For healthy individuals, it is increasingly accepted that lung function follows along an individual percentile established early in life and that the level of maximal function reached as a young adult can affect the subsequent development of lung disease that occurs with the normal aging process. This emphasizes the need to maximize early lung function. The trajectories of lung function are at least partially established by perinatal factors, including prematurity and in utero exposures (tobacco exposure, nutrition, inflammation, etc), although they can also be affected by a variety of additional factors and exposures throughout the life span. Whether lung function trajectories can be impacted or reset if established under suboptimal conditions is an unanswered question, offering new avenues for research. In this review, we will summarize important articles outlining lung function trajectories and linking pediatric lung function tests to adult lung function tests decades later. We will focus on perinatal factors and outline progress and opportunities for further investigation into the potential ability to reset trajectories to impact long-term lung health.

Subjects:
Fetus/Newborn Infant, Neonatology, Pulmonology, Respiratory Tract
Topics:
pulmonary function, pulmonary function tests, respiratory physiology, infant, premature, lung

During an individual’s life span, the human lung is exposed to multiple positive and negative influences that begin preconception and continue through fetal development, childhood, and early adulthood, cumulatively establishing lung health. There is increased appreciation of the importance of early life factors in lifelong lung trajectory, but important challenges and questions remain in this area. In this review, we will highlight the evidence for pulmonary function trajectories from infancy through adulthood and the link between these trajectories and subsequent clinical outcomes. We will focus on the perinatal factors known to affect early trajectories, particularly through the prism of premature delivery (Table 1). We will also identify key limitations in current studies and knowledge gaps in this area that frame opportunities for future research. For instance, are there potential perinatal interventions that can mitigate negative modifiers of lung function or augment positive modifiers? What can be learned from individuals who demonstrate increases in their lung function percentiles over time (catch up) compared with those who do not? Are there windows of opportunity to optimize early lung function and encourage maximum function?

