Does the effectiveness of IUI in couples with unexplained subfertility depend on their prognosis of natural conception? A replication of the H2Oil study.
Can we replicate the finding that the benefit of IUI-ovarian stimulation (IUI-OS) compared to expectant management for couples with unexplained subfertility depends on the prognosis of natural conception?
The estimated benefit of IUI-OS did not depend on the prognosis of natural conception but did depend on when treatment was started after diagnosis, with starting IUI-OS later yielding a larger absolute and relative benefit of treatment.
IUI-OS is often the first-line treatment for couples with unexplained subfertility. Two randomized controlled trials (RCTs) compared IUI-OS to expectant management using different thresholds for the prognosis of natural conception as inclusion criteria and found different results. In a previous study (a Dutch national cohort), it was found that the benefit of IUI-OS compared to expectant management seemed dependent on the prognosis of natural conception, but this finding warrants replication.
We conducted a secondary analysis of the H2Oil study (n = 1119), a multicentre RCT that evaluated the effect of oil-based contrast versus water-based contrast during hysterosalpingography (HSG). Couples were randomized before HSG and followed up for 3-5 years. We selected couples with unexplained subfertility who received HSG and had follow-up or pregnancy data available. Follow-up was censored at the start of IVF, after the last IUI cycle or at last contact and was truncated at a maximum of 18 months after the fertility workup.
The endpoint was time to conception leading to an ongoing pregnancy. We used the sequential Cox approach comparing in each month the ongoing pregnancy rates over the next 6 months of couples who started IUI-OS to couples who did not. We calculated the prognosis of natural conception for individual couples, updated this over consecutive failed cycles and evaluated whether prognosis modified the effect of starting IUI-OS. We corrected for known predictors of conception using inverse probability weighting.
Data from 975 couples were available. There were 587 couples who received at least one IUI-OS cycle within 18 months after HSG of whom 221 conceived leading to an ongoing pregnancy (rate: 0.74 per couple per year over a median follow-up for IUI of 5 months). The median period between HSG and starting IUI-OS was 4 months. Out of 388 untreated couples, 299 conceived naturally (rate: 0.56 per couple per year over a median follow-up of 4 months). After creating our mimicked trial datasets, starting IUI-OS was associated with a higher chance of ongoing pregnancy by a pooled, overall hazard ratio of 1.50 (95% CI: 1.19-1.89) compared to expectant management. We did not find strong evidence that the effect of treatment was modified by a couple's prognosis of achieving natural conception (Akaike's Information Criterion (AIC) decreased by 1 point). The effect of treatment was dependent on when couples started IUI-OS (AIC decreased by more than 2 points). The patterns of estimated absolute chances over time for couples with increasingly better prognoses were different from the previous study but the finding that starting later yields a larger benefit of treatment was similar. We found IUI-OS increased the absolute chance of pregnancy by at least 5% compared to expectant management. The absolute chance of pregnancy after IUI-OS seems less variable between couples and starting times of treatment than the absolute chance after expectant management.
This is a secondary analysis, as the H2Oil trial was not designed with this research question in mind. Owing to sample size restrictions, it remained difficult to distinguish between the ranges of prognoses in which true benefit was found.
We replicated the finding that starting IUI-OS later after diagnosis yields a larger absolute and relative benefit of treatment. We did not replicate the dependency of the effect of IUI-OS on the prognosis of natural conception and could not identify clear thresholds for the prognosis of natural conception when IUI-OS was and/or was not effective. Because many of these couples still have good chances of natural conception at the time of diagnosis, we suggest clinicians should advise couples to delay the start of IUI-OS for several months to avoid unnecessary treatment.
The H2Oil study (NTR 3270) was an investigator-initiated study that was funded by the two academic institutions (AMC and VUmc) of the Amsterdam UMC. The follow-up study (NTR 6577) was also an investigator-initiated study with funding by Guerbet, France. The funders had no role in study design, collection, analysis and interpretation of the data. B.W.M. is supported by an Investigator grant (GNT1176437) from the Australian National Health and Medical Research Council (NHMRC). K.D. reports receiving travel and speaker fees from Guerbet. B.W.M. reports consultancy for ObsEva, Merck, Merck KGaA, iGenomix and Guerbet. V.M. reports receiving travel- and speaker fees as well as research grants from Guerbet.
van Eekelen R
，Rosielle K
，van Welie N
，Dreyer K
，van Wely M
，Mol BW
，Eijkemans MJ
，Mijatovic V
，van Geloven N
... -
《-》
Expectant management versus IUI in unexplained subfertility and a poor pregnancy prognosis (EXIUI study): a randomized controlled trial.
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?
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.
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.
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.
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.
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.
Our trial did not reach the planned sample size, therefore the results are limited by the number of participants.
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.
