Prenatal exposure to nitrosatable drugs and timing of puberty in sons and daughters: A nationwide cohort study
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N-nitroso compounds (NOCs) can be formed by endogenous reactions between nitrosatable drugs and nitrite. Animal studies have found that several NOCs are teratogenic, and epidemiological studies report associations between prenatal exposure to nitrosatable drugs and adverse birth outcomes. It is unknown whether prenatal exposure to nitrosatable drugs is harmful to the child's reproductive health, including pubertal development.
Objectives
We investigated whether prenatal exposure to nitrosatable drugs was associated with timing of puberty and whether nitrate, nitrite and antioxidant intake modified any association.
Methods
The population-based Danish National Birth Cohort (DNBC) Puberty Cohort, which includes 15,819 children, was used to investigate the association between prenatal exposure to nitrosatable drugs and timing of puberty. Around gestational week 11 and gestational week 18, mothers provided information about drug use during pregnancy. The children's self-reported information on onset of pubertal milestones was collected every six months from 11 years of age and throughout puberty. To investigate potential effect modification by nitrite, nitrate and antioxidant intake, information on these factors was obtained from a food frequency questionnaire completed by the mothers in gestational week 25, and information on nitrate concentration in maternal drinking water at her residential address was obtained from monitoring data from public waterworks. Data were analysed using a multivariable regression model for interval-censored data estimating difference in months in timing of puberty between exposure groups.
Results
A total of 2,715 children were prenatally exposed to nitrosatable drugs. We did not find an association between prenatal exposure to nitrosatable drugs and timing of puberty. This finding was supported by null-findings in the following sub-analyses investigating: 1. subtypes of nitrosatable drugs (secondary and tertiary amines and amides), 2. dose-dependency (duration of drug intake), 3. effect modification by maternal intake of nitrate, nitrite, and antioxidants. 4. confounding by indication.
Conclusions
Prenatal exposure to nitrosatable drugs was not associated with timing of puberty. Nitrosatable drugs are commonly used drugs in pregnancy, and further research is needed to allow firm conclusions on the potential effect of prenatal exposure to nitrosatable drugs on the child's reproductive health.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 114271 |
| Tidsskrift | International Journal of Hygiene and Environmental Health |
| Vol/bind | 254 |
| Antal sider | 9 |
| ISSN | 1438-4639 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
The Danish National Birth Cohort was established with a significant grant from the Danish National Research Foundation . Additional support was obtained from the Danish Regional Committees , the Pharmacy Foundation , the Egmont Foundation , the March of Dimes Birth Defects Foundation , the Health Foundation and other minor grants. The DNBC Biobank has been supported by the Novo Nordisk Foundation and the Lundbeck Foundation . Follow-up of mothers and children have been supported by the Danish Medical Research Council ( SSVF 0646 , 271-08-0839/06–066023 , O602–01042B , 0602–02738B ), the Lundbeck Foundation ( 195/04 , R100-A9193 ), The Innovation Fund Denmark 0603-00294B ( 09–067124 ), the Nordea Foundation ( 02-2013-2014 ), Aarhus Ideas ( AU R9-A959-13-S804 ), University of Copenhagen Strategic Grant ( IFSV 2012 ), and the Danish Council for Independent Research ( DFF – 4183-00594 and DFF - 4183-00152 ).
Funding Information:
This study has been supported by the Graduate School of Health, Aarhus University and The Health Foundation (19-B-0075). The project was co-funded by Christian and Ottilia Brorsons travelling scholarship, the Gangsted foundation , Torben and Alice Frimodts Foundation and Department of Public Health, Aarhus University . The project was further co-funded by the European Union ( ERC , BIOSFER , 101071773 ). Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible for them.
Funding Information:
The nitrosatable OTC drug and drinking water nitrate exposure assessment was supported by a grant from the United States National Institute of Environmental Health Sciences ( R01 ES027823-01A1 ) and BERTHA - the Danish Big Data Centre for Environment and Health funded by the Novo Nordisk Foundation Challenge Programme (grant NNF17OC0027864 ).
Funding Information:
This study has been supported by the Graduate School of Health, Aarhus University and The Health Foundation (19-B-0075). The project was co-funded by Christian and Ottilia Brorsons travelling scholarship, the Gangsted foundation, Torben and Alice Frimodts Foundation and Department of Public Health, Aarhus University. The project was further co-funded by the European Union (ERC, BIOSFER, 101071773). Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible for them.The nitrosatable OTC drug and drinking water nitrate exposure assessment was supported by a grant from the United States National Institute of Environmental Health Sciences (R01 ES027823-01A1) and BERTHA - the Danish Big Data Centre for Environment and Health funded by the Novo Nordisk Foundation Challenge Programme (grant NNF17OC0027864). The Danish National Birth Cohort was established with a significant grant from the Danish National Research Foundation. Additional support was obtained from the Danish Regional Committees, the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Health Foundation and other minor grants. The DNBC Biobank has been supported by the Novo Nordisk Foundation and the Lundbeck Foundation. Follow-up of mothers and children have been supported by the Danish Medical Research Council (SSVF 0646, 271-08-0839/06–066023, O602–01042B, 0602–02738B), the Lundbeck Foundation (195/04, R100-A9193), The Innovation Fund Denmark 0603-00294B (09–067124), the Nordea Foundation (02-2013-2014), Aarhus Ideas (AU R9-A959-13-S804), University of Copenhagen Strategic Grant (IFSV 2012), and the Danish Council for Independent Research (DFF – 4183-00594 and DFF - 4183-00152). Access to data from the DNBC can be obtained. The procedure for application for data access is available at the website: https://www.dnbc.dk/access-to-dnbc-data.
Publisher Copyright:
© 2023 The Authors
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