TABLE 1

Compilation of Studies of Pediatric Lung Function

Study and LocationEraInclusion CriteriaNo. ParticipantsGA at BirthBirth wtTiming of PFTsPFT ParametersFindings
Anand et al,1  2003; Liverpool, United Kingdom 1980–1981 Preterm survivors born <1500 g and term controls 128 preterm ∼31 wk  ∼1250 g ∼15 y FEV1, FVC, FEF25–75 Compared with term controls, former very low birth wt infants had greater medium and small airway obstruction (lower FEF25–75 and FEV1/FVC) when measured in adolescence. 
128 term Term ∼3300 g 
Bader et al,2  1987; Los Angeles, California, United States 1973–1979 Preterm infants with severe BPD and term controls 10 preterm ∼29 wk ∼1200 g ∼10 y FEV1, FRC, FEF25–75, FEFmax, TLC, VC Small study of former premature infants with BPD, FEV1, FEV1/FVC, FEF25–75, and other measures of maximum expiratory flows were lower than controls measured at ∼10 y. 
8 term ∼40 wk ∼3250 g 
Baraldi et al,3  1997; Padova, Italy 1990–1991 Preterm infants <1250 g, requiring 10 d on ventilator, oxygen at 28 d, and CXR findings 28 ∼28 wk ∼952 g 10–20 d; 3, 6, 9, 12, and 24 mo Crs, Rrs, FRC, and VmaxFRC In infants with BPD, measurements of FRC, Crs, and Rrs were lower than normal in the first year and increased over time, reaching normalcy by 2 y. Forced expiratory flows remained abnormally low throughout the study. 
Bisgaard et al,4  2012; Copenhagen, Denmark nr COPSAC cohort: birth cohort of children born to mothers with asthma ∼350 nr nr 1 mo and 7 y FEV0.5, FEF50, FEV1, FVC Children diagnosed with asthma at age 7 y had reduced lung function (FEV0.5) as neonates. 
Bröstrom et al,5  2010; Stockholm, Sweden 1992–97 Infants <32 wk GA with BPD or RDS (controls) 32 with BPD ∼28 wk ∼1000 g 6–8 y FEV1, FVC, FEF25–75, Rrs Former premature infants with BPD had evidence of impaired lung function (FEV1) at school age. 
28 with RDS ∼30 wk ∼1500 g 
Bui et al,6  2018; Tasmania, Australia After 1968 Population-based birth cohort: Tasmanian Longitudinal Health Cohort ∼2500 nr nr 7, 13, 18, 45, 50, and 53 y FEV1 Six trajectories of lung function were identified: early below average, accelerated decline (4%), persistently low (6%), early low, accelerated growth, and normal decline (8%), persistently high (12%), below average (32%), and average (39%). 
den Dekker et al,7  2018; Netherlands 2002 Population-based birth cohort: Generation R Study ∼5600 Term ∼3400 g ∼10 y FEV1, FVC, FEF25–75, FEF75, Term infants with IUGR had lower FEV1 than unaffected peers. Accelerated postnatal growth velocity and body wt predisposed infants with IUGR to lower lung function in later childhood. 
Dezateux et al,8  1994; London, United Kingdom nr Healthy term infants 220 Term ∼3400 g 5–13 wk and 1 y FRC, TPTEF:TE In infants, TPTEF:TE was significantly lower in infant with a previous history of lower respiratory tract infection and wheezing than in those without. 
Doyle et al,9  2017; Victoria, Australia 1991–1992 Preterm survivors born <28 wk 297 preterm ∼27 wk ∼888 g 8 and 18 y FEV1, FVC, FEF25–75, FEF75 Preterm infants had greater airway obstruction (FEV1) and greater increase in small airways obstruction (FEF25–75) than controls. Airway obstruction was also associated with history of BPD or smoking. 
260 term ∼39 wk ∼3400 g 
Doyle et al,10  2017; Melbourne, Australia 1991–1992 Preterm infants <1000 g in 3 epochs 225 in 1991–1992 cohort  ∼26 wk ∼890 g ∼8 y FEV1, FVC, FEF25-75 Among extremely premature infants, duration of assisted ventilation (mostly CPAP) increased from 1991 to 2005, but rates of oxygen need at 36 wk PMA, duration of oxygen use, and measures of airway flows worsened over that time period. 
1997 151 in 1997 cohort ∼26 wk ∼820 g 
2005 170 in 2005 cohort ∼26 wk ∼870 g 
Fakhoury et al,11  2010; Houston, Texas, United States 1999–2003 Premature infants with BPD 44 ∼26 wk ∼767 g 6, 12, 24 mo after DC FRC, V̇maxFRC Compared with normative data, children with BPD had lower z scores for V̇ maxFRC, remaining stably low over the first 2 y. FRC, although initially low, increased slowly over the same time period. 
Fillipone et al,12  2003; Padova, Italy 1990–1991 Preterm infants <1250 g, on ventilation >10 d, O2 at 28 d, and abnormal CXR at 1 mo 18 ∼28 wk ∼952 g 24 mo and ∼8.8 y FEV1, FRC V̇maxFRC, FEF25–75 In 18 children with moderate to severe BPD, 15 showed below normal FEV1 and FEF25–75 at school age. V̇ maxFRC at 2 y showed significant positive correlation to FEV1 and FEF25–75. 
Friedrich et al,13  2006; Brazil ∼2000 Preterm infants without respiratory morbidity and term controls 62 preterm ∼33 wk ∼2000 g Within 1 mo after birth FEF50,FEF75, FEF25–75, FEV0.5, FVC Compared with term infants, preterm infants have reduced measures of expiratory flows including FEF50, FEF25–75, and FEV0.5. 
27 controls ∼39 wk ∼3000 g 
Gibson et al,14  2015; Melbourne, Australia 1977–1981 Birth weight–based cohorts 47<1 kg ∼28 wk ∼875 g ∼25 y FEV1, FVC, FEF25–75, RV, TLC Adults born <1500 g have significantly more airway obstruction (FEV1) at age 25 than normal controls. Those with a history of BPD had significantly lower z scores for FEV1 than those without BPD. 
21 1–1.5 kg ∼30 wk ∼1225 g 
12<2.5 kg ∼40 wk ∼3550 g 
Gross et al,15  1998; New York, United States 1985–1986 Preterm infants <32 wk PMA and term controls 96 preterm ∼28 wk ∼1200 g ∼7 y FEV1, FVC, FEF25–75 Preterm infants with BPD had greater evidence of flow obstruction than those without BPD or term controls. Lung function among preterm infants without BPD was similar to that of term controls. 
108 term ∼40 wk ∼3500 g 
Haland et al,16  2006; Olso, Norway 1992–1993 Population-based birth cohort ∼600 Term 3.59 kg After birth and at 10 y Crs, TPTEF:TE Children with TPTEF:TE or Crs below the median were more likely to have asthma, history of asthma, or airway reactivity at age 10 than peers. 
Hayatbakhsh et al,17  2009; Australia 1981 Infants born to mothers in Mater-University Study of Pregnancy −2600 nr nr ∼21 y FEV1, FVC, FEF25–75 In utero exposure to smoking was associated with lower FEV1 and FEF25–75 at 21 y of age, particularly among the male individuals in the study. 
Heldt et al,18  1980; California, United States 1968–1974 Preterm infants with hyaline membrane disease 62 ∼33 wk ∼2100 g Mean ∼8 y V̇o2, CO2 production In a cohort of premature infants from the 1960–70s, most survivors had normal heart rates and V̇o2 with exercise. 
Hibbert et al,19  1993; Melbourne, Australia 1980s Population-based cohort ∼500 Term nr Yearly from 8 to 19 y FEV1, FVC FEF25–75 PEFR Population norms show increases between age 8 and 19 y. 
Hjalmarson and Sandberg, 20  2002; Sweden ∼2000 Preterm infants without respiratory morbidity and term controls 32 preterm ∼30 wk, ∼1420 g 40 wk PMA Crs, Rrs, Grs, and, FRC At the same PMA, preterm infants had lower FRC/kg, lower Crs/kg, impaired gas mixing efficiency, and higher dead space ventilation than term infants. 
53 controls ∼40 wk ∼3550g 
Hoo et al,21  2002; London, United Kingdom nr <36 wk GA without respiratory disease and term controls 92 ∼33 wk ∼1900 g Before DC after birth V̇maxFRC, TPTEF:TE Normative data for V̇maxFRC was determined from 4 cohorts. Sex, length, and age were significant predictors of V̇maxFRC. 
367 ∼40 wk ∼3400 g 
Hoo et al,22  2002; London, United Kingdom nr <36 wk GA, <6 h of ventilation support, <24 h of supplemental O2 89 ∼33 wk ∼1890 g 3 wk of age and at 1 y V̇ maxFRC For premature infants, standard scores for V̇maxFRC at 3 wk were highly correlated with those at 1 y, suggesting significant tracking over this time period. 
Jacob et al,23  1998; Montreal, Canada 1981–1987 Preterm infants with BPD and age-matched controls without BPD 15 with BPD ∼29 wk ∼1100 g Term PMA FEV1, FVC, RV, DLCO, FEF25–75, FRC, TLC Former premature infants with BPD had significantly lower FEV1 and more gas trapping at ∼1 y than those without BPD. Duration of supplemental oxygen use was inversely correlated with FEV1. 
15 without BPD ∼29 wk ∼1050 g 
Karmaus et al,24  2019; Isle of Wight, United Kingdom 1989–1990 Population-based birth cohort 1456 nr nr 10, 18, and 26 y FEV1, FVC, FEF25–75 Lung function trajectories for FEV1, FVC, FEV1/FVC, and FEF25–75 are defined between ages 10 and 26 y. 
Kilbride et al,25  2003; Kansas City, Missouri, United States 1983–1989 Preterm infants <800 g and term controls 50 preterm ∼26 wk ∼700 g ∼11 y FEV1, FEF25–75, FVC, PEFR Former premature infants with chronic lung disease had lower FEV1, FEV1/FVC, and FEF25–75 than those without chronic lung disease. 
25 term >37 wk >2500 g 
Kotecha et al,26  2010; London, United Kingdom 1991–1992 Avon Longitudinal Study of Parents and Children Cohort 576 IUGR Term ∼2750 g 8–9 y FEV1, FVC FEV0.5, FEF25–75, FEF25, 50, 75 In children at 8–9 y of age, FEV1 and FEF25–75 are lower in those with a history of IUGR compared with those in the normal birth weight wt control group. 
3462 controls Term ∼3450 g 
Lam et al,27  2019; Portland, Oregon, United States 2014–2016 Preterm infants <32 wk GA 22 study group ∼29 wk ∼1400 g At study entry and at 2 wk FRC In a prospective study of premature infants, those randomly assigned to an extended duration of CPAP had greater increase in FRC at discharge than those randomized to usual care. 
   22 usual care ∼29 wk ∼1220 g     
Landry et al,28  2016; Quebec, Canada 1987–1993 Preterm with BPD, preterm with RDS, health preterm, term controls 31 27 wk ∼1000 g ∼22 y FEV1, FVC, FEF25–75, DLCO At ∼22 y, adults born preterm with history of BPD have significantly greater obstruction (FEV1 and FEF25–75) than those with history of RDS only, healthy preterm infants, or term controls. 
Preterm with RDS 31 32 wk ∼2000 g 
Health preterm 26 33 wk ∼2200 g 
Term controls 35 40 wk ∼3500 g 
Lange et al,29  2015; Framingham, Massachusetts, United States; Copenhagen, Denmark; Albuquerque, New Mexico, United States 1940s–present Framingham Offspring Cohort ∼1600 nr nr 50–65 y FEV1, FVC for all 3 studies After 22 y of follow-up, 26% of adults with FEV1 <80% before age 40 developed COPD, compared with 7% of adults with FEV1 >80% before age 40. 
Copenhagen City Heart Cohort ∼1200 
Lovelace Smokers Cohort ∼1550 
Lawlor et al,30  2006; England, United Kingdom Born ∼1920–1940 British Women’s Heart and Health Study ∼2257 nr nr 60–79 y FEV1, FEF25–75 A modest positive correlation is found between birth wt and lung function at 60–70 y, suggesting a role for intrauterine factors in lung function. 
McEvoy et al,31  2013; Portland, Oregon, United States ∼2011–2012 33–36 wk premature infants without respiratory support and term controls 31 preterm ∼31 wk ∼2150 g At term Crs, Rrs, FRC, TPTEF:TE Compared with term infants, late preterm infants (∼34 wk) had lower Crs, lower TPTEF:TE, and higher Rrs when measured at term corrected age. 
31 controls ∼39 wk ∼3500 g 
McEvoy et al,32  2014; Portland, Oregon, United States ∼2007–2011 Infants of women who smoked during pregnancy ∼150 ∼39 wk ∼3200 g <72 h of age and at 1 y Crs, Rrs, FRC, TPTEF:TE Newborns of smokers receiving vitamin C supplementation during pregnancy had higher TPTEF:TE, higher Crs/kg, and less wheezing at 1 y than infants whose mothers received placebo. 
McEvoy,33  2020; Portland, Oregon, United States ∼2012–2017 Infants of pregnant smokers ∼150 ∼38.6 ∼3100g 3 and 12 mo of age FEF75, FEF50, FEF25–75 Offspring of pregnant smokers randomly assigned to vitamin C supplementation during pregnancy had significantly increased forced expiratory flows at 3 and 12 mo of age. 
Morrow et al,34  2015; Portland, Oregon, United States 2014–2015 Preterm infants <1500 g 40 preterm infants ∼27 wk ∼850 g ∼35 wk PMA Crs, Rrs In a retrospective study of extremely low birth wt infants, 52.5% had a significant decrease in Rrs after brochodilator therapy, 12.5% had a moderate response, and 35% had no measurable response. 
Moschino et al,35  2018; Padua, Italy 1991–1993 Preterm infants <1250g and <31 wk GA with moderate or severe BPD 17 ∼28 wk ∼930 g 9, 15, 20, and 24 y FEV1, FVC, FEF25–75 Former extremely low birth wt infants with BPD have persistently lower than normal FEV1, FVC, FEV1/FVC, and FEF25–75 throughout childhood, never reaching optimal peak function in adulthood. These measures also show significant tracking. 
Northway et al,36  1990; San Francisco, California, United States 1964–1973 Preterm infants with RDS 26 preterm with BPD ∼33 wk ∼1900 g Mean age 18 y FEV1, FVC, FEF25–75, PEFR,TLC FRC, DLCO, V̇max50 In a cohort of premature infants from the 1960–70s, 68% of those with BPD had airway obstruction (by FEV1, FEF25–75, FEF50). Of these, 24% had fixed obstruction, 52% reactive airways disease. 
26 preterm without BPD ∼35 wk ∼2000 g 
53 term controls ∼term nr 
Örtqvist,37 2017; Sweden 2011–2014 Population-based birth cohort of twins 539 ∼37 wk ∼2700 g Mean age 12.5 y FEV1, FVC Decreased postbronchodilator FEV1 and FVC were associated with low birth wt and fetal growth restriction. 
Owens et al,38  2018; Perth, Australia 1987–1990 Population-based birth cohort 253 Term nr 1, 6, 12 mo and 6, 11, 18, 24 y V̇maxFRC, FEV1, FVC, FEF25–75 V̇ maxFRC at 1 mo positively correlates with FEF25–75 from 6 to 24 y and with FEV1/FVC at 11 and 24 y and is inversely correlated to airway responsiveness at 6 and 18 y. 
Sears et al,39  2003;. New Zealand 1972–1974 Population-based birth cohort 613 Term nr 9, 11, 13, 15, 18, and 26 y FEV1, FVC By 26 y, 14.5% had persistent wheezing, 27.4% had remission, 12.4% relapsed. Sensitization to dust mites, airway hyperresponsiveness, female sex, smoking, and early onset predicted persistent wheezing or relapse. 
Shepherd et al,40  2018; Columbus, Ohio, United States 2003–2016 Premature infants with BPD 110 ∼26 wk ∼707 g ∼52 wk PMA Crs, FVC, FEV0.5, FEF50, FVC FEF75, TLC, FEF25–75 Among infants with severe BPD, 51% showed obstructive lung disease, 9% with restrictive, and 44% mixed. Moderate to severe obstruction was found in 86% of the obstructive group and 78% of the mixed. 
Simpson et al,41  2017; Perth, Australia 1997–2003 Premature infants <32 wk and term controls 163 preterm ∼28 wk ∼955 g 9–11 y FEV1, FEF25–75, TLC, FRC, FVC, LCI Measured in mid-childhood, former preterm infants showed impairment in expiratory flows and hyperinflation. Z score for FEV1 increased by 0.1 per additional week of gestation. 
58 term >37 wk nr 
Stern et al,42  2007; Tuscon, Arizona, United States 1980–1984 Population-based birth cohort 123 Term nr Infancy and 11, 16, 22 y FEV1, FVC, FEF25–75 Infants with V̇ maxFRC in the lowest quartile had lower values for the FEV1/FVC ratio (−5·2%), FEF25–75 (−663 mL/s), and FEV1 (−233 mL) age ≤22 than those in the upper 3 quartiles. 
Tager et al,43  1995; Boston, Massachusetts, United States ∼late 1980s, early 1990s Population-based birth cohort 159 ∼38 wk ∼3400 g 2–6 wk, 4–6 mo, 9–12 mo, 15–18 mo V̇ maxFRC, FRC Infants exposed to in utero tobacco had lower FRC (−9.4 mL) and lower V̇ maxFRC (−33 mL/s) than unexposed peers. Postnatal tobacco exposure did not affect these measures. 
Tai et al,44  2014; Melbourne, Australia 1957 Population-based birth cohort: Melbourne Asthma Cohort ∼200 nr nr 10, 14, 21, 28, 35, 42, and 50 y FEV1, FVC Children with severe asthma at age 7 were 32 times higher risk of developing COPD in adulthood than children without asthma. 
Turner et al,45  2002; Perth, Australia nr Population-based birth cohort ∼200 Term nr 6 and 11 y V̇maxFRC, FEV1, FVC, FEF25–75 Infants with flow limitation (based on V̇ maxFRC) had increased airway responsiveness, reduced FEV1 and FEF25–75 at 6 y. They had persistently increased airway responsiveness and a trend toward reduced FEF25–75 at 11 y. 
Turner et al,46  2004; Perth, Australia 1987–1990 Healthy term infants 63 Term 3.43 kg 1 mo and 11 y V̇maxFRC and airway responsiveness Reduced airway function at 1 mo (decreased z score for V̇ maxFRC) was associated with recent and persistent wheezing at age 11 y. 
Turner et al,47  2014; Perth, Australia nr Population-based birth cohort 241 Term nr 1, 6, 12 mo; 6, 11, 18 y FEV1, FVC, FEF25–75, V̇maxFRC FRC In a longitudinal model of healthy children, lung function was independently modified by maternal asthma, flow limitation, infant atopy, and maternal smoking. 
van Putte-Katier et al,48  2011; Netherlands 2001 Population-based birth (WHISTLER) cohort and their parents 546 infants Term ∼3500 g < 2 mo (infants) Crs, Rrs, FEV1, FVC, FEF25–75 Parental lung function was compared with lung function of their infants. Parental lung function (FEF25–75 and FEV1) predicted infant lung function (Crs). 
Vollsaeter et al,49  2013; Norway 1982–1985 Premature infants <28 wk, <1000 g, and term controls 81 preterm ∼27 wk ∼1000 g 10, 18, and 25 y FEV1, FVC, FEF25–75 Preterm infants showed greater reduction in FEV1 and FEF25–75 than term controls. Flow obstruction was worst among those with a history of BPD. 
1991–1992 81 term ∼term ∼3500 g 
Vollsaeter et al,50  2015; Norway 1982–1985 Premature infants <28 wk, <1000 g, and term controls 45 preterm ∼27 wk ∼1000 g 18 and 25 y FEV1, FVC, FEF25–75, DLCO, FRC Preterm infants had a significant decrease in FEV1 and FEF25–75 compared to term controls, although still within the normal range overall. Significantly more airway reactivity was found among former premature infants. 
39 term ∼term ∼3500 g 
Vrijlandt et al,51  2006; Netherlands 1983 Premature infants <32 wk, <1500 g and term controls 42 ∼30 wk ∼1250 g ∼19 y FEV1, FVC, FEF25, 50, 75, DLCO, FRC Adults born prematurely had greater airway obstruction on forced expiratory flows and lower DLCO, although these values remained within the normal range. 
48 ∼term nr 
Wang et al,52 1993; United States 1967–1982 Population-based birth cohort 13 737 nr nr Yearly from 6 to 18 y FEV1, FVC, FEF25–75 Population norms for FEV1, FVC, FEV1/FVC, and FEF25–75 show increases between age 6 and 18 y. 
Wong,53  2008; Perth, Australia 1980–1987 Former premature infants with BPD 21 ∼27 wk ∼900 g ∼19 y FEV1, FVC, FEF25–75 DLCO, TLC Among young adult survivors of BPD, there is a correlation between decrease in expiratory flows (FEV1 and FEF25–75) and emphysematous changes on computed tomography imaging. 
Young et al,54  1994; Perth, Australia 1987–1991 Population-based birth cohort 252 Term nr 1, 6, and 12 mo V̇maxFRC, TPTEF:TE, Crs and Rrs Infants with family history of asthma, atopy or smoking had reduced V̇ maxFRC, Crs, TPTEF:TE and increased Rrs at 1 mo. They had persistently lower lung function than peers at 6 and 12 mo. 
