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A multinational cohort study led by Australian researchers finds no clear evidence that prenatal exposure to smoking cessation pharmacotherapies causes congenital malformations in babies
Tobacco smoking during pregnancy is a leading cause of avoidable harms to mothers and children including preterm birth, low birth weight, congenital malformations and even infant death. Despite this, almost 1 in 10 mothers in Australia report smoking during pregnancy. If pregnant women quit smoking during the first trimester, the risk of adverse outcomes is reduced, although not to the level experienced by women who do not smoke at all during pregnancy. This highlights a clear need for support with quitting among pregnant women.
Psychosocial interventions such as counselling, feedback and financial incentives are recommended as first-line treatment for pregnancy based on evidence that they can increase smoking cessation and reduce the risk of adverse birth outcomes in some contexts. If these behavioural approaches are unsuccessful, pharmacotherapy can be considered. There are three pharmaceutical products registered as smoking cessation aids in Australia and most other high income countries; all three are listed on the Pharmaceutical Benefits Scheme (PBS). They include nicotine replacement therapy (NRT), varenicline and bupropion.
Uncertainty about the fetal safety of these medicines, however, presents a barrier to their use among pregnant women. There is a lack of clear evidence particularly in relation to the risk of congenital malformations, with previous studies not large enough to provide precise estimates of risk (here and here) even when findings from multiple studies were pooled in a meta-analysis. An additional weakness of some studies was the failure to take into account the underlying risk from maternal smoking (here, here and here). Given this uncertainty, clinical guidelines advise that NRT be used with caution and that varenicline and bupropion be avoided altogether during pregnancy.
How did our research address this uncertainty?
We assessed the potential teratogenic effects of smoking cessation pharmacotherapies by conducting a large multinational cohort study using data that were routinely collected through interactions with the health system. The research was led out of UNSW Sydney where we have constructed a database containing records of all births in NSW since 2001. These birth records are linked to a range of other data sources including PBS dispensing records, hospital admissions and death records. Using this linked data platform and similar data platforms held by our collaborators in New Zealand, Norway and Sweden, we calculated the rates of major congenital malformations among babies born to women who were dispensed a prescription smoking cessation pharmacotherapy in the first trimester of pregnancy. We compared these rates to those among babies born to women who smoked during early pregnancy but did not use a prescription smoking cessation medicine. To reduce bias due to confounding, we used a statistical matching technique that ensured the groups being compared were similar in terms of a wide range of maternal sociodemographic, obstetric and health characteristics.
Our study included 9325 babies prenatally exposed to prescription NRT. When compared with babies of women who smoked during early pregnancy without using any of these smoking cessation pharmacotherapies, we found no difference in the overall rates of major congenital malformations (3.76% vs 3.44%). We also measured the risk in 12 malformation subcategories defined by body system. These analyses yielded an elevated risk only for digestive system malformations, however, post-hoc adjustment for the large number of comparisons in the study suggests this finding could have arisen by chance.
In the 3031 babies exposed to varenicline, we found no difference in the rate of malformations overall (3.27% vs 3.66%). Across the 12 malformation subcategories, we found an elevated risk for kidney and urinary tract malformations, which again was potentially due to chance.
Bupropion was also not associated with an increased risk of malformation overall (3.55% vs 3.88%), but with only 1042 exposed babies, we could not draw any conclusions about the risk of malformation subcategories.
While this is the largest study of prenatal exposure to smoking cessation pharmacotherapies conducted to date, it is subject to limitations. This includes that assignment to treatment was not randomised, and although we controlled for a comprehensive range of potential confounders, residual differences between the treatment groups are still possible. In addition, because we did not have data on NRT purchased over the counter, it is possible that some babies in the comparison group were exposed to over-the-counter NRT. However, we expect such misclassification to be minor and unlikely to bias the results because our results for NRT were largely based on data from New Zealand, where anecdotal evidence suggests that the majority of NRT obtained by individuals is likely to be via prescription. Other potential limitations, including the potential non-use of the dispensed pharmacotherapy, were acknowledged and tested in supplementary analyses.
What are the implications of this new evidence?
The evidence from this study represents a major step forward in what we know about the safety of smoking cessation pharmacotherapies during pregnancy, finding no clear evidence that these medicines increase the risk of congenital malformations. While we observed potentially elevated risks of digestive system malformations for NRT and kidney and urinary tract malformations for varenicline, the numbers of affected infants were small. This information, in combination with existing evidence that these medicines do not increase the risk of other adverse maternal and child health outcomes, should reassure mothers who inadvertently expose their babies to these medicines before becoming aware of their pregnancy.
There are, however, remaining uncertainties. In addition to needing further data on the risk of certain malformation subcategories, particularly for bupropion, we need more convincing evidence regarding the effectiveness of these medicines when used during pregnancy. While they are established as effective in the general population, this evidence may not generalise to pregnancy because of changes in medicine absorption, metabolism and excretion. These uncertainties make it challenging to decide whether to use one of these pharmacotherapies, and if so, which one. Nonetheless, this new evidence will help inform these decisions, supporting mothers and their health care providers to better weigh the potential benefits of these medicines against the potential risks.
Dr Alys Havard is an associate professor at the National Drug and Alcohol Research Centre and in the Medicines Intelligence Research Program in the School of Population Health at UNSW Sydney. She is also deputy director at the National Drug and Alcohol Research Centre.
Dr Duong (Danielle) Tran is a senior research fellow at the National Drug and Alcohol Research Centre at UNSW Sydney.
The authors do not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.
The statements or opinions expressed in this article reflect the views of the authors and do not necessarily represent the official policy of the AMA, the MJA or InSight+ unless so stated.
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