Environmental Modifiers of Chronic Lung Disease of Prematurity During Infancy

Abstract

Chronic lung disease is a common complication of prematurity with substantial mortality and morbidity. Although the variation seen in bronchopulmonary dysplasia has a strong genetic component, the limited environmental variation in neonatal intensive care units may lead to underestimates of the contribution of environmental factors to lung disease variation. Once discharged from the hospital, preterm infants are exposed to a variety of environmental factors that likely worsen their disease. Recognition of these factors may lead to improved outcomes in this vulnerable population through more effective guidelines and counseling. This review examines the role of selected outpatient environmental factors on respiratory outcomes during infancy in preterm infants with lung disease.

Introduction

As defined by oxygen use at 36 weeks postmenstrual age bronchopulmonary dysplasia (BPD) is a common complication of prematurity.¹ An estimated 44%–77% of infants born with a birth weight of <1,000 g and at ≤32 weeks of gestation will develop BPD.² Heritability studies have demonstrated a strong genetic contribution to the development of BPD^3,4; however, this finding should be interpreted in the context of the more uniform environment of the neonatal intensive care unit (NICU) where many premature infants are hospitalized through the diagnosis age of BPD (36 weeks postmenstrual age). Environmental variation may be limited by the standardized protocols of NICUs, and thus the environmental contribution to variation seen in BPD may be underestimated.

The sequelae to BPD, chronic lung disease of prematurity (CLDP), likely demonstrates a wider variation in phenotype. CLDP can certainly vary in severity from infants who are nearly asymptomatic to infants requiring home ventilation, but it can also vary in types of phenotypes observed. Specifically, the presentation of CLDP in a particular infant may be the sum of a number of contributing pathophysiological components. For example, some infants may manifest a more vascular component as manifested by pulmonary hypertension, others a more small airway component as manifested by chronic cough or wheeze, others an alveolar hypoplasia component as manifested by persistent supplemental oxygen requirements, and yet still others a combination of these components. The wider variation in disease phenotype is a distinction between BPD and CLDP and suggests an increased role for environmental modifiers in the development of CLDP as compared with BPD; however, studies of heritability for CLDP have not been performed. Environmental variation may include increased variation in outpatient management as well as variation in home environmental exposures compared with the NICU. Throughout the remainder of this review, the term CLDP will used to refer to lung disease in preterm infants and children older than 36 weeks postmenstrual age, excepting where the cited literature uses the term BPD.

The burden of disease for infants and children with CLDP is observed clearly in respiratory morbidity rates and healthcare costs. Approximately 50% of preterm infants previously found to have BPD are re-hospitalized within the first 2 years of life,^5–7 and the presence of BPD is associated with a 1.6-fold increased risk for re-hospitalization for any reason among infants <1,000 g at birth.⁸ While the incidence of BPD may be declining (4.3% annually between 1993 and 2006), costs associated with BPD remain high as hospital charges for birth hospitalization are increasing (4.9% annually).⁹ Even the same illnesses in a preterm infant result in greater morbidity and higher costs than in the term infant. For example, a study of 271 episodes of pneumonia requiring ICU-level care in infants tabulated median stays of 7.1 days and costs of $55,122 for full-term infants, but 11.7 days and $85,151 for preterm infants <32 weeks of gestation.¹⁰ It is critical to determine the environmental factors that aggravate this burden of disease, thus to develop preventative strategies, and ultimately to improve outcomes for these vulnerable infants and children.

The remainder of this review focuses on specific environmental factors that a preterm infant is exposed to after discharge from the NICU that affect primarily short-term outcomes such as respiratory symptoms during infancy or acute care visits. Factors to be discussed have been either demonstrated to affect outcomes or may affect outcomes based on research in other pediatric chronic respiratory diseases. Unfortunately, many of these factors have received only limited study in infants with CLDP; thus, many of the studies discussed may include a cross-section of all preterm infants, rather than just those who developed CLDP. A study of all preterm infants that finds an association between an environmental factor and a respiratory outcome is highly suggestive that the same factor may operate in preterm infants with CLDP. However, a negative study for all preterm infants does not necessarily rule out that environmental factor's role in affecting preterm infants with CLDP.

