Epidemiology of Wheezing in Preterm Infants and Children
There have been numerous studies of wheezing in preterm infants and children after discharge from the NICU. Differences in study design, definitions of wheezing outcomes, and study populations make it difficult to make direct comparisons between studies. However, there are several common findings amongst all the studies. Wheezing is very common in preterm infants and children, especially in the first two years of life, with a reported prevalence ranging from 46% to 59% [12-15]. The prevalence of wheezing decreases over time, but is still higher in school aged preterm children compared to their term peers [16-22]. As summarized in Table 1, preterm children with a history of BPD are more likely to have symptoms of wheezing or be prescribed asthma medications such as bronchodilators (BD) or inhaled corticosteroids (ICS). However, there is still a substantial percentage of children without a history of BPD who wheeze or are prescribed these medications.
Risk factors for wheezing in the first 2-3 years of life in preterm infants are summarized in Table 2 and include many antenatal (parental) factors, host factors, and post-natal exposures. In the first three years of life antenatal and host risk factors include gestational age (GA), antenatal maternal tobacco use, parental asthma, intrauterine growth retardation, infant African-American race, and infant male sex [23, 24]. Post-natal risk factors included suboptimal growth or nutrition (low breastmilk exposure and growth failure at 36 weeks post-menstrual age), signs of significant early respiratory disease via associated interventions (delivery room surfactant, cumulative oxygen exposure), indomethacin prophylaxis, and public health insurance [23, 24]. BPD is associated with a higher incidence of wheezing compared to preterm children who did not develop BPD, but up to 59% of preterm children without the diagnosis of BPD also have wheezing [15]. Additional post-natal risk factors for wheeze in late pre-term infants included a marker or significant, early respiratory disease (mechanical ventilation) in addition to infant atopy (atopic dermatitis) and day care [13]. In term children, the ratio of the time to peak expiratory flow over total expiratory time (Tpef/Te) is a risk factor for wheezing in the first few years of life and asthma in childhood [25-27], but measurements of Tpef/Te in preterm children have not proven useful in predicting subsequent wheezing risk [14, 28, 29].
Follow up studies of preterm infants and children have also identified factors associated with a lower risk of wheezing (Table 3). There are several therapeutic interventions in the NICU that have been associated with a lower rate of subsequent respiratory problems. Early continuous positive airway pressure (CPAP) therapy was associated with decreased diagnosis of asthma, lower diagnosis of any respiratory condition, and decreased ER visits for respiratory cause in the first 2 years of life [15]. Both CPAP and low oxygen saturation goals were associated with lower wheeze apart from colds [15]. Late surfactant was associated with decreased home respiratory support while nitric oxide (NO) therapy was associated with decreased respiratory medication exposure within the first 12 months [12, 30]. Taken together, these demonstrate that at least early in life, therapeutic interventions may increase (mechanical ventilation)[13] or decrease the risk of early pulmonary morbidity. Other factors linked to lower risk of wheezing include higher birth weight, breastfeeding, and bacterial tracheal colonization [19, 20, 24, 31]. Palivizumab therapy has been associated with a lower risk of subsequent wheezing in the first few years of life, but its effect on wheezing and asthma in later childhood is not as clear [32-39]. Both low and high maternal body mass index have been associated with increased wheezing in preterm infants [19]. The mechanism in both cases is unclear. Growth has been associated with differing risks of wheezing. Fourth quartile weight velocity in the first year of life was associated with later wheezing risk in former 23-27 w GA infants, [31] while weight gain ≥3 percentiles in the first year of life was protective in 32-35 w GA infants [20].
