Skip to main content
Top
Published in: BMC Infectious Diseases 1/2018

Open Access 01-12-2018 | Research article

Oseltamivir in pregnancy and birth outcomes

Authors: Vera Ehrenstein, Nickolaj Risbo Kristensen, Brigitta Ursula Monz, Barry Clinch, Andy Kenwright, Henrik Toft Sørensen

Published in: BMC Infectious Diseases | Issue 1/2018

Login to get access

Abstract

Background

Prenatal exposure to influenza or fever is associated with risk of congenital malformations. Oseltamivir is used to treat influenza and to provide post-exposure prophylaxis. We examined the association between oseltamivir use during pregnancy and birth outcomes.

Methods

This was a nationwide registry-based prevalence study with individual level data linkage, in a setting of universal health care access. We included all recorded pregnancies in Denmark in 2002–2013, and used data from population registries to examine associations between dispensings for oseltamivir during pregnancy (first trimester, second/third trimester, none) and congenital malformations, foetal death, preterm birth, foetal growth, and low 5-min Apgar score. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed using propensity score matching.

Results

The study included 946,176 pregnancies. Of these, 449 had first-trimester exposure and 1449 had second/third-trimester exposure to oseltamivir. Adjusted ORs following first-trimester exposure were 0.94 (95% CI 0.49 to 1.83) for any major congenital malformation and 1.75 (95% CI 0.51 to 5.98) for congenital heart defects, based on 7 exposed cases. The association with congenital heart defects was present for etiologically implausible exposure periods and for known safe exposures. There was no evidence of an association between prenatal exposure to oseltamivir and any of the other birth outcomes assessed.

