Smoking and infertility: multivariable regression and Mendelian randomization analyses in the Norwegian Mother, Father and Child Cohort Study

Álvaro Hernáez; Abigail Fraser; Robyn E Wootton; Debbie A Lawlor; Maria C Magnus; Christian M Page

doi:10.1016/j.fertnstert.2022.04.001

Smoking and infertility: multivariable regression and Mendelian randomization analyses in the Norwegian Mother, Father and Child Cohort Study

Álvaro Hernáez^*, Abigail Fraser, Robyn E Wootton, Debbie A Lawlor, Maria C Magnus, Christian M Page

^*Corresponding author for this work

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

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159 Downloads (Pure)

Abstract

Objective
To investigate the association between smoking and infertility.
Design
Prospective study.
Setting
Nationwide cohort.
Patients
28,606 women and 27,096 men with questionnaire and genotype information from the Norwegian Mother, Father, and Child Cohort Study.
Intervention
Self-reported information on smoking (having ever smoked [both sexes], age at initiation [women only], cessation [women only], and cigarettes/week in current smokers [both sexes]) was gathered. Genetically predetermined levels or likelihood of presenting these traits were estimated for Mendelian randomization.
Main outcome measure
Infertility (time-to-pregnancy ≥12 months).
Results
Having ever smoked was unrelated to infertility in women or men. Higher smoking intensity in women was associated with greater infertility odds (+1 standard deviation [SD, 48 cigarettes/week]: odds ratio [OR]crude, 1.19; 95% confidence interval [CI] 1.11–1.28; ORadjusted 1.12; 95% CI, 1.03–1.21), also after adjusting for the partner’s tobacco use. Later smoking initiation (+1 SD [3.2 years]: ORcrude, 0.94; 95% CI, 0.88–0.99; ORadjusted 0.89; 95% CI, 0.84–0.95) and smoking cessation (vs. not quitting: ORcrude, 0.83; 95% CI, 0.75–0.91; ORadjusted, 0.83; 95% CI, 0.75–0.93) were linked to decreased infertility in women. Nevertheless, Mendelian randomization results were not directionally consistent for smoking intensity and cessation and were estimated imprecisely in the 2-sample approach. In men, greater smoking intensity was not robustly associated with infertility in multivariable regression and Mendelian randomization.
Conclusions
We did not find robust evidence of an effect of smoking on infertility. This may be due to a true lack of effect, weak genetic instruments, or other kinds of confounding.

Original language	English
Pages (from-to)	180-190
Number of pages	11
Journal	Fertility and Sterility
Volume	118
Issue number	1
Early online date	10 May 2022
DOIs	https://doi.org/10.1016/j.fertnstert.2022.04.001
Publication status	E-pub ahead of print - 10 May 2022

Bibliographical note

Funding Information:
The authors thank all participating families in Norway who take part in this ongoing cohort study, and those who contributed to the recruitment and the infrastructure of the cohort. We also thank the Norwegian Institute of Public Health for generating high-quality genomic data and the NORMENT Centre for providing genotype data, South East Norway Health Authority, and Stiftelsen Kristian Gerhard Jebsen. The authors further thank the Center for Diabetes Research (University of Bergen) for providing genotype information and performing quality control and imputation of the data in research projects funded by the European Research Council Advanced Grant SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, the Trond Mohn Foundation, the Research Council of Norway, the Novo Nordisk Foundation, the University of Bergen, and the Western Norway Health Authority. This work was performed on the Tjeneste for Sensitive Data (TSD) facilities, owned by the University of Oslo, operated and developed by the TSD service group at the University of Oslo, IT-Department ( [email protected] ). This study does not necessarily reflect the position or policy of the Norwegian Research Council.

Funding Information:
The Mother, Father, and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Norwegian Ministry of Education and Research. Supported by funding from the European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreement No 947684). Supported in part by the Research Council of Norway through its Centres of Excellence funding scheme, project number 262700, and the project “Women's fertility–an essential component of health and well-being,” number 320656. Open Access funding was provided by the Folkehelseinstituttet/Norwegian Institute of Public Health. Supported by grant no. R01 DK10324 from the US National Institutes of Health and grant agreement No 669545 from European Research Council Advanced Grant (to D.A.L.). The funders had no role in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.The authors thank all participating families in Norway who take part in this ongoing cohort study, and those who contributed to the recruitment and the infrastructure of the cohort. We also thank the Norwegian Institute of Public Health for generating high-quality genomic data and the NORMENT Centre for providing genotype data, South East Norway Health Authority, and Stiftelsen Kristian Gerhard Jebsen. The authors further thank the Center for Diabetes Research (University of Bergen) for providing genotype information and performing quality control and imputation of the data in research projects funded by the European Research Council Advanced Grant SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, the Trond Mohn Foundation, the Research Council of Norway, the Novo Nordisk Foundation, the University of Bergen, and the Western Norway Health Authority. This work was performed on the Tjeneste for Sensitive Data (TSD) facilities, owned by the University of Oslo, operated and developed by the TSD service group at the University of Oslo, IT-Department ([email protected]). This study does not necessarily reflect the position or policy of the Norwegian Research Council. DIALOG: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/34132