Study and LocationEraInclusion CriteriaNo. ParticipantsGA at BirthBirth wtTiming of PFTsPFT ParametersFindings
Anand et al,1  2003; Liverpool, United Kingdom 1980–1981 Preterm survivors born <1500 g and term controls 128 preterm ∼31 wk  ∼1250 g ∼15 y FEV1, FVC, FEF25–75 Compared with term controls, former very low birth wt infants had greater medium and small airway obstruction (lower FEF25–75 and FEV1/FVC) when measured in adolescence. 
128 term Term ∼3300 g 
Bader et al,2  1987; Los Angeles, California, United States 1973–1979 Preterm infants with severe BPD and term controls 10 preterm ∼29 wk ∼1200 g ∼10 y FEV1, FRC, FEF25–75, FEFmax, TLC, VC Small study of former premature infants with BPD, FEV1, FEV1/FVC, FEF25–75, and other measures of maximum expiratory flows were lower than controls measured at ∼10 y. 
8 term ∼40 wk ∼3250 g 
Baraldi et al,3  1997; Padova, Italy 1990–1991 Preterm infants <1250 g, requiring 10 d on ventilator, oxygen at 28 d, and CXR findings 28 ∼28 wk ∼952 g 10–20 d; 3, 6, 9, 12, and 24 mo Crs, Rrs, FRC, and VmaxFRC In infants with BPD, measurements of FRC, Crs, and Rrs were lower than normal in the first year and increased over time, reaching normalcy by 2 y. Forced expiratory flows remained abnormally low throughout the study. 
Bisgaard et al,4  2012; Copenhagen, Denmark nr COPSAC cohort: birth cohort of children born to mothers with asthma ∼350 nr nr 1 mo and 7 y FEV0.5, FEF50, FEV1, FVC Children diagnosed with asthma at age 7 y had reduced lung function (FEV0.5) as neonates. 
Bröstrom et al,5  2010; Stockholm, Sweden 1992–97 Infants <32 wk GA with BPD or RDS (controls) 32 with BPD ∼28 wk ∼1000 g 6–8 y FEV1, FVC, FEF25–75, Rrs Former premature infants with BPD had evidence of impaired lung function (FEV1) at school age. 
28 with RDS ∼30 wk ∼1500 g 
Bui et al,6  2018; Tasmania, Australia After 1968 Population-based birth cohort: Tasmanian Longitudinal Health Cohort ∼2500 nr nr 7, 13, 18, 45, 50, and 53 y FEV1 Six trajectories of lung function were identified: early below average, accelerated decline (4%), persistently low (6%), early low, accelerated growth, and normal decline (8%), persistently high (12%), below average (32%), and average (39%). 
den Dekker et al,7  2018; Netherlands 2002 Population-based birth cohort: Generation R Study ∼5600 Term ∼3400 g ∼10 y FEV1, FVC, FEF25–75, FEF75, Term infants with IUGR had lower FEV1 than unaffected peers. Accelerated postnatal growth velocity and body wt predisposed infants with IUGR to lower lung function in later childhood. 
Dezateux et al,8  1994; London, United Kingdom nr Healthy term infants 220 Term ∼3400 g 5–13 wk and 1 y FRC, TPTEF:TE In infants, TPTEF:TE was significantly lower in infant with a previous history of lower respiratory tract infection and wheezing than in those without. 
Doyle et al,9  2017; Victoria, Australia 1991–1992 Preterm survivors born <28 wk 297 preterm ∼27 wk ∼888 g 8 and 18 y FEV1, FVC, FEF25–75, FEF75 Preterm infants had greater airway obstruction (FEV1) and greater increase in small airways obstruction (FEF25–75) than controls. Airway obstruction was also associated with history of BPD or smoking. 
260 term ∼39 wk ∼3400 g 
Doyle et al,10  2017; Melbourne, Australia 1991–1992 Preterm infants <1000 g in 3 epochs 225 in 1991–1992 cohort  ∼26 wk ∼890 g ∼8 y FEV1, FVC, FEF25-75 Among extremely premature infants, duration of assisted ventilation (mostly CPAP) increased from 1991 to 2005, but rates of oxygen need at 36 wk PMA, duration of oxygen use, and measures of airway flows worsened over that time period. 
1997 151 in 1997 cohort ∼26 wk ∼820 g 
2005 170 in 2005 cohort ∼26 wk ∼870 g 
Fakhoury et al,11  2010; Houston, Texas, United States 1999–2003 Premature infants with BPD 44 ∼26 wk ∼767 g 6, 12, 24 mo after DC FRC, V̇maxFRC Compared with normative data, children with BPD had lower z scores for V̇ maxFRC, remaining stably low over the first 2 y. FRC, although initially low, increased slowly over the same time period. 
Fillipone et al,12  2003; Padova, Italy 1990–1991 Preterm infants <1250 g, on ventilation >10 d, O2 at 28 d, and abnormal CXR at 1 mo 18 ∼28 wk ∼952 g 24 mo and ∼8.8 y FEV1, FRC V̇maxFRC, FEF25–75 In 18 children with moderate to severe BPD, 15 showed below normal FEV1 and FEF25–75 at school age. V̇ maxFRC at 2 y showed significant positive correlation to FEV1 and FEF25–75. 
Friedrich et al,13  2006; Brazil ∼2000 Preterm infants without respiratory morbidity and term controls 62 preterm ∼33 wk ∼2000 g Within 1 mo after birth FEF50,FEF75, FEF25–75, FEV0.5, FVC Compared with term infants, preterm infants have reduced measures of expiratory flows including FEF50, FEF25–75, and FEV0.5. 
27 controls ∼39 wk ∼3000 g 
Gibson et al,14  2015; Melbourne, Australia 1977–1981 Birth weight–based cohorts 47<1 kg ∼28 wk ∼875 g ∼25 y FEV1, FVC, FEF25–75, RV, TLC Adults born <1500 g have significantly more airway obstruction (FEV1) at age 25 than normal controls. Those with a history of BPD had significantly lower z scores for FEV1 than those without BPD. 
21 1–1.5 kg ∼30 wk ∼1225 g 
12<2.5 kg ∼40 wk ∼3550 g 
Gross et al,15  1998; New York, United States 1985–1986 Preterm infants <32 wk PMA and term controls 96 preterm ∼28 wk ∼1200 g ∼7 y FEV1, FVC, FEF25–75 Preterm infants with BPD had greater evidence of flow obstruction than those without BPD or term controls. Lung function among preterm infants without BPD was similar to that of term controls. 
108 term ∼40 wk ∼3500 g 
Haland et al,16  2006; Olso, Norway 1992–1993 Population-based birth cohort ∼600 Term 3.59 kg After birth and at 10 y Crs, TPTEF:TE Children with TPTEF:TE or Crs below the median were more likely to have asthma, history of asthma, or airway reactivity at age 10 than peers. 
Hayatbakhsh et al,17  2009; Australia 1981 Infants born to mothers in Mater-University Study of Pregnancy −2600 nr nr ∼21 y FEV1, FVC, FEF25–75 In utero exposure to smoking was associated with lower FEV1 and FEF25–75 at 21 y of age, particularly among the male individuals in the study. 
Heldt et al,18  1980; California, United States 1968–1974 Preterm infants with hyaline membrane disease 62 ∼33 wk ∼2100 g Mean ∼8 y V̇o2, CO2 production In a cohort of premature infants from the 1960–70s, most survivors had normal heart rates and V̇o2 with exercise. 
Hibbert et al,19  1993; Melbourne, Australia 1980s Population-based cohort ∼500 Term nr Yearly from 8 to 19 y FEV1, FVC FEF25–75 PEFR Population norms show increases between age 8 and 19 y. 
Hjalmarson and Sandberg, 20  2002; Sweden ∼2000 Preterm infants without respiratory morbidity and term controls 32 preterm ∼30 wk, ∼1420 g 40 wk PMA Crs, Rrs, Grs, and, FRC At the same PMA, preterm infants had lower FRC/kg, lower Crs/kg, impaired gas mixing efficiency, and higher dead space ventilation than term infants. 
53 controls ∼40 wk ∼3550g 
Hoo et al,21  2002; London, United Kingdom nr <36 wk GA without respiratory disease and term controls 92 ∼33 wk ∼1900 g Before DC after birth V̇maxFRC, TPTEF:TE Normative data for V̇maxFRC was determined from 4 cohorts. Sex, length, and age were significant predictors of V̇maxFRC. 
367 ∼40 wk ∼3400 g 
Hoo et al,22  2002; London, United Kingdom nr <36 wk GA, <6 h of ventilation support, <24 h of supplemental O2 89 ∼33 wk ∼1890 g 3 wk of age and at 1 y V̇ maxFRC For premature infants, standard scores for V̇maxFRC at 3 wk were highly correlated with those at 1 y, suggesting significant tracking over this time period. 
Jacob et al,23  1998; Montreal, Canada 1981–1987 Preterm infants with BPD and age-matched controls without BPD 15 with BPD ∼29 wk ∼1100 g Term PMA FEV1, FVC, RV, DLCO, FEF25–75, FRC, TLC Former premature infants with BPD had significantly lower FEV1 and more gas trapping at ∼1 y than those without BPD. Duration of supplemental oxygen use was inversely correlated with FEV1. 
15 without BPD ∼29 wk ∼1050 g 
Karmaus et al,24  2019; Isle of Wight, United Kingdom 1989–1990 Population-based birth cohort 1456 nr nr 10, 18, and 26 y FEV1, FVC, FEF25–75 Lung function trajectories for FEV1, FVC, FEV1/FVC, and FEF25–75 are defined between ages 10 and 26 y. 
Kilbride et al,25  2003; Kansas City, Missouri, United States 1983–1989 Preterm infants <800 g and term controls 50 preterm ∼26 wk ∼700 g ∼11 y FEV1, FEF25–75, FVC, PEFR Former premature infants with chronic lung disease had lower FEV1, FEV1/FVC, and FEF25–75 than those without chronic lung disease. 
25 term >37 wk >2500 g 
Kotecha et al,26  2010; London, United Kingdom 1991–1992 Avon Longitudinal Study of Parents and Children Cohort 576 IUGR Term ∼2750 g 8–9 y FEV1, FVC FEV0.5, FEF25–75, FEF25, 50, 75 In children at 8–9 y of age, FEV1 and FEF25–75 are lower in those with a history of IUGR compared with those in the normal birth weight wt control group. 
3462 controls Term ∼3450 g 
Lam et al,27  2019; Portland, Oregon, United States 2014–2016 Preterm infants <32 wk GA 22 study group ∼29 wk ∼1400 g At study entry and at 2 wk FRC In a prospective study of premature infants, those randomly assigned to an extended duration of CPAP had greater increase in FRC at discharge than those randomized to usual care. 
   22 usual care ∼29 wk ∼1220 g     
Landry et al,28  2016; Quebec, Canada 1987–1993 Preterm with BPD, preterm with RDS, health preterm, term controls 31 27 wk ∼1000 g ∼22 y FEV1, FVC, FEF25–75, DLCO At ∼22 y, adults born preterm with history of BPD have significantly greater obstruction (FEV1 and FEF25–75) than those with history of RDS only, healthy preterm infants, or term controls. 
Preterm with RDS 31 32 wk ∼2000 g 
Health preterm 26 33 wk ∼2200 g 
Term controls 35 40 wk ∼3500 g 
Lange et al,29  2015; Framingham, Massachusetts, United States; Copenhagen, Denmark; Albuquerque, New Mexico, United States 1940s–present Framingham Offspring Cohort ∼1600 nr nr 50–65 y FEV1, FVC for all 3 studies After 22 y of follow-up, 26% of adults with FEV1 <80% before age 40 developed COPD, compared with 7% of adults with FEV1 >80% before age 40. 
Copenhagen City Heart Cohort ∼1200 
Lovelace Smokers Cohort ∼1550 
Lawlor et al,30  2006; England, United Kingdom Born ∼1920–1940 British Women’s Heart and Health Study ∼2257 nr nr 60–79 y FEV1, FEF25–75 A modest positive correlation is found between birth wt and lung function at 60–70 y, suggesting a role for intrauterine factors in lung function. 
McEvoy et al,31  2013; Portland, Oregon, United States ∼2011–2012 33–36 wk premature infants without respiratory support and term controls 31 preterm ∼31 wk ∼2150 g At term Crs, Rrs, FRC, TPTEF:TE Compared with term infants, late preterm infants (∼34 wk) had lower Crs, lower TPTEF:TE, and higher Rrs when measured at term corrected age. 
31 controls ∼39 wk ∼3500 g 
McEvoy et al,32  2014; Portland, Oregon, United States ∼2007–2011 Infants of women who smoked during pregnancy ∼150 ∼39 wk ∼3200 g <72 h of age and at 1 y Crs, Rrs, FRC, TPTEF:TE Newborns of smokers receiving vitamin C supplementation during pregnancy had higher TPTEF:TE, higher Crs/kg, and less wheezing at 1 y than infants whose mothers received placebo. 
McEvoy,33  2020; Portland, Oregon, United States ∼2012–2017 Infants of pregnant smokers ∼150 ∼38.6 ∼3100g 3 and 12 mo of age FEF75, FEF50, FEF25–75 Offspring of pregnant smokers randomly assigned to vitamin C supplementation during pregnancy had significantly increased forced expiratory flows at 3 and 12 mo of age. 
Morrow et al,34  2015; Portland, Oregon, United States 2014–2015 Preterm infants <1500 g 40 preterm infants ∼27 wk ∼850 g ∼35 wk PMA Crs, Rrs In a retrospective study of extremely low birth wt infants, 52.5% had a significant decrease in Rrs after brochodilator therapy, 12.5% had a moderate response, and 35% had no measurable response. 
Moschino et al,35  2018; Padua, Italy 1991–1993 Preterm infants <1250g and <31 wk GA with moderate or severe BPD 17 ∼28 wk ∼930 g 9, 15, 20, and 24 y FEV1, FVC, FEF25–75 Former extremely low birth wt infants with BPD have persistently lower than normal FEV1, FVC, FEV1/FVC, and FEF25–75 throughout childhood, never reaching optimal peak function in adulthood. These measures also show significant tracking. 
Northway et al,36  1990; San Francisco, California, United States 1964–1973 Preterm infants with RDS 26 preterm with BPD ∼33 wk ∼1900 g Mean age 18 y FEV1, FVC, FEF25–75, PEFR,TLC FRC, DLCO, V̇max50 In a cohort of premature infants from the 1960–70s, 68% of those with BPD had airway obstruction (by FEV1, FEF25–75, FEF50). Of these, 24% had fixed obstruction, 52% reactive airways disease. 
26 preterm without BPD ∼35 wk ∼2000 g 
53 term controls ∼term nr 
Örtqvist,37 2017; Sweden 2011–2014 Population-based birth cohort of twins 539 ∼37 wk ∼2700 g Mean age 12.5 y FEV1, FVC Decreased postbronchodilator FEV1 and FVC were associated with low birth wt and fetal growth restriction. 
Owens et al,38  2018; Perth, Australia 1987–1990 Population-based birth cohort 253 Term nr 1, 6, 12 mo and 6, 11, 18, 24 y V̇maxFRC, FEV1, FVC, FEF25–75 V̇ maxFRC at 1 mo positively correlates with FEF25–75 from 6 to 24 y and with FEV1/FVC at 11 and 24 y and is inversely correlated to airway responsiveness at 6 and 18 y. 
Sears et al,39  2003;. New Zealand 1972–1974 Population-based birth cohort 613 Term nr 9, 11, 13, 15, 18, and 26 y FEV1, FVC By 26 y, 14.5% had persistent wheezing, 27.4% had remission, 12.4% relapsed. Sensitization to dust mites, airway hyperresponsiveness, female sex, smoking, and early onset predicted persistent wheezing or relapse. 
Shepherd et al,40  2018; Columbus, Ohio, United States 2003–2016 Premature infants with BPD 110 ∼26 wk ∼707 g ∼52 wk PMA Crs, FVC, FEV0.5, FEF50, FVC FEF75, TLC, FEF25–75 Among infants with severe BPD, 51% showed obstructive lung disease, 9% with restrictive, and 44% mixed. Moderate to severe obstruction was found in 86% of the obstructive group and 78% of the mixed. 
Simpson et al,41  2017; Perth, Australia 1997–2003 Premature infants <32 wk and term controls 163 preterm ∼28 wk ∼955 g 9–11 y FEV1, FEF25–75, TLC, FRC, FVC, LCI Measured in mid-childhood, former preterm infants showed impairment in expiratory flows and hyperinflation. Z score for FEV1 increased by 0.1 per additional week of gestation. 
58 term >37 wk nr 
Stern et al,42  2007; Tuscon, Arizona, United States 1980–1984 Population-based birth cohort 123 Term nr Infancy and 11, 16, 22 y FEV1, FVC, FEF25–75 Infants with V̇ maxFRC in the lowest quartile had lower values for the FEV1/FVC ratio (−5·2%), FEF25–75 (−663 mL/s), and FEV1 (−233 mL) age ≤22 than those in the upper 3 quartiles. 
Tager et al,43  1995; Boston, Massachusetts, United States ∼late 1980s, early 1990s Population-based birth cohort 159 ∼38 wk ∼3400 g 2–6 wk, 4–6 mo, 9–12 mo, 15–18 mo V̇ maxFRC, FRC Infants exposed to in utero tobacco had lower FRC (−9.4 mL) and lower V̇ maxFRC (−33 mL/s) than unexposed peers. Postnatal tobacco exposure did not affect these measures. 
Tai et al,44  2014; Melbourne, Australia 1957 Population-based birth cohort: Melbourne Asthma Cohort ∼200 nr nr 10, 14, 21, 28, 35, 42, and 50 y FEV1, FVC Children with severe asthma at age 7 were 32 times higher risk of developing COPD in adulthood than children without asthma. 
Turner et al,45  2002; Perth, Australia nr Population-based birth cohort ∼200 Term nr 6 and 11 y V̇maxFRC, FEV1, FVC, FEF25–75 Infants with flow limitation (based on V̇ maxFRC) had increased airway responsiveness, reduced FEV1 and FEF25–75 at 6 y. They had persistently increased airway responsiveness and a trend toward reduced FEF25–75 at 11 y. 
Turner et al,46  2004; Perth, Australia 1987–1990 Healthy term infants 63 Term 3.43 kg 1 mo and 11 y V̇maxFRC and airway responsiveness Reduced airway function at 1 mo (decreased z score for V̇ maxFRC) was associated with recent and persistent wheezing at age 11 y. 
Turner et al,47  2014; Perth, Australia nr Population-based birth cohort 241 Term nr 1, 6, 12 mo; 6, 11, 18 y FEV1, FVC, FEF25–75, V̇maxFRC FRC In a longitudinal model of healthy children, lung function was independently modified by maternal asthma, flow limitation, infant atopy, and maternal smoking. 
van Putte-Katier et al,48  2011; Netherlands 2001 Population-based birth (WHISTLER) cohort and their parents 546 infants Term ∼3500 g < 2 mo (infants) Crs, Rrs, FEV1, FVC, FEF25–75 Parental lung function was compared with lung function of their infants. Parental lung function (FEF25–75 and FEV1) predicted infant lung function (Crs). 
Vollsaeter et al,49  2013; Norway 1982–1985 Premature infants <28 wk, <1000 g, and term controls 81 preterm ∼27 wk ∼1000 g 10, 18, and 25 y FEV1, FVC, FEF25–75 Preterm infants showed greater reduction in FEV1 and FEF25–75 than term controls. Flow obstruction was worst among those with a history of BPD. 
1991–1992 81 term ∼term ∼3500 g 
Vollsaeter et al,50  2015; Norway 1982–1985 Premature infants <28 wk, <1000 g, and term controls 45 preterm ∼27 wk ∼1000 g 18 and 25 y FEV1, FVC, FEF25–75, DLCO, FRC Preterm infants had a significant decrease in FEV1 and FEF25–75 compared to term controls, although still within the normal range overall. Significantly more airway reactivity was found among former premature infants. 
39 term ∼term ∼3500 g 
Vrijlandt et al,51  2006; Netherlands 1983 Premature infants <32 wk, <1500 g and term controls 42 ∼30 wk ∼1250 g ∼19 y FEV1, FVC, FEF25, 50, 75, DLCO, FRC Adults born prematurely had greater airway obstruction on forced expiratory flows and lower DLCO, although these values remained within the normal range. 
48 ∼term nr 
Wang et al,52 1993; United States 1967–1982 Population-based birth cohort 13 737 nr nr Yearly from 6 to 18 y FEV1, FVC, FEF25–75 Population norms for FEV1, FVC, FEV1/FVC, and FEF25–75 show increases between age 6 and 18 y. 
Wong,53  2008; Perth, Australia 1980–1987 Former premature infants with BPD 21 ∼27 wk ∼900 g ∼19 y FEV1, FVC, FEF25–75 DLCO, TLC Among young adult survivors of BPD, there is a correlation between decrease in expiratory flows (FEV1 and FEF25–75) and emphysematous changes on computed tomography imaging. 
Young et al,54  1994; Perth, Australia 1987–1991 Population-based birth cohort 252 Term nr 1, 6, and 12 mo V̇maxFRC, TPTEF:TE, Crs and Rrs Infants with family history of asthma, atopy or smoking had reduced V̇ maxFRC, Crs, TPTEF:TE and increased Rrs at 1 mo. They had persistently lower lung function than peers at 6 and 12 mo. 