Conclusions

The study does not provide evidence of risk associated with oseltamivir treatment additional to that associated with influenza infection.
Appendix
Available only for authorised users
Literature
1.
go back to reference Luteijn JM, Brown MJ, Dolk H. Influenza and congenital anomalies: a systematic review and meta-analysis. Hum Reprod. 2014;29:809–23.CrossRef Luteijn JM, Brown MJ, Dolk H. Influenza and congenital anomalies: a systematic review and meta-analysis. Hum Reprod. 2014;29:809–23.CrossRef
2.
go back to reference Acs N, Banhidy F, Puho E, Czeizel AE. Maternal influenza during pregnancy and risk of congenital abnormalities in offspring. Birth Defects Res A Clin Mol Teratol. 2005;73:989–96.CrossRef Acs N, Banhidy F, Puho E, Czeizel AE. Maternal influenza during pregnancy and risk of congenital abnormalities in offspring. Birth Defects Res A Clin Mol Teratol. 2005;73:989–96.CrossRef
4.
go back to reference Mosby LG, Rasmussen SA, Jamieson DJ. 2009 pandemic influenza A (H1N1) in pregnancy: a systematic review of the literature. Am J Obstet Gynecol. 2011;205:10–8.CrossRef Mosby LG, Rasmussen SA, Jamieson DJ. 2009 pandemic influenza A (H1N1) in pregnancy: a systematic review of the literature. Am J Obstet Gynecol. 2011;205:10–8.CrossRef
5.
go back to reference Pierce M, Kurinczuk JJ, Spark P, Brocklehurst P, Knight M. Perinatal outcomes after maternal 2009/H1N1 infection: national cohort study. BMJ. 2011;342:d3214.CrossRef Pierce M, Kurinczuk JJ, Spark P, Brocklehurst P, Knight M. Perinatal outcomes after maternal 2009/H1N1 infection: national cohort study. BMJ. 2011;342:d3214.CrossRef
6.
go back to reference Muthuri SG, Venkatesan S, Myles PR, Leonardi-Bee J, Al Khuwaitir TS, Al Mamun A, Anovadiya AP, Azziz-Baumgartner E, Baez C, Bassetti M, et al. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data. Lancet Respir Med. 2014;2:395–404.CrossRef Muthuri SG, Venkatesan S, Myles PR, Leonardi-Bee J, Al Khuwaitir TS, Al Mamun A, Anovadiya AP, Azziz-Baumgartner E, Baez C, Bassetti M, et al. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data. Lancet Respir Med. 2014;2:395–404.CrossRef
7.
go back to reference McKimm-Breschkin JL. Influenza neuraminidase inhibitors: antiviral action and mechanisms of resistance. Influenza Other Respir Viruses. 2013;7(Suppl 1):25–36.CrossRef McKimm-Breschkin JL. Influenza neuraminidase inhibitors: antiviral action and mechanisms of resistance. Influenza Other Respir Viruses. 2013;7(Suppl 1):25–36.CrossRef
8.
go back to reference Beau AB, Hurault-Delarue C, Vial T, Montastruc JL, Damase-Michel C, Lacroix I. Safety of oseltamivir during pregnancy: a comparative study using the EFEMERIS database. BJOG. 2014;121:895–900.CrossRef Beau AB, Hurault-Delarue C, Vial T, Montastruc JL, Damase-Michel C, Lacroix I. Safety of oseltamivir during pregnancy: a comparative study using the EFEMERIS database. BJOG. 2014;121:895–900.CrossRef
9.
go back to reference Berveiller P, Mir O, Vinot C, Bonati C, Duchene P, Giraud C, Gil S, Treluyer JM. Transplacental transfer of oseltamivir and its metabolite using the human perfused placental cotyledon model. Am J Obstet Gynecol. 2012;206:92 e1–6.CrossRef Berveiller P, Mir O, Vinot C, Bonati C, Duchene P, Giraud C, Gil S, Treluyer JM. Transplacental transfer of oseltamivir and its metabolite using the human perfused placental cotyledon model. Am J Obstet Gynecol. 2012;206:92 e1–6.CrossRef
10.
go back to reference Dunstan HJ, Mill AC, Stephens S, Yates LM, Thomas SH. Pregnancy outcome following maternal use of zanamivir or oseltamivir during the 2009 influenza a/H1N1 pandemic: a national prospective surveillance study. BJOG. 2014;121:901–6.CrossRef Dunstan HJ, Mill AC, Stephens S, Yates LM, Thomas SH. Pregnancy outcome following maternal use of zanamivir or oseltamivir during the 2009 influenza a/H1N1 pandemic: a national prospective surveillance study. BJOG. 2014;121:901–6.CrossRef
11.