Discharge Factors

Although NICU factors are not within the scope of this review, the timing and location of discharge may affect events immediately after discharge.

Back transport

Following acute management in regional NICUs, many preterm infants are “back transported” to community hospitals for ongoing care prior to discharge. Respiratory outcomes may be impacted by where convalescent care is received as the regional NICU may have a pediatric pulmonologist available for consultation and more formalized parental teaching, but a community hospital may provide more individualized attention. A recent study of 255 infants <1,500 g at birth found a higher risk of re-hospitalization within 2 weeks of discharge for infants discharged from community hospitals as opposed to regional NICUs, but no differences within 4 months of discharge, suggesting that any differences associated with location of convalescent care may subside quickly.¹¹

Season of discharge

Timing of birth relative to the peak of the respiratory viral season has been associated with the development of asthma in infants, regardless of prematurity.¹² A study of 55 infants <32 weeks of gestation with BPD in Hong Kong found that those born earlier in the calendar year were more likely to have current asthma than those born later in the year.¹³ This finding matches what is seen in the general population in Hong Kong, where wheezing is more common in children born in January/February.^13,14 The discharge of preterm infants during particular seasons may affect short-term outcomes such as re-hospitalization rates,^15,16 but this is not always consistently observed.⁵ The season of discharge does not appear to impact inhaled beta-agonist or inhaled corticosteroid use.¹⁷

Social Agents

Socioeconomic factors impact the outcomes in many chronic diseases. For example, in cystic fibrosis associations between lower lung function and lower income¹⁸ or public insurance coverage exist.^19,20 Although limited data exist for CLDP, studies suggest that socioeconomic status may not play as an important role in determining respiratory outcomes compared with asthma and cystic fibrosis. It may be that the education and social support provided by NICU clinicians and staff provide a protective effect. Alternatively, confounding factors such as advanced maternal age and/or in vitro fertilization, typically associated with higher socioeconomic status and possibly worse outcomes, may obscure the relationship between socioeconomic factors and respiratory outcomes in the preterm population.

Caregiver education

Infants and children with CLDP are frequently discharged on complex medication regimens, which may include 1 or 2 diuretics, an inhaled corticosteroid, and/or 1 or 2 medications for gastro-esophageal reflux, in addition to a home cardio-respiratory monitor and/or supplemental oxygen. Given that a >6th-grade reading level may be necessary to understand prescription labels,²¹ caregivers with lower levels of education may find it difficult to cope with the complex care regimens required. However, maternal education has been found not to impact re-hospitalizations for respiratory reasons in all preterm infants^5,8,22 or just preterm infants with BPD.⁵ Maternal education level does not affect the presence of respiratory symptoms in infants <1,500 g at birth, but may impact the prevalence of lower respiratory infections.²² It may be that education received from nurses, physicians, and therapists within the NICU setting provides families with an adequate skill set for caring for their premature infant.

Household income

Limited data exist for the role of household income, but it could be hypothesized that lower income could limit access to care or prescriptions, particularly if co-pays are involved. A study of 715 infants <1,500 g at birth found that higher family income was associated with reduced risk of re-hospitalization for respiratory symptoms and reduced prevalence of cough, asthma attacks, and lower respiratory infections,²² but a larger study of 1,405 infants <1,000 g at birth found no association between family income and re-hospitalization for respiratory reasons.⁸

Insurance status

Limited data exist for the role of insurance provider in outcomes. Medicaid (versus private insurance) has been associated with a 2-fold increased risk for respiratory-related re-hospitalizations in infants <1,000 g at birth,⁸ but the population of infants covered by Medicaid may be enriched for patients with more severe disease that have been dis-enrolled by their private insurers. Thus, being enrolled in Medicaid may not discriminate between different levels of socioeconomic status in this population well.