Although the incidence of wheezing declines after the age of 3 years in preterm children, it still remains higher than that of term children during the school-age years [18, 19]. A history of maternal and paternal atopy and maternal smoking during pregnancy are associated with increased wheezing in older preterm children [18-20]. Higher maternal age (35-39 years) is also associated with increased wheezing risk [19]. Lower GA (24-32 w) is associated with an increased risk of wheeze at 7 and 11 years of life [19]. This contrasts with data at age 3 and 5 when all preterm infants were noted to have increased wheeze compared to term infants [19]. Both infantile atopic dermatitis and childhood atopy or atopic dermatitis were associated with increased school-aged wheeze, indicating that risk factors for pediatric asthma also contribute to wheezing in preterm children [19, 20]. Antibiotic use in the first 3 years of life was also associated with increased school-aged wheeze, supporting the influence of a growing area of inquiry related to asthma and the microbiome [20]. Additional home or familial factors such as urban environment, formal childcare, post-natal smoke exposure, and public health insurance were also associated with an increased likelihood of wheezing [18-20, 31].
Although extremely low gestational age neonates born at <29 weeks GA (ELGANs) are at highest risk of wheezing following discharge from the NICU, infants born at ≥32 w GA, including late preterm infants (34-37 w GA) also demonstrate increased rates of wheezing compared to term infants [13, 20-22]. In the first three years of life, physician diagnosed wheeze in the last 12 months was present in 41-54% of 32-35 w GA infants, and in nearly half of this group wheezing was recurrent [13]. Similar to ELGANs, the wheezing prevalence decreased with time from ~50% of infants the first three years [13] to 23% at age six [20] to 10-14% in 13-14 year olds [21]. A large study of preterm infants of all GA demonstrated increased wheeze in all preterm infants at 3 and 5 years, but only in those less than 32 weeks at 7 and 11 years of age [19]. This contrasts with studies of increased wheeze or asthma diagnosis of school aged former 32 to 35 w GA [20].
Caregiver-reported wheezing is subjective and potentially inaccurate. However, numerous studies have also reported that large percentages of preterm infants and children have are prescribed medications frequently used to treat wheezing, such as BD or ICS [12, 30, 40]. Nearly half of ELGANs receive a bronchodilator [12, 18, 31, 40] and approximately 25% receive ICS [12, 30, 40] in the first year after birth. While the increase in reported wheeze is increased only slightly among infants with BPD [15], the increase in respiratory medications among premature infants with BPD is much higher than premature infants without this diagnosis [15, 18, 31, 40]. Systemic corticosteroid use in the first 2 years has rarely been reported by BPD status, but studies that have analyzed this outcome measure haven not found statistically significant increased systemic corticosteroid use in children with BPD compared to those without BPD [15, 40]. Although the proportion of preterm children prescribed asthma medications declines with age, it remains higher in preterm children compared to term children even at 11 years, and by this age there is no difference in medication use between children with a BPD compared to those without BPD [16]. In addition to high rates of respiratory medication use, 16-39% of preterm children also require hospitalization in the first 2 years of life for respiratory illnesses.[12, 14, 15, 29, 30] The risk is also present in infants born at 32-35 w GA, as 6% are hospitalized for respiratory reasons in the first year of life [13]. Infants with BPD are at higher risk for hospitalization than those without BPD [15]. These data on medication use and hospitalizations provide further evidence of the substantial impact that wheezing has on the health of preterm children.
Numerous studies have shown that wheezing occurs commonly amongst preterm infants and children. However, as discussed previously, wheezing associated with preterm birth does not necessarily represent asthma. Biomarkers that are elevated in atopic asthma, such as the fraction of exhaled NO (FeNO) are not elevated in children with a history of BPD [41, 42]. Using a time-oriented logistic regression model to analyze data from a 10 year follow up study of ELGANs, Jackson, et al found that although BPD was a risk factor for preschool wheezing, it was not for asthma [31]. While wheezing due to preterm birth occurs through mechanisms independent of those for asthma, there is certainly a degree of overlap, as evidenced by the observation that well-establish asthma risk factors, such as atopic dermatitis, are also associated with increased wheezing in preterm children [13, 19, 20].