Medically assisted reproduction in the context of time - Chapter 9: Summary

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Medically assisted reproduction in the context of time

Scholten, I.

Publication date

2015

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Final published version

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Citation for published version (APA):

Scholten, I. (2015). Medically assisted reproduction in the context of time.

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SUMMARY

This thesis describes several studies on medically assisted reproduction in the context of time.

Chapter 1 gives an outline of the research presented in this thesis

In Chapter 2, we present a new prediction model on the chance for natural conception in subfertile couples. In contrast to the currently used Hunault model, this model is able to recalculate couples chances at various moments in time. We studied couples who participated in a prospective cohort study of subfertile couples in 38 centres in The Netherlands between January 2002 and February 2004. The model was developed using the same predictors as in the Hunault model: female age, duration of subfertility, subfertility being primary or secondary, sperm motility and referral status. A beta-geometric model was used, focussing on the pregnancy probability per menstrual cycle. This probability differs considerably between couples, but we assumed that for one couple, the probability remains stable during the follow up time of the study. This means that there are couples with higher and lower pregnancy chances per cycle, who cannot be identified at the start of follow up. Of the 4,996 couples in the cohort, 1,086 (22%) women reached a naturally conceived ongoing pregnancy within a mean follow up of 10 months (range 1-70 months). The pregnancy prognosis in the first year after completion of the fertility workup was 26%. If pregnancy did not occur in this first year, the chance of conceiving in the next year was 13%. The yearly chance lowered to 8% after 2 years of unsuccessful expectant management. Discrimination and calibration of the repeated predictions was fair up to 3 years after the fertility workup. This dynamic prediction model enables to re-assess the natural pregnancy chances after various periods of unsuccessful expectant management. This model hands the clinician a tool for treatment decisions in couples with unexplained unfulfilled child wish. Before implementation, the dynamic prediction model needs to be validated in an external population. In Chapter 3, we assess whether randomized clinical trials on In Vitro Fertilisation (IVF), Intrauterine Insemination (IUI) and Ovulation Induction (OI) report multiple cycles of treatment. We collected a sample of trials on medically assisted reproduction published in the periods 1999/2000, 2004/2005 and 2009/2010 in 11 pre-specified peer-reviewed journals. 223 trials -172 on in vitro fertilization (IVF), 32 on intrauterine insemination (IUI) and 19 on ovulation induction (OI)- were included. Of all 223 RCTs, 41 (18%) reported on multiple cycles. Reporting of multiple cycles was significantly more common in trials on IUI (n=18, 56%) and OI (n=12, 63%) compared to trials on IVF (n= 11, 7%, p<0.01). Our analysis shows that the majority of randomized clinical trials, especially those on IVF, do not report cumulative pregnancy rates over a longer time horizon. Since infertile couples usually undergo multiple cycles, the clinical significance of these trials is limited.

In Chapter 4 we compared IUI versus no treatment in couples with poor prognosis on natural conception. We matched the couples for female age, duration of subfertility, diagnosis and subfertility being primary or secondary. After three years, there were 18 ongoing pregnancies in the no treatment

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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). Treatment with IUI seems not to add to expectant management. These data indicate a need for a randomized clinical trial comparing IUI with expectant management in these couples.

In Chapter 5, we present the three year outcome of 99 couples with isolated cervical factor who were previously randomized between immediate treatment with IUI and six months expectant management. A beneficial effect of IUI on the ongoing pregnancy rate in these couples was suggested after the initial six months. Hereafter, couples in both groups were offered further treatment according to local protocol, usually consisting of up to nine cycles of IUI followed by IVF if necessary. After three years, there were 36 ongoing pregnancies in the immediate IUI group (71%) and 38 ongoing pregnancies in the expectant management group (79%) (RR 0.89 (95% confidence interval (CI) 0.7 to 1.1)). We conclude that 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.

In Chapter 6, we present the three year follow up of 391 couples previously randomized between immediate mobilisation after IUI and fifteen minute of immobilisation after IUI. After the initial three cycles, there were significantly higher ongoing pregnancy rates in the immobilisation group. Hereafter couples in both groups were offered treatment according to local protocol. After three years, there were 143 ongoing pregnancies in the immobilisation group (72%) and 112 ongoing pregnancies in the immediate mobilisation group (58%)(RR 1.2 (95% CI 1.1-1.4). Although there is no clear cut biological rationale for this data, the persistent significant difference in ongoing pregnancy rates underpins the importance of immobilisation after IUI. We conclude that there is no valid excuse to deny women immobilizing for 15 minutes after IUI.

In Chapter 7 we address the problem of multiple pregnancy after medically assisted reproduction (MAR) from a broader point of view. We incorporated population statistics with MAR statistics and assessed the contribution of MAR multiple pregnancies to all multiple pregnancies for the year 2006 in seven countries with differences in utilisation of MAR and usage of single embryo transfer. The contribution of MAR multiple gestation infants to all multiple gestation infants varied between 14.7% and 29.0%, which was influenced by both the SET rate per cycle and MAR utilization rates. Our study provides further evidence of the importance of SET in clinical practice, but also demonstrates the need to consider the implications of MAR on a population level. As a consequence, standardized population based measures that reflect MAR utilisation and SET rates should be developed as an additional indicator of MAR efficacy and safety.