The challenges of selective fertility and carryover effects in within-sibship analyses: the effect of assisted reproductive technology on perinatal mortality as an example

Westvik-Johari Kjersti; Siri Eldevik Håberg; Debbie A Lawlor; Liv Bente Romundstad; Christina  Bergh; Ulla-Britt Wennerholm; Mika Gissler; Anna-Karina Aaris Henningsen; Alia Tiitinen; Anja Pinborg; Signe Opdahl

doi:10.1093/ije/dyad003

The challenges of selective fertility and carryover effects in within-sibship analyses: the effect of assisted reproductive technology on perinatal mortality as an example

Westvik-Johari Kjersti ^*, Siri Eldevik Håberg, Debbie A Lawlor, Liv Bente Romundstad , Christina Bergh, Ulla-Britt Wennerholm, Mika Gissler, Anna-Karina Aaris Henningsen, Alia Tiitinen, Anja Pinborg, Signe Opdahl

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

2 Citations (Scopus)

Abstract

Background
Within sibship analyses show lower perinatal mortality after assisted reproductive technology (ART) compared to natural conception (NC), a finding that appears biologically unlikely. We investigated whether this may be attributed to bias from selective fertility and carryover effects.

Methods
Using data from national registries in Denmark (1994-2014), Finland (1990-2014), Norway and Sweden (1988-2015), we studied 5 722 826 singleton pregnancies, including 119 900 ART-conceived and 37 590 exposure-discordant sibships. Perinatal mortality at the population level and within sibships was compared using multilevel logistic regression with random and fixed intercept, respectively. We estimated selective fertility as the proportion of primiparous women with and without perinatal loss who had a second delivery, and carryover effects through bi-directional and crosswise associations.

Results
Population analysis showed higher perinatal mortality among ART-conceived compared to NC (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.13 to 1.30), while within sibship analysis showed the opposite (OR 0.36, 95% CI 0.31 to 0.43). Primiparous women with perinatal loss were more likely to give birth again (selective fertility) and to utilize ART in this subsequent pregnancy (carryover effects), resulting in strong selection of double-discordant sibships with death of the naturally conceived and survival of the ART-conceived sibling. After controlling for conception method and outcome in first pregnancy, ART was not consistently associated with perinatal mortality in second pregnancy.

Conclusions
While population estimates may be biased by residual confounding, within sibship estimates were biased by selective fertility and carryover effects. It remains unclear whether ART-conception contributes to perinatal mortality.

Original language	English
Article number	dyad003
Pages (from-to)	403-413
Number of pages	11
Journal	International Journal of Epidemiology
Volume	52
Issue number	2
Early online date	28 Jan 2023
DOIs	https://doi.org/10.1093/ije/dyad003
Publication status	Published - 1 Apr 2023

Bibliographical note

Funding Information:
This work was supported by the Nordic Trial Alliance (a pilot project jointly funded by the Nordic Council of Ministers and NordForsk, grant number 71450), the Central Norway Regional Health Authorities (grant number 46045000 to LBR), the Nordic Federation of Obstetrics and Gynaecology (grant numbers NF13041, NF15058, NF16026 and NF17043 to U.B.W. and A.T.), the Interreg Öresund-Kattegat-Skagerrak European Regional Development Fund (ReproUnion project) to A.P. and C.B., the Research Council of Norway’s Centre of Excellence funding scheme (grant number 262700 to S.E.H. and L.B.R.), the European Research Council (ART-HEALTH 101021566 ERC Advanced Grant to D.A.L.), Medical Research Council (MC_UU_00011/6 to D.A.L.), Bristol National Institute of Health (NIHR) Research Biomedical Research Centre to D.A.L., NIHR Senior Investigator award (NF-0616–10102 to D.A.L.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Publisher Copyright:
© The Author(s) 2023; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

Research Groups and Themes

Bristol Population Health Science Institute

Keywords

Cohort study
sibship design
assisted conception
perinatal death
perinatal mortality
selection bias
selective fertility
carryover effects
continuation rate

Access to Document

10.1093/ije/dyad003

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Persistent link

8073 MRC IEU - Programme 6
Lawlor, D. A. (Principal Investigator)
1/04/18 → 31/03/23
Project: Research

Cite this

Kjersti , W.-J., Håberg, S. E., Lawlor, D. A., Romundstad , L. B., Bergh, C., Wennerholm, U.-B., Gissler, M., Henningsen, A.-K. A., Tiitinen, A., Pinborg, A., & Opdahl, S. (2023). The challenges of selective fertility and carryover effects in within-sibship analyses: the effect of assisted reproductive technology on perinatal mortality as an example. International Journal of Epidemiology, 52(2), 403-413. Article dyad003. https://doi.org/10.1093/ije/dyad003