COPSAC, Copenhagen Prospective Studies on Asthma in Childhood; CXR, chest radiograph; DC, discharge; DLCO, diffusion capacity for carbon monoxide; FEF85, forced expiratory flow at 85% of forced vital capacity; LCI, lung clearance index; nr, not reported; PEFR, peak expiratory flow rate; RDS, respiratory distress syndrome; Trs, time constant of the respiratory system; V̇max80, maximum expiratory flow at 80% of TLC; WHISTLER, Wheezing Illnesses Study Leidsche Rijn.

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A growing body of evidence has established the paradigm that lung function changes over time along predictable trajectories. Among healthy individuals, lung function increases throughout childhood, plateaus in early adulthood, and declines in adulthood with the normal aging process.6,29,39,55  Longitudinal studies of lung function have demonstrated that these trajectories of lung function are established in early infancy and that lung function measured in early infancy is predictive of peak adult lung function.38,42  One of the earliest and most influential studies on trajectories of lung function through childhood was performed in a population-based cohort of healthy infants born in Arizona in the early 1980s. In this 22-year study, Stern et al42  showed that measurements of maximal flow at functional residual capacity (V̇maxFRC; an early measurement of flow obstruction) taken in infancy were associated with deficits in forced expiratory volume in 1 second / forced vital capacity (FEV1/FVC; also a measurement of flow obstruction) at 22 years of age. Infants in the lowest quartile for V̇maxFRC had values for FEV1/FVC at age 22 that were on average 5.2% lower than the rest of the cohort. In a similar longitudinal cohort of 250 Australian infants performed in the late 1980s, Owens et al38  demonstrated that V̇maxFRC at 1 month was positively correlated to measurements of forced expiratory flows (FEV1/FVC and forced expiratory flow between 25% and 75% of forced vital capacity [FEF25–75]) at 24 years.

