Natural conception: repeated predictions over time

Eekelen, Rik van; Scholten, I.; Tjon-Kon-Fat, R. I.; Steeg, Jan Willem van der; Steures, Pieternel; Hompes, Peter G.A.; Wely, Madelon van; Veen, Fulco van der; Mol, BW; Eijkemans, Marinus J.C.; Velde, Egbert R. te; Geloven, Nan van

doi:10.1093/humrep/dew309

Cited by 44 publications

(30 citation statements)

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“…We defined subfertility as not conceiving within 1 year of trying. Unexplained subfertility was defined as couples with no major causes explaining the fertility problem, regular menstrual cycles of length between 23 and 35 days, at least one patent fallopian tube and semen analyses with a total motile sperm count of >1 × 10 6 ( van Eekelen et al , 2017a ). We chose 38 years as the age limit for women as for couples in which the woman over 38 years of age, the treatment choice is complicated by the rapid decline in the probability of live birth after IVF and after EM as female age increases, such that IVF-EM-EM might be preferred ( McLernon et al , 2016 ; van Eekelen et al , 2019b ).…”

Section: Methodsmentioning

confidence: 99%

“…As the baseline probability of live birth after EM in the model, we chose to use our dynamic prediction model for natural conception ( van Eekelen et al , 2017a ). This prediction model has been externally validated in Scottish data and can be used to not only predict the probability of natural conception after completion of the fertility workup that leads to ongoing pregnancy, but also to update predictions when couples return to the clinic later after a period of EM ( van Eekelen et al , 2018 ).…”

Section: Methodsmentioning

confidence: 99%

“…Because couples with better prognoses conceive before couples with poorer prognoses, this leads to a selection over time in which eventually a subgroup with a particularly low prognosis remains ( van Eekelen et al , 2017a ). This low prognosis group might benefit from MAR treatment ( van Eekelen et al , 2017b ).…”

Section: Introductionmentioning

confidence: 99%

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Cost-effectiveness of medically assisted reproduction or expectant management for unexplained subfertility: when to start treatment?

et al. 2020

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STUDY QUESTION Over a time period of 3 years, which order of expectant management (EM), IUI with ovarian stimulation (IUI-OS) and IVF is the most cost-effective for couples with unexplained subfertility with the female age below 38 years? SUMMARY ANSWER If a live birth is considered worth €32 000 or less, 2 years of EM followed by IVF was the most cost-effective, whereas above €32 000 this was 1 year of EM, 1 year of IUI-OS and then 1 year of IVF. WHAT IS KNOWN ALREADY IUI-OS and IVF are commonly used fertility treatments for unexplained subfertility although many couples can conceive naturally, as no identifiable barrier to conception could be found by definition. Few countries have guidelines on when to proceed with medically assisted reproduction (MAR), mostly based on the expected probability of live birth after treatment, but there is a lack of evidence to support the strategies proposed by these guidelines. The increased uptake of IUI-OS and IVF over the past decades and costs related to reimbursement of these treatments are pressing concerns to health service providers. For MAR to remain affordable, sustainable and a responsible use of public funds, guidance is needed on the cost-effectiveness of treatment strategies for unexplained subfertility, including EM. STUDY DESIGN, SIZE, DURATION We developed a decision analytic Markov model that follows couples with unexplained subfertility of which the woman is under 38 years of age for a time period of 3 years from completion of the fertility workup onwards. We divided the time axis of 3 years into three separate periods, each comprising 1 year. The model was based on contemporary evidence, most notably the dynamic prediction model for natural conception, which was combined with MAR treatment effects from a network meta-analysis on randomized controlled trials. We changed the order of options for managing unexplained subfertility for the 1 year periods to yield five different treatment policies in total: IVF-EM-EM (immediate IVF), EM-IVF-EM (delayed IVF), EM-EM-IVF (postponed IVF), IUIOS-IVF-EM (immediate IUI-OS) and EM-IUIOS-IVF (delayed IUI-OS). PARTICIPANTS/MATERIALS, SETTING, METHODS The main outcomes per policy over the 3-year period were the probability of live birth, the average treatment and delivery costs, the probability of multiple pregnancy, the incremental cost-effectiveness ratio (ICER) and finally, which policy yields the highest net benefit in which costs for a policy were deducted from the health effects, i.e. live births gained. We chose the Dutch societal perspective, but the model can be easily modified for other locations or other perspectives. The probability of live birth after EM was taken from the dynamic prediction model for natural conception and updated for Years 2 and 3. The relative effects of IUI-OS and IVF in terms of odds ratios, taken from the network meta-analysis, were applied to the probability of live birth after EM. We applied standard discounting procedures for economic analyses for Years 2 and 3. The uncertainty around effectiveness, costs and other parameters was assessed by probabilistic sensitivity analysis in which we drew values from distributions and repeated this procedure 20 000 times. In addition, we changed model assumptions to assess their influence on our results. MAIN RESULTS AND THE ROLE OF CHANCE From IVF-EM-EM to EM-IUIOS-IVF, the probability of live birth varied from approximately 54–64% and the average costs from approximately €4000 to €9000. The policies IVF-EM-EM and EM-IVF-EM were dominated by EM-EM-IVF as the latter yielded a higher cumulative probability of live birth at a lower cost. The policy IUIOS-IVF-EM was dominated by EM-IUIOS-IVF as the latter yielded a higher cumulative probability of live birth at a lower cost. After removal of policies that were dominated, the ICER for EM-IUIOS-IVF was approximately €31 000 compared to EM-EM-IVF. The range of ICER values between the lowest 25% and highest 75% of simulation replications was broad. The net benefit curve showed that when we assume a live birth to be worth approximately €20 000 or less, the policy EM-EM-IVF had the highest probability to achieve the highest net benefit. Between €20 000 and €50 000 monetary value per live birth, it was uncertain whether EM-EM-IVF was better than EM-IUIOS-IVF, with the turning point of €32 000. When we assume a monetary value per live birth over €50 000, the policy with the highest probability to achieve the highest net benefit was EM-IUIOS-IVF. Results for subgroups with different baseline prognoses showed the same policies dominated and the same two policies that were the most likely to achieve the highest net benefit but at different threshold values for the assumed monetary value per live birth. LIMITATIONS, REASONS FOR CAUTION Our model focused on population level and was thus based on average costs for the average number of cycles conducted. We also based the model on a number of key assumptions. We changed model assumptions to assess the influence of these assumptions on our results. The change in relative effectiveness of IVF over time was found to be highly influential on results and their interpretation. WIDER IMPLICATIONS OF THE FINDINGS EM-EM-IVF and EM-IUIOS-IVF followed by IVF were the most cost-effective policies. The choice depends on the monetary value assigned to a live birth. The results of our study can be used in discussions between clinicians, couples and policy makers to decide on a sustainable treatment protocol based on the probability of live birth, the costs and the limitations of MAR treatment. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the ZonMw Doelmatigheidsonderzoek (80-85200-98-91072). The funder had no role in the design, conduct or reporting of this work. B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck KGaA and Guerbet and travel and research support from ObsEva, Merck and Guerbet. TRIAL REGISTRATION NUMBER N/A.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Cost-effectiveness of medically assisted reproduction or expectant management for unexplained subfertility: when to start treatment?