go back to reference Wollenhaupt M, Chandrasekaran A, Tomianovic D. The safety of oseltamivir in pregnancy: an updated review of post-marketing data. Pharmacoepidemiol Drug Saf. 2014;23:1035–42.CrossRef Wollenhaupt M, Chandrasekaran A, Tomianovic D. The safety of oseltamivir in pregnancy: an updated review of post-marketing data. Pharmacoepidemiol Drug Saf. 2014;23:1035–42.CrossRef
12.
go back to reference Xie HY, Yasseen AS 3rd, Xie RH, Fell DB, Sprague AE, Liu N, Smith GN, Walker MC, Wen SW. Infant outcomes among pregnant women who used oseltamivir for treatment of influenza during the H1N1 epidemic. Am J Obstet Gynecol. 2013;208:293 e1–7.CrossRef Xie HY, Yasseen AS 3rd, Xie RH, Fell DB, Sprague AE, Liu N, Smith GN, Walker MC, Wen SW. Infant outcomes among pregnant women who used oseltamivir for treatment of influenza during the H1N1 epidemic. Am J Obstet Gynecol. 2013;208:293 e1–7.CrossRef
13.
go back to reference Greer LG, Sheffield JS, Rogers VL, Roberts SW, McIntire DD, Wendel GD Jr. Maternal and neonatal outcomes after antepartum treatment of influenza with antiviral medications. Obstet Gynecol. 2010;115:711–6.CrossRef Greer LG, Sheffield JS, Rogers VL, Roberts SW, McIntire DD, Wendel GD Jr. Maternal and neonatal outcomes after antepartum treatment of influenza with antiviral medications. Obstet Gynecol. 2010;115:711–6.CrossRef
14.
go back to reference Donner B, Niranjan V, Hoffmann G. Safety of oseltamivir in pregnancy: a review of preclinical and clinical data. Drug Saf. 2010;33:631–42.CrossRef Donner B, Niranjan V, Hoffmann G. Safety of oseltamivir in pregnancy: a review of preclinical and clinical data. Drug Saf. 2010;33:631–42.CrossRef
15.
go back to reference Saito S, Minakami H, Nakai A, Unno N, Kubo T, Yoshimura Y. Outcomes of infants exposed to oseltamivir or zanamivir in utero during pandemic (H1N1) 2009. Am J Obstet Gynecol. 2013;209:130.e1–9.CrossRef Saito S, Minakami H, Nakai A, Unno N, Kubo T, Yoshimura Y. Outcomes of infants exposed to oseltamivir or zanamivir in utero during pandemic (H1N1) 2009. Am J Obstet Gynecol. 2013;209:130.e1–9.CrossRef
16.
go back to reference Graner S, Svensson T, Beau AB, Damase-Michel C, Engeland A, Furu K, Hviid A, Haberg SE, Molgaard-Nielsen D, Pasternak B, et al. Neuraminidase inhibitors during pregnancy and risk of adverse neonatal outcomes and congenital malformations: population based European register study. BMJ. 2017;356:j629.CrossRef Graner S, Svensson T, Beau AB, Damase-Michel C, Engeland A, Furu K, Hviid A, Haberg SE, Molgaard-Nielsen D, Pasternak B, et al. Neuraminidase inhibitors during pregnancy and risk of adverse neonatal outcomes and congenital malformations: population based European register study. BMJ. 2017;356:j629.CrossRef
17.
go back to reference Schmidt M, Pedersen L, Sorensen HT. The Danish civil registration system as a tool in epidemiology. Eur J Epidemiol. 2014;29:541–9.CrossRef Schmidt M, Pedersen L, Sorensen HT. The Danish civil registration system as a tool in epidemiology. Eur J Epidemiol. 2014;29:541–9.CrossRef
18.
go back to reference Knudsen LB, Olsen J. The Danish medical birth registry. Dan Med Bull. 1998;45:320–3.PubMed Knudsen LB, Olsen J. The Danish medical birth registry. Dan Med Bull. 1998;45:320–3.PubMed
19.
go back to reference Schmidt M, Schmidt SA, Sandegaard JL, Ehrenstein V, Pedersen L, Sorensen HT. The Danish National Patient Registry: a review of content, data quality, and research potential. Clin Epidemiol. 2015;7:449–90.CrossRef Schmidt M, Schmidt SA, Sandegaard JL, Ehrenstein V, Pedersen L, Sorensen HT. The Danish National Patient Registry: a review of content, data quality, and research potential. Clin Epidemiol. 2015;7:449–90.CrossRef
20.
go back to reference Kildemoes HW, Sorensen HT, Hallas J. The Danish National Prescription Registry. Scand J Public Health. 2011;39:38–41.CrossRef Kildemoes HW, Sorensen HT, Hallas J. The Danish National Prescription Registry. Scand J Public Health. 2011;39:38–41.CrossRef
21.
