Citation: Poole, G.; Harris, C.;
Greenough, A. Exercise Capacity in
Very Low Birth Weight Adults: A
Systematic Review and
Meta-Analysis. Children 2023, 10,
1427. https://doi.org/10.3390/
children10081427
Academic Editor: Srinivas Bolisetty
Received: 28 June 2023
Revised: 31 July 2023
Accepted: 5 August 2023
Published: 21 August 2023
Copyright:
© 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
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Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
children
Systematic Review
Exercise Capacity in Very Low Birth Weight Adults: A
Systematic Review and Meta-Analysis
Grace Poole 1, Christopher Harris 1 and Anne Greenough 2,*
1
Neonatal Intensive Care Centre, King’s College Hospital NHS Foundation Trust, London SE5 9RS, UK;
grace.poole5@nhs.net (G.P.); christopher.harris@kcl.ac.uk (C.H.)
2
Department of Women and Children’s Health, Faculty of Life Sciences and Medicine, King’s College London,
London SE5 9RS, UK
*
Correspondence: anne.greenough@kcl.ac.uk
Abstract: There is an association between very low birth weight (VLBW) and cardiovascular mor-
bidity and mortality in adulthood. Aerobic ﬁtness, measured as the maximal oxygen consumption
(VO2 max), is a good indicator of cardiopulmonary health and predictor of cardiovascular mortal-
ity. Our aim was to determine the effect of birth weight on aerobic exercise capacity and physical
activity. We systematically identiﬁed studies reporting exercise capacity (VO2 max and VO2 peak)
and physical activity levels in participants born at VLBW aged eighteen years or older compared
to term-born controls from six databases (MEDLINE, OVID, EMBASE, CI NAHL, CENTRAL, and
Google Scholar). Meta-analysis of eligible studies was conducted using a random effect model.
We screened 6202 articles and identiﬁed 15 relevant studies, 10 of which were eligible for meta-
analysis. VLBW participants had a lower VO2 max compared to their term counterparts (−3.35,
95% CI: −5.23 to −1.47, p = 0.0005), as did VLBW adults who had developed bronchopulmonary
dysplasia (−6.08, 95% CI −11.26 to −0.90, p = 0.02). Five of nine studies reported signiﬁcantly re-
duced self-reported physical activity levels. Our systematic review and meta-analysis demonstrated
reduced maximal aerobic exercise capacity in adults born at VLBW compared to term-born controls.
Keywords: very low birth weight; VLBW; neonatal intensive care; VO2 max; exercise capacity;
exercise tolerance; physical activity
1. Introduction
According to the World Health Organization (WHO), 15–20% infants worldwide are
born at a low birth weight (LBW, <2500 g) [1]. Since the introduction of neonatal intensive
care units, there has been a dramatic improvement in survival rates of very low birth weight
infants (VLBW, <1500 g) [2,3]. The increased survival has resulted in a focus on morbidity
and mortality of these cohorts in later life.
The impact of preterm birth on multi-organ development can have deleterious effects
on the cardiopulmonary system [4–7]. Cardiac magnetic resonance imaging (CMR) has
demonstrated structural myocardial changes in adolescents and adults born prematurely
which may be associated with reduced functional reserve [4,8]. A study of 102 adults
born prematurely demonstrated they had greater left ventricular (LV) mass, smaller in-
ternal diameters, and poorer LV strain compared to term-born controls [4]. Mohamed
et al. supported those ﬁndings reporting smaller LV volumes and reduced LV function in
200 preterm adults [9]. On stress echocardiography, a lower ejection fraction (EF) propor-
tional to exercise intensity was demonstrated [8].
Given the increased prevalence of cardiovascular risk factors described in prematurely
born individuals, it is not surprising that birthweight is inversely proportional to adult
morbidity and mortality from cardiovascular disease [6,10,11]. In 1991, Barker et al. re-
ported diminished airway function in adults born of reduced birthweight and speculated
Children 2023, 10, 1427. https://doi.org/10.3390/children10081427
https://www.mdpi.com/journal/children
Children 2023, 10, 1427
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that this may be secondary to poor prenatal nutrition [12]. Subsequent evidence has shown
that LBW is associated with excess respiratory morbidity, independent of or secondary
to premature birth or in utero growth retardation (small for gestational age—SGA) [7].