Several other similar studies have provided support for the premise that lung function follows predictable trajectories by measuring forced expiratory flows at different time points throughout childhood and into adulthood. Two separate population-based longitudinal cohorts demonstrated increases in forced expiratory flows commensurate with growth in individuals spanning the ages of 6 to 18 years and 10 to 26 years.24,52  In a highly selected cohort of 543 preadolescent Australians without respiratory disease, Hibbert et al19  showed similar gains in measures of expiratory flows paralleling linear growth. Although normative data for adult lung function has previously been defined from within the Third NHANES and Global Lung Function Initiative cohorts, the Tasmanian Health Study has extended lung function trajectories from childhood (age 7) into adulthood (age 53), suggesting that they may be more variable after peak lung function is achieved.6,56,57  Taken together, these studies have established a paradigm that children have predictable increases in lung function as they grow, with early measures of lung function being at least partially predictive of maximum function in early adulthood (Fig 1).

FIGURE 1
FIGURE 1. Trajectories of lung function for term and preterm infants. The solid blue shows the trajectory of lung function for healthy term infants, which peaks in early adulthood before declining with age, but without becoming symptomatic because of considerable pulmonary reserve. The dashed red line depicts the theorized trajectory of lung function for premature infants, never reaching full potential and therefore becoming symptomatic with just normal aging. The dotted black line shows how the early abnormal lung function of premature infants could be increased to achieve normal function in adulthood by identifying and ultimately treating risk factors. Adapted from Stocks et al.55
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Trajectories of lung function for term and preterm infants. The solid blue shows the trajectory of lung function for healthy term infants, which peaks in early adulthood before declining with age, but without becoming symptomatic because of considerable pulmonary reserve. The dashed red line depicts the theorized trajectory of lung function for premature infants, never reaching full potential and therefore becoming symptomatic with just normal aging. The dotted black line shows how the early abnormal lung function of premature infants could be increased to achieve normal function in adulthood by identifying and ultimately treating risk factors. Adapted from Stocks et al.55 

FIGURE 1
FIGURE 1. Trajectories of lung function for term and preterm infants. The solid blue shows the trajectory of lung function for healthy term infants, which peaks in early adulthood before declining with age, but without becoming symptomatic because of considerable pulmonary reserve. The dashed red line depicts the theorized trajectory of lung function for premature infants, never reaching full potential and therefore becoming symptomatic with just normal aging. The dotted black line shows how the early abnormal lung function of premature infants could be increased to achieve normal function in adulthood by identifying and ultimately treating risk factors. Adapted from Stocks et al.55
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Trajectories of lung function for term and preterm infants. The solid blue shows the trajectory of lung function for healthy term infants, which peaks in early adulthood before declining with age, but without becoming symptomatic because of considerable pulmonary reserve. The dashed red line depicts the theorized trajectory of lung function for premature infants, never reaching full potential and therefore becoming symptomatic with just normal aging. The dotted black line shows how the early abnormal lung function of premature infants could be increased to achieve normal function in adulthood by identifying and ultimately treating risk factors. Adapted from Stocks et al.55 

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Identifying low lung function in early childhood is important because it correlates with subsequent respiratory symptoms and disease, even in infants who clinically appear healthy after birth. In addition to the 2 studies published by Stern and Owens above, Turner et al45  reported that healthy infants with reduced V̇maxFRC at 4 weeks of age showed reduced FEV1 and FEF25–75 at 6 years. The persistently lower lung function demonstrated in these studies correlated with both respiratory symptoms and adverse respiratory outcomes. For example, in the same cohort demonstrating the individual tracking of lung function percentile, Turner et al46  also demonstrated that infants with a reduced V̇maxFRC in infancy also had increased wheezing and airway reactivity at 11 years of age. Similarly, asymptomatic infants with flow restriction on lung function tests at 1 month of age (V̇maxFRC and the ratio of time to peak tidal expiratory flow over expiratory time [TPTEF:TE]) demonstrated a reduced lung function at 1 year and had an increased risk of physician-diagnosed asthma in childhood (odds ratio [OR]: 7.4, 95% confidence interval: 1.4–35.2) compared with infants without flow restriction.54  Low TPTEF:TE, measured shortly after birth in healthy infants, has been shown to precede and predict wheezing at 3 months.8  In a prospective cohort of infants selected for a maternal history of early childhood asthma, those with decreased lung function (forced expiratory volume in 0.5 seconds [FEV0.5] and forced expiratory flow at 50% of forced vital capacity [FEF50]) and increased airway hyperreactivity as neonates were more likely to be diagnosed with asthma before age 7.4  Finally, in a population-based birth cohort of 614 infants, those whose TPTEF:TE was below the median at 1 month of age were significantly more likely at 10 years of age to have a history of asthma (24.3% vs 16.2%, P = .01; OR of 1.58), have current asthma (14.6% vs 7.5%, P = .005; OR of 2.10), and have severe bronchial hyperresponsiveness (9.1% vs 4.9%, P = .05) than those whose TPTEF:TE was above the median.16  Together, these studies support the premise that low lung function in childhood is not only predictive of low function later but also associated with important clinical illness, including asthma, later in childhood.

The studies described in the previous paragraph are focused on the relationship between neonatal lung function and later childhood lung function as well as to disease states. Similarly, there is substantial evidence that lung function measured in childhood is predictive of later lung function and of clinical disease including persistent asthma and chronic obstructive pulmonary disease (COPD) in adulthood.58  In 2003, Sears et al39  showed in a population-based cohort from New Zealand that children with reduced FEV1/FVC at 9 years of age also had reduced FEV1/FVC at 26 years, concluding that lung function was persistently impaired throughout childhood for those with persistent asthma in adulthood. In a prospective study of lung function in Australia, 7-year-olds with severe asthma were found to be 32 times more likely to have COPD at age 50 than children without asthma.44  Commenting on this important study, Martinez pointed out that most of the impairments in lung function (in FEV1/FVC) in patients with COPD at age 50 were apparent in lung function tests measured in adolescence.58  In a Tasmanian cohort of 2438 subjects followed for >50 years, Bui et al6  described 6 distinct trajectories of lung function (FEV1) tracking from childhood, 3 of which accounted for >75% of participants who were ultimately diagnosed with COPD. These studies support the conclusion that low childhood lung function has lifelong consequences including the risk of developing COPD. This phenomenon of tracking is particularly noteworthy when identified among asymptomatic “healthy” infants noted to have reduced lung function in infancy. Especially if subject to other toxic exposures or conditions in early infancy such as secondhand smoke, air pollution, or respiratory syncytial virus bronchiolitis, among others, these infants will be predisposed to lower maximum adult lung function and early respiratory symptoms in adulthood. Identifying lower lung function trajectories in early infancy also offers the opportunity to explore the possibility that perinatal and early childhood interventions could improve their long-term lung trajectories.

The presence of lung function trajectories identified from delivery and early infancy suggests that genetic endowment, fetal programming, and perinatal factors play major roles in defining future lung function (Fig 2). A Dutch study of >600 infant-parent triads demonstrated the role of genetics, showing that parental lung function predicted infant lung function at 2 months of age, after adjusting for confounders.48  However, further elucidation of the genetic underpinnings of specific pulmonary function parameters is hampered by the fact that lung function itself is likely a complex trait controlled by multiple loci.59 

FIGURE 2
FIGURE 2. Primary prevention for BPD. Windows of opportunity. BPD most commonly occurs in extremely premature infants born during the canalicular or early saccular phases of lung development. However, not all extremely premature infants develop BPD, suggesting BPD can be prevented. Reprinted with permission of the American Thoracic Society. Copyright 2019 American Thoracic Society. McEvoy et al.60
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Primary prevention for BPD. Windows of opportunity. BPD most commonly occurs in extremely premature infants born during the canalicular or early saccular phases of lung development. However, not all extremely premature infants develop BPD, suggesting BPD can be prevented. Reprinted with permission of the American Thoracic Society. Copyright 2019 American Thoracic Society. McEvoy et al.60 

FIGURE 2
FIGURE 2. Primary prevention for BPD. Windows of opportunity. BPD most commonly occurs in extremely premature infants born during the canalicular or early saccular phases of lung development. However, not all extremely premature infants develop BPD, suggesting BPD can be prevented. Reprinted with permission of the American Thoracic Society. Copyright 2019 American Thoracic Society. McEvoy et al.60
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Primary prevention for BPD. Windows of opportunity. BPD most commonly occurs in extremely premature infants born during the canalicular or early saccular phases of lung development. However, not all extremely premature infants develop BPD, suggesting BPD can be prevented. Reprinted with permission of the American Thoracic Society. Copyright 2019 American Thoracic Society. McEvoy et al.60 

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There are several perinatal factors that have been shown to be associated with decreased lung function trajectories. Intrauterine growth restriction (IUGR) is a risk factor for decreased lung function in infancy, childhood, and adulthood.21,26,30  For example, 2 studies have shown that term infants with IUGR had significantly lower FEV1 than normally grown age-matched school-aged peers.7,37  Several studies have shown decreased lung function in infants with in utero exposure to maternal smoking even before potential postnatal exposures,43,61,62  and a prospective study of 2400 patients demonstrated decreased FEV1 and other forced expiratory flows to 21 years of age after in utero smoke exposure.17  These studies suggest a critical role for both prenatal and perinatal factors on lung development and function. However, of all the perinatal factors, premature birth and its long-term sequelae may have the greatest effect on lung function trajectory.

Premature birth has a profound effect on lung function because premature infants are born during a critical window of rapid lung development and then continue their development in the extrauterine environment. In contrast to term infants, premature infants are born before the onset of alveolarization, during the late canalicular or early saccular stages of lung development (Fig 2). Because premature infants must use their developing lungs for survival, they are especially susceptible to damage, altered development, and lower maximum function in adulthood.14  Premature infants born at <28 weeks' gestation, particularly those born near the margin of viability, often develop bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity characterized by impaired lung and airway function and increased risk of obstructive lung disease in adulthood.63 

Many studies have demonstrated lower lung function in former premature infants, particularly among those with BPD, compared with healthy term-born controls.64  However, only a few researchers have tried to parse out the effect of prematurity alone in healthy preterm infants without BPD. In one such study, McEvoy et al31  reported significantly decreased passive respiratory system compliance (Crs) and TPTEF:TE as well as increased passive respiratory system resistance (Rrs) in healthy late preterm infants (defined as needing <12 hours of supplemental O2, continuous positive airway pressure [CPAP], or nasal cannula, no exposure to in utero smoke) studied at term corrected age compared with healthy infants born at term. Friedrich et al13  found decreases in FEF50, forced expiratory flow at 75% of forced vital capacity (FEF75), and FEF25–75 in healthy preterm infants tested at ∼8 weeks of age compared with those of healthy infants born at term. Hjalmarson and Sandberg20  studied healthy premature infants born at an average gestational age (GA) of 29.5 weeks and reported decreased lung volume as measured by functional residual capacity (FRC) per kilogram at 40 weeks postmenstrual age (PMA) compared with healthy term infants also studied at 40 weeks PMA. In a study of healthy preterm infants with an average GA of 33.4 weeks at birth, Hoo et al22  found normal V̇maxFRC at 3 weeks of age compared with normative data. However, they found a significant reduction in V̇maxFRC when the same infants were retested at 1 year of age. Importantly, the V̇maxFRC measured before discharge in these healthy preterm infants was significantly correlated to the measurement at 1 year, suggesting “marked tracking of airway function during this period.”22  Taken together, these studies suggest that lung function among even healthy premature infants at term is abnormal compared with that of term infants but increases over time along the same established trajectories. Given the evidence of lung function tracking, potential interventions to improve the lung function trajectory of even healthy preterm infants after delivery remains a knowledge gap and an opportunity for future study.

