I. Scholten

Impact of assisted reproductive technology on the incidence of multiple-gestation infants: a population perspective.

OBJECTIVE To study the value of a population view in assessing assisted reproductive technology (ART) multiple-gestation infants. DESIGN Descriptive comparison of ART treatment and population statistics in seven developed countries (United States [U.S.], South Korea, United Kingdom, the Netherlands, Australia, Belgium, Denmark) with varying ART utilization and single-embryo transfer (SET) rates. SETTING Not applicable. PATIENT(S) Not applicable. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) The contribution of ART multiple-gestation infants to the total number of multiple-gestation infants in a population was calculated in relation to utilization of ART and SET rates. RESULT(S) The number of ART treatments leading to embryo transfer varied from 304 per million inhabitants in the U.S. to 1,518 in Denmark. The percentage of ART cycles that utilized SET varied from 8.8% in South Korea to 53.3% in Australia. Reflecting both utilization rates and SET rates, the percentage of multiple-gestation infants in the population attributed to ART ranged from 14.7% in South Korea to 29.0% in Denmark. CONCLUSION(S) In seven countries, the contribution of ART multiple-gestation infants to all multiple-gestation infants varies from 14.7% to 29.0%, a percentage that was influenced by both the SET rate per cycle and ART utilization rates. In the monitoring of safety and efficacy of fertility treatment, registration of the percentage of SET cycles alone might not be sufficient.

Prediction of recurrence of hypertensive disorders of pregnancy between 34 and 37 weeks of gestation: a retrospective cohort study

Please cite this paper as: van Oostwaard M, Langenveld J, Bijloo R, Wong K, Scholten I, Loix S, Hukkelhoven C, Vergouwe Y, Papatsonis D, Mol B, Ganzevoort W. Prediction of recurrence of hypertensive disorders of pregnancy between 34 and 37 weeks of gestation: a retrospective cohort study. BJOG 2012;119:840–847.

Natural conception: repeated predictions over time

STUDY QUESTION How can we predict chances of natural conception at various time points in couples diagnosed with unexplained subfertility? SUMMARY ANSWER We developed a dynamic prediction model that can make repeated predictions over time for couples with unexplained subfertility that underwent a fertility workup at a fertility clinic. WHAT IS KNOWN ALREADY The most frequently used prediction model for natural conception (the ‘Hunault model’) estimates the probability of natural conception only once per couple, that is, after completion of the fertility workup. This model cannot be used for a second or third time for couples who wish to know their renewed chances after a certain period of expectant management. STUDY DESIGN, SIZE, DURATION A prospective cohort studying the long-term follow-up of subfertile couples included in 38 centres in the Netherlands between January 2002 and February 2004. Couples with bilateral tubal occlusion, anovulation or a total motile sperm count <1 × 106 were excluded. PARTICIPANTS/MATERIALS, SETTING, METHODS The primary endpoint was time to natural conception, leading to an ongoing pregnancy. Follow-up time was censored at the start of treatment or at the last date of contact. In developing the new dynamic prediction model, we used the same predictors as the Hunault model, i.e. female age, duration of subfertility, female subfertility being primary or secondary, sperm motility and referral status. The performance of the model was evaluated in terms of calibration and discrimination. Additionally, we assessed the utility of the model in terms of the variability of the calculated predictions. MAIN RESULTS AND THE ROLE OF CHANCE Of the 4999 couples in the cohort, 1053 (21%) women reached a natural conception leading to an ongoing pregnancy within a mean follow-up of 8 months (5th and 95th percentile: 1–21). Our newly developed dynamic prediction model estimated the median probability of conceiving in the first year after the completion of the fertility workup at 27%. For couples not yet pregnant after half a year, after one year and after one and a half years of expectant management, the median probability of conceiving over the next year was estimated at 20, 15 and 13%, respectively. The model performed fair in an internal validation. The prediction ranges were sufficiently broad to aid in counselling couples for at least two years after their fertility workup. LIMITATIONS, REASONS FOR CAUTION The dynamic prediction model needs to be validated in an external population. WIDER IMPLICATIONS OF THE FINDINGS This dynamic prediction model allows reassessment of natural conception chances after various periods of unsuccessful expectant management. This gives valuable information to counsel couples with unexplained subfertility that are seen for a fertility workup. STUDY FUNDING/COMPETING INTEREST(S) This study was facilitated by grant 945/12/002 from ZonMW, The Netherlands Organization for Health Research and Development, The Hague, The Netherlands. No competing interests.