Funding Information:
The Mother, Father, and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Norwegian Ministry of Education and Research. Supported by funding from the European Research Council under the European Union’s Horizon 2020 research and innovation program (grant agreement No 947684). Supported in part by the Research Council of Norway through its Centres of Excellence funding scheme, project number 262700, and the project “Women’s fertility–an essential component of health and well-being,” number 320656. Open Access funding was provided by the Folkehelseinstituttet/Norwegian Institute of Public Health. Supported by grant no. R01 DK10324 from the US National Institutes of Health and grant agreement No 669545 from European Research Council Advanced Grant (to D.A.L.). The funders had no role in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.

Publisher Copyright:
© 2022 The Authors

Keywords

smoking
infertility
Mendelian randomization

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@article{4612b9b8a21749be972fee3935c947df,

title = "Smoking and infertility: multivariable regression and Mendelian randomization analyses in the Norwegian Mother, Father and Child Cohort Study",

abstract = "ObjectiveTo investigate the association between smoking and infertility.DesignProspective study.SettingNationwide cohort.Patients28,606 women and 27,096 men with questionnaire and genotype information from the Norwegian Mother, Father, and Child Cohort Study.InterventionSelf-reported information on smoking (having ever smoked [both sexes], age at initiation [women only], cessation [women only], and cigarettes/week in current smokers [both sexes]) was gathered. Genetically predetermined levels or likelihood of presenting these traits were estimated for Mendelian randomization.Main outcome measureInfertility (time-to-pregnancy ≥12 months).ResultsHaving ever smoked was unrelated to infertility in women or men. Higher smoking intensity in women was associated with greater infertility odds (+1 standard deviation [SD, 48 cigarettes/week]: odds ratio [OR]crude, 1.19; 95% confidence interval [CI] 1.11–1.28; ORadjusted 1.12; 95% CI, 1.03–1.21), also after adjusting for the partner{\textquoteright}s tobacco use. Later smoking initiation (+1 SD [3.2 years]: ORcrude, 0.94; 95% CI, 0.88–0.99; ORadjusted 0.89; 95% CI, 0.84–0.95) and smoking cessation (vs. not quitting: ORcrude, 0.83; 95% CI, 0.75–0.91; ORadjusted, 0.83; 95% CI, 0.75–0.93) were linked to decreased infertility in women. Nevertheless, Mendelian randomization results were not directionally consistent for smoking intensity and cessation and were estimated imprecisely in the 2-sample approach. In men, greater smoking intensity was not robustly associated with infertility in multivariable regression and Mendelian randomization.ConclusionsWe did not find robust evidence of an effect of smoking on infertility. This may be due to a true lack of effect, weak genetic instruments, or other kinds of confounding.",

keywords = "smoking, infertility, Mendelian randomization",

author = "{\'A}lvaro Hern{\'a}ez and Abigail Fraser and Wootton, {Robyn E} and Lawlor, {Debbie A} and Magnus, {Maria C} and Page, {Christian M}",

