Nicotine replacement therapy (NRT) is now being used as a smoking cessation aid during pregnancy, although little is known about fetal safety. We assessed the relationship between early pregnancy exposure to NRT or smoking with major congenital anomalies (MCA) in offspring.
We studied 192 498 children born in the United Kingdom between 2001 and 2012 with linked mother–child primary care records. The absolute risks of MCAs in the NRT group (women prescribed NRT during the first trimester or 1 month before conception [and therefore likely consumed during the first trimester]) and odds ratios (ORs) and 99% confidence intervals (CIs) were compared with those of women who smoked during pregnancy and with a control group (women who neither smoked nor were prescribed NRT); logistic regression models adjusted for maternal morbidities that increase MCA risk were used for analysis.
MCA prevalence was 288 per 10 000 live births (5535 children with ≥1 MCA). Maternal morbidities were most common in the NRT group (35%) followed by smokers (27%) and the control group (20%). Compared with the control group, adjusted ORs for MCAs in the NRT group and smokers were 1.12 (99% CI: 0.84–1.48) and 1.05 (99% CI: 0.89–1.23), respectively. The OR comparing the NRT group directly with smokers was 1.07 (99% CI: 0.78–1.47). There were no statistically significant associations between maternal NRT and system-specific anomalies except for respiratory anomalies (OR: 4.65 [99% CI: 1.76–12.25]; absolute risk difference: 3 per 1000 births), which was based on 10 exposed cases.
For most system-specific MCAs, we found no statistically significant increased risks associated with maternal NRT prescribed during pregnancy, except for respiratory anomalies. Although this study is the largest published to date, NRT use in pregnancy remains rare; thus, the statistical power was limited. Higher morbidities in those women prescribed NRT may also be an explanatory factor. Nevertheless, absolute MCA risks were similar between women who smoked and those prescribed NRT during pregnancy.
Comments
Nicotine Replacement Therapy in Pregnancy
Nicotine replacement therapy (NRT) is promoted not only by UK but also by French authorities (1) and as Dhalwani et al.(2) point out "despite the inconclusive evidence regarding its general maternal or fetal safety" as a Cochrane meta-analysis concluded (3). Dhalwani et al.'s (2) paper has the highest power and probably the best quality to date to show an association between NRT use and major congenital anomalies (MCA). However, my reading of the results is less optimistic than that of the authors.
Absolute risk of MCA was 336, 315 and 285/10000 live births in the NRT exposed group, among smokers and non-smokers (controls), respectively, with adjusted odds ratios (AOR) of 1.12 (99% CI 0.84-1.48) and 1.05 (99% CI 0.89-1.23) for the NRT and smokers' group compared to controls. Among the system specific congenital anomalies (SSCA) only respiratory anomalies showed a significant increase with NRT compared both to non-smoking (AOR=4.65, 99% CI 1.76-12.25, p<0.001) and smoking pregnant women (AOR=3.49, 99% CI 1.05-11.62, p=0.007) but the smokers' group was not different from controls (AOR=1.34, 99% CI: 0.54-3.31). Looking at Table 3 the absolute risks for most SSCA shows the same "dose-dependent" pattern than MCA: NTR>smokers>controls.
As the authors note, it is difficult to disentangle the effects of smoking from those of NRT. Prevalence of asthma and mental illnesses was higher among pregnant smokers on NRT than among smokers without NRT who had in turn higher prevalence than non-smokers but the authors controlled for these differences. It is also probable that "women prescribed NRT may have been heavier smokers"2 and "unmeasured confounding factors" (2) may have contributed to the increased absolute risk, significant or not, observed among offspring exposed to NRT. However, I cannot support the view that "simultaneous use of NRT and cigarettes should" (2) have been "minimal" (2). Two recent, randomized, placebo controlled, multicenter studies have shown that pregnant smokers' response (abstinence) to NRT is extremely low, not different from placebo (4,5) and continuous abstinence is as low as 5 % (5). Difficulty to quit is either a specific feature of pregnant smoking i.e. higher level of addiction and/or pregnant smokers need much higher NRT doses than other population of smokers. Therefore it is of high likelihood that pregnant smokers on NRT in the Dhalwani et al.(2) study were not able to stop completely smoking and this dual use: NRT and smoking could lead to the observed additional absolute risks which became significant only for respiratory CA.
Thus my reading of the findings is that until having straightforward, biologically verified abstinence data to separate NRT's specific effect on MCA from smoking, NRT should be used long-term in pregnancy if it is associated with complete abstinence to avoid an additional risk. When starting NRT in pregnant smokers, health care professionals should point out that complete and continuous abstinence is the therapeutic target.
1. Agence national de securite du medicament et des produits de sante. Utilisation des traitements de substitution nicotinique (TSN) chez les femmes enceintes - Point d'information/point d'etape. 2006
2. Dhalwani NN, Szatkowski L, Coleman T, Fiaschi L, Tata LJ. Nicotine Replacement Therapy in Pregnancy and Major Congenital Anomalies in Offspring. Pediatrics. 2015 Apr 6. pii: peds.2014-2560. [Epub ahead of print]
3. Coleman T, Chamberlain C, Davey MA, Cooper SE, Leonardi-Bee J. Pharmacological interventions for promoting smoking cessation during pregnancy.Cochrane Database Syst Rev. 2012 Sep 12;9:CD010078.
4.Coleman T, Cooper S, Thornton JG, Grainge MJ, Watts K, Britton J, Lewis S; Smoking, Nicotine, and Pregnancy (SNAP) Trial Team. A randomized trial of nicotine-replacement therapy patches in pregnancy.N Engl J Med. 2012 Mar 1;366(9):808-818.
5. Berlin I, Grang? G, Jacob N, Tanguy ML.Nicotine patches in pregnant smokers: randomised, placebo controlled, multicentre trial of efficacy.BMJ. 2014 Mar 11;348:g1622
Conflict of Interest:
None declared