TY - JOUR
T1 - Expectant management versus IUI in unexplained subfertility and a poor pregnancy prognosis (EXIUI study): a randomized controlled trial
AU - Wessel, J.A.
AU - Mochtar, M.H.
AU - Besselink, D.E.
AU - Betjes, H.
AU - de Bruin, J.P.
AU - Cantineau, A.E.P.
AU - Groenewoud, E.R.
AU - Hooker, A.B.
AU - Lambalk, C.B.
AU - Kwee, J.
AU - Kaaijk, E.M.
AU - Louwe, L.A.
AU - Maas, J.W.M.
AU - Mol, B.W.J.
AU - van Rumste, M.M.E.
AU - Traas, M.A.F.
AU - Goddijn, M.
AU - van Wely, M.
AU - Mol, F.
N1 - PT FHML (ML): in overleg met GROW de RS-lijn GROW R2 handmatig toegevoegd.
PY - 2022/11/24
Y1 - 2022/11/24
N2 - STUDY QUESTION: For couples with unexplained subfertility and a poor prognosis for natural conception, is 6 months expectant management (EM) inferior to IUI with ovarian stimulation (IUI-OS), in terms of live births?SUMMARY ANSWER: In couples with unexplained subfertility and a poor prognosis for natural conception, 6 months of EM is inferior compared to IUI-OS in terms of live births.WHAT IS KNOWN ALREADY: Couples with unexplained subfertility and a poor prognosis are often treated with IUI-OS. In couples with unexplained subfertility and a relatively good prognosis for natural conception (>30% in 12 months), IUI-OS does not increase the live birth rate as compared to 6 months of EM. However, in couples with a poor prognosis for natural conception (<30% in 12 months), the effectiveness of IUI-OS is uncertain.STUDY DESIGN, SIZE, DURATION: We performed a non-inferiority multicentre randomized controlled trial within the infrastructure of the Dutch Consortium for Healthcare Evaluation and Research in Obstetrics and Gynaecology. We intended to include 1091 couples within 3 years. The couples were allocated in a 1:1 ratio to 6 months EM or 6 months IUI-OS with either clomiphene citrate or gonadotrophins.PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied heterosexual couples with unexplained subfertility and a poor prognosis for natural conception (<30% in 12 months). The primary outcome was ongoing pregnancy leading to a live birth. Non-inferiority would be shown if the lower limit of the one-sided 90% risk difference (RD) CI was less than minus 7% compared to an expected live birth rate of 30% following IUI-OS. We calculated RD, relative risks (RRs) with 90% CI and a corresponding hazard rate for live birth over time based on intention-to-treat and per-protocol (PP) analysis.MAIN RESULTS AND THE ROLE OF CHANCE: Between October 2016 and September 2020, we allocated 92 couples to EM and 86 to IUI-OS. The trial was halted pre-maturely owing to slow inclusion. Mean female age was 34 years, median duration of subfertility was 21 months. Couples allocated to EM had a lower live birth rate than couples allocated to IUI-OS (12/92 (13%) in the EM group versus 28/86 (33%) in the IUI-OS group; RR 0.40 90% CI 0.24 to 0.67). This corresponds to an absolute RD of minus 20%; 90% CI: -30% to -9%. The hazard ratio for live birth over time was 0.36 (95% CI 0.18 to 0.70). In the PP analysis, live births rates were 8 of 70 women (11%) in the EM group versus 26 of 73 women (36%) in the IUI-OS group (RR 0.32, 90% CI 0.18 to 0.59; RD -24%, 90% CI -36% to -13%) in line with inferiority of EM.LIMITATIONS, REASONS FOR CAUTION: Our trial did not reach the planned sample size, therefore the results are limited by the number of participants.WIDER IMPLICATIONS OF THE FINDINGS: This study confirms the results of a previous trial that in couples with unexplained subfertility and a poor prognosis for natural conception, EM is inferior to IUI-OS.
AB - STUDY QUESTION: For couples with unexplained subfertility and a poor prognosis for natural conception, is 6 months expectant management (EM) inferior to IUI with ovarian stimulation (IUI-OS), in terms of live births?SUMMARY ANSWER: In couples with unexplained subfertility and a poor prognosis for natural conception, 6 months of EM is inferior compared to IUI-OS in terms of live births.WHAT IS KNOWN ALREADY: Couples with unexplained subfertility and a poor prognosis are often treated with IUI-OS. In couples with unexplained subfertility and a relatively good prognosis for natural conception (>30% in 12 months), IUI-OS does not increase the live birth rate as compared to 6 months of EM. However, in couples with a poor prognosis for natural conception (<30% in 12 months), the effectiveness of IUI-OS is uncertain.STUDY DESIGN, SIZE, DURATION: We performed a non-inferiority multicentre randomized controlled trial within the infrastructure of the Dutch Consortium for Healthcare Evaluation and Research in Obstetrics and Gynaecology. We intended to include 1091 couples within 3 years. The couples were allocated in a 1:1 ratio to 6 months EM or 6 months IUI-OS with either clomiphene citrate or gonadotrophins.PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied heterosexual couples with unexplained subfertility and a poor prognosis for natural conception (<30% in 12 months). The primary outcome was ongoing pregnancy leading to a live birth. Non-inferiority would be shown if the lower limit of the one-sided 90% risk difference (RD) CI was less than minus 7% compared to an expected live birth rate of 30% following IUI-OS. We calculated RD, relative risks (RRs) with 90% CI and a corresponding hazard rate for live birth over time based on intention-to-treat and per-protocol (PP) analysis.MAIN RESULTS AND THE ROLE OF CHANCE: Between October 2016 and September 2020, we allocated 92 couples to EM and 86 to IUI-OS. The trial was halted pre-maturely owing to slow inclusion. Mean female age was 34 years, median duration of subfertility was 21 months. Couples allocated to EM had a lower live birth rate than couples allocated to IUI-OS (12/92 (13%) in the EM group versus 28/86 (33%) in the IUI-OS group; RR 0.40 90% CI 0.24 to 0.67). This corresponds to an absolute RD of minus 20%; 90% CI: -30% to -9%. The hazard ratio for live birth over time was 0.36 (95% CI 0.18 to 0.70). In the PP analysis, live births rates were 8 of 70 women (11%) in the EM group versus 26 of 73 women (36%) in the IUI-OS group (RR 0.32, 90% CI 0.18 to 0.59; RD -24%, 90% CI -36% to -13%) in line with inferiority of EM.LIMITATIONS, REASONS FOR CAUTION: Our trial did not reach the planned sample size, therefore the results are limited by the number of participants.WIDER IMPLICATIONS OF THE FINDINGS: This study confirms the results of a previous trial that in couples with unexplained subfertility and a poor prognosis for natural conception, EM is inferior to IUI-OS.
KW - unexplained subfertility
KW - expectant management
KW - intrauterine insemination
KW - IUI
KW - randomized controlled trial
KW - RCT
KW - live birth
KW - INTRAUTERINE INSEMINATION
KW - PREDICTION
KW - COUPLES
U2 - 10.1093/humrep/deac236
DO - 10.1093/humrep/deac236
M3 - Article
C2 - 36331493
SN - 0268-1161
VL - 37
SP - 2808
EP - 2816
JO - Human Reproduction
JF - Human Reproduction
IS - 12
ER -