Indeed, prematurity and being born SGA are associated with different risk factors, but
many prematurely born infants are SGA. Individuals who developed bronchopulmonary
dysplasia (BPD) are particularly at increased risk of chronic respiratory morbidity includ-
ing an increased requirement for supplementary oxygen following neonatal discharge,
more hospital readmissions particularly for respiratory viral infections, and lung function
abnormalities persisting even into adulthood. Sadly, such infants may also suffer hear-
ing and visual impairment, feeding difﬁculties, growth restriction, and chronic kidney
disease [13,14].
The impact of preterm birth on multi-organ development can have deleterious effects
on the cardiopulmonary system [4–7]. Furthermore, birthweight has been shown to be
inversely proportional to adult morbidity and mortality from cardiovascular disease [8,9].
Measurement of the maximal oxygen consumption (VO2 max) is considered the gold
standard assessment of cardiorespiratory ﬁtness [15]. It has been shown to be a strong
predictor of cardiovascular health, morbidity, and mortality [16,17]. A systematic review
of studies of maximal aerobic exercise capacity found a 13% reduction in VO2 max in
children and adults born prematurely, compared to their term-born counterparts. While
the pooled results were signiﬁcantly different, it was highlighted that the majority of
included observational studies showed no signiﬁcant difference in VO2 max between the
two groups [18–20]. To our knowledge, no systematic review has exclusively focused
on determining whether there was an association between VLBW and maximal aerobic
exercise capacity in adults.
As a strong predictor of cardiovascular health, an improvement in VO2 max may re-
duce the risk of cardiovascular disease and associated mortality [21]. It is well-established
that regular exercise is an effective means of increasing VO2 max [22]. In addition to its
important association with VO2 max, physical activity levels are an important independent
protective factor for cardiovascular health [23]. Several studies have suggested that prema-
turely born individuals are less physically active than their term-born peers, independent
of whether they had developed bronchopulmonary dysplasia (BPD) and socio-economic
confounders during childhood [24–26]. However, the evidence is conﬂicting [27]; the
Epicure study did not reveal any signiﬁcant differences in physical activity levels between
school-age children born prematurely and term-born controls when measured using ac-
celerometers. Therefore, the relationship between birth weight and physical activity levels
in adulthood would beneﬁt from further clariﬁcation.
The evidence, however, is conﬂicting [19]. A study of 61 children found no signiﬁcant
differences in physical activity levels assessed using an accelerometer [19]. In addition to
its important association with VO2 max, physical activity levels are also an independent
risk factor that may contribute to cardiovascular morbidity and mortality.
Our primary aim was to undertake a systematic review to evaluate the impact of
VLBW on exercise capacity in adults as assessed by VO2 max. Our secondary outcome was
to compare self-reported physical activity levels between VLBW and term-born adults and
assess whether this impacted on exercise capacity.
2. Materials and Methods
2.1. Methods
This systematic review and meta-analysis was prospectively registered on PROSPERO
at https://www.crd.york.ac.uk/prospero/ (accessed on 25 May 2023) as CRD42023429309 [28].
The literature search was conducted according to the Meta-analysis of Observational
Studies in Epidemiology (MOOSE) guidelines [29]. The Preferred Reporting Items for
Systematic Reviews and Meta-analyses (PRIMSA) guidelines were used to prepare the
manuscript [30].
Children 2023, 10, 1427
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2.2. Search Strategy
Relevant studies were identiﬁed through searching six electronic databases (EMBASE,
OVID MEDLINE(R.), Scopus, CENTRAL, CINAHL, and Google Scholar) between the
1 March 2023 and 15 March 2023. A repeat search was conducted on the 1 June 2023 to
identify any further articles that met inclusion criteria. We also hand-searched references
from included articles. Search strategies were based on the Cochrane library Neonatal
Search Terms [31].
