Preterm Birth, Developmental Smoke/Nicotine Exposure, and Life-Long Pulmonary Sequelae

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TL;DR

This narrative review examines the lifelong pulmonary consequences of preterm birth and perinatal tobacco/nicotine exposure, highlighting that both independently increase risk for chronic respiratory morbidity including asthma, reduced lung function, and airway hyperresponsiveness. Preterm birth disrupts normal lung development across five stages, while nicotine exposure upregulates Wnt signaling and downregulates PPARγ pathways, leading to excessive airway smooth muscle and fixed airflow obstruction. The clinical significance lies in the need for continued respiratory surveillance in preterm-born individuals across the lifespan and for intensified tobacco cessation efforts during pregnancy, as epigenetic and transgenerational effects may propagate pulmonary risk to subsequent generations.

Full summary

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**Background:** Preterm birth (PTB), defined as delivery before 37 weeks' gestation, is the leading cause of death in children under five years, with approximately 1 million annual deaths globally and an estimated 15 million preterm deliveries per year worldwide. The global PTB rate increased from 9.8% in 2000 to 10.6% in 2014. The United States ranks sixth among countries with the highest number of PTBs, with 517,000 cases annually. The U.S. spends approximately USD 26 billion yearly on medical care for preterm infants, excluding costs of long-term sequelae such as chronic lung disease and asthma. Maternal smoking during pregnancy is independently associated with both preterm delivery and increased respiratory morbidities including asthma. Despite public health initiatives like Healthy People 2030 aiming to reduce PTB to 9.4% and increase smoking abstinence to 95.7%, sustainable declines have not been achieved. This review synthesizes evidence on the pulmonary consequences of PTB and perinatal smoke/nicotine exposure across the lifespan, including potential transgenerational effects.

**Methods:** This is a narrative review that synthesizes published literature on normal lung development, PTB epidemiology, respiratory outcomes following PTB at various life stages, and mechanisms of tobacco/nicotine-induced pulmonary damage. The authors draw on epidemiological data from WHO, U.S. National Vital Statistics, and the National Health Interview Survey, as well as experimental animal models (rodent, sheep, primate) and in vitro studies examining nicotine's effects on lung cell types including alveolar type II cells, fibroblasts, endothelial cells, and stem cells.

**Key Results:** Former preterm infants demonstrate more respiratory symptoms (cough, wheezing) during preschool and school-age years compared to term-born controls, independent of bronchopulmonary dysplasia (BPD) status, though symptoms are more frequent in those with BPD. The overall wheezing risk in former preterm-born individuals is increased by 1.71-fold, with inverse correlation to gestational age. Exercise capacity is reduced in preterm-born individuals both with and without BPD. Lung volumes measured at term equivalent in infants born before 28 weeks are lower than term-born infants, and lung function worsens across ages 3–6, 7–11, and 12–20 years. Preterm-born individuals do not achieve optimal peak lung function as adults. Regarding perinatal smoke/nicotine exposure, subjects born to mothers who smoked during pregnancy had an adjusted hazard ratio of 1.79 (95% CI, 1.20–2.67) for asthma compared to non-smoking mothers. Nicotine crosses the placenta with minimal biotransformation, and fetal serum nicotine concentrations can be 15% higher than maternal concentrations. Mechanistically, perinatal nicotine exposure upregulates Wnt signaling and downregulates PPARγ signaling in the developing lung, resulting in excessive myofibroblast differentiation and proliferation. Epigenetic changes including DNA methylation alterations in genes such as AHRR, GFI1, FOXP3, CYP1A1, and RUNX have been identified in cord blood following prenatal smoke exposure, with some persisting up to 18 months of age. Experimental rat models demonstrate transgenerational transmission of airway hyperresponsiveness to second and third-generation offspring without subsequent nicotine exposure beyond the F0 generation. In the U.S., maternal smoking during pregnancy declined from 7.2% (2016) to 5.5% (2020), and adult cigarette smoking reached 12.5% in 2020, the lowest since 1965.

**Clinical Implications:** The review emphasizes that inquiry into PTB and perinatal exposures should be part of routine adult health care, with emphasis on tobacco/nicotine avoidance, regular exercise, and annual influenza immunization. Routine spirometry in adult follow-up clinics for preterm-born individuals may be valuable but remains unproven. Bronchodilator and/or inhaled corticosteroid therapy should be based on individualized risk-benefit analysis rather than the presence of audible wheeze alone. The authors note that pulmonary outcomes differ between pre-surfactant and post-surfactant eras, and future outcomes will continue to evolve with changing thresholds of viability and improvements in perinatal care. Given the dose-effect relationship between nicotine intake and pregnancy outcomes, smoking cessation strategies at any stage during pregnancy should be emphasized. The review suggests that deeper mechanistic understanding of nicotine-mediated damage may enable future epigenetic-targeted therapeutics for those with perinatal tobacco/nicotine exposure.