Predicting the chances of having a baby with or without treatment at different time points in couples with unexplained subfertility

D. J. McLernon (Corresponding Author), A. J. Lee, A. Maheshwari, R. van Eekelen, N. van Geloven, H. Putter, M. J. Eijkemans, J. W. van der Steeg, F. van der Veen, E. W. Steyerberg, B. W. Mol, Siladitya Bhattacharya

Research output: Contribution to journalArticle

Abstract

STUDY QUESTION
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?

SUMMARY ANSWER
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.

WHAT IS KNOWN ALREADY
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.

STUDY DESIGN, SIZE, DURATION
A population-based study of 1316 couples with unexplained subfertility attending a regional clinic between 1998 and 2011.

PARTICIPANTS/MATERIALS, SETTING, METHODS
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.

MAIN RESULTS AND THE ROLE OF CHANCE
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.

LIMITATIONS, REASONS FOR CAUTION
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.

WIDER IMPLICATIONS OF THE FINDINGS
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.

STUDY FUNDING/COMPETING INTEREST(S)
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.
Original languageEnglish
Pages (from-to)1126-1138
Number of pages13
JournalHuman Reproduction
Volume34
Issue number6
Early online date23 May 2019
DOIs
Publication statusPublished - 4 Jun 2019

Fingerprint

Infertility
Clomiphene
Fertility
Fertilization in Vitro
Live Birth
Therapeutics
Referral and Consultation
Reproductive Medicine
Conflict of Interest
Ovulation Induction
Insemination
Birth Rate
Health Services Research
Population Density
Netherlands
Decision Making
Public Health
Confidence Intervals
Research

Keywords

  • clinical prediction models
  • live birth
  • unexplained infertility
  • subfertility
  • in vitro fertilisation

ASJC Scopus subject areas

  • Obstetrics and Gynaecology
  • Reproductive Medicine

Cite this

Predicting the chances of having a baby with or without treatment at different time points in couples with unexplained subfertility. / McLernon, D. J. (Corresponding Author); Lee, A. J.; Maheshwari, A.; van Eekelen, R.; van Geloven, N.; Putter, H.; Eijkemans, M. J.; van der Steeg, J. W. ; van der Veen, F.; Steyerberg, E. W.; Mol, B. W.; Bhattacharya, Siladitya.

In: Human Reproduction, Vol. 34, No. 6, 04.06.2019, p. 1126-1138.

Research output: Contribution to journalArticle

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 2019, 'Predicting the chances of having a baby with or without treatment at different time points in couples with unexplained subfertility' Human Reproduction, vol. 34, no. 6, pp. 1126-1138. https://doi.org/10.1093/humrep/dez049
McLernon, D. J. ; Lee, A. J. ; Maheshwari, A. ; van Eekelen, R. ; van Geloven, N. ; Putter, H. ; Eijkemans, M. J. ; van der Steeg, J. W. ; van der Veen, F. ; Steyerberg, E. W. ; Mol, B. W. ; Bhattacharya, Siladitya. / Predicting the chances of having a baby with or without treatment at different time points in couples with unexplained subfertility. In: Human Reproduction. 2019 ; Vol. 34, No. 6. pp. 1126-1138.
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abstract = "STUDY QUESTIONCan 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?SUMMARY ANSWERYes, 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.WHAT IS KNOWN ALREADYCouples 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.STUDY DESIGN, SIZE, DURATIONA population-based study of 1316 couples with unexplained subfertility attending a regional clinic between 1998 and 2011.PARTICIPANTS/MATERIALS, SETTING, METHODSA 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.MAIN RESULTS AND THE ROLE OF CHANCEA 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.LIMITATIONS, REASONS FOR CAUTIONWe 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.WIDER IMPLICATIONS OF THE FINDINGSFor 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.STUDY FUNDING/COMPETING INTEREST(S)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.",
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note = "Acknowledgements: We acknowledge the data management support of the Grampian Data Safe Haven (DaSH) and the associated financial support of NHS Research Scotland, through NHS Grampian investment in the Grampian DaSH. For more information, visit the DaSH website http://www.abdn.ac.uk/iahs/facilities/grampian-data-safe-haven.php. We would like to thank Kar Yee Lor, a medical student at the University of Aberdeen, for searching case notes, and all the staff at Aberdeen Fertility Clinic for their help with database queries and case note searching. Funding: 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). The views expressed here are those of the authors and not necessarily those of the Chief Scientist Office. The funders had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; or decision to submit the manuscript for publication.",
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T1 - Predicting the chances of having a baby with or without treatment at different time points in couples with unexplained subfertility

AU - McLernon, D. J.

AU - Lee, A. J.

AU - Maheshwari, A.

AU - van Eekelen, R.

AU - van Geloven, N.

AU - Putter, H.

AU - Eijkemans, M. J.

AU - van der Steeg, J. W.

AU - van der Veen, F.

AU - Steyerberg, E. W.

AU - Mol, B. W.

AU - Bhattacharya, Siladitya

N1 - Acknowledgements: We acknowledge the data management support of the Grampian Data Safe Haven (DaSH) and the associated financial support of NHS Research Scotland, through NHS Grampian investment in the Grampian DaSH. For more information, visit the DaSH website http://www.abdn.ac.uk/iahs/facilities/grampian-data-safe-haven.php. We would like to thank Kar Yee Lor, a medical student at the University of Aberdeen, for searching case notes, and all the staff at Aberdeen Fertility Clinic for their help with database queries and case note searching. Funding: 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). The views expressed here are those of the authors and not necessarily those of the Chief Scientist Office. The funders had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; or decision to submit the manuscript for publication.

PY - 2019/6/4

Y1 - 2019/6/4

N2 - STUDY QUESTIONCan 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?SUMMARY ANSWERYes, 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.WHAT IS KNOWN ALREADYCouples 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.STUDY DESIGN, SIZE, DURATIONA population-based study of 1316 couples with unexplained subfertility attending a regional clinic between 1998 and 2011.PARTICIPANTS/MATERIALS, SETTING, METHODSA 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.MAIN RESULTS AND THE ROLE OF CHANCEA 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.LIMITATIONS, REASONS FOR CAUTIONWe 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.WIDER IMPLICATIONS OF THE FINDINGSFor 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.STUDY FUNDING/COMPETING INTEREST(S)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.

AB - STUDY QUESTIONCan 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?SUMMARY ANSWERYes, 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.WHAT IS KNOWN ALREADYCouples 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.STUDY DESIGN, SIZE, DURATIONA population-based study of 1316 couples with unexplained subfertility attending a regional clinic between 1998 and 2011.PARTICIPANTS/MATERIALS, SETTING, METHODSA 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.MAIN RESULTS AND THE ROLE OF CHANCEA 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.LIMITATIONS, REASONS FOR CAUTIONWe 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.WIDER IMPLICATIONS OF THE FINDINGSFor 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.STUDY FUNDING/COMPETING INTEREST(S)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.

KW - clinical prediction models

KW - live birth

KW - unexplained infertility

KW - subfertility

KW - in vitro fertilisation

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