Risk of adverse birth outcomes after maternal varenicline use: A population‐based observational study in Denmark and Sweden

Abstract

Purpose: To examine risks of adverse birth outcomes in women exposed to varenicline during pregnancy.Methods: Population-based cohort study including live-born and stillborn infants from 1 May 2007 to 31 December 2012. Data from health and administrative registries in Denmark and Sweden, two Nordic countries with universal health care and routine registration of major life and health events. Infants were allocated to three cohorts on the basis of their in utero exposure: the exposed cohort consisting of infants whose mothers were dispensed varenicline during pregnancy; the unexposed cohort comprised infants unexposed to varenicline, but exposed to maternal smoking in utero; and the reference cohort of infants unexposed to varenicline and maternal smoking in utero.The primary outcome was major congenital malformations diagnosed from birth to the first year of life. Secondary outcomes included stillbirth, fetal growth restriction (measured as small for gestational age), preterm delivery, preterm premature rupture of membranes, and sudden infant death syndrome. We estimated the prevalence of the primary outcome and secondary outcomes in the exposed, unexposed, and reference cohorts. Prevalence odds ratios with 95% confidence intervals (CIs) were computed using logistic regression with propensity score adjustment to control for potential confounders. Results:The combined cohort included 885 185 infants. Of these, 335 infants were exposed, 78 412 were unexposed, and the remaining 806 438 comprised the reference cohort. Major congenital malformations were detected among 3.6% of exposed infants, 4.3% of unexposed infants, and 4.2% of infants in the reference cohort. The propensity score-adjusted prevalence odds ratio for major congenital malformations was 0.80 (95% CI, 0.45-1.42) for exposed vs unexposed infants. All analyses of primary and secondary outcomes comparing exposed with unexposed infants yielded odds ratio estimates below or close to unity.Use of varenicline during pregnancy does not appear to increase the risk of major congenital malformations or other adverse birth outcomes. KEYWORDSobservational study, pharmacoepidemiology, pregnancy outcome, vareniclineMaternal smoking is associated with a wide range of adverse pregnancy outcomes, such as placental complications, preterm birth, and fetal death. 1 Whether smoking during pregnancy increases the prevalence of congenital malformations remains unsettled; the existing literature shows no strong teratogenic effect on congenital malformations overall. 2,3 But smoking may increase the risk of specific malformations such as cardiovascular defects and oral clefts. 3,4 Smoking cessation programs should always be offered to smokers who plan a pregnancy, but the safety of nicotine substitute use in pregnancy is unknown. 5 One previous study found that nicotine replacement therapy was associated with increased risk of congenital malformations in children born to nonsmoking mothers, 6 while several other studies found no association with risk of stillbirth or low birthw...

The Swedish medical birth register during five decades: documentation of the content and quality of the register

“…Data will be pseudonymized before sent to the researcher. large studies, by using similar data from the Nordic countries (Denmark, Norway, Finland, Iceland, and Sweden) [30][31][32][33][34].…”

Tobacco use during pregnancy

“…There have been no randomised studies evaluating the effects of varenicline when used during pregnancy [83], and only one observational study of varenicline's effectiveness during pregnancy, finding that pregnant women using varenicline were almost threefold more likely to quit smoking than women using nicotine patches (RR 2.8, 95% CI 1.4 to 5.7) [85]. In the two controlled observational studies of the safety of varenicline during pregnancy that have been conducted, varenicline was not associated with an increased risk of adverse birth outcomes [86,87]. In the larger of these two studies, varenicline was found to reduce the risk of preterm birth and small for gestational age compared to women who smoked during pregnancy [87].…”

Transferability of real-world data across borders for regulatory and health technology assessment decision-making

“…When imported RWD are submitted for safety and/or efficacy evaluations, it may not be clear if regulatory agencies consider the transferability of RWD. For example, the FDA required the sponsor of varenicline (CHANTIX ® /CHAMPIX ® ) to submit a post-marketing safety study to compare pregnancy and birth outcomes among pregnant women exposed to varenicline with women who smoked during pregnancy and with non-smoking pregnant women ( 27 ). The sponsor submitted a population-based, prospective cohort study based on registries in Denmark and Sweden, countries that routinely track major life and health events, including pregnancy and birth outcomes ( 27 ).…”

“…For example, the FDA required the sponsor of varenicline (CHANTIX ® /CHAMPIX ® ) to submit a post-marketing safety study to compare pregnancy and birth outcomes among pregnant women exposed to varenicline with women who smoked during pregnancy and with non-smoking pregnant women ( 27 ). The sponsor submitted a population-based, prospective cohort study based on registries in Denmark and Sweden, countries that routinely track major life and health events, including pregnancy and birth outcomes ( 27 ). The publicly available label update and supplemental approval letter note potential misclassification of the outcomes and exposure but do not comment on the use of data from outside the US ( 28 ).…”