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. ×100. (b) In nicotine-exposed fetus, greatly enhanced α7 staining is seen in cartilaginous airway and vessel walls. ×100. No immunostaining was seen with nonimmune serum (not shown). (c and d) High-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. ×400. AEC was used as immunoperoxidase substrate, and hematoxylin was used as counterstain. A airway lumen, V blood vessel lumen, C cartilage,AEC3-amino-9-ethylcarbazole,MAB monoclonal antibody (Reprinted with permission obtained from the American Society for Clinical Investigation publications Sekhon et al. )
Studies in mice have suggested the potential mechanism by which prenatal nicotine exposure leads to decreases in expiratory flows is by affecting airway growth. Nicotine stimulated lung branching and dysnaptic/disproportionate lung growth in a dose-dependent fashion in embryonic murine lung explants . This was further studied in vivo in a murine model of in utero nicotine exposure in which pregnant mice were treated with nicotine from gestation day 7 to postnatal day 14. Similar to changes seen in humans and nonhuman primates, this combination of prenatal and postnatal nicotine exposure caused significant decreases in forced expiratory flows in the offspring . A primary mediator of this effect appeared to be the α7 nAChR, as the effect of nicotine was lost in α7 nAChR knockout mice . Further studies in this model demonstrated that the critical period for perinatal nicotine exposure to alter forced expiratory flows was exposure that corresponded to the end of the pseudoglandular period through the canalicular and saccular periods, but before most of the alveolarization  and suggests a primary effect of nicotine on airway growth. This was confirmed by stereological analysis of airway size and diameter which showed an increased number of airways of small diameter with nicotine treatment. These data suggest that prenatal nicotine exposure leads to decreased forced expiratory flows by stimulating epithelial cell growth and potentially lung branching to result in longer and more tortuous airways.
Smoking Cessation/Decreasing Maternal Smoking Reduces Preterm Birth
A recent Cochrane review  concluded that smoking cessation programs reduce the proportion of women who smoke and reduce the rate of preterm birth. This review concluded that the effect was larger when counseling was combined with other strategies such as providing feedback with biochemical measures. It also found incentive-based interventions to be effective, but these randomized controlled trials (RCTs) were underpowered to assess the effect on preterm births. A recent meta-analysis  involving 1.3 million women demonstrated that the introduction of antismoking legislation reduced preterm birth rates by 10 %. This was likely due to cessation in the smoking mother but also in those around her with subsequent decreased exposure to passive smoke. Cnattingius et al.  studied 250,000 women who delivered consecutive singletons examining women who either began smoking or stopped smoking in between the two deliveries. The risk of preterm birth was either increased or decreased respectively in a dose-dependent fashion, indicating that effective smoking cessation efforts should reduce preterm birth and by translation decrease post NICU respiratory morbidities.
Nicotine Replacement Therapies (NRT)
Nicotine replacement therapies have also been studied as a means of smoking cessation; however, based on the studies discussed above, nicotine itself will continue to have significant adverse effects on lung development. Also, randomized clinical trials have not demonstrated that nicotine replacement is effective or safe in promoting smoking cessation during pregnancy. A recent Cochrane review  examined the safety and efficacy of six trials of NRT in 1745 pregnant smokers, and no significant differences for smoking cessation or other important birth-related outcomes were demonstrated between randomized groups. The U.S. Food and Drug Administration recently announced that it is extending its regulatory authority over all the electronic nicotine delivery systems which are being increasingly used, especially by middle and high school students .
Vitamin Supplementation to Decrease the Effects of In Utero Nicotine on Offspring Pulmonary Function
Evidence from animal studies  and from a recent randomized clinical trial  of vitamin C supplementation (500 mg/day) to pregnant smokers unable to quit smoking indicates that vitamin C may help mediate some of the effects of in utero smoke exposure on offspring respiratory health. The newborns whose mothers had been randomized to vitamin C had significantly improved newborn pulmonary function tests and a decreased incidence of wheeze at 1 year of age compared to those whose mothers had been randomized to placebo. The effect of maternal smoking on newborn lung function was also associated with the maternal genotype for the α5 nAChR (rs16969968) (p < 0.001 for interaction), which is the α5 nAChR structural polymorphism that has the strongest link to lung disease  (Fig. 2). This study was not powered to examine preterm births between the randomized groups, but a large RCT  of vitamin C (1000 mg) and vitamin E (400 IU) supplementation during pregnancy found a reduction in preterm birth (RR 0.76; 95 % CI 0.58–0.99) and placenta abruption in the treated versus untreated smokers. Although the results of the initial trial of vitamin C supplementation to pregnant smokers were encouraging, a second randomized trial of a more diverse population with measurements of offspring forced expiratory flows as a sensitive measure of the peripheral airways is currently underway.
