Trajectories of Lung Function in Infants and Children: Setting a Course for Lifelong Lung Health

Perinatal factors including prematurity can alter lung function trajectories and lifelong lung health. Approaches to maximize early lung function are needed to optimize function in adulthood.

Abstract

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.

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 Location	Era	Inclusion Criteria	No. Participants	GA at Birth	Birth wt	Timing of PFTs	PFT Parameters	Findings
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,372017; 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,521993; 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; DL_CO, 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.

Lung Function Increases Along Predictable Trajectories Throughout Childhood and Into Early Adulthood

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 (V̇max_FRC; an early measurement of flow obstruction) taken in infancy were associated with deficits in forced expiratory volume in 1 second / forced vital capacity (FEV_1/FVC; also a measurement of flow obstruction) at 22 years of age. Infants in the lowest quartile for V̇max_FRC 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 V̇max_FRC 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 [FEF_25–75]) 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.

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

Low Lung Function in Infancy Correlates With Clinical Symptoms in Later Childhood

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 V̇max_FRC at 4 weeks of age showed reduced FEV₁ and FEF_25–75 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 V̇max_FRC 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 (V̇max_FRC and the ratio of time to peak tidal expiratory flow over expiratory time [T_PTEF:T_E]) 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 T_PTEF:T_E, 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 [FEV_0.5] 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 T_PTEF:T_E 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 T_PTEF:T_E 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.

Low Lung Function in Childhood Presages Lung Disease in Adulthood

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.

How Are Trajectories of Lung Function Established?

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.

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

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.

Decreased Lung Function Among Premature Infants

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

Lung Function in Healthy Premature Infants

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 T_PTEF:T_E 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 FEF_25–75 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 V̇max_FRC at 3 weeks of age compared with normative data. However, they found a significant reduction in V̇max_FRC when the same infants were retested at 1 year of age. Importantly, the V̇max_FRC 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.

Pulmonary Function in Former Premature Infants With BPD

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 V̇max_FRC 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 BPD^{9,12,14,28,50} 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.

To Catch up or Not to Catch up: Can Lung Function Percentiles Increase in Former Premature Infants?

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 FEF_25–75 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 FEF_25–75 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 FEF_25–75 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.

Can Early Lung Function be Maximized and Lung Trajectories Be Positively Redirected Toward Higher Maximum Function?

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.

Limitations in Lung Function Trajectory Studies

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.

Conclusions and Unanswered Questions

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.

Glossary

BPD

bronchopulmonary dysplasia

COPD

chronic obstructive pulmonary disease

Crs

passive respiratory system compliance

FEF_25–75

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

FEV_0.5

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

T_PTEF:T_E

time to peak tidal expiratory flow over expiratory time

V̇max_FRC

maximal flow at functional residual capacity

V̇o₂

oxygen consumption