2.3. Eligibility Criteria
Studies on exercise capacity in adults (deﬁned as greater than 18 years old) born at
VLBW compared to term controls with results of VO2 max (mL/kg/min) or VO2 Peak
(mL/kg/min) using a treadmill or cycle ergometer were eligible. VO2 max refers to the
maximum rate of oxygen consumption attainable during physical exertion. VO2 peak,
directly reﬂective of VO2 max, is the highest value VO2 attained upon incremental or
other high-intensity exercise testing [32]. The recruitment of subjects in some papers was
based on gestational age, but only those which reported birthweight were included in the
review. BPD was deﬁned as either dependence on supplementary oxygen at 28 days of life
or dependence on supplementary oxygen at 36 weeks postmenstrual age (PMA). Other
measures of cardiorespiratory exercise capacity were reviewed (such as anaerobic threshold
and minute ventilation), but there were insufﬁcient data for a meta-analysis. Given the
authors’ capabilities, studies were restricted to those reported in the English language.
Using pre-agreed inclusion criteria, two independent authors (GP and CH) removed
duplicates, screened titles and abstracts of retrieved articles, and obtained full-text articles.
Any disagreements were resolved through discussion between the two reviewers until a
consensus was achieved.
2.4. Data Analysis
Data extraction was performed by a single reviewer (GP) using a pre-speciﬁed data
extraction form. A second reviewer (CH) independently checked the accuracy of the ﬁrst
extraction. Study characteristics, sample size, the method of assessing exercise capacity,
and reference values were summarised for each study. For each study, VO2 max, VO2 peak,
and activity levels were extracted for adults born at VLBW and term-born controls.
To be eligible for meta-analysis, a study had to fulﬁl the following criteria, deﬁned a
priori: an original report on the relation between exercise capacity in adults that were born
at VLBW, odds ratios (OR), and 95% conﬁdence intervals (95% CI) for exercise tolerance
in at least two strata of birth weight. To assess exercise capacity, we analysed results for
VO2 max and VO2 peak. Meta-analyses were conducted using Review Manager (RevMan)
version 5.4 [33].
2.5. Quality Assessment
The risk of bias for each study was assessed by two independent reviewers (GP
and CH) using the Newcastle–Ottawa Scale for cohort and cross-sectional studies [34,35].
Studies were scored across three domains: case selection, comparability, and outcome.
Scores across three domains were tabulated to give an overall rating of good, fair, or poor
quality. The data extraction for quality was performed by a single reviewer (GP) and three
randomly chosen papers were checked for consistency by a second reviewer (CH), with
no discrepancies being identiﬁed. For cohort studies, we considered that participants lost
to follow-up were unlikely to introduce bias if follow-up rates were greater than 80% or
between 70% and 80% with an accompanying statement describing those lost to follow up.
3. Results
3.1. Identiﬁed Studies and Characteristics
The course of the systematic review is outlined in a PRIMSA 2020 ﬂow diagram
(Figure 1). Seven thousand, eight hundred and seven studies were identiﬁed through
Children 2023, 10, 1427
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database searching. A total of 1605 duplicates were removed, and 6202 abstracts were
screened. Eighty-one full-text articles were screened for eligibility, and the quality of
ﬁfteen studies was evaluated [8,24,36–47]. The characteristics of the studies included are
summarised in Table 1. From all included studies, there were 1132 VLBW participants,
914 controls, and 75 VLBW who had had BPD. Individuals were born between 1984 and
1998. Participants were assessed at ages 18 to 30 years old [8,24,36–47].
Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRIMSA) ﬂow
diagram outlining the course of our systematic literature search for articles evaluating maximal
aerobic exercise capacity in adults born at very low birth weight. Six databases (SCOPUS, EMBASE,
MEDLINE, CINAHL, CENTRAL, and Google Scholar) were searched. A total of 6202 articles were
screened and 81 articles assessed for eligibility. Fifteen studies were included in the review and ten in
the meta-analysis.
Children 2023, 10, 1427
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Table 1. Study characteristics of included studies.