note = "Funding Information: The authors thank all participating families in Norway who take part in this ongoing cohort study, and those who contributed to the recruitment and the infrastructure of the cohort. We also thank the Norwegian Institute of Public Health for generating high-quality genomic data and the NORMENT Centre for providing genotype data, South East Norway Health Authority, and Stiftelsen Kristian Gerhard Jebsen. The authors further thank the Center for Diabetes Research (University of Bergen) for providing genotype information and performing quality control and imputation of the data in research projects funded by the European Research Council Advanced Grant SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, the Trond Mohn Foundation, the Research Council of Norway, the Novo Nordisk Foundation, the University of Bergen, and the Western Norway Health Authority. This work was performed on the Tjeneste for Sensitive Data (TSD) facilities, owned by the University of Oslo, operated and developed by the TSD service group at the University of Oslo, IT-Department ( [email protected] ). This study does not necessarily reflect the position or policy of the Norwegian Research Council. Funding Information: The Mother, Father, and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Norwegian Ministry of Education and Research. Supported by funding from the European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreement No 947684). Supported in part by the Research Council of Norway through its Centres of Excellence funding scheme, project number 262700, and the project “Women's fertility–an essential component of health and well-being,” number 320656. Open Access funding was provided by the Folkehelseinstituttet/Norwegian Institute of Public Health. Supported by grant no. R01 DK10324 from the US National Institutes of Health and grant agreement No 669545 from European Research Council Advanced Grant (to D.A.L.). The funders had no role in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.The authors thank all participating families in Norway who take part in this ongoing cohort study, and those who contributed to the recruitment and the infrastructure of the cohort. We also thank the Norwegian Institute of Public Health for generating high-quality genomic data and the NORMENT Centre for providing genotype data, South East Norway Health Authority, and Stiftelsen Kristian Gerhard Jebsen. The authors further thank the Center for Diabetes Research (University of Bergen) for providing genotype information and performing quality control and imputation of the data in research projects funded by the European Research Council Advanced Grant SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, the Trond Mohn Foundation, the Research Council of Norway, the Novo Nordisk Foundation, the University of Bergen, and the Western Norway Health Authority. This work was performed on the Tjeneste for Sensitive Data (TSD) facilities, owned by the University of Oslo, operated and developed by the TSD service group at the University of Oslo, IT-Department ([email protected]). This study does not necessarily reflect the position or policy of the Norwegian Research Council. DIALOG: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/34132 Funding Information: The Mother, Father, and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Norwegian Ministry of Education and Research. Supported by funding from the European Research Council under the European Union{\textquoteright}s Horizon 2020 research and innovation program (grant agreement No 947684). Supported in part by the Research Council of Norway through its Centres of Excellence funding scheme, project number 262700, and the project “Women{\textquoteright}s fertility–an essential component of health and well-being,” number 320656. Open Access funding was provided by the Folkehelseinstituttet/Norwegian Institute of Public Health. Supported by grant no. R01 DK10324 from the US National Institutes of Health and grant agreement No 669545 from European Research Council Advanced Grant (to D.A.L.). The funders had no role in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = may,

day = "10",

doi = "10.1016/j.fertnstert.2022.04.001",

language = "English",

volume = "118",

pages = "180--190",

journal = "Fertility and Sterility",

issn = "0015-0282",

publisher = "Elsevier Inc.",

number = "1",

}

TY - JOUR

T1 - Smoking and infertility

T2 - multivariable regression and Mendelian randomization analyses in the Norwegian Mother, Father and Child Cohort Study

AU - Hernáez, Álvaro

AU - Fraser, Abigail

AU - Wootton, Robyn E

AU - Lawlor, Debbie A

AU - Magnus, Maria C

AU - Page, Christian M

N1 - Funding Information: The authors thank all participating families in Norway who take part in this ongoing cohort study, and those who contributed to the recruitment and the infrastructure of the cohort. We also thank the Norwegian Institute of Public Health for generating high-quality genomic data and the NORMENT Centre for providing genotype data, South East Norway Health Authority, and Stiftelsen Kristian Gerhard Jebsen. The authors further thank the Center for Diabetes Research (University of Bergen) for providing genotype information and performing quality control and imputation of the data in research projects funded by the European Research Council Advanced Grant SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, the Trond Mohn Foundation, the Research Council of Norway, the Novo Nordisk Foundation, the University of Bergen, and the Western Norway Health Authority. This work was performed on the Tjeneste for Sensitive Data (TSD) facilities, owned by the University of Oslo, operated and developed by the TSD service group at the University of Oslo, IT-Department ( [email protected] ). This study does not necessarily reflect the position or policy of the Norwegian Research Council. Funding Information: The Mother, Father, and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Norwegian Ministry of Education and Research. Supported by funding from the European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreement No 947684). Supported in part by the Research Council of Norway through its Centres of Excellence funding scheme, project number 262700, and the project “Women's fertility–an essential component of health and well-being,” number 320656. Open Access funding was provided by the Folkehelseinstituttet/Norwegian Institute of Public Health. Supported by grant no. R01 DK10324 from the US National Institutes of Health and grant agreement No 669545 from European Research Council Advanced Grant (to D.A.L.). The funders had no role in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.The authors thank all participating families in Norway who take part in this ongoing cohort study, and those who contributed to the recruitment and the infrastructure of the cohort. We also thank the Norwegian Institute of Public Health for generating high-quality genomic data and the NORMENT Centre for providing genotype data, South East Norway Health Authority, and Stiftelsen Kristian Gerhard Jebsen. The authors further thank the Center for Diabetes Research (University of Bergen) for providing genotype information and performing quality control and imputation of the data in research projects funded by the European Research Council Advanced Grant SELECTionPREDISPOSED, Stiftelsen Kristian Gerhard Jebsen, the Trond Mohn Foundation, the Research Council of Norway, the Novo Nordisk Foundation, the University of Bergen, and the Western Norway Health Authority. This work was performed on the Tjeneste for Sensitive Data (TSD) facilities, owned by the University of Oslo, operated and developed by the TSD service group at the University of Oslo, IT-Department ([email protected]). This study does not necessarily reflect the position or policy of the Norwegian Research Council. DIALOG: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/34132 Funding Information: The Mother, Father, and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Norwegian Ministry of Education and Research. Supported by funding from the European Research Council under the European Union’s Horizon 2020 research and innovation program (grant agreement No 947684). Supported in part by the Research Council of Norway through its Centres of Excellence funding scheme, project number 262700, and the project “Women’s fertility–an essential component of health and well-being,” number 320656. Open Access funding was provided by the Folkehelseinstituttet/Norwegian Institute of Public Health. Supported by grant no. R01 DK10324 from the US National Institutes of Health and grant agreement No 669545 from European Research Council Advanced Grant (to D.A.L.). The funders had no role in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. Publisher Copyright: © 2022 The Authors