The trial was supported by a grant of the SEENEZ healthcare initiative. The subsidizing parties were The Dutch Organisation for Health Research and Development (ZonMW 837004023, www.zonmw.nl) and the umbrella organization of 10 health insurers in The Netherlands. E.R.G. receives personal fees from Titus Health care outside the submitted work. M.G. declares unrestricted research and educational grants from Guerbet, Merck and Ferring not related to the presented work, paid to their institution VU medical centre. A.B.H. reports receiving travel and speakers fees from Nordic Pharma and Merck and he is member of the Nordic Pharma ANGEL group and of the Safety Monitoring Board of Womed. C.B.L. reports speakers fee from Inmed and Yingming, and his department receives research grants from Ferring, Merck and Guerbet paid to VU medical centre. B.W.J.M. is supported by a NHMRC Investigator grant (GNT1176437) and reports consultancy for ObsEva and Merck. M.v.W. received a grant from the Netherlands Organisation for Health Research and Development ZonMW (80-8520098-91072). F.M. received two grants from the Netherlands Organisation for Health Research and Development ZonMW (NTR 5599 and NTR 6590). The other authors report no competing interest.
Dutch Trial register NL5455 (NTR5599).
18 December 2015.
26 January 2017.
Wessel JA
，Mochtar MH
，Besselink DE
，Betjes H
，de Bruin JP
，Cantineau AEP
，Groenewoud ER
，Hooker AB
，Lambalk CB
，Kwee J
，Kaaijk EM
，Louwé LA
，Maas JWM
，Mol BWJ
，van Rumste MME
，Traas MAF
，Goddijn M
，van Wely M
，Mol F
... -
《-》
Predicting the chances of having a baby with or without treatment at different time points in couples with unexplained subfertility.
Can we develop a prediction model that can estimate the chances of conception leading to live birth with and without treatment at different points in time in couples with unexplained subfertility?
Yes, a dynamic model was developed that predicted the probability of conceiving under expectant management and following active treatments (in vitro fertilisation (IVF), intrauterine insemination with ovarian stimulation (IUI + SO), clomiphene) at different points in time since diagnosis.
Couples with no identified cause for their subfertility continue to have a realistic chance of conceiving naturally, which makes it difficult for clinicians to decide when to intervene. Previous fertility prediction models have attempted to address this by separately estimating either the chances of natural conception or the chances of conception following certain treatments. These models only make predictions at a single point in time and are therefore inadequate for informing continued decision-making at subsequent consultations.
A population-based study of 1316 couples with unexplained subfertility attending a regional clinic between 1998 and 2011.
A dynamic prediction model was developed that estimates the chances of conception within 6 months from the point when a diagnosis of unexplained subfertility was made. These predictions were recomputed each month to provide a dynamic assessment of the individualised chances of conception while taking account of treatment status in each month. Conception must have led to live birth and treatments included clomiphene, IUI + SO, and IVF. Predictions for natural conception were externally validated using a prospective cohort from The Netherlands.
A total of 554 (42%) couples started fertility treatment within 2 years of their first fertility consultation. The natural conception leading to live birth rate was 0.24 natural conceptions per couple per year. Active treatment had a higher chance of conception compared to those who remained under expectant management. This association ranged from weak with clomiphene to strong with IVF [clomiphene, hazard ratio (HR) = 1.42 (95% confidence interval, 1.05 to 1.91); IUI + SO, HR = 2.90 (2.06 to 4.08); IVF, HR = 5.09 (4.04 to 6.40)]. Female age and duration of subfertility were significant predictors, without clear interaction with the relative effect of treatment.
We were unable to adjust for other potentially important predictors, e.g. measures of ovarian reserve, which were not available in the linked Grampian dataset that may have made predictions more specific. This study was conducted using single centre data meaning that it may not be generalizable to other centres. However, the model performed as well as previous models in reproductive medicine when externally validated using the Dutch cohort.
For the first time, it is possible to estimate the chances of conception following expectant management and different fertility treatments over time in couples with unexplained subfertility. This information will help inform couples and their clinicians of their likely chances of success, which may help manage expectations, not only at diagnostic workup completion but also throughout their fertility journey.
This work was supported by a Chief Scientist Office postdoctoral training fellowship in health services research and health of the public research (ref PDF/12/06). B.W.M. is supported by an NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck, and Guerbet. None of the other authors declare any conflicts of interest.
McLernon DJ
，Lee AJ
，Maheshwari A
，van Eekelen R
，van Geloven N
，Putter H
，Eijkemans MJ
，van der Steeg JW
，van der Veen F
，Steyerberg EW
，Mol BW
，Bhattacharya S
... -
《-》
Birthweight and other perinatal outcomes of singletons conceived after assisted reproduction compared to natural conceived singletons in couples with unexplained subfertility: follow-up of two randomized clinical trials.
Does assisted reproduction, such as ovarian stimulation and/or laboratory procedures, have impact on perinatal outcomes of singleton live births compared to natural conception in couples with unexplained subfertility?
Compared to natural conception, singletons born after intrauterine insemination with ovarian stimulation (IUI-OS) had a lower birthweight, while singletons born after IVF had comparable birthweights, in couples with unexplained subfertility.