Race/ethnicity

The effects of race/ethnicity are often difficult to tease out as they may include a genetic component, a cultural component, and/or a disparities component. Although Non-Hispanic blacks have a higher rate of premature birth (18.3%) than do other groups in the United States (Non-Hispanic white, 11.5%; Hispanic, 12.3%),²³ no differences have been seen in the proportion of preterm infants with BPD among different racial/ethnic groups.^5,8 No difference was seen by race/ethnicity in terms of acute care visits,²⁴ or re-hospitalizations for preterm infants,^5,8,16,22,25 and no difference was seen by race/ethnicity in terms of re-hospitalizations in a study of 238 infants <33 weeks of gestation with BPD.⁵ However, black preterm infants may be more likely to be prescribed respiratory medications²²; specifically, in a study of 1,436 infants ≤34 weeks of gestation, black infants were more likely to be prescribed inhaled beta-agonists than white infants, and Hispanic infants were more likely to be prescribed inhaled beta-agonists and/or inhaled corticosteroids than white infants.¹⁷

Infectious Risk Factors

Respiratory infections are a large source of morbidity and mortality among infants with BPD.²⁶ As discussed above, the timing of birth or hospital discharge relative to the respiratory viral season may lead to higher risks for the development of long-term sequelae, but other factors may also impact on acute care outcomes. These factors include risk factors for contracting respiratory infections such as the presence of any viral vector, including children at daycare or siblings within the home. Protective factors against infection may include breastfeeding and immunoprophylaxis.

Daycare

Attending daycare was found to be associated with a 3.7-fold increased risk in emergency department visits, a 2.2-fold increased risk of systemic steroid use for respiratory symptoms, a 2.4-fold increased risk of antibiotic use for respiratory symptoms, and 2.7-fold increased risk for days with trouble breathing in a study of 111 infants ≤32 weeks of gestation with CLDP.²⁷ These findings may be independent of CLDP as there is an increased risk of acute care visits, respiratory symptoms, and respiratory medication use associated with daycare attendance in infants <1,500 g at birth independent of CLDP status.^22,24 Given that attending daycare leads to a higher rate of contracting respiratory viral infections,²⁸ it is presumed that these infections result in the higher rates of acute care use observed.

Siblings

The presence of older siblings in the home may serve as an infectious vector as these children may attend daycare or school and contract viral infections; alternatively, these siblings also require parental time and family resources, which may decrease time/resources for the preterm infant at home. A study of 435 infants born at 29–36 weeks of gestation found that for the presence of each additional sibling, the risk of re-hospitalization for respiratory disease increased by 1.7-fold,²⁹ and the risk may be increased with increasing prematurity (<29 weeks of gestation) and the presence of siblings <6 years old.¹⁵ Additionally, a study of 1,436 infants ≤34 weeks of gestation found that for the presence of each additional child in the household, the odds of inhaled beta-agonist use increased 1.2-fold and the odds of inhaled corticosteroid use increased 1.3-fold.¹⁷

Breastfeeding

There are many barriers to breastfeeding preterm infants, including their prolonged hospitalization, possible swallowing dyscoordination, and financial constraints such as purchasing a breast pump and having appropriate facilities in the workplace to use it, and this is reflected in preterm infants being less likely to receive breast milk compared with term infants.³⁰ However, breastfeeding is hypothesized to reduce the risk of infections owing to passive transfer of immunoglobulin A and possibly other immunomodulatory factors.^31,32 A study of 538 infants <33 weeks of gestation demonstrated that breastfeeding for >1 month was associated with a reduced risk of re-hospitalization (Adjusted relative risk [RR]: 0.70) compared with formula feeding,³³ and a case–control study (n=186 cases) of infants born at 33–35 weeks of gestation found that breastfeeding for ≤2 months was associated with a 3.3-fold increased risk of hospitalization for respiratory syncytial virus (RSV).³⁴ The effects of breast milk may also be gender-specific as a study of 119 infants <1,500 g at birth found that breast milk was protective for girls, but not boys, against hospitalization.³² Finally, in a small study of 39 infants <2,000 g at birth, infants who received any breast milk were shown to have fewer days of upper respiratory symptoms in the first year of life than those who only received formula.³⁵