Author
Country
Study
Design
Number of
VLBW
Infants
Number of
Control
Subjects
Age at
Follow Up
(Years)
Outcome Measures
Vrijlandt et al.,
2006 [36]
Netherlands
Prospective
cohort study
42
48
18–22
•
VO2 max
•
Physical activity level
Evensen et al.,
2009 [37]
Norway
Prospective
cohort study
32
51
18
•
VO2 max
Narang et al.,
2009 [38]
UK
Prospective
cohort study
57
50
20–25
•
Physical activity level
Sipola-
Leppanen et al.,
2011 [39]
Finland
Prospective
cohort study
116
118
20–28
•
Physical activity level
Lovering et al.,
2013 [40]
USA
Prospective
cohort study
12
12
18–27
•
VO2 peak
Clemm et al.,
2014 [24]
Norway
Prospective
cohort study
34
33
24–25
•
VO2 peak
•
VO2 peak at anaerobic
threshold
•
Physical activity level
Duke et al.,
2014 [48]
USA
Prospective
cohort study
13
14
20–25
•
VO2 peak
Saarenpaa et al.,
2015 [42]
Finland
Prospective
cohort study
160
162
20–25
•
Physical activity level
Farrell et al.,
2015 [43]
USA
Prospective
cohort study
14
16
20–23
•
VO2 max
Caskey et al.,
2016 [44]
UK
Prospective
cohort study
20
24
23–30
•
VO2 peak
Kasaeva et al.,
2012 [45]
Finland
Prospective
cohort study
94
101
21–27
•
Physical activity level
Haraldsdottir
et al., 2020 [46]
USA
Prospective
cohort study
12
12
24–28
•
VO2 max at normoxia
and hypoxia
Huckstep et al.,
2018 [8]
UK
Prospective
cohort study
47
54
20–26
•
VO2 max
•
Physical activity level
Yang et al., 2022
[47]
New
Zealand
Prospective
cohort study
202
93
26–30
•
VO2 peak
•
Physical activity level
Cheong et al.,
2023 [49]
Australia
Prospective
cohort study
128
126
25
•
Six-minute walk test
•
Maximum beep test
level
3.2. VO2 Max in VLBW Infants
Ten studies assessed VO2
max in VLBW adults compared to term-born
controls [24,36,37,40,41,43,44].
Three studies undertook a subgroup analysis for VLBW individuals who had BPD,
including 75 participants. Table 2 summarises the characteristics and results of the studies
included in the analysis. The average weight of VLBW adults at follow-up was 68.85 kg,
compared to 73.75 kg in the control group (Student’s t test, p = 0.034). Four studies assessed
VO2 max, three of which used a cycle ergometer [8,36,37,46]. Six studies assessed VO2 peak
using a combination of cycle ergometry and treadmill exercise protocols [24,40–43,47].
Children 2023, 10, 1427
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Table 2. Summary of physical maximum aerobic exercise capacity in adults born at very low birth weight.
Study
Birth
Weight
VLBW
Infants (g)
Birth
Weight
Control
Subjects
(g)
Age at
Follow
Up
(years)
Weight
VLBW
Adults
(kg)
Weight
Control
Group
(kg)
VO2 Max/Peak
Measurement
VO2 Mea-
surement
in VLBW
Group
(mL/kg/min)
VO2 Mea-
surement
in Control
Group
(mL/kg/min)
VO2 Mea-
surement
in BPD
Group
(mL/kg/min)
Vrijlandt
et al., 2006
[36]
1246 ± 232
-
18–22
65 ± 10
72 ± 10
•
VO2 Max
•
Cycle
Ergometer
35.3 ± 6.9
20.8 ± 1.2
-
Evensen
et al., 2009
[37]
1245
(800–1500)
3700 (2670–
5140)
18
64.2 ± 1.7
69.8 ± 1.3
•
VO2 Max
•
Treadmill
48.8 ± 1.4
48.5 ± 1.1
-
Lovering
et al., 2013
[40]
1160 ± 450
-
21–24
64.7 ± 9.3
75.7 ±
10.4
•
VO2 Peak
•
Cycle
Ergometer
40.6 ± 9.4
48.8 ± 7.6
40.7 ± 14.3
Clemm
et al., 2014
[24]
1173 ± 163