Singletons conceived by assisted reproduction have different perinatal outcomes such as low birthweight and a higher risk of premature birth than naturally conceived singletons. This might be due to the assisted reproduction, such as laboratory procedures or the ovarian stimulation, or to an intrinsic factor in couples with subfertility.
We performed a prospective cohort study using the follow-up data of two randomized clinical trials performed in couples with unexplained subfertility. We evaluated perinatal outcomes of 472 live birth singletons conceived after assisted reproduction or after natural conception within the time horizon of the studies.
To assess the possible impact of ovarian stimulation we compared the singletons conceived after IUI with FSH or clomiphene citrate (CC) and IVF in a modified natural cycle (IVF-MNC) or standard IVF with single embryo transfer (IVF-SET) to naturally conceived singletons in the same cohorts. To further look into the possible effect of the laboratory procedures, we put both IUI and IVF groups together into IUI-OS and IVF and compared both to singletons born after natural conception. We only included singletons conceived after fresh embryo transfers. The main outcome was birthweight presented as absolute weight in grams and gestational age- and gender-adjusted percentiles. We calculated differences in birthweight using regression analyses adjusted for maternal age, BMI, smoking, parity, duration of subfertility and child gender.
In total, there were 472 live birth singletons. Of the 472 singleton pregnancies, 209 were conceived after IUI-OS (136 with FSH and 73 with CC as ovarian stimulation), 138 after IVF (50 after IVF-MNC and 88 after IVF-SET) and 125 were conceived naturally.Singletons conceived following IUI-FSH and IUI-CC both had lower birthweights compared to naturally conceived singletons (adjusted difference IUI-FSH -156.3 g, 95% CI -287.9 to -24.7; IUI-CC -160.3 g, 95% CI -316.7 to -3.8). When we compared IVF-MNC and IVF-SET to naturally conceived singletons, no significant difference was found (adjusted difference IVF-MNC 75.8 g, 95% CI -102.0 to 253.7; IVF-SET -10.6 g, 95% CI -159.2 to 138.1). The mean birthweight percentile was only significantly lower in the IUI-FSH group (-7.0 percentile, 95% CI -13.9 to -0.2). The IUI-CC and IVF-SET group had a lower mean percentile and the IVF-MNC group a higher mean percentile, but these groups were not significant different compared to the naturally conceived group (IUI-CC -5.1 percentile, 95% CI -13.3 to 3.0; IVF-MNC 4.4 percentile, 95% CI -4.9 to 13.6; IVF-SET -1.3 percentile, 95% CI -9.1 to 6.4).Looking at the laboratory process that took place, singletons conceived following IUI-OS had lower birthweights than naturally conceived singletons (adjusted difference -157.7 g, 95% CI -277.4 to -38.0). The IVF group had comparable birthweights with the naturally conceived group (adjusted difference 20.9 g, 95% CI -110.8 to 152.6). The mean birthweight percentile was significantly lower in the IUI-OS group compared to the natural group (-6.4 percentile, 95% CI -12.6 to -0.1). The IVF group was comparable (0.7 percentile, 95% CI -6.1 to 7.6).
The results are limited by the number of cases. The data were collected prospectively alongside the randomized controlled trials, but analyzed as treated.
Our data suggest IUI in a stimulated cycle may have a negative impact on the birthweight of the child and possibly on pre-eclampsia. Further research should look into the effect of different methods of ovarian stimulation on placenta pathology and pre-eclampsia in couples with unexplained subfertility using naturally conceived singletons in the unexplained population as a reference.
Both initial trials were supported by a grant from ZonMW, the Dutch Organization for Health Research and Development (INeS 120620027, SUPER 80-83600-98-10192). The INeS study also had a grant from Zorgverzekeraars Nederland, the Dutch association of healthcare insurers (09-003). B.W.J.M. is supported by an NHMRC investigator Grant (GNT1176437) and reports consultancy for ObsEva, Merck Merck KGaA, Guerbet and iGenomix, outside the submitted work. A.H. reports grants from Ferring Pharmaceutical company (the Netherlands), outside the submitted work. F.J.M.B. receives monetary compensation as a member of the external advisory board for Merck Serono (the Netherlands), Ferring Pharmaceutics BV (the Netherlands) and Gedeon Richter (Belgium), he receives personal fees from educational activities for Ferring BV (the Netherlands) and for advisory and consultancy work for Roche and he receives research support grants from Merck Serono and Ferring Pharmaceutics BV, outside the submitted work. The remaining authors have nothing to disclose.
INeS study Trial NL915 (NTR939); SUPER Trial NL3895 (NTR4057).
Wessel JA
，Mol F
，Danhof NA
，Bensdorp AJ
，Tjon-Kon Fat RI
，Broekmans FJM
，Hoek A
，Mol BWJ
，Mochtar MH
，van Wely M
，INeS and SUPER Study Group
... -
《-》
ResearchGate
(全网免费下载)
钛学术
(全网免费下载)