Long-term follow up of couples initially randomized between immobilization and immediate mobilization subsequent to IUI

A previous randomized clinical trial compared immobilization for 15 min with immediate mobilization subsequent to intrauterine insemination (IUI) and showed higher ongoing pregnancy rates in couples immobilizing subsequent to IUI. The current study compared the long-term effectiveness of immobilization subsequent to IUI. All couples (n = 391) included in the trial were followed for 3 years after randomization and pregnancies and treatments were recorded. After the initial trial period, couples in both groups were offered treatment according to local protocol. The primary outcome was an ongoing pregnancy during the 3 years after the initial trial. In this time period, there were 143 ongoing pregnancies in the immobilization group (n = 199 couples) and 112 ongoing pregnancies in the immediate mobilization group (n = 192). The ongoing pregnancy rates were 72% and 58%, respectively (relative risk 1.2, 95% CI 1.1-1.4). The persistent significant difference in ongoing pregnancy rates underpins the importance of immobilization after IUI. There is no valid reason to withhold women from immobilizing for 15 min after IUI.

Long term outcome in subfertile couples with isolated cervical factor

OBJECTIVE A previous randomized clinical trial (RCT) compared immediate treatment with intrauterine insemination (IUI) to expectant management for six months in subfertile couples with an isolated cervical factor. That study showed higher ongoing pregnancy rates in couples receiving intrauterine insemination. The current study compared the long-term effectiveness and costs of this intervention. STUDY DESIGN We followed all couples (N=99) who were previously included in the RCT for three years after randomization and registered pregnancies and treatments. After the initial trial period, couples in both groups were offered further treatment according to local protocol. The primary outcome was an ongoing pregnancy after three years. RESULTS After three years, there were 36 ongoing pregnancies in the immediate IUI group (N=51 couples) and 38 ongoing pregnancies in the expectant management group (N=48 couples). The ongoing pregnancy rates were 71% and 79% respectively (RR 0.89 (95% confidence interval (CI) 0.7-1.1)). CONCLUSIONS In couples with an isolated cervical factor, a treatment strategy including immediate treatment with IUI does not result in higher ongoing pregnancy rates on the long term. Initial expectant management is therefore justified in these couples and identifying a cervical factor by a post-coital test is unnecessary.

Reporting multiple cycles in trials on medically assisted reproduction

Trials assessing effectiveness in medically assisted reproduction (MAR) should aim to study the desired effect over multiple cycles, as this reflects clinical practice and captures the relevant perspective for the couple. The aim of this study was to assess the extent to which multiple cycles are reported in MAR trials. A sample of randomized controlled trials (RCT) was collected on MAR, published in four time periods, in 11 pre-specified peer-reviewed journals; 253 trials were included: 196 on IVF, 37 on intrauterine insemination and 20 on ovulation induction. Forty-eight (19%) reported on multiple cycles, which was significantly more common in trials on intrauterine insemination and ovulation induction compared with trials on IVF (P < 0.01). Both trials on IVF were multi-centre trials, and those using live birth as primary outcome, reported significantly more often on multiple cycles (OR 3.7 CI 1.1 to 12.5) and (OR 8.7 CI 1.8 to 40.3), respectively. Trials designed to compare protocol variations reported multiple cycles less often (OR 0.07 CI 0.01 to 0.74). Most RCT on MAR, especially those on IVF, do not report cumulative pregnancy rates. As not all women become pregnant in their first cycle, the clinical significance of these trials is limited.