-
24–25
71.5 ± 4.3
72.3 ± 5.9
•
VO2 Peak
•
Treadmill
40.7 ± 2.8
44.2 ± 3.2
-
Duke et al.,
2014 [48]
1080 ± 430
-
20–25
65 ± 10
72 ± 12
•
VO2 Peak
•
Cycle
Ergometer
35.0 ± 9.0
48.0 ± 9.0
-
Farrell
et al., 2015
[43]
1027 ± 296
>1500
20–23
76.3 ± 5.0
71.8 ± 5.4
•
VO2 Peak
•
Cycle
Ergometer
39.5 ± 1.7
38.9 ± 1.6
-
Caskey
et al., 2016
[44]
1234 ± 205
3569 ± 297
21–30
-
-
•
VO2 Peak
•
Cycle
Ergometer
45.2 ±11.3
39.3 ± 8.8
35.6 ± 7.5
Haraldsdottir
et al., 2020
[46]
<1500 g
-
24–28
70.1 ±
13.3
75.6 ± 0.7
•
VO2 Max
•
Cycle
Ergometer
34.88 ±
9.26
45.79 + 8.71
-
Huckstep
et al., 2021
[50]
1916 ± 806
3390 ± 424
22–27
-
-
•
VO2 Max
•
Cycle
Ergometer
33.6 ± 8.6
40.1 ± 9.0
-
Yang et al.,
2022 [47]
1131 ± 233
3362 ± 529
28–29
74.1 ±
18.8
80.8 ±
16.3
•
VO2 Peak
•
Cycle
Ergometer
30.46 ±
8.06
31.45 ±
7.86
28.3 ± 1.1
Meta-analysis indicated that adults born at VLBW had a signiﬁcantly lower VO2
max/VO2 peak compared to controls (mean difference: −3.35 [95% CI −5.23 to −1.47]
mL/kg/min, p = 0.0005) (Figure 2). However, there was high heterogeneity between
studies included in the analysis (I2 = 87%). Meta-analysis of studies solely reporting on
those who had BPD found they were more likely to have a lower VO2 max (mean difference:
−6.08 [95% CI −11.26 to −0.90] mL/kg/min, p = 0.02,) than term-born controls. There
were no signiﬁcant differences in VO2 max between VLBW participants who had BPD and
those that did not (p = 0.33).
Children 2023, 10, 1427
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Children 2023, 10, x. https://doi.org/10.3390/xxxxx 
www.mdpi.com/journal/children 
 
 
 
 
 
 
 
 
Figure 2. Forest plot of aerobic exercise capacity (VO2 max/VO2 peak) in adults born at very low
birth weight compared to their term-born counterparts [24,36,37,40,43,44,46–48,50].
3.3. Levels of Physical Activity in VLBW Infants
Nine studies from ﬁve different countries reported on physical activity levels in VLBW
adults compared to controls (Table 3) [8,26,37–39,42,44,47]. Three studies followed up
individuals from the Helsinki Study of VLBW Adults [39,41,44]. Three studies used the
European Community Respiratory Health Survey II to identify adult’s physical activity
levels [36,44,47,51]. Five studies did not report on questionnaires or tools utilised to assess
physical activity levels [8,24,37,39,42].
Five studies found signiﬁcant differences in self-reported activity levels in VLBW
adults compared to controls [36,39,44,45,47]. In four studies, VLBW adults were less likely
to engage in weekly vigorous physical activity [36,44,45,47]. In one study, despite no
signiﬁcant difference in the frequency of exercise, VLBW adults were more likely to engage
in less intense physical activity for a shorter duration of time [39]. Four studies found
no signiﬁcant difference in the frequency of physical activity between VLBW and control
groups [8,24,37,42]. Due to a difference in measurable outcomes and assessment tools, the
results were unsuitable for meta-analysis.
Children 2023, 10, 1427
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Table 3. Summary of physical activity levels in adults born at very low birth weight.