@article{2cebdb827e534ba89d499c6febd26877,

title = "The challenges of selective fertility and carryover effects in within-sibship analyses: the effect of assisted reproductive technology on perinatal mortality as an example",

abstract = "Background Within sibship analyses show lower perinatal mortality after assisted reproductive technology (ART) compared to natural conception (NC), a finding that appears biologically unlikely. We investigated whether this may be attributed to bias from selective fertility and carryover effects. Methods Using data from national registries in Denmark (1994-2014), Finland (1990-2014), Norway and Sweden (1988-2015), we studied 5 722 826 singleton pregnancies, including 119 900 ART-conceived and 37 590 exposure-discordant sibships. Perinatal mortality at the population level and within sibships was compared using multilevel logistic regression with random and fixed intercept, respectively. We estimated selective fertility as the proportion of primiparous women with and without perinatal loss who had a second delivery, and carryover effects through bi-directional and crosswise associations. Results Population analysis showed higher perinatal mortality among ART-conceived compared to NC (odds ratio [OR] 1.21, 95\% confidence interval [CI] 1.13 to 1.30), while within sibship analysis showed the opposite (OR 0.36, 95\% CI 0.31 to 0.43). Primiparous women with perinatal loss were more likely to give birth again (selective fertility) and to utilize ART in this subsequent pregnancy (carryover effects), resulting in strong selection of double-discordant sibships with death of the naturally conceived and survival of the ART-conceived sibling. After controlling for conception method and outcome in first pregnancy, ART was not consistently associated with perinatal mortality in second pregnancy. Conclusions While population estimates may be biased by residual confounding, within sibship estimates were biased by selective fertility and carryover effects. It remains unclear whether ART-conception contributes to perinatal mortality. ",

keywords = "Cohort study, sibship design, assisted conception, perinatal death, perinatal mortality, selection bias, selective fertility, carryover effects, continuation rate",

author = "Westvik-Johari Kjersti and H{\aa}berg, \{Siri Eldevik\} and Lawlor, \{Debbie A\} and Romundstad, \{Liv Bente\} and Christina Bergh and Ulla-Britt Wennerholm and Mika Gissler and Henningsen, \{Anna-Karina Aaris\} and Alia Tiitinen and Anja Pinborg and Signe Opdahl",

note = "Funding Information: This work was supported by the Nordic Trial Alliance (a pilot project jointly funded by the Nordic Council of Ministers and NordForsk, grant number 71450), the Central Norway Regional Health Authorities (grant number 46045000 to LBR), the Nordic Federation of Obstetrics and Gynaecology (grant numbers NF13041, NF15058, NF16026 and NF17043 to U.B.W. and A.T.), the Interreg {\"O}resund-Kattegat-Skagerrak European Regional Development Fund (ReproUnion project) to A.P. and C.B., the Research Council of Norway{\textquoteright}s Centre of Excellence funding scheme (grant number 262700 to S.E.H. and L.B.R.), the European Research Council (ART-HEALTH 101021566 ERC Advanced Grant to D.A.L.), Medical Research Council (MC\_UU\_00011/6 to D.A.L.), Bristol National Institute of Health (NIHR) Research Biomedical Research Centre to D.A.L., NIHR Senior Investigator award (NF-0616–10102 to D.A.L.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Publisher Copyright: {\textcopyright} The Author(s) 2023; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.",

year = "2023",

month = apr,

day = "1",

doi = "10.1093/ije/dyad003",

language = "English",

volume = "52",

pages = "403--413",

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Kjersti , W-J, Håberg, SE, Lawlor, DA, Romundstad , LB, Bergh, C, Wennerholm, U-B, Gissler, M, Henningsen, A-KA, Tiitinen, A, Pinborg, A & Opdahl, S 2023, 'The challenges of selective fertility and carryover effects in within-sibship analyses: the effect of assisted reproductive technology on perinatal mortality as an example', International Journal of Epidemiology, vol. 52, no. 2, dyad003, pp. 403-413. https://doi.org/10.1093/ije/dyad003

The challenges of selective fertility and carryover effects in within-sibship analyses: the effect of assisted reproductive technology on perinatal mortality as an example. / Kjersti , Westvik-Johari; Håberg, Siri Eldevik; Lawlor, Debbie A et al.
In: International Journal of Epidemiology, Vol. 52, No. 2, dyad003, 01.04.2023, p. 403-413.

