
authors.affiliation: Medical Centre Leeuwarden, Obstetrics and Gynaecology, Leeuwarden, Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: Perquin
authors.affiliation: Elisabeth Hospital, Department of Obstetrics and Gynaecology, Tilburg, Netherlands.
authors.forename: J M
authors.initials: JM
authors.lastname: Smeenk
authors.affiliation: Scheper Hospital, Department of Obstetrics and Gynaecology, Emmen, Netherlands.
authors.forename: M J
authors.initials: MJ
authors.lastname: Pelinck
authors.affiliation: Kennemer Gasthuis, Department of Obstetrics and Gynaecology, Haarlem, Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Gianotten
authors.affiliation: Medical Spectrum Twente, Department of Obstetrics and Gynaecology, Enschede, Netherlands.
authors.forename: D A
authors.initials: DA
authors.lastname: Hoozemans
authors.affiliation: Máxima Medical Centre, Department of Obstetrics and Gynaecology, Veldhoven, Netherlands.
authors.forename: J W M
authors.initials: JW
authors.lastname: Maas
authors.affiliation: University Medical Centre Utrecht, Julius Centre for Health Sciences and Primary Care, Utrecht, Netherlands.
authors.forename: M J C
authors.initials: MJ
authors.lastname: Eijkemans
authors.affiliation: Centre for Reproductive Medicine, Academic Medical Centre, University of Amsterdam, 1100 DD Amsterdam, Netherlands.
authors.forename: F
authors.initials: F
authors.lastname: van der Veen
authors.affiliation: The Robinson Research Institute, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, Australia.
authors.forename: B W J
authors.initials: BW
authors.lastname: Mol
authors.affiliation: Centre for Reproductive Medicine, Academic Medical Centre, University of Amsterdam, 1100 DD Amsterdam, Netherlands m.vanwely@amc.nl.
authors.forename: M
authors.initials: M
authors.lastname: van Wely
mesh_terms: D000293:Adolescent; D000328:Adult; D004624:Embryo Transfer / Q000379:methods*; D005260:Female; D005307:Fertilization in Vitro / Q000379:methods*; D005500:Follow-Up Studies; D006801:Humans; D007248:Infertility, Male; D007315:Insemination, Artificial / Q000379:methods*; D008297:Male; D009426:Netherlands; D011247:Pregnancy; D011256:Pregnancy Outcome; D011272:Pregnancy, Multiple / Q000706:statistics & numerical data*; D056826:Single Embryo Transfer; D055815:Young Adult