Pulmonary Effects of Maternal Smoking on the Fetus and Child: Effects on Lung Development, Respiratory Morbidities, and Life Long Lung Health

Abstract

Maternal smoking during pregnancy is the largest preventable cause of abnormal in-utero lung development. Despite well known risks, rates of smoking during pregnancy have only slightly decreased over the last ten years, with rates varying from 5-40% worldwide resulting in tens of millions of fetal exposures. Despite multiple approaches to smoking cessation about 50% of smokers will continue to smoke during pregnancy. Maternal genotype plays an important role in the likelihood of continued smoking during pregnancy and the degree to which maternal smoking will affect the fetus. The primary effects of maternal smoking on offspring lung function and health are decreases in forced expiratory flows, decreased passive respiratory compliance, increased hospitalization for respiratory infections, and an increased prevalence of childhood wheeze and asthma. Nicotine appears to be the responsible component of tobacco smoke that affects lung development, and some of the effects of maternal smoking on lung development can be prevented by supplemental vitamin C. Because nicotine is the key agent for affecting lung development, e-cigarette usage during pregnancy is likely to be as dangerous to fetal lung development as is maternal smoking.

Keywords: Asthma; Forced expiratory flows; In-utero smoke; Lung development; Preterm birth; Wheeze.

Figure 1. Prenatal nicotine exposure increases α7 nAChR expression in fetal monkey lung (134 days gestation)

Immunohistochemical localization of nicotinic receptor subtypes in 134- day fetal monkey lung. a and c from control fetus; b and d from nicotine exposed fetus. (a) Anti-α7 (MAB 319) showing brownish-red staining in fibroblast cell layer in cartilaginous airways and vessel walls. X 100. (b) In nicotine-exposed fetus, greatly enhanced α7 staining is seen in cartilaginous airway and vessel walls. X 100. No immunostaining was seen with nonimmune serum (not shown). (c and d) Higher-power view of smaller cartilaginous airways showing relatively little α7 in airway wall and epithelial cell lining in control lung, but intense staining in airway wall and epithelial cells (arrows) from nicotine exposed lung. X 400. AEC was used as immunoperoxidase substrate, and hematoxylin was used as counterstain. A, airway lumen; V, blood vessel lumen; C, cartilage; AEC, 3-amino-9-ethylcarbazole; MAB, monoclonal antibody. (Reprinted with permission from J. Clin. Invest (43)).

Figure 2

Adult mice exposed to prenatal nicotine have significantly greater numbers of small bronchioles compared with unexposed control animals. C57BL6/J female mice were administered either untreated water or water containing 100 μg/ml nicotine before timed breeding and through gestation. Lungs were obtained from age-matched offspring at 8 weeks of age. Whole lungs were embedded and sectioned in an isotropic, uniform random manner to create unbiased samples for examination. Airway diameter was measured for each visible bronchus and bronchiole. Mice exposed to prenatal nicotine had significantly greater numbers of small bronchioles, with diameters between 60–90 μm (n = 8 per group). Error bars denote SD. *P < 0.05 compared with control. (Reprinted with permission of the American Thoracic Society (47) The American Journal of Respiratory Cell and Molecular Biology is an official journal of the American Thoracic Society).

Figure 3. Effect of Maternal Smoking During Pregnancy on Newborn Pulmonary Function as Modulated by Maternal α5 Genotype (rs16969968)

Newborns whose mothers were homozygous for the risk allele in which amino acid 398 of the α5 nAChR is changed from Asp to Asn showed the largest decrease in TPTEF:TE comparing placebo to vitamin C treatment. Values presented are means and 95% confidence intervals. Asp/Asp indicates mothers homozygous for non-risk allele, Asp/Asn indicates heterozygous mothers, Asn/Asn indicates mothers homozygous for risk allele. P values comparing TPTEF:TE values from newborns of mothers randomized to vitamin C versus placebo are 0.02, 0.32, 0.07 and < 0.0001 for mothers of all genotypes, Asp/Asp, Asp/Asn and Asn/Asn respectively. P values are from linear mixed models (used to allow for unequal variance) adjusting for gestational age at randomization (≤ 16 versus > 16 weeks), birthweight, and gestational age < 37 weeks, and allowing for different SD's within each genotype. (Reprinted with permission from JAMA (33)).