et al. 2020

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“…Another study showed that allostatic load that is specific in chronic situation like infertility was not associated with fertility outcomes like conception, spontaneous abortion, and live birth (16). However, a cohort study on 4,999 couples showed that the prediction ranges could help in counselling couples for at least two years after their fertility work-up (17). Additionally, a longitudinal cohort study showed a 71.6% live birth after ART and 28% after SPs or both up to five years (18).…”

Section: Discussionmentioning

confidence: 99%

Spontaneous pregnancies and determinant factors in infertility: A cross-sectional study

Saadati

Nikbakht

Sattari

et al. 2020

IJRM

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Background: The phenomenon of infertility may be derived from different factors - either in males or females or both genders, including few unexplained factors. It is generally managed by medical and surgical treatments. Objective: To find a relation of occurrence of spontaneous pregnancy (SP) with effective factors in infertility. Materials and Methods: This cross-sectional study was conducted at two referral infertility centers (university and privacy center) in the southwest of Iran from March 2015 and March 2016 on 655 infertile couples, who were divided in two groups of with (n = 31) and without (n = 624) SP. The variables included female and male age, male smoking, male job, the place of living, the causes of infertility, the type and duration of infertility, and the subgroups of infertility causes. Results: Infertility may be caused due to both male- and female- related factors (47.5%). While female-related infertility was found in 31.5%, male-related infertility in 14.5%, and infertility due to unexplained factors in 6.6% of our patients. The rate of SP was 4.7%, which had a significant relation with the duration of infertility (p = 0.01), with women’s age (p = 0.048), unexplained infertility (p = 0.001), and husband’s job (p = 0.004). Conclusion: The occurrence of SP in infertile couples was related to age of the female partner, the duration of unexplained infertility, and the male partner’s job. Key words: Male infertility, Female infertility, Spontaneous pregnancy, Epidemiology, Etiology.

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“…Traditional logistic regression would not be able to utilise such patient information as it violates the independence assumption, that each observation (for an individual) is independent of other observations. An alternative model to handle cycles of patient information is a beta-geometric model that has been used to predict natural conception for women, after multiple cycles of a relevant procedure [31]. Time-varying effects [25], time-since-measurement as a predictor [27], aggregated covariate [26].…”

Section: Generalised Estimating Equationsmentioning

confidence: 99%

Harnessing repeated measurements of predictor variables for clinical risk prediction: a review of existing methods

et al. 2020

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Background: Clinical prediction models (CPMs) predict the risk of health outcomes for individual patients. The majority of existing CPMs only harness cross-sectional patient information. Incorporating repeated measurements, such as those stored in electronic health records, into CPMs may provide an opportunity to enhance their performance. However, the number and complexity of methodological approaches available could make it difficult for researchers to explore this opportunity. Our objective was to review the literature and summarise existing approaches for harnessing repeated measurements of predictor variables in CPMs, primarily to make this field more accessible for applied researchers. Methods: MEDLINE, Embase and Web of Science were searched for articles reporting the development of a multivariable CPM for individual-level prediction of future binary or time-to-event outcomes and modelling repeated measurements of at least one predictor. Information was extracted on the following: the methodology used, its specific aim, reported advantages and limitations, and software available to apply the method. Results: The search revealed 217 relevant articles. Seven methodological frameworks were identified: time-dependent covariate modelling, generalised estimating equations, landmark analysis, two-stage modelling, joint-modelling, trajectory classification and machine learning. Each of these frameworks satisfies at least one of three aims: to better represent the predictor-outcome relationship over time, to infer a covariate value at a pre-specified time and to account for the effect of covariate change. Conclusions: The applicability of identified methods depends on the motivation for including longitudinal information and the method's compatibility with the clinical context and available patient data, for both model development and risk estimation in practice.

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Natural conception: repeated predictions over time

Abstract: 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.

Cited by 44 publications

References 28 publications

Cost-effectiveness of medically assisted reproduction or expectant management for unexplained subfertility: when to start treatment?

Cost-effectiveness of medically assisted reproduction or expectant management for unexplained subfertility: when to start treatment?

Spontaneous pregnancies and determinant factors in infertility: A cross-sectional study

Harnessing repeated measurements of predictor variables for clinical risk prediction: a review of existing methods

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