PY - 2022/5/10

Y1 - 2022/5/10

N2 - ObjectiveTo investigate the association between smoking and infertility.DesignProspective study.SettingNationwide cohort.Patients28,606 women and 27,096 men with questionnaire and genotype information from the Norwegian Mother, Father, and Child Cohort Study.InterventionSelf-reported information on smoking (having ever smoked [both sexes], age at initiation [women only], cessation [women only], and cigarettes/week in current smokers [both sexes]) was gathered. Genetically predetermined levels or likelihood of presenting these traits were estimated for Mendelian randomization.Main outcome measureInfertility (time-to-pregnancy ≥12 months).ResultsHaving ever smoked was unrelated to infertility in women or men. Higher smoking intensity in women was associated with greater infertility odds (+1 standard deviation [SD, 48 cigarettes/week]: odds ratio [OR]crude, 1.19; 95% confidence interval [CI] 1.11–1.28; ORadjusted 1.12; 95% CI, 1.03–1.21), also after adjusting for the partner’s tobacco use. Later smoking initiation (+1 SD [3.2 years]: ORcrude, 0.94; 95% CI, 0.88–0.99; ORadjusted 0.89; 95% CI, 0.84–0.95) and smoking cessation (vs. not quitting: ORcrude, 0.83; 95% CI, 0.75–0.91; ORadjusted, 0.83; 95% CI, 0.75–0.93) were linked to decreased infertility in women. Nevertheless, Mendelian randomization results were not directionally consistent for smoking intensity and cessation and were estimated imprecisely in the 2-sample approach. In men, greater smoking intensity was not robustly associated with infertility in multivariable regression and Mendelian randomization.ConclusionsWe did not find robust evidence of an effect of smoking on infertility. This may be due to a true lack of effect, weak genetic instruments, or other kinds of confounding.

AB - ObjectiveTo investigate the association between smoking and infertility.DesignProspective study.SettingNationwide cohort.Patients28,606 women and 27,096 men with questionnaire and genotype information from the Norwegian Mother, Father, and Child Cohort Study.InterventionSelf-reported information on smoking (having ever smoked [both sexes], age at initiation [women only], cessation [women only], and cigarettes/week in current smokers [both sexes]) was gathered. Genetically predetermined levels or likelihood of presenting these traits were estimated for Mendelian randomization.Main outcome measureInfertility (time-to-pregnancy ≥12 months).ResultsHaving ever smoked was unrelated to infertility in women or men. Higher smoking intensity in women was associated with greater infertility odds (+1 standard deviation [SD, 48 cigarettes/week]: odds ratio [OR]crude, 1.19; 95% confidence interval [CI] 1.11–1.28; ORadjusted 1.12; 95% CI, 1.03–1.21), also after adjusting for the partner’s tobacco use. Later smoking initiation (+1 SD [3.2 years]: ORcrude, 0.94; 95% CI, 0.88–0.99; ORadjusted 0.89; 95% CI, 0.84–0.95) and smoking cessation (vs. not quitting: ORcrude, 0.83; 95% CI, 0.75–0.91; ORadjusted, 0.83; 95% CI, 0.75–0.93) were linked to decreased infertility in women. Nevertheless, Mendelian randomization results were not directionally consistent for smoking intensity and cessation and were estimated imprecisely in the 2-sample approach. In men, greater smoking intensity was not robustly associated with infertility in multivariable regression and Mendelian randomization.ConclusionsWe did not find robust evidence of an effect of smoking on infertility. This may be due to a true lack of effect, weak genetic instruments, or other kinds of confounding.

KW - smoking

KW - infertility

KW - Mendelian randomization

U2 - 10.1016/j.fertnstert.2022.04.001

DO - 10.1016/j.fertnstert.2022.04.001

M3 - Article (Academic Journal)

C2 - 35562204

SN - 0015-0282

VL - 118

SP - 180

EP - 190

JO - Fertility and Sterility

JF - Fertility and Sterility

IS - 1

ER -

Smoking and infertility: multivariable regression and Mendelian randomization analyses in the Norwegian Mother, Father and Child Cohort Study

Abstract

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Keywords

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