Several studies have evaluated the effect of BPD on lung function in former premature infants, who also demonstrate lung function tracking.65,66  Although comparison of these studies are in general challenged by the lack of a single PFT technique that can be applied throughout an individual’s lifetime, the evolving definition of BPD, and the different eras of study, common themes can be identified. In a small study of former premature infants with BPD, Baraldi et al3  showed that in serial measurements, Crs increased and Rrs decreased during the first 2 years of life. They also demonstrated that lung function measured at 24 months and again at 8 years tended to track along decreased trajectories.3  A similar study of 44 infants with BPD showed that total FRC increased over time, although without a change in percentile.11  They also showed that V̇maxFRC remains lower in infants with BPD, reflecting a persistent limitation to airflow compared with normative data. Several studies have demonstrated that former premature infants with BPD had significantly lower expiratory flows (FEV1) both in childhood and in adulthood than those without BPD9,12,14,28,50  In a cohort of 163 former premature infants (born at ∼28 weeks’ gestation and studied at 9–11 years of age), Simpson et al41  showed both expiratory flow obstruction and associated structural lung changes compared with term controls. A similar study confirmed that for former premature infants with BPD, the correlation between decreased FEV1 and emphysematous changes on computed tomography imaging persisted into adulthood.53  Further refining the description of these deficits in lung function among former premature infants, Shepherd et al40  reported 3 distinct phenotypes of lung function among infants studied at 55 weeks of PMA with severe BPD: obstructive (51%), restrictive (9%), and mixed (40%). This phenotyping redemonstrates the consistent finding of expiratory flow obstruction, with 91% of infants with severe BPD having at least some degree of obstruction. It also frames these impairments in lung function in terms that help link it to adult lung diseases such as COPD. In one of the longest running longitudinal studies of former premature infants, Vollsæter et al49  showed that former extremely premature infants born at <28 weeks’ gestation (∼80% of whom had BPD), who were studied at ages 10, 18, and 25 years, demonstrate significant reductions in expiratory flows. These findings further support the evidence that at least some subsets of premature infants, particularly those with the greatest flow reduction, are at highest risk of COPD in adulthood.

In an attempt to isolate the effect of BPD from that of prematurity, authors of 3 studies have compared the pulmonary function of former premature infants with BPD to that of former premature infants without BPD.5,23,36  In each of these studies, former premature infants with BPD were found to have decreased lung function compared with age-matched former premature infants without BPD when studied at 10 to 11 years,23  6 to 8 years,5  and 18 years.36  In these studies, the effect of BPD, separate from the effect of prematurity, is associated with diminished long-term lung function. These studies also suggest that former premature infants display a range of subsequent lung function, some of which overlaps with the lung function of healthy children.

Former premature infants clearly demonstrate decreased lung function compared with healthy term controls, but they also achieve gains in lung function as they grow. The question then becomes: Does the trajectory of this improvement allow them to “catch up” to term-born peers or does their lung function remain decreased for life? At least 5 studies of former premature infants who had below normal lung function in early childhood suggest that they can ultimately achieve lung function at the lower end of the normal range, especially among those without BPD.1,15,18,25,47  However, among those with a history of BPD, 3 additional studies showed similar ongoing deficits in lung function, but in these 3 studies, the deficit in FEV1 and FEF25–75 was not only statistically significantly lower than controls but also below the range of normal in childhood and early adulthood.2,35,36  Although there is heterogeneity among lung function trajectory studies in infants with BPD in terms of the era in which the studies were conducted, inclusion criteria, and PFT parameters, several common themes emerge regarding the issue of whether low functioning lungs can catch up as children grow. All studies measuring FEV1 and FEF25–75 found persistent mean differences between premature infants and term controls. In some studies, these overlapped the lower end of the normal range, but in others, they remained abnormally low. In these same infants, other parameters of lung function (FVC, residual volume [RV], total lung capacity [TLC]) remained normal. Not surprisingly, healthy premature infants without BPD tended to show smaller reductions in FEV1 and FEF25–75 than premature infants with BPD. The majority of these studies found those deficits to be statistically significantly different but also at the lower end of the normal range. In addition, postnatal exposures, such as tobacco, can confound the evaluation of potential catch up in lung function trajectories. Among former extremely premature infants studied at 8 and 18 years of age, those who smoked as teenagers showed significant worsening of expiratory flows between the 2 sets of measurements compared with those who did not smoke.9  In those with a history of IUGR, accelerated growth velocity and increased weight had a negative impact on catch-up lung function.7 

As to the clinical relevance of the above differences, 2 studies published in the 1980s revealed no difference in exercise capacity (oxygen consumption [V̇o2]) between those with BPD and controls when measured at school age.2,18  However, a third study which also showed no difference in V̇o2 did demonstrate a significant deficit in anaerobic threshold among former premature infants when measured at 19 years.51  The long-term clinical consequences of these differences, particularly as they relate to peak lung function in early adulthood and rapidity of decline thereafter, remain unknown. A fuller examination of the differences between those who exhibit catch-up growth and those who do not could offer insights into optimizing lung function for those at highest risk.

There are encouraging clues in many of the studies reviewed in this article that these trajectories can be improved, particularly when coupled with more sophisticated “omics” approaches to better understand the systems biology of underlying lung disease.67  Among the 6 trajectories of lung function described in the Tasmanian Longitudinal Health Study cohort, Bui et al6  describe 2 that are of particular interest regarding catch-up gains. First, the “early low, accelerated growth, normal decline” group (accounting for 8% of participants), which begins with below normal function but demonstrates catch-up gains and ultimately achieves normal function in adulthood. Understanding this cohort could inform a new approach to infants and children who have poor early lung function, like former premature infants. Second, those in the persistently “high” group (accounting for 12% of subjects) demonstrate high-normal function throughout their lives. Understanding this cohort might offer insights into therapies aimed at improving lung function or resiliency against damage.

Several studies of perinatal factors and interventions to improve PFT trajectories have been published recently. Morrow et al34  demonstrated that in utero smoke was a risk factor for BPD independent of its effect on increased preterm delivery. Two separate randomized trials have shown that vitamin C supplementation to pregnant women unable to quit smoking improved the lung function of their offspring through 12 months of age.32,33,68  Interventions to decrease in utero smoke exposure or mitigate its effects will likely improve airway function trajectories in both preterm and term infants particularly with the increased use of electroniccigarettes.69  In the postnatal period, a randomized trial of premature infants has revealed that extending treatment with CPAP until 34 weeks PMA significantly increased lung volumes as measured by FRC at discharge,27  a finding that suggests one postnatal pathway to improve lung trajectories. Vitamin D supplementation for African American preterm infants has been shown to decrease recurrent wheeze through 12 months of age70  and may be applicable more broadly. Finer tuning of oxygen titration in the preterm period for premature infants has been proposed to support improved lung growth and function.9  Similarly, given the particular susceptibility to decreased lung function among former premature infants who smoke as young adults, targeted smoking prevention and cessation programs is critical to prevent further deterioration of lung function. Of note, one recent study suggests that current approaches to respiratory care for extremely premature infants could actually be worsening subsequent flow obstruction. Doyle et al10  reported lung function outcomes in extremely premature infants from 3 distinct epochs (early 1990s, late 1990s, and mid-2000s) and unexpectedly showed greater flow obstruction (FEV1/FVC) at 8 years of age for the most recent cohort compared with the older two, despite similar demographic characteristics and fewer ventilator days for the most recent cohort. This finding requires further study and may be related to practice changes (such as decreased use of postnatal dexamethasone), which may be beneficial to infants on the whole depending on the degree of lung disease and the association of potential neurodevelopmental deficits.

Other interventions may be simple, such as increased awareness of hand-washing, avoidance of ill contacts, and vaccinations particularly in at-risk infants. Given the importance of maximizing early life lung function, research focused on the perinatal time period is needed to define the ability to reset lung trajectories in infants born after suboptimal perinatal circumstances, including those born prematurely.

Collectively, these studies have significantly increased our understanding of lung function trajectories, particularly in well-phenotyped subsets of patients such as preterm infants. However, there are limitations to these trials and to comparisons among them. Many of the trials are observational birth cohorts that can be limited by cohort retention, potential unaccounted confounders, different time epochs of study, different PFT techniques used throughout the individual’s life, and challenges in separating out prenatal versus postnatal influences on lung function. For instance, the studies of patients with BPD represent children born between 1964 and 2011, an almost 50-year time span during which volume-targeted mechanical ventilation with neonatal ventilators, pulmonary surfactant, antenatal corticosteroids, and noninvasive assisted ventilation were introduced. These changes in the standards of care have altered the phenotype of chronic lung disease in prematurity from the old BPD, characterized by extensive fibrosis,71  to the new BPD, characterized by arrested alveolarization.63  Furthermore, the definition of BPD itself has changed over time, making comparison of cohorts across time problematic. Given the mortality and morbidities associated with extreme prematurity, survival bias or the inability for severely affected infants to participate in studies can skew results. A key limitation in many of these studies is the use of different PFT techniques in different patient populations. Addressing this unmet need will be a key component of better linking neonatal lung and adult lung function.

This heterogeneous body of research on lung function trajectories offers two overarching conclusions: first, that human lung function changes over an individual’s life span along predictable trajectories, and second, that perinatal circumstances, the focus of this review, can impact these trajectories. But important questions remain unanswered. Are there perinatal treatments available that can mitigate negative modifiers of lung function? Could early therapies positively alter these trajectories to encourage resiliency and higher maximum function in adulthood? What lessons could be learned by a greater understanding of why some individuals demonstrate more catch-up gains in lung function than others? Could focusing on individuals in the highest quartile for lung function teach us how to manage those in the lowest? Could early noninvasive lung function screening of at-risk preterm infants be developed to identify a window of opportunity to intervene and improve their lung function? These questions frame areas for future research to enhance our understanding and potential treatment of perinatal factors on subsequent respiratory health and disease.

We thank Dr A. Sonia Buist for her review of the article.

Drs Jordan and McEvoy conceptualized the review, drafted the initial manuscript, and critically reviewed and revised the manuscript; and both authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: Supported by the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) under award number KL2 TR002370 and NIH National Heart, Lung, and Blood Institute under award number K23 HL144918, HL105447, HL129060 and UH3OD023288. The funders had no role in the study design, data collection, analysis, decision to publish, or preparation of the article. Funded by the National Institutes of Health (NIH).