Immunoprophylaxis

Prevention of respiratory viral infections is a more direct solution to decreasing infection morbidity than decreasing risk factors, and to that end several active and passive immunizations are available for the preterm infant. It should be noted that preterm infants are less likely (Adjusted odds ratio [OR]: 0.40) to have immunization delay at 2 years of age compared with full-term infants.³⁶ Recent guidelines for the use of palivizumab highlight its efficacy in decreasing RSV-related hospitalizations in selected preterm infants, but its use has not been shown to reduce the rate of mortality due to RSV or the development of recurrent wheezing.^37,38 The heptavalent pneumococcal conjugate vaccine (PCV7) has been shown to be effective in preventing invasive pneumococcal disease in preterm infants with likely comparable immunogenicity compared with full-term infants,^39,40 but data are lacking for preterm infants with CLDP. The magnitude of the humoral response to the influenza vaccine (given in infants and children ≥6 months of age) may be affected by BPD and the immunogenicity of the vaccine strains from year to year, but preterm infants, including those with BPD, have been shown to have a good response to influenza vaccines.^41,42

Indoor Physical Agents

A frequent clinical recommendation for families caring for preterm infants with CLDP is avoiding exposure to any sick contacts, and in practice, many families rarely take their infant outside the residence except for healthcare-related appointments. Thus, infants with CLDP spend the vast majority of their time within the home environment. As such, exposure to indoor physical agents, such as secondhand smoke, may impact respiratory outcomes in the preterm infants more than outdoor agents such as air pollution.

Secondhand smoke

Secondhand smoke may be a particularly problematic toxicant for premature infants, as it may exert direct toxicity on respiratory epithelium, or may lead to inflammation as a predisposing factor to a higher risk of infections⁴³ or more severe infections.⁴⁴ Additionally, prenatal and/or postnatal secondhand smoke exposure may result in epigenetic/mutagenic changes in the developing lung.^45,46 However, in preterm infants the effects of secondhand smoke may be confounded by other socioeconomic factors as studies have generated differing results. For example, one study of 124 infants <1,500 g at birth demonstrated that living with a smoker was associated in a 2.6-fold increased risk of ≥1 acute care visit for respiratory symptoms,²⁴ but another showed no association risk with re-hospitalization.²² Likewise, secondhand smoke exposure may result in an increased risk of recurrent wheezing during infancy⁴⁷ and later in childhood⁴⁸ for preterm infants, but this has not been consistently observed.²² Alternatively, it should be noted that inconsistent results between studies may be due to difficulties in assessing the total cumulative dose of secondhand smoke exposure during infancy. No studies of the effects of tertiary smoke exposure and preterm infants have been published to date.

Pests

Pests requiring chemical extermination have been associated with 4.4-fold increased risk of ≥1 acute care visit for respiratory symptoms in a study of 124 infants <1,500 g at birth.²⁴ It is not clear whether the pests, the chemical means of controlling them, or both are responsible for the observed finding.

Pets

In contrast to pests, the presence of cats, dogs, birds, and/or other furry animals in the home has not been associated with respiratory symptoms or re-hospitalizations for respiratory reasons in preterm infants.^22,24

Future Directions

The burden of lung disease seen with premature births is likely second only to asthma among chronic pediatric respiratory diseases, thus understanding risk factors to improve outcomes is crucial. However, difficulty in diagnosing severity of disease and variability in treatment strategies confound efforts to identify environmental factors that worsen or ameliorate lung disease of prematurity.⁴⁹ Less invasive and more convenient means of assessing lung function than current infant pulmonary function testing with sedation are needed. In contrast to asthma and cystic fibrosis, the lack of consensus guidelines for the outpatient management of CLDP likely leads to substantial variation in treatment patterns among clinicians, which may lead to differing outcomes as well as difficulty in determining the relative risk of environmental factors in multicenter studies. There are other environmental factors which likely impact outcomes for CLDP that deserve future study, and with well-designed multicenter studies it should be possible to identify environmental interventions to improve outcomes for these vulnerable infants and children.

Footnotes

Author Disclosure Statement

The author discloses that he has no financial interests in the subject of this article.

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