go back to reference Larsen H, Nielsen GL, Bendsen J, Flint C, Olsen J, Sorensen HT. Predictive value and completeness of the registration of congenital abnormalities in three Danish population-based registries. Scand J Public Health. 2003;31:12–6.CrossRef Larsen H, Nielsen GL, Bendsen J, Flint C, Olsen J, Sorensen HT. Predictive value and completeness of the registration of congenital abnormalities in three Danish population-based registries. Scand J Public Health. 2003;31:12–6.CrossRef
22.
go back to reference Olsen M, Garne E, Svaerke C, Sondergaard L, Nissen H, Andersen HO, Hjortdal VE, Johnsen SP, Videbaek J. Cancer risk among patients with congenital heart defects: a nationwide follow-up study. Cardiol Young. 2014;24:40–6.CrossRef Olsen M, Garne E, Svaerke C, Sondergaard L, Nissen H, Andersen HO, Hjortdal VE, Johnsen SP, Videbaek J. Cancer risk among patients with congenital heart defects: a nationwide follow-up study. Cardiol Young. 2014;24:40–6.CrossRef
23.
go back to reference Savitz DA, Hertz-Picciotto I, Poole C, Olshan AF. Epidemiologic measures of the course and outcome of pregnancy. Epidemiol Rev. 2002;24:91–101.CrossRef Savitz DA, Hertz-Picciotto I, Poole C, Olshan AF. Epidemiologic measures of the course and outcome of pregnancy. Epidemiol Rev. 2002;24:91–101.CrossRef
24.
go back to reference Lawlor DA, Tilling K, Davey Smith G. Triangulation in aetiological epidemiology. Int J Epidemiol. 2016;45:1866–86.CrossRef Lawlor DA, Tilling K, Davey Smith G. Triangulation in aetiological epidemiology. Int J Epidemiol. 2016;45:1866–86.CrossRef
25.
go back to reference Austin PC. A tutorial and case study in propensity score analysis: an application to estimating the effect of in-hospital smoking cessation counseling on mortality. Multivariate Behav Res. 2011;46:119–51.CrossRef Austin PC. A tutorial and case study in propensity score analysis: an application to estimating the effect of in-hospital smoking cessation counseling on mortality. Multivariate Behav Res. 2011;46:119–51.CrossRef
26.
go back to reference Buhimschi CS, Weiner CP. Medications in pregnancy and lactation: part 1. Teratology. Obstet Gynecol. 2009;113:166–88.CrossRef Buhimschi CS, Weiner CP. Medications in pregnancy and lactation: part 1. Teratology. Obstet Gynecol. 2009;113:166–88.CrossRef
27.
go back to reference Dusetzina SB, Brookhart MA, Maciejewski ML. Control outcomes and exposures for improving internal validity of nonrandomized studies. Health Serv Res. 2015;50:1432–51.CrossRef Dusetzina SB, Brookhart MA, Maciejewski ML. Control outcomes and exposures for improving internal validity of nonrandomized studies. Health Serv Res. 2015;50:1432–51.CrossRef
28.
go back to reference Jepsen P, Skriver MV, Floyd A, Lipworth L, Schonheyder HC, Sorensen HT. A population-based study of maternal use of amoxicillin and pregnancy outcome in Denmark. Br J Clin Pharmacol. 2003;55:216–21.CrossRef Jepsen P, Skriver MV, Floyd A, Lipworth L, Schonheyder HC, Sorensen HT. A population-based study of maternal use of amoxicillin and pregnancy outcome in Denmark. Br J Clin Pharmacol. 2003;55:216–21.CrossRef
29.
go back to reference Dreier JW, Andersen AM, Berg-Beckhoff G. Systematic review and meta-analyses: fever in pregnancy and health impacts in the offspring. Pediatrics. 2014;133:e674–88.CrossRef Dreier JW, Andersen AM, Berg-Beckhoff G. Systematic review and meta-analyses: fever in pregnancy and health impacts in the offspring. Pediatrics. 2014;133:e674–88.CrossRef
30.
go back to reference Weiss NS. Can the “specificity” of an association be rehabilitated as a basis for supporting a causal hypothesis? Epidemiology. 2002;13:6–8.CrossRef Weiss NS. Can the “specificity” of an association be rehabilitated as a basis for supporting a causal hypothesis? Epidemiology. 2002;13:6–8.CrossRef
Metadata
Title
Oseltamivir in pregnancy and birth outcomes
Authors
Vera Ehrenstein
Nickolaj Risbo Kristensen
Brigitta Ursula Monz
Barry Clinch
Andy Kenwright
Henrik Toft Sørensen
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Infectious Diseases / Issue 1/2018
Electronic ISSN: 1471-2334
DOI
https://doi.org/10.1186/s12879-018-3423-z

Other articles of this Issue 1/2018

BMC Infectious Diseases 1/2018 Go to the issue