IVF or IUI as first-line treatment in unexplained subfertility: the conundrum of treatment selection markers.
Are there treatment selection markers that could aid in identifying couples, with unexplained or mild male subfertility, who would have better chances of a healthy child with IVF with single embryo transfer (IVF-SET) than with IUI with ovarian stimulation (IUI-OS)?



We did not find any treatment selection markers that were associated with better chances of a healthy child with IVF-SET instead of IUI-OS in couples with unexplained or mild male subfertility.



A recent trial, comparing IVF-SET to IUI-OS, found no evidence of a difference between live birth rates and multiple pregnancy rates. It was suggested that IUI-OS should remain the first-line treatment instead of IVF-SET in couples with unexplained or mild male subfertility and female age between 18 and 38 years. The question remains whether there are some couples that may have higher pregnancy chances if treated with IVF-SET instead of IUI.



We performed our analyses on data from the INeS trial, where couples with unexplained or mild male subfertility and an unfavourable prognosis for natural conception were randomly allocated to IVF-SET, IVF in a modified natural cycle or IUI-OS. In view of the aim of this study, we only used data of the comparison between IVF-SET (201 couples) and IUI-OS (207 couples).



We pre-defined the following baseline characteristics as potential treatment selection markers: female age, ethnicity, smoking status, type of subfertility (primary/secondary), duration of subfertility, BMI, pre-wash total motile count and Hunault prediction score. For each potential treatment selection marker, we explored the association with the chances of a healthy child after IVF-SET and IUI-OS and tested if there was an interaction with treatment. Given the exploratory nature of our analysis, we used a P-value of 0.1.



None of the markers were associated with higher chances of a healthy child from IVF-SET compared to IUI-OS (P-value for interaction >0.10).



Since this is the first large study that looked at potential treatment selection markers for IVF-SET compared to IUI-OS, we had no data on which to base a power calculation. The sample size was limited, making it difficult to detect any smaller associations.



We could not identify couples with unexplained or mild male subfertility who would have had higher chances of a healthy child from immediate IVF-SET than from IUI-OS. As in the original trial IUI-OS had similar effectiveness and was less costly compared to IVF-SET, IUI-OS should remain the preferred first-line treatment in these couples.



The study was supported by a grant from the Netherlands Organization for Health Research and Development, and a grant from the Netherlands' association of health care insurers. There are no conflicts of interest.



The trial was registered at the Dutch trial registry (NTR939).
Department of Obstetrics and Gynaecology, Centre for Reproductive Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
R I
RI
Tjon-Kon-Fat
Department of Obstetrics and Gynaecology, Centre for Reproductive Medicine, Academic Medical Centre, Amsterdam, The Netherlands.|Department of Epidemiology, Biostatistics and Bioinformatics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
P
P
Tajik
Department of Obstetrics and Gynaecology, Centre for Reproductive Medicine, Academic Medical Centre, Amsterdam, The Netherlands.|Department of Public Health, Academic Medical Centre, Amsterdam, The Netherlands.
M H
MH
Zafarmand
Department of Obstetrics and Gynaecology, Centre for Reproductive Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
A J
AJ
Bensdorp
Department of Epidemiology, Biostatistics and Bioinformatics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
P M M
PMM
Bossuyt
Department of Obstetrics and Gynaecology, St. Antonius Hospital, Nieuwegein, The Netherlands.
G J E
GJE
Oosterhuis
Department of Obstetrics and Gynaecology, University Medical Centre Maastricht, Maastricht, The Netherlands.
R
R
van Golde
Department of Obstetrics and Gynaecology, Centre for Reproductive Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
S
S
Repping
Department of Obstetrics and Gynaecology, Albert Schweitzer Hospital, Dordrecht, The Netherlands.
M D A
MDA
Lambers
Elisabeth Tweesteden Ziekenhuis, Centrum Voortplantingsgeneeskunde Brabant, Tilburg, The Netherlands.
E
E
Slappendel
Department of Obstetrics and Gynaecology, Medical Centre Leeuwarden, Leeuwarden, The Netherlands.
D
D
Perquin
Department of Obstetrics and Gynaecology, Treant Zorggroep, locatie Scheper Hospital, Emmen, The Netherlands.
M J
MJ
Pelinck
Department of Obstetrics and Gynaecology, Spaarne Gasthuis, Haarlem, The Netherlands.
J
J
Gianotten
Department of Obstetrics and Gynaecology, Maxima Medical Centre, Veldhoven, The Netherlands.
J W M
JWM
Maas
Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, The Netherlands.
M J C
MJC
Eijkemans
Department of Obstetrics and Gynaecology, Centre for Reproductive Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
F
F
van der Veen
School of Medicine, The Robinson Institute, University of Adelaide, Adelaide, Australia.|The South Australian Health and Medical Research Institute, Adelaide, Australia.
B W
BW
Mol
Department of Obstetrics and Gynaecology, Centre for Reproductive Medicine, Academic Medical Centre, Amsterdam, The Netherlands.
M
M
van Wely
D000328:Adult; D001723:Birth Rate; D005260:Female; D005306:Fertilization; D005307:Fertilization in Vitro / Q000379:methods*; D006801:Humans; D007248:Infertility, Male / Q000628:therapy*; D007315:Insemination, Artificial / Q000379:methods*; D008297:Male; D018579:Patient Selection; D011247:Pregnancy; D018873:Pregnancy Rate; D011379:Prognosis
IUI; IVF; marker-treatment interaction; treatment selection markers; unexplained subfertility