Study
Weight
VLBW
Infants (g)
Weight
Control
Subjects (g)
Age at
Follow Up
VLBW
Infants
(Years)
Age at Follow Up
Control Subjects
(Years)
PA Assessment Measure
Results
Summary of
Impact
Vrijlandt et al.,
2006 [36]
1246 ± 232
-
19 ± 0.3
20.8 ± 1.2
•
European Community Respiratory
Health Survey II
•
Mean hours of vigorous exercise per
week
•
Preterm born infants undertake
signiﬁcantly less vigorous exercise per
week (1.9 h ± 2) compared to term
born controls (2.9 h ± 2)
Narang et al., 2009
[38]
1440 ± 550
3410 ± 2390
21.7 ± 1.2
23.1 ± 2.0
•
No formal questionnaire reported
•
Mean days engaged with physical
activity per week
•
There was no statistical difference in
time spent being active per week
between VLBW infants (3.0 ± 2.42) and
the control group (3.0 ± 1.79)
Sippola-Leppanen
et al., 2011 [39]
1125 ± 223
3606 ± 469
22.3 ± 2.2
22.6 ± 2.2
•
No formal questionnaire reported
•
Frequency, duration, and intensity of
exercise
•
There was signiﬁcant difference
between VLBW and control subjects in
the intensity and duration of physical
activity during a typical week
•
There was no difference in the
frequency of activity between groups
Kaseva et al., 2012
[45]
1157 ± 208.7
3608 ± 492
24.9 ± 2.1
25.1 ± 2.2
•
Modiﬁed Kuopio Ischaemic Heart
Disease Risk Factor Study
•
Frequency, time, and intensity of
conditioning exercise
•
Frequency, time, and intensity of
leisure-time physical activity
•
No signiﬁcant difference in commuting,
leisure-time, or conditioning physical
activity between groups
•
VLBW infants were more likely to do
less vigorous activity compared to their
counterparts
Clemm et al., 2014
[24]
1173 ± 163
-
24.7 ± 1.2
25.1 ± 1.2
•
No formal questionnaire reported
•
Categorical hours spent exercising per
week
•
No statistically signiﬁcant difference in
leisure time spent doing physical
activity between EP and term-born
individuals.
Caskey et al., 2016
[44]
1234 ± 205
3569 ± 297
26.4 ± 3.7
28.3 ± 3.3
•
European Community Respiratory
Health Survey II
•
Frequency exercised 2–3 h per week
•
Statistically signiﬁcant difference in the
frequency individuals exercised 2–3 h
per week between BPD, non-BPD
adults, and term-born controls
Saarenpaa et al.,
2015 [42]
1126 ± 218
3599 ± 466
22.4 ± 2.1
22.5 ± 2.5
•
No formal questionnaire reported
•
Frequency of exercise per week
•
No statistically signiﬁcant difference in
the frequency of exercise per week
between VLBW and non VLBW
individuals
Children 2023, 10, 1427
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Table 3. Cont.
Study
Weight
VLBW
Infants (g)
Weight
Control
Subjects (g)
Age at
Follow Up
VLBW
Infants
(Years)
Age at Follow Up
Control Subjects
(Years)
PA Assessment Measure
Results
Summary of
Impact
Huckstep et al.,
2018 [8]
1916 ±806
3390 ± 424
22.7 ± 3.04
23.6 ± 3.8
•
No formal questionnaire reported
•
Hours spent doing moderate and
vigorous physical activity per week
•
No statistical difference in hours spent
doing moderate or vigorous activity
between groups
Yang et al.,
2022 [47]
1131 ±233
3362 ± 529
28.3 ± 1.1
28.2 ± 0.9
•
European Community Respiratory
Health Survey II
•
Mean days engaged with physical
activity per week
•
VLBW exercised signiﬁcantly less (2.9
h ± 2.6) per week compared to
term-born controls (37 ± 2.4).
Children 2023, 10, 1427
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4. Discussion
We have demonstrated that exercise capacity is signiﬁcantly reduced in adults born
at VLBW, independent of whether they had BPD, compared to term born controls. It is
important to consider the origin of differences in VO2 max between VLBW adults and TB
term-born controls. Maximal aerobic exercise capacity is impacted by age, sex, weight,
size, body composition, and physical activity levels. Due to a lack of data reported in
individual papers, we were unable to analyse results to determine if there were differences
related to sex. A follow-up study of 150 adults born prematurely recruited into the United
Kingdom Oscillation Study (UKOS) found males compared to females completed signiﬁ-
cantly greater distances during shuttle sprint testing and reported exercising more each
week [52]. While VO2 max was not assessed in that study, sex differences in the amount
of exercise undertaken could potentially impact on VO2 max. Furthermore, in a study of
elite endurance athletes, women were found to have a VO2 max 10% lower than their male
counterparts [53].