Research output: Contribution to journal › Article (Academic Journal) › peer-review

TY - JOUR

T1 - The challenges of selective fertility and carryover effects in within-sibship analyses

T2 - the effect of assisted reproductive technology on perinatal mortality as an example

AU - Kjersti , Westvik-Johari

AU - Håberg, Siri Eldevik

AU - Lawlor, Debbie A

AU - Romundstad , Liv Bente

AU - Bergh, Christina

AU - Wennerholm, Ulla-Britt

AU - Gissler, Mika

AU - Henningsen, Anna-Karina Aaris

AU - Tiitinen, Alia

AU - Pinborg, Anja

AU - Opdahl, Signe

N1 - Funding Information: This work was supported by the Nordic Trial Alliance (a pilot project jointly funded by the Nordic Council of Ministers and NordForsk, grant number 71450), the Central Norway Regional Health Authorities (grant number 46045000 to LBR), the Nordic Federation of Obstetrics and Gynaecology (grant numbers NF13041, NF15058, NF16026 and NF17043 to U.B.W. and A.T.), the Interreg Öresund-Kattegat-Skagerrak European Regional Development Fund (ReproUnion project) to A.P. and C.B., the Research Council of Norway’s Centre of Excellence funding scheme (grant number 262700 to S.E.H. and L.B.R.), the European Research Council (ART-HEALTH 101021566 ERC Advanced Grant to D.A.L.), Medical Research Council (MC_UU_00011/6 to D.A.L.), Bristol National Institute of Health (NIHR) Research Biomedical Research Centre to D.A.L., NIHR Senior Investigator award (NF-0616–10102 to D.A.L.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Publisher Copyright: © The Author(s) 2023; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

PY - 2023/4/1

Y1 - 2023/4/1

N2 - Background Within sibship analyses show lower perinatal mortality after assisted reproductive technology (ART) compared to natural conception (NC), a finding that appears biologically unlikely. We investigated whether this may be attributed to bias from selective fertility and carryover effects. Methods Using data from national registries in Denmark (1994-2014), Finland (1990-2014), Norway and Sweden (1988-2015), we studied 5 722 826 singleton pregnancies, including 119 900 ART-conceived and 37 590 exposure-discordant sibships. Perinatal mortality at the population level and within sibships was compared using multilevel logistic regression with random and fixed intercept, respectively. We estimated selective fertility as the proportion of primiparous women with and without perinatal loss who had a second delivery, and carryover effects through bi-directional and crosswise associations. Results Population analysis showed higher perinatal mortality among ART-conceived compared to NC (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.13 to 1.30), while within sibship analysis showed the opposite (OR 0.36, 95% CI 0.31 to 0.43). Primiparous women with perinatal loss were more likely to give birth again (selective fertility) and to utilize ART in this subsequent pregnancy (carryover effects), resulting in strong selection of double-discordant sibships with death of the naturally conceived and survival of the ART-conceived sibling. After controlling for conception method and outcome in first pregnancy, ART was not consistently associated with perinatal mortality in second pregnancy. Conclusions While population estimates may be biased by residual confounding, within sibship estimates were biased by selective fertility and carryover effects. It remains unclear whether ART-conception contributes to perinatal mortality.

AB - Background Within sibship analyses show lower perinatal mortality after assisted reproductive technology (ART) compared to natural conception (NC), a finding that appears biologically unlikely. We investigated whether this may be attributed to bias from selective fertility and carryover effects. Methods Using data from national registries in Denmark (1994-2014), Finland (1990-2014), Norway and Sweden (1988-2015), we studied 5 722 826 singleton pregnancies, including 119 900 ART-conceived and 37 590 exposure-discordant sibships. Perinatal mortality at the population level and within sibships was compared using multilevel logistic regression with random and fixed intercept, respectively. We estimated selective fertility as the proportion of primiparous women with and without perinatal loss who had a second delivery, and carryover effects through bi-directional and crosswise associations. Results Population analysis showed higher perinatal mortality among ART-conceived compared to NC (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.13 to 1.30), while within sibship analysis showed the opposite (OR 0.36, 95% CI 0.31 to 0.43). Primiparous women with perinatal loss were more likely to give birth again (selective fertility) and to utilize ART in this subsequent pregnancy (carryover effects), resulting in strong selection of double-discordant sibships with death of the naturally conceived and survival of the ART-conceived sibling. After controlling for conception method and outcome in first pregnancy, ART was not consistently associated with perinatal mortality in second pregnancy. Conclusions While population estimates may be biased by residual confounding, within sibship estimates were biased by selective fertility and carryover effects. It remains unclear whether ART-conception contributes to perinatal mortality.

KW - Cohort study

KW - sibship design

KW - assisted conception

KW - perinatal death

KW - perinatal mortality

KW - selection bias

KW - selective fertility

KW - carryover effects

KW - continuation rate

U2 - 10.1093/ije/dyad003

DO - 10.1093/ije/dyad003

M3 - Article (Academic Journal)

C2 - 36715050

SN - 0300-5771

VL - 52

SP - 403

EP - 413

JO - International Journal of Epidemiology

JF - International Journal of Epidemiology

IS - 2

M1 - dyad003

ER -

The challenges of selective fertility and carryover effects in within-sibship analyses: the effect of assisted reproductive technology on perinatal mortality as an example

Abstract

Bibliographical note

Research Groups and Themes

Keywords

Access to Document

Handle.net

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Projects

8073 MRC IEU - Programme 6

Cite this