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 nonrisk 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), birth weight, and gestational age <37 weeks, and allowing for different SDs within each genotype (Reprinted with permission from the American Medical Association publications McEvoy et al. )
The independent and joint effects of prenatal smoking and LBW on subsequent childhood asthma were studied in 3389 prospectively followed children at 11–12 years of age . This study demonstrated a strong interaction of LBW and prenatal smoking on the risk of physician-diagnosed asthma. The association of prenatal smoking with physician-diagnosed asthma in LBW infants had a risk ratio of 8.8 versus a risk ratio of 1.3 in normal birth weight children .
Decrease in Air Pollution to Decrease Preterm Birth
A recent meta-analysis of 62 studies examining the association of LBW and preterm birth with outdoor air pollution demonstrated that third trimester exposure to carbon monoxide (CO) and particulate matter with aerodynamic diameter of <10 μm (PM10) was significantly associated with a higher preterm birth risk . Particulate matter with aerodynamic diameter of <2.5 μm (PM2.5) and sulfur dioxide (SO2) have also been associated with higher risks of preterm delivery as have polycyclic aromatic hydrocarbons . A study of 223,502 electronic medical records in the United Stated found that mothers with asthma may experience a higher risk for preterm birth after exposure to traffic-related pollutants such as CO and nitrogen dioxide (NO2), especially for exposures 3 months preconception and in the early weeks of pregnancy . In the last 6 weeks of pregnancy, preterm birth risk associated with particulate matter with aerodynamic diameter of <10 μm was higher among women with asthma .
The association between prenatal exposure to fine particulate matter PM2.5 (inhalable material <2.5 μm diameter) and early childhood lung function was investigated by Jedrychowski et al. . Pregnant women had measurements of PM2.5 performed over a 48-h period during the second trimester of pregnancy, and the offspring were followed through 5 years of age. Pulmonary function tests were done in 176 children of nonsmokers at 5 years of age and showed a significant decrease in FVC at the highest quartile of PM2.5 exposure . The increased exposure to PM2.5 was in turn associated with increased wheezing at 2 years, though this effect was no longer significant by 4 years of age . Mortimer et al. similarly saw negative associations with prenatal and early exposures to PM10 (inhalable material <10 μm in diameter), NO2, and CO in asthmatic children, though associations were for specific subgroups of children . Conversely, exposure to increased levels of CO during pregnancy increased allergic sensitization in children with asthma . In a retrospective study of 37,401 children born in British Columbia , the incidence of asthma in 3–4 year olds was correlated with estimated levels of in utero and first year of life exposures to air pollution, and an increase in asthma risk was seen with increased exposure to NO2, CO, and PM10. Animal models have been developed to examine effects of both particulate and gaseous pollution, but the exact mechanisms by which exposure to air pollution alters lung development and leads to increased respiratory disease are still not completely clear.
Normalizing or Maximizing Prenatal Growth
Although it is difficult to distinguish the effects of prematurity and intrauterine growth restriction (IUGR) due to frequent difficulties in establishing gestational age, epidemiological data  suggest that IUGR is associated with persistently impaired respiratory development. In sheep, it was demonstrated that fetal growth restriction affected lung structure at 8 weeks, and 2 years after birth with thicker intra-alveolar septa and thicker alveolar blood–air barrier . Fetal lambs with induced IUGR have decreased alveolar and vascular growth . Therefore, decreasing any modifiable underlying etiology for IUGR such as in utero smoke or optimizing prenatal growth in the face of IUGR would likely improve lung development and decrease postnatal NICU respiratory morbidities.