BPD

bronchopulmonary dysplasia

COPD

chronic obstructive pulmonary disease

Crs

passive respiratory system compliance

FEF25–75

forced expiratory flow between 25% and 75% of forced vital capacity

FEF50

forced expiratory flow at 50% of forced vital capacity

FEF75

forced expiratory flow at 75% of forced vital capacity

FEV1

forced expiratory volume in 1 second

FEV0.5

forced expiratory volume in 0.5 seconds

FRC

functional residual capacity

FVC

forced vital capacity

GA

gestational age

IUGR

intrauterine growth restriction

Rrs

passive respiratory system resistance

RV

residual volume

TLC

total lung capacity

TPTEF:TE

time to peak tidal expiratory flow over expiratory time

V̇maxFRC

maximal flow at functional residual capacity

V̇o2

oxygen consumption

1
Anand
 
D
,
Stevenson
 
CJ
,
West
 
CR
,
Pharoah
 
POD
.
Lung function and respiratory health in adolescents of very low birth weight
.
Arch Dis Child
.
2003
;
88
(
2
):
135
–
138
Google Scholar
Crossref
Search ADS
 
2
Bader
 
D
,
Ramos
 
AD
,
Lew
 
CD
,
Platzker
 
ACG
,
Stabile
 
MW
,
Keens
 
TG
.
Childhood sequelae of infant lung disease: exercise and pulmonary function abnormalities after bronchopulmonary dysplasia
.
J Pediatr
.
1987
;
110
(
5
):
693
–
699
Google Scholar
Crossref
Search ADS
 
3
Baraldi
 
E
,
Filippone
 
M
,
Trevisanuto
 
D
,
Zanardo
 
V
,
Zacchello
 
F
.
Pulmonary function until two years of life in infants with bronchopulmonary dysplasia
.
Am J Respir Crit Care Med
.
1997
;
155
(
1
):
149
–
155
Google Scholar
Crossref
Search ADS
 
4
Bisgaard
 
H
,
Jensen
 
SM
,
Bønnelykke
 
K
.
Interaction between asthma and lung function growth in early life
.
Am J Respir Crit Care Med
.
2012
;
185
(
11
):
1183
–
1189
Google Scholar
Crossref
Search ADS
 
5
Broström
 
EB
,
Thunqvist
 
P
,
Adenfelt
 
G
,
Borling
 
E
,
Katz-Salamon
 
M
.
Obstructive lung disease in children with mild to severe BPD
.
Respir Med
.
2010
;
104
(
3
):
362
–
370
Google Scholar
Crossref
Search ADS
 
6
Bui
 
DS
,
Lodge
 
CJ
,
Burgess
 
JA
, et al.
Childhood predictors of lung function trajectories and future COPD risk: a prospective cohort study from the first to the sixth decade of life
.
Lancet Respir Med
.
2018
;
6
(
7
):
535
–
544
Google Scholar
Crossref
Search ADS
 
7
den Dekker
 
HT
,
Jaddoe
 
VWV
,
Reiss
 
IK
,
de Jongste
 
JC
,
Duijts
 
L
.
Fetal and infant growth patterns and risk of lower lung function and asthma. The generation R study
.
Am J Respir Crit Care Med
.
2018
;
197
(
2
):
183
–
192
Google Scholar
Crossref
Search ADS
 
8
Dezateux
 
CA
,
Stocks
 
J
,
Dundas
 
I
,
Jackson
 
EA
,
Fletcher
 
ME
.
The relationship between tPTEF:tE and specific airway conductance in infancy
.
Pediatr Pulmonol
.
1994
;
18
(
5
):
299
–
307
Google Scholar
Crossref
Search ADS
 
9
Doyle
 
LW
,
Adams
 
AM
,
Robertson
 
C
, et al;
Victorian Infant Collaborative Study Group
.
Increasing airway obstruction from 8 to 18 years in extremely preterm/low-birthweight survivors born in the surfactant era
.
Thorax
.
2017
;
72
(
8
):
712
–
719
Google Scholar
Crossref
Search ADS
 
10
Doyle
 
LW
,
Carse
 
E
,
Adams
 
AM
,
Ranganathan
 
S
,
Opie
 
G
,
Cheong
 
JLY
;
Victorian Infant Collaborative Study Group
.
Ventilation in extremely preterm infants and respiratory function at 8 Years
.
N Engl J Med
.
2017
;
377
(
4
):
329
–
337
Google Scholar
Crossref
Search ADS
 
11
Fakhoury
 
KF
,
Sellers
 
C
,
Smith
 
EO
,
Rama
 
JA
,
Fan
 
LL
.
Serial measurements of lung function in a cohort of young children with bronchopulmonary dysplasia
.
Pediatrics
.
2010
;
125
(
6
).
Available at: www.pediatrics.org/cgi/content/full/125/6/e1441
Google Scholar
 
12
Filippone
 
M
,
Sartor
 
M
,
Zacchello
 
F
,
Baraldi
 
E
.
Flow limitation in infants with bronchopulmonary dysplasia and respiratory function at school age
.
Lancet
.
2003
;
361
(
9359
):
753
–
754
Google Scholar
Crossref
Search ADS
 
13
Friedrich
 
L
,
Stein
 
RT
,
Pitrez
 
PMC
,
Corso
 
AL
,
Jones
 
MH
.
Reduced lung function in healthy preterm infants in the first months of life
.
Am J Respir Crit Care Med
.
2006
;
173
(
4
):
442
–
447
Google Scholar
Crossref
Search ADS
 
14
Gibson
 
A-M
,
Reddington
 
C
,
McBride
 
L
,
Callanan
 
C
,
Robertson
 
C
,
Doyle
 
LW
.
Lung function in adult survivors of very low birth weight, with and without bronchopulmonary dysplasia
.
Pediatr Pulmonol
.
2015
;
50
(
10
):
987
–
994
Google Scholar
Crossref
Search ADS
 
15
Gross
 
SJ
,
Iannuzzi
 
DM
,
Kveselis
 
DA
,
Anbar
 
RD
.
Effect of preterm birth on pulmonary function at school age: a prospective controlled study
.
J Pediatr
.
1998
;
133
(
2
):
188
–
192
Google Scholar
Crossref
Search ADS
 
16
Håland
 
G
,
Carlsen
 
KCL
,
Sandvik
 
L
, et al;
ORAACLE
.
Reduced lung function at birth and the risk of asthma at 10 years of age
.
N Engl J Med
.
2006
;
355
(
16
):
1682
–
1689
Google Scholar
Crossref
Search ADS
 
17
Hayatbakhsh
 
MR
,
Sadasivam
 
S
,
Mamun
 
AA
,
Najman
 
JM
,
Williams
 
GM
,
O’Callaghan
 
MJ
.
Maternal smoking during and after pregnancy and lung function in early adulthood: a prospective study
.
Thorax
.
2009
;
64
(
9
):
810
–
814
Google Scholar
Crossref
Search ADS
 
18
Heldt
 
GP
,
McIlroy
 
MB
,
Hansen
 
TN
,
Tooley
 
WH
.
Exercise performance of the survivors of hyaline membrane disease
.
J Pediatr
.
1980
;
96
(
6
):
995
–
999
Google Scholar
Crossref
Search ADS
 
19
Hibbert
 
ME
,
Lannigan
 
A
,
Landau
 
LI
,
Phelan
 
PD
.
Lung function values from a longitudinal study of healthy children and adolescents
.
Pediatr Pulmonol
.
1989
;
7
(
2
):
101
–
109
Google Scholar
Crossref
Search ADS
 
20
Hjalmarson
 
O
,
Sandberg
 
K
.
Abnormal lung function in healthy preterm infants
.
Am J Respir Crit Care Med
.
2002
;
165
(
1
):
83
–
87
Google Scholar
Crossref
Search ADS
 
21
Hoo
 
AF
,
Dezateux
 
C
,
Hanrahan
 
JP
,
Cole
 
TJ
,
Tepper
 
RS
,
Stocks
 
J
.
Sex-specific prediction equations for Vmax(FRC) in infancy: a multicenter collaborative study
.
Am J Respir Crit Care Med
.
2002
;
165
(
8
):
1084
–
1092
Google Scholar
Crossref
Search ADS
 
22
Hoo
 
A-F
,
Dezateux
 
C
,
Henschen
 
M
,
Costeloe
 
K
,
Stocks
 
J
.
Development of airway function in infancy after preterm delivery
.
J Pediatr
.
2002
;
141
(
5
):
652
–
658
Google Scholar
Crossref
Search ADS
 
23
Jacob
 
SV
,
Coates
 
AL
,
Lands
 
LC
, et al.
Long-term pulmonary sequelae of severe bronchopulmonary dysplasia
.
J Pediatr
.
1998
;
133
(
2
):
193
–
200
Google Scholar
Crossref
Search ADS
 
24
Karmaus
 
W
,
Mukherjee
 
N
,
Janjanam
 
VD
, et al.
Distinctive lung function trajectories from age 10 to 26 years in men and women and associated early life risk factors - a birth cohort study
.
Respir Res
.
2019
;
20
(
1
):
98
Google Scholar
Crossref
Search ADS
 
25
Kilbride
 
HW
,
Gelatt
 
MC
,
Sabath
 
RJ
.
Pulmonary function and exercise capacity for ELBW survivors in preadolescence: effect of neonatal chronic lung disease
.
J Pediatr
.
2003
;
143
(
4
):
488
–
493
Google Scholar
Crossref
Search ADS
 
26
Kotecha
 
SJ
,
Watkins
 
WJ
,
Heron
 
J
,
Henderson
 
J
,
Dunstan
 
FD
,
Kotecha
 
S
.
Spirometric lung function in school-age children: effect of intrauterine growth retardation and catch-up growth
.
Am J Respir Crit Care Med
.
2010
;
181
(
9
):
969
–
974
Google Scholar
Crossref
Search ADS
 
27
Lam
 
R
,
Schilling
 
D
,
Scottoline
 
B
, et al.
The effect of extended continuous positive airway pressure on changes in lung volumes in stable premature infants: a randomized controlled trial
.
J Pediatr
.
2020
;
217
:
66
–
72.e1
Google Scholar
Crossref
Search ADS
 
28
Landry
 
JS
,
Tremblay
 
GM
,
Li
 
PZ
,
Wong
 
C
,
Benedetti
 
A
,
Taivassalo
 
T
.
Lung function and bronchial hyperresponsiveness in adults born prematurely. A cohort study
.
Ann Am Thorac Soc
.
2016
;
13
(
1
):
17
–
24
Google Scholar
Crossref
Search ADS
 
29
Lange
 
P
,
Celli
 
B
,
Agustí
 
A
, et al.
Lung-function trajectories leading to chronic obstructive pulmonary disease
.
N Engl J Med
.
2015
;
373
(
2
):
111
–
122
Google Scholar
Crossref
Search ADS
 
30
Lawlor
 
DA
,
Ebrahim
 
S
,
Davey Smith
 
G
.
Association of birth weight with adult lung function: findings from the British Women’s Heart and Health Study and a meta-analysis
.
Thorax
.
2005
;
60
(
10
):
851
–
858
Google Scholar
Crossref
Search ADS
 
31
McEvoy
 
C
,
Venigalla
 
S
,
Schilling
 
D
,
Clay
 
N
,
Spitale
 
P
,
Nguyen
 
T
.
Respiratory function in healthy late preterm infants delivered at 33-36 weeks of gestation
.
J Pediatr
.
2013
;
162
(
3
):
464
–
469
Google Scholar
Crossref
Search ADS
 
32
McEvoy
 
CT
,
Schilling
 
D
,
Clay
 
N
, et al.
Vitamin C supplementation for pregnant smoking women and pulmonary function in their newborn infants: a randomized clinical trial
.
JAMA
.
2014
;
311
(
20
):
2074
–
2082
Google Scholar
Crossref
Search ADS
 
33
McEvoy
 
CT
,
Shorey-Kendrick
 
LE
,
Milner
 
K
, et al.
Vitamin C to pregnant smokers persistently improves infant airway function to 12 months of age: a randomised trial [published online July 2, 2020]
.
Eur Respir J
.
doi:10.1183/13993003.02208-2019
34
Morrow
 
DK
,
Schilling
 
D
,
McEvoy
 
CT
.
Response to bronchodilators in very preterm infants with evolving bronchopulmonary dysplasia
.
Res Rep Neonatol
.
2015
;
5
:
113
–
117
Google Scholar
 
35
Moschino
 
L
,
Stocchero
 
M
,
Filippone
 
M
,
Carraro
 
S
,
Baraldi
 
E
.
Longitudinal assessment of lung function in survivors of bronchopulmonary dysplasia from birth to adulthood. The padova BPD study
.
Am J Respir Crit Care Med
.
2018
;
198
(
1
):
134
–
137
Google Scholar
Crossref
Search ADS
 