Selective outcome reporting and sponsorship in randomized controlled trials in IVF and ICSI

STUDY QUESTION Are randomized controlled trials (RCTs) on IVF and ICSI subject to selective outcome reporting and is this related to sponsorship? SUMMARY ANSWER There are inconsistencies, independent from sponsorship, in the reporting of primary outcome measures in the majority of IVF and ICSI trials, indicating selective outcome reporting. WHAT IS KNOWN ALREADY RCTs are subject to bias at various levels. Of these biases, selective outcome reporting is particularly relevant to IVF and ICSI trials since there is a wide variety of outcome measures to choose from. An established cause of reporting bias is sponsorship. It is, at present, unknown whether RCTs in IVF/ICSI are subject to selective outcome reporting and whether this is related with sponsorship. STUDY DESIGN, SIZE, DURATION We systematically searched RCTs on IVF and ICSI published between January 2009 and March 2016 in MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and the publisher subset of PubMed. We analysed 415 RCTs. PARTICIPANTS/MATERIALS, SETTING, METHODS Per included RCT, we extracted data on impact factor of the journal, sample size, power calculation, and trial registry and thereafter data on primary outcome measure, the direction of trial results and sponsorship. MAIN RESULTS AND THE ROLE OF CHANCE Of the 415 identified RCTs, 235 were excluded for our primary analysis, because the sponsorship was not reported. Of the 180 RCTs included in our analysis, 7 trials did not report on any primary outcome measure and 107 of the remaining 173 trials (62%) reported on surrogate primary outcome measures. Of the 114 registered trials, 21 trials (18%) provided primary outcomes in their manuscript that were different from those in the trial registry. This indicates selective outcome reporting. We found no association between selective outcome reporting and sponsorship. We ran additional analyses to include the trials that had not reported sponsorship and found no outcomes that differed from our primary analysis. LIMITATIONS, REASONS FOR CAUTION Since the majority of the trials did not report on sponsorship, there is a risk on sampling bias. WIDER IMPLICATIONS OF THE FINDINGS IVF and ICSI trials are subject, to a large extent, to selective outcome reporting. Readers should be aware of this to avoid implementation of false or misleading results in clinical practice. STUDY FUNDING/COMPETING INTERESTS No funding received and there are no conflicts of interest. TRIAL REGISTRATION NUMBER N/A.

The effectiveness of intrauterine insemination: A matched cohort study

OBJECTIVE To study the effectiveness of an intrauterine insemination (IUI) program compared to no treatment in subfertile couples with unexplained subfertility and a poor prognosis on natural conception. STUDY DESIGN A retrospective matched cohort study in which ongoing pregnancy rates in 72 couples who voluntarily dropped out of treatment with IUI were compared to ongoing pregnancy rates in 144 couples who continued treatment with IUI. Couples with unexplained subfertility, mild male subfertility or cervical factor subfertility who started treatment with IUI between January 2000 and December 2008 were included. Couples were matched on hospital, age, duration of subfertility, primary or secondary subfertility and diagnosis. Primary outcome was cumulative ongoing pregnancy rate after three years. Time to pregnancy was censored at the moment couples were lost to follow up or when their child wish ended and, for the no-treatment group, when couples re-started treatment. RESULTS After three years, there were 18 pregnancies in the stopped treatment group (25%) versus 41 pregnancies in the IUI group (28%) (RR 1.1 (0.59-2.2)(p=0.4)). The cumulative pregnancy rate after three years was 40% in both groups, showing no difference in time to ongoing pregnancy (shared frailty model p=0.86). CONCLUSIONS In couples with unexplained subfertility and a poor prognosis for natural conception, treatment with IUI does not to add to expectant management. There is need for a randomized clinical trial comparing IUI with expectant management in these couples.