Avoiding Iatrogenic Preterm Deliveries and Cesarean Sections
Decreasing preterm delivery is the holy grail in the protection of lung development, since premature delivery is the most common cause of altered lung development . Recent studies have shown that progesterone administration in high-risk women with a prior spontaneous preterm birth and those with ultrasound confirmed shortened cervix can decrease preterm deliveries including births at <37 weeks . Preterm delivery can be spontaneous or indicated in response to adverse maternal or fetal conditions. The risks and benefits of iatrogenic pregnancy interruption need to be carefully considered and reviewed. In the United States, the preterm birth rate increased by 31 % from 1981 to 2003, largely because of increased deliveries of late preterm infants (340/7 to 366/7 weeks gestation) . In 2003, 12.3 % of births in the United States were preterm . This increased rate of preterm deliveries was highlighted by a number of organizations, and since 2005, there has been consistent decrease with 9.6 % of deliveries being preterm in 2014 . A recent study noted that this decline was due to a decrease of equal magnitude in both spontaneous and indicated preterm deliveries . This should enhance the optimization of lung development of those infants who avoided a preterm delivery and therefore their post NICU respiratory morbidities. Delivery by cesarean section can also influence the relationship between the gut microbiota, immune regulation, and offspring lung health , but further study is required.
Growth and Nutrition
Optimizing postnatal growth in preterm infants is critical to respiratory outcomes and therefore decreasing post NICU morbidities. In extremely preterm infants, BPD occurs more frequently in those with poor somatic growth , and nutritional intake in these infants at 7 days is associated with their growth velocity over the first month of life , and important factor for lung development. Vitamin A administration has also been shown to decrease BPD in at-risk patients , but translation to the bedside has been variable. With reference to late preterm infants, the importance of early postnatal nutrition is extrapolated from data in term infants who develop growth restriction during the final weeks of the pregnancy . In these infants, the lower rates of fetal growth are associated with impaired lung development . Late preterm infants are at increased risk of decreased nutritional intake due to their immature suck and swallow, but there have been no studies evaluating nutrition and growth velocities in late preterm infants and subsequent respiratory outcomes.
Early and comprehensive lactation and breast-feeding support may present a unique opportunity to improve the respiratory health of all preterm and especially late-preterm infants. The global benefits of breast milk are such that the American Academy of Pediatrics (AAP) recommends all preterm infants receive human milk, either mother’s own milk or pasteurized donor milk . Breast-feeding or the administration of human milk has been associated with decreased occurrence of factors associated with long-term respiratory health of preterm infants including infections, necrotizing enterocolitis, and rehospitalization for respiratory illness . The anti-infective and anti-inflammatory action of human milk is thought to be related to its unique composition, which includes high concentrations of Lactoferrin , antibodies including targeted IgA, glycoproteins, interleukin-2 receptor antagonist, and other anti-infectious agents .
Difficulty with breast-feeding also effects postnatal growth in preterm infants, which as previously been discussed is another component driving respiratory outcomes . For the mother and her late preterm infant, breast-feeding or mechanical/manual expression of human milk may be altered by maternal factors (delayed lactogenesis) , offspring factors (immature feeding behaviors, comorbidities, and increased nutrition requirements) , and/or facility factors (maternal–infant separation, inaccessible mechanical expression equipment, lack of provider knowledge) . As late preterm infants may remain on nonspecialized obstetrical units, it is important that clinicians and their interdisciplinary colleagues who care for these mother–infant dyads strive to follow the World Health Organization’s “Ten Steps to Successful Breastfeeding” endorsed by the AAP .
Several studies suggest that breast-feeding may be protective against respiratory disease in infancy. The Italian FLIP study  (Factors Leading to Respiratory Syncytial Virus-related Infection and Hospitalization among Premature infants) reported breast-feeding as one of the seven variables predicting RSV-related hospitalization in infants born at 33–35 weeks’ gestation . A follow-up study of 39 infants with birth weights <2000 g demonstrated those who received human milk had significantly fewer days of upper respiratory symptoms at 1 month and at 7 months corrected age (p < 0.025) . A birth cohort in the study by Copenhagen  was followed through 2 years of age and demonstrated that breast-feeding reduced the risk of wheezy episodes and severe wheezy exacerbations, but preterm infants were not specifically broken out in the analysis.