Given the absolute value is highly impacted by body weight, VO2 max and VO2
peak are typically expressed as milliliter/kg/minute. While this enables results to be
adjusted for body weight, body composition remains a likely confounder. Eight out
of ten included studies reported the participants’ weight [8,24,36,37,40,41,43,46,47]. On
pooled analysis, there was a signiﬁcant difference in the mean weight of adults born at
VLBW compared to term-born controls. While impossible to predict based exclusively
on weight, BMI is generally well-correlated to percentage body fat [54–56]. One study of
25 female athletes aged between 17 and 22 years found a non-signiﬁcant negative correlation
between percentage body fat and VO2 max [57]. Goren et al. demonstrated a strong
correlation between fat-free mass (FFM) and VO2 max [58]. This may explain the greater
effect size observed in our meta-analysis which focused exclusively on adults compared
to the results of Edwards et al. which also included children [18]. Dual energy X-ray
absorptiometry (DXA) of 433 healthy subjects demonstrated a decline in FFM with age [59].
This emphasises the importance of including anthropometric measurements in studies
investigating maximal aerobic exercise capacity in future.
There is a well-established association between physical activity levels and maximal
aerobic exercise capacity. Meta-regression and analysis of 28 articles highlighted an increase
in VO2 max with physical activity training, independent of the volume and intensity of
exercise sessions [60]. Crowley et al. reported in their systematic review that both high and
low intensity training when undertaken frequently increased VO2 max [61]. Interestingly,
despite adjusting for physical activity levels, Gostelow and Stohr found a signiﬁcantly
lower VO2 max in individuals born at VLBW [19]. In our review, ﬁve studies reported
that adults born at VLBW exercised less than their term-born counterparts [36,39,44,45,47],
whereas four studies found no such association [4,8,24,38]. This highlights the need for
further research assessing the relationship of physical activity levels and VO2 max in
relation to birth weight. If frequent exercise improves maximal aerobic exercise capacity, an
important predictor of cardiovascular morbidity and mortality, a pertinent public health
strategy would be to target educational interventions and physical activity programs at
VLBW adults.
Interestingly, despite adjusting for PA levels, Gostelow and Stohr found a signiﬁcantly
lower VO2 max in individuals born at VLBW [52,53]. There is improvement in maximal
aerobic exercise capacity with regular exercise, that PA may be used as a potential interven-
tion [52,53]. This raises a question as to whether VLBW infants should be recommended
targeted exercise regimens as a preventative cardiovascular strategy. The physiological
mechanisms resulting in reduced maximal aerobic exercise capacity in adults born at VLBW
remain poorly understood. Aerobic exercise capacity is determined by the integrative
responses of the cardiovascular and respiratory systems, in addition to oxygen uptake by
skeletal muscles [62]. Several studies have demonstrated that [54]. Our ﬁndings support
previous research demonstrating a reduced maximal aerobic exercise capacity, independent
of prematurity-related perinatal factors such as BPD [40]. Pulmonary gas exchange during
Children 2023, 10, 1427
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exercise, assessed by the alveolar-to-arterial oxygen difference (A-aDO2), is comparable
between prematurely born and term-born TB adults during exercise [40,43,63]. It has
however been hypothesised that adults born at VLBW may have higher airway resistance
and smaller peripheral airways, requiring a greater concentration of oxygen to maintain
ventilation respiration during exercise [64]. Follow-up of the UKOS cohort found males
born prematurely were more likely to have poorer smaller airway function, however, they
performed better on exercise testing compared to their female counterparts, possibly in-
dicating that other factors’ physiological mechanisms may have a greater inﬂuence [52].
Adults born prematurely have been shown to have a signiﬁcantly increased pulmonary ar-
terial pressure during exercise, which may reduce pulmonary blood ﬂow and subsequently
VO2 max [64,65]. Physiological mechanisms contributing to a reduced maximal aerobic
exercise capacity are multi-factorial and complex, where further research is required to
fully understand the impact of birth weight and prematurity.
In addition to a reduced VO2 max, a predictor of increased cardiopulmonary mortality,
adults born at VLBW are also at higher risk due to the increased prevalence of hyperten-
sion [66], heart failure [67], diabetes [68], and cardiometabolic syndromes [66]. Given this,
a more detailed cardiovascular risk assessment in adults known to be born at VLBW may
be of beneﬁt. One suggestion is to screen adults born at VLBW in general practice using
a risk scoring system, such as the widely utilised QRISK2, to predict individuals 10-year
risk of cardiovascular disease [69]. It would be important however to evaluate the ﬁnancial
cost, resource implications, and the most appropriate and effective age-range to target such
an intervention.
