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].