36
Northway
 
WH
 Jr.,
Moss
 
RB
,
Carlisle
 
KB
, et al.
Late pulmonary sequelae of bronchopulmonary dysplasia
.
N Engl J Med
.
1990
;
323
(
26
):
1793
–
1799
Google Scholar
Crossref
Search ADS
 
37
Örtqvist
 
AK
,
Ullemar
 
V
,
Lundholm
 
C
, et al.
Fetal growth and childhood lung function in the Swedish Twin Study on Prediction and Prevention of asthma
.
Ann Am Thorac Soc
.
2017
;
14
(
7
):
1147
–
1153
Google Scholar
 
38
Owens
 
L
,
Laing
 
IA
,
Zhang
 
G
,
Turner
 
S
,
Le Souëf
 
PN
.
Airway function in infancy is linked to airflow measurements and respiratory symptoms from childhood into adulthood
.
Pediatr Pulmonol
.
2018
;
53
(
8
):
1082
–
1088
Google Scholar
Crossref
Search ADS
 
39
Sears
 
MR
,
Greene
 
JM
,
Willan
 
AR
, et al.
A longitudinal, population-based, cohort study of childhood asthma followed to adulthood
.
N Engl J Med
.
2003
;
349
(
15
):
1414
–
1422
Google Scholar
Crossref
Search ADS
 
40
Shepherd
 
EG
,
Clouse
 
BJ
,
Hasenstab
 
KA
, et al.
Infant pulmonary function testing and phenotypes in severe bronchopulmonary dysplasia
.
Pediatrics
.
2018
;
141
(
5
):
e20173350
Google Scholar
Crossref
Search ADS
 
41
Simpson
 
SJ
,
Logie
 
KM
,
O’Dea
 
CA
, et al.
Altered lung structure and function in mid-childhood survivors of very preterm birth
.
Thorax
.
2017
;
72
(
8
):
702
–
711
Google Scholar
Crossref
Search ADS
 
42
Stern
 
DA
,
Morgan
 
WJ
,
Wright
 
AL
,
Guerra
 
S
,
Martinez
 
FD
.
Poor airway function in early infancy and lung function by age 22 years: a non-selective longitudinal cohort study
.
Lancet
.
2007
;
370
(
9589
):
758
–
764
Google Scholar
Crossref
Search ADS
 
43
Tager
 
IB
,
Ngo
 
L
,
Hanrahan
 
JP
.
Maternal smoking during pregnancy. Effects on lung function during the first 18 months of life
.
Am J Respir Crit Care Med
.
1995
;
152
(
3
):
977
–
983
Google Scholar
Crossref
Search ADS
 
44
Tai
 
A
,
Tran
 
H
,
Roberts
 
M
,
Clarke
 
N
,
Wilson
 
J
,
Robertson
 
CF
.
The association between childhood asthma and adult chronic obstructive pulmonary disease
.
Thorax
.
2014
;
69
(
9
):
805
–
810
Google Scholar
Crossref
Search ADS
 
45
Turner
 
SW
,
Palmer
 
LJ
,
Rye
 
PJ
, et al.
Infants with flow limitation at 4 weeks: outcome at 6 and 11 years
.
Am J Respir Crit Care Med
.
2002
;
165
(
9
):
1294
–
1298
Google Scholar
Crossref
Search ADS
 
46
Turner
 
SW
,
Palmer
 
LJ
,
Rye
 
PJ
, et al.
The relationship between infant airway function, childhood airway responsiveness, and asthma
.
Am J Respir Crit Care Med
.
2004
;
169
(
8
):
921
–
927
Google Scholar
Crossref
Search ADS
 
47
Turner
 
S
,
Fielding
 
S
,
Mullane
 
D
, et al.
A longitudinal study of lung function from 1 month to 18 years of age
.
Thorax
.
2014
;
69
(
11
):
1015
–
1020
Google Scholar
Crossref
Search ADS
 
48
van Putte-Katier
 
N
,
Koopmans
 
M
,
Uiterwaal
 
CSPM
, et al;
WHISTLER study group
.
Relationship between parental lung function and their children’s lung function early in life
.
Eur Respir J
.
2011
;
38
(
3
):
664
–
671
Google Scholar
Crossref
Search ADS
 
49
Vollsæter
 
M
,
Røksund
 
OD
,
Eide
 
GE
,
Markestad
 
T
,
Halvorsen
 
T
.
Lung function after preterm birth: development from mid-childhood to adulthood
.
Thorax
.
2013
;
68
(
8
):
767
–
776
Google Scholar
Crossref
Search ADS
 
50
Vollsæter
 
M
,
Clemm
 
HH
,
Satrell
 
E
, et al.
Adult respiratory outcomes of extreme preterm birth. A regional cohort study
.
Ann Am Thorac Soc
.
2015
;
12
(
3
):
313
–
322
Google Scholar
Crossref
Search ADS
 
51
Vrijlandt
 
EJLE
,
Gerritsen
 
J
,
Boezen
 
HM
,
Grevink
 
RG
,
Duiverman
 
EJ
.
Lung function and exercise capacity in young adults born prematurely
.
Am J Respir Crit Care Med
.
2006
;
173
(
8
):
890
–
896
Google Scholar
Crossref
Search ADS
 
52
Wang
 
X
,
Dockery
 
DW
,
Wypij
 
D
,
Fay
 
ME
,
Ferris
 
BG
 Jr..
Pulmonary function between 6 and 18 years of age
.
Pediatr Pulmonol
.
1993
;
15
(
2
):
75
–
88
Google Scholar
Crossref
Search ADS
 
53
Wong
 
PM
,
Lees
 
AN
,
Louw
 
J
, et al.
Emphysema in young adult survivors of moderate-to-severe bronchopulmonary dysplasia
.
Eur Respir J
.
2008
;
32
(
2
):
321
–
328
Google Scholar
Crossref
Search ADS
 
54
Young
 
S
,
Arnott
 
J
,
Le Souef
 
PN
,
Landau
 
LI
.
Flow limitation during tidal expiration in symptom-free infants and the subsequent development of asthma
.
J Pediatr
.
1994
;
124
(
5, pt 1
):
681
–
688
Google Scholar
Crossref
Search ADS
 
55
Stocks
 
J
,
Hislop
 
A
,
Sonnappa
 
S
.
Early lung development: lifelong effect on respiratory health and disease
.
Lancet Respir Med
.
2013
;
1
(
9
):
728
–
742
Google Scholar
Crossref
Search ADS
 
56
Hankinson
 
JL
,
Odencrantz
 
JR
,
Fedan
 
KB
.
Spirometric reference values from a sample of the general US population
.
Am J Respir Crit Care Med
.
1999
;
159
(
1
):
179
–
187
Google Scholar
Crossref
Search ADS
 
57
Quanjer
 
PH
,
Stanojevic
 
S
,
Cole
 
TJ
, et al;
ERS Global Lung Function Initiative
.
Multi-ethnic reference values for spirometry for the 3–95-yr age range: the global lung function 2012 equations
.
Eur Respir J
.
2012
;
40
(
6
):
1324
–
1343
Google Scholar
Crossref
Search ADS
 
58
Martinez
 
FD
. Early-Life Origins of Chronic Obstructive Pulmonary Disease. In:
N Engl J Med
, vol.
375
.
2016
:
871
–
878
Google Scholar
 
59
Chen
 
Y
,
Horne
 
SL
,
Rennie
 
DC
,
Dosman
 
JA
.
Segregation analysis of two lung function indices in a random sample of young families: the Humboldt Family Study
.
Genet Epidemiol
.
1996
;
13
(
1
):
35
–
47
Google Scholar
Crossref
Search ADS
 
60
McEvoy
 
CT
,
Jain
 
L
,
Schmidt
 
B
,
Abman
 
S
,
Bancalari
 
E
,
Aschner
 
JL
.
Bronchopulmonary dysplasia: NHLBI Workshop on the primary prevention of chronic lung diseases
.
Ann Am Thorac Soc
.
2014
;
11
(
suppl 3
):
S146
–
S153
Google Scholar
Crossref
Search ADS
 
61
Sekhon
 
HS
,
Keller
 
JA
,
Benowitz
 
NL
,
Spindel
 
ER
.
Prenatal nicotine exposure alters pulmonary function in newborn rhesus monkeys
.
Am J Respir Crit Care Med
.
2001
;
164
(
6
):
989
–
994
Google Scholar
Crossref
Search ADS
 
62
Sekhon
 
HS
,
Keller
 
JA
,
Proskocil
 
BJ
,
Martin
 
EL
,
Spindel
 
ER
.
Maternal nicotine exposure upregulates collagen gene expression in fetal monkey lung. Association with alpha7 nicotinic acetylcholine receptors
.
Am J Respir Cell Mol Biol
.
2002
;
26
(
1
):
31
–
41
Google Scholar
Crossref
Search ADS
 
63
Jobe
 
AH
,
Bancalari
 
E
.
Bronchopulmonary dysplasia
.
Am J Respir Crit Care Med
.
2001
;
163
(
7
):
1723
–
1729
Google Scholar
Crossref
Search ADS
 
64
Stocks
 
J
,
Sonnappa
 
S
.
Early life influences on the development of chronic obstructive pulmonary disease
.
Ther Adv Respir Dis
.
2013
;
7
(
3
):
161
–
173
Google Scholar
Crossref
Search ADS
 
65
Jones
 
M
.
Effect of preterm birth on airway function and lung growth
.
Paediatr Respir Rev
.
2009
;
10
(
suppl 1
):
9
–
11
Google Scholar
Crossref
Search ADS
 
66
Urs
 
R
,
Kotecha
 
S
,
Hall
 
GL
,
Simpson
 
SJ
.
Persistent and progressive long-term lung disease in survivors of preterm birth
.
Paediatr Respir Rev
.
2018
;
28
:
87
–
94
Google Scholar
 
67
Carraro
 
S
,
Giordano
 
G
,
Pirillo
 
P
, et al.
Airway metabolic anomalies in adolescents with bronchopulmonary dysplasia: new insights from the metabolomic approach
.
J Pediatr
.
2015
;
166
(
2
):
234
–
239.e1
Google Scholar
Crossref
Search ADS
 
68
McEvoy
 
CT
,
Shorey-Kendrick
 
LE
,
Milner
 
K
, et al.
Oral vitamin C (500 mg/d) to pregnant smokers improves infant airway function at 3 Months (VCSIP). A randomized trial
.
Am J Respir Crit Care Med
.
2019
;
199
(
9
):
1139
–
1147
Google Scholar
Crossref
Search ADS
 
69
Spindel
 
ER
,
McEvoy
 
CT
.
The role of nicotine in the effects of maternal smoking during pregnancy on lung development and childhood respiratory disease. Implications for dangers of E-cigarettes
.
Am J Respir Crit Care Med
.
2016
;
193
(
5
):
486
–
494
Google Scholar
Crossref
Search ADS
 
70
Hibbs
 
AM
,
Ross
 
K
,
Kerns
 
LA
, et al.
Effect of vitamin D supplementation on recurrent wheezing in black infants who were born preterm: the D-wheeze randomized clinical trial
.
JAMA
.
2018
;
319
(
20
):
2086
–
2094
Google Scholar
Crossref
Search ADS
 
71
Northway
 
WH
 Jr.,
Rosan
 
RC
,
Porter
 
DY
.
Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia
.
N Engl J Med
.
1967
;
276
(
7
):
357
–
368
Google Scholar
Crossref
Search ADS
 

Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

Copyright © 2020 by the American Academy of Pediatrics
2020