Avoidance of Second Hand Smoke
Second hand tobacco smoke remains a significant burden to young children who spend the majority of their time in their home environment where second hand smoke (SHS) is present. This continues despite the implementation of laws requiring smoke-free public and working places. Former preterm infants are particularly vulnerable to the effects of SHS, which is an additional predictor of increased respiratory morbidity, asthma, and worsened asthma morbidity throughout childhood . Smoke-free legislation in England was immediately followed by a decrease in admissions for respiratory tract infections (RTI) in children <15 years old, primarily lower RTI with upper RTI being more incremental, and 11,000 fewer hospital admissions for RTI per year . A randomized trial of brief asthma education plus motivational interviewing counseling versus asthma education alone to families with infants ≤ 32 weeks gestation demonstrated more home smoking bans, but these differences did not persist . At 8 months post NICU discharge, the treatment group had lower salivary cotinine levels, but there was no difference in respiratory clinical outcomes of the children in the groups.
Avoiding Early Postnatal Pollution Exposure
Multiple studies have associated increased environmental air pollution with increased risk of childhood asthma, respiratory infections, and indices of reduced lung function [84, 85], although the specific impact on people born preterm is unknown. Types of air pollution that have been associated with altered lung development include particulate matter, ozone, NO2, SO2, and CO. Studies exposing infant monkeys to ozone demonstrated decreased lung branching, hyperplastic airway epithelium, alterations in alveolar development, and smooth muscle remodeling . The combination of ozone and allergen also leads to hyperinnervation of airway epithelium  and increased CD25+ cells in airway epithelium, which could provide a link between ozone and asthma. Thus, there is likely a considerable interaction between multiple pollutants and prenatal and postnatal exposures.
Importance of Avoidance of Viral Infections and Prophylaxis When Available
As discussed in other chapters in this book, the preterm infant is vulnerable to viral infections due to underlying structural weaknesses in lung development and issues with innate immunity. Olicker et al.  compared the incidence of respiratory morbidity in preterm infants born between 32 0/7 and 34 6/7 weeks gestation (without BPD) before and after the American Academy of Pediatric (AAP) change in the administration guidelines of palivizumab, and found a significant increase in the incidence of recurrent wheeze through 12 months of age (46.2 % vs 28.8 %; p = 0.03) after the administration policy change. The Dutch RSV Neonatal Network  randomized 429 healthy preterm infants born at 33–35 weeks of gestational age to monthly palivizumab or placebo during the RSV season. The palivizumab-treated infants had a relative reduction of 61 % in the total number of wheezing days during the first year of life and significantly less demonstrated recurrent wheeze (11 % vs 21 %; p = 0.01). This double-blinded RCT further implicates RSV infection as an important mechanism of recurrent wheeze in healthy preterm infants born at 32–35 weeks of gestation and revisits the importance of prophylaxis to decrease both short-term and long-term respiratory morbidity.
The Barry Caerphilly Growth Study  collected information on childhood upper and lower RTI from birth to 5 years on 14 occasions and followed subjects prospectively with lung function measured at 25 years. They found that the lower RTI were associated with an obstructive lung function deficit, and the first year of life appeared to be a sensitive period for these infections. Drysdale et al.  prospectively studied the impact of lower RTI in 70 infants born at 24–35 weeks gestation with pulmonary function tests measured at 36 weeks postmenstrual age and at 1 year corrected age. There were no significant differences in lung function at 36 weeks, but at 1 year, the infants who had suffered a viral RTI had a significantly higher mean airway resistance (23 vs 17 cm H2O/L/s; p = 0.0068), which remained after adjustments for significant covariates . One hundred and fifty-three infants born at 23–35 weeks were followed to 12 months of age, and in this cohort, human rhinovirus C infection was associated with increased wheeze, use of respiratory medication, and use of inhaler .
