Use of smoking cessation pharmacotherapies during pregnancy is not associated with increased risk of adverse pregnancy outcomes: a population-based cohort study

Abstract

Background: Varenicline, bupropion and nicotine replacement therapy (NRT) are three effective pharmacotherapies for smoking cessation, but data about their safety in pregnancy are limited. We assessed the risk of adverse perinatal outcomes and major congenital anomalies associated with the use of these therapies in pregnancy in Australia. Methods: Perinatal data for 1,017,731 deliveries (2004 to 2012) in New South Wales and Western Australia were linked to pharmaceutical dispensing, hospital admission and death records. We identified 97,875 women who smoked during pregnancy; of those, 233, 330 and 1057 were exposed to bupropion, NRT and varenicline in pregnancy, respectively. Propensity scores were used to match exposed women to those who were unexposed to any smoking therapy (1:10 ratio). Propensity scores and gestational age at exposure were used to match varenicline-exposed to NRT-exposed women (1:1 ratio). Time-dependent Cox proportional hazards models estimated hazard ratios (HR) with 95% confidence intervals (95% CI) for any adverse perinatal event (a composite of 10 unfavourable maternal and neonatal outcomes) and any major congenital anomaly. Results: The risk of any adverse perinatal event was not significantly different between bupropion-exposed and unexposed women (39.2% versus 39.3%, HR 0.93, 95% CI 0.73-1.19) and between NRT-exposed and unexposed women (44.8% vs 46.3%, HR 1.02, 95% CI 0.84-1.23), but it was significantly lower in women exposed to varenicline (36.9% vs 40.1%, HR 0.86, 95% CI 0.77-0.97). Varenicline-exposed infants were less likely than unexposed infants to be born premature (6.5% vs 8.9%, HR 0.72, 95% CI 0.56-0.92), be small for gestational age (11.4% vs 15.4%, HR 0.68, 95% CI 0.56-0.83) and have severe neonatal complications (6.6% vs 8.2%, HR 0.74, 95% CI 0.57-0.96). Among infants exposed to varenicline in the first trimester, 2.9% had a major congenital anomaly (3.5% in unexposed infants, HR 0.91, 95% CI 0.72-1.15). Varenicline-exposed women were less likely than NRT-exposed women to have an adverse perinatal event (38.7% vs 51.4%, HR 0.58, 95% CI 0.33-1.05).

Selective Expression of Nicotinic Receptor Sub-unit mRNA in Early Human Fetal Forebrain

“…For these reasons, nicotine replacement therapy has been proposed as advisable for pregnant women who find it hard to stop smoking during pregnancy (Benowitz and Dempsey, 2004). A recent study has shown that nicotine replacement therapy may be relatively protective of the fetus, compared to smoking, for those births that reach full term (Tran et al, 2020). Nevertheless nicotine, which is the major psychoactive component of tobacco smoke and the primary cause of addiction, has been shown to cross the placenta, enter fetal circulation and accumulate in the fetus from as early as 7 weeks of gestation (Jauniaux et al, 1999).…”

Fetal safety of nicotine replacement therapy in pregnancy: systematic review and meta‐analysis

“…Eleven were conducted in health‐care settings, used routine clinical data [32–42], compared women prescribed or issued NRT with those who were not and were derived from five discrete birth cohorts. A UK cohort reported outcomes in two manuscripts [32,34] and a PhD [38]; a Danish cohort reported outcomes in five papers [33,35,37,39,42] and Canadian [40], US [36] and Australian [41] cohorts were reported in single studies. Eleven studies described NRT administration to small, experimental interventional cohorts of inpatient pregnant women who usually smoked but were temporarily abstinent [43–53], and were based in Sweden [43,48], the United States [45,46,49–53], the United Kingdom [44] and Finland [47].…”

“…Maternal age was reported by 17 studies [32–36,38–40,43,45,46,48–53] and used as a confounder in analyses, but not reported in three [33,37,41,42]. Socio‐economic status or education level was reported by 11 studies [32–40,42,51].…”

“…Table 3 reports outcomes by study. Two studies excluded from the preterm birth meta‐analysis compared risks of preterm birth following NRT use in women who smoked; there was a significantly reduced risk in NRT users compared to non‐users in one paper (adjusted OR = 0.21, 95% CI = 0.13–0.34) [40], while the second showed no significant difference (HR = 1.00, 95% CI = 0.71–1.42) [41].…”

“…Compared with no NRT use, exposure was associated with reduced risk of fetal death (OR = 0.44, 99% CI = 0.38–0.50, P < 0.001) [38] and of assisted delivery (relative RR (RRR) = 0.68, 99% CI = 0.54–0.85, P < 0.001) but not with increased risk of caesarean section [38]. A study of women who smoked who were exposed to NRT reported a composite outcome: ‘any adverse perinatal event’, encompassing a number of separate birth outcomes [41]. Table 2 reports the individual outcome HRs, but there was no significant change in overall risk of any adverse perinatal event when comparing women who smoked who were exposed to NRT and those who were not (HR = 1.02, 95% CI = 0.84–1.23).…”