Avoidance of Personal Smoking in Former Premature Infants
Doyle et al.  reported follow-up of a cohort of 60 consecutive extremely low birth weight survivors with pulmonary function testing at 8 and 20.2 years of age. Respiratory function was compared between the smokers (n = 14) and the nonsmokers (n = 30). There was a significantly larger decrease in the FEV1/FVC ratio between the ages of 8 and 20 in the smokers versus nonsmokers demonstrating that active smoking by young adult survivors of extremely low birth weight is associated with reduced respiratory function. Upton et al.  studied the effects of former and current personal smoking on FEV1/FVC across the range of exposure to maternal (and paternal) smoking in adult offspring of couples who also had participated in a population study conducted from 1972 to 1976. They documented that maternal smoking-impaired lung volume, regardless of personal smoking, was associated with greater smoking intensity and less quitting in the offspring who took up smoking, and synergized with the offspring’s smoking to increase airflow limitation in adults. Although this study did not focus specifically on preterm infants, the implication for preterm infants is likely even more significant.
Treatment of Post-NICU Respiratory Morbidity
As outlined in other chapters, prematurity including late preterm birth increases the risk of a number of respiratory morbidities including childhood wheeze, asthma, and viral and bacterial pneumonias . As outlined in chapter “The Bronchopulmonary Dysplasia Diagnosis: Definitions, Utility, Limitations”, there also continues to be discussion with regards to the limitations of the current definition of BPD. In addition, investigation continues into the likely multifactorial etiology of wheeze in former preterm infants . Interestingly, there is relatively little evidence available on the pathophysiology and treatment of wheezing in preschool children (whether born term or preterm) in general [96, 97]. Currently, the treatment of the respiratory symptoms in former preterm infants, both late preterm and survivors with the diagnosis of BPD, is primarily symptomatic with their symptoms decreasing over time as they age, similar to that of the general history of preschool wheeze . There are few randomized trials of therapy in the general population of children with preschool wheeze (and even fewer/none done specifically in populations of preterm infants), but increasing publications of the incidence of clinical symptoms and treatment approaches.
Vrijlandt et al.  reported follow-up at 12 months of age in 77 preterm infants delivered at a mean gestational age of 28–29 weeks with and without BPD. Of those with BPD, 39 % used a beta-agonist bronchodilator and 37 % used an inhaled corticosteroid versus 50 % and 31 %, respectively of those without BPD . A number of large trials in extremely preterm infants have recently reported the respiratory follow-up of the children through 1–2 years of age [98, 99]. Follow-up of the Support Trial by Stevens et al.  reported follow-up on 918 infants born between 240/7 to 276/7 weeks for the first 18–22 months of life. Overall, 47.9 % of patients reported wheezing more than twice per week during the worst 2-week period, 31 % reported a cough lasting more than 3 days without a cold, 26.3 % used inhaled steroids, and/or 9.4 % used systemic steroids . Hibbs et al.  reported follow-up at 12 months of age on 456 infants with birth weights of 500–1250 g who had been ventilated and randomized to inhaled nitric oxide versus placebo. Overall, the incidence of wheeze was 52.3 %, with the use of bronchodilators at 47 % and inhaled steroids at 25.9 %.
Vrijlandt et al.  also reported that at 4 years of age, moderate preterm infants born at 32–36 weeks gestation were receiving the following therapies: 13 % were receiving treatment with a beta-agonist, 9 % an inhaled corticosteroid, and 2 % a combination of a beta-agonist and an inhaled corticosteroid. For the most part, these therapies were used less in moderate preterm infants than early preterm infants, but more in the moderate preterm infants than in the term infants.
Research Priorities for the Primary Prevention of Post NICU Respiratory Morbidities in Premature Infants
The key to treatment of post NICU respiratory morbidity is the optimization of lung development in the face of prematurity, particularly since lung function tracks from infancy through early adulthood along percentiles established very early in life . There are multiple opportunities to address specific research priorities in the prenatal and early perinatal focus to promote lifelong lung health in the premature infant as outlined in Table 1. Foremost is the prevention and cessation of smoking which promotes lung health at multiple levels.
Research opportunities to prevent/decrease post NICU respiratory morbidities grouped by the timing of the factors on lung development
Study the effectiveness of smoking cessation strategies on incidence of preterm birth and offspring respiratory outcomes
Evaluate the impact of preconception weight loss in obese patients on subsequent preterm birth and respiratory outcomes
Investigate the role of epigenetic modification in mediating effects of nicotine and air pollution
Increased study into effective approaches to increase smoking cessation in all populations
Evaluate the effect of Electronic Nicotine Delivery Systems on the developing lung
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