Furthermore, adults born preterm have been shown to have a signiﬁcant increase in
pulmonary arterial pressure during exercise, which may reduce pulmonary blood ﬂow and
subsequently VO2 max [59,60]. Physiological mechanisms contributing to the observed
reduction in maximal aerobic exercise capacity are multi-factorial and it is clear further
research is required to fully understand the impact of birth weight and prematurity.
Adults born at VLBW are at a higher risk of hypertension [61], heart failure [62], dia-
betes [63], and cardiometabolic syndromes [61]. Interestingly, despite a greater prevalence
of cardiovascular risk factors, an association with ischemic heart disease remains inconclu-
sive [64,65]. An increased relative-risk of all-cause mortality in adults born prematurely,
however, is well-established [66]. A more detailed cardiovascular health assessment in
adults known to be born at VLBW may be of beneﬁt, but evaluation of the efﬁcacy and
resource implications of adult-targeted interventions would be important. Studies such as
the trial of exercise to prevent hypertension in young adults are therefore very welcome,
even though only 38.7% of those born prematurely were born at less than 32 weeks of
gestation [70].
Despite our efforts to generate a precise effect of being born at VLBW on maximal
aerobic exercise capacity, our review has some limitations. On analysis, there was a high
proportion of heterogeneity between studies reporting maximal aerobic exercise capacity.
In part, this may be secondary to our decision to include studies reporting VO2 peak and
VO2 max, however, prior studies have shown that VO2 peak is reﬂective of VO2 max [32].
The heterogeneity is possibly attributable to different methodologies and protocols used
between studies to estimate maximal aerobic exercise capacity. Eight studies utilised
cycle ergometry [8,36,37,39,41,44,46,47] whereas two studies utilised a treadmill [24,27].
While studies utilising a treadmill demonstrated comparable results to those using a cycle
ergometer in this review, prior studies have commented on lower values of VO2 max
using cycle ergometry when intra-subject comparisons of both methods were utilised in
the same study [71,72]. While challenging, this perhaps highlights a need to standardise
methodology and protocols utilised to measure maximal aerobic exercise capacity.
All participants included in the meta-analysis were between their second and third
decade of life, a period well-established to correlate to peak maximal aerobic exercise
capacity. Generally, it is estimated that VO2 max declines 10% per decade after the age
of 25 years and 15% between the ages of 50 and 75 [73–75]. Most studies included in our
Children 2023, 10, 1427
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meta-analysis followed up participants in their third decade of life, with latter follow-up. It
will be interesting to observe the impact of age on differences in VO2 max between adults
born at VLBW and at term.
Due to differences in outcome measures between studies, a meta-analysis could not be
performed to assess self-reported physical activity levels in adults born at VLBW. Given the
correlation between physical activity levels and cardiovascular morbidity and mortality, in
addition to the possibility of reduced activity levels in adults born at VLBW, standardisation
of outcome measures between studies is of vital importance. In studies evaluating maximal
aerobic exercise capacity and physical activity levels, it is important to critically evaluate
participant recruitment given the high risk of recruitment bias associated with exercise-
based studies [76].
5. Conclusions
In conclusion, maximal aerobic exercise capacity was signiﬁcantly reduced in adults
born at VLBW compared to term-born controls. Given the relationship between exercise
capacity and cardiovascular morbidity and mortality, this could have signiﬁcant impli-
cations for individuals’ long-term health. The variability in outcome measures assessing
physical activity meant it was difﬁcult to accurately assess the association with birthweight.
We recommend a standardised approach of assessing physical activity levels for future
studies, such as the European Respiratory Health Community Questionnaire II or Metabolic
Equivalent of a Task levels.
Author Contributions: Conceptualization, G.P. and A.G.; methodology, G.P.; validation, C.H.; formal
analysis, G.P.; writing—original draft preparation, G.P.; writing—review and editing, A.G.; visual-
ization, G.P.; supervision, A.G. All authors have read and agreed to the published version of the
manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Acknowledgments: The authors would like to acknowledge the work of Deidre Gibbons in the
preparation of this manuscript.
Conﬂicts of Interest: The authors declare no conﬂict of interest.
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Exercise Capacity in Very Low Birth Weight Adults: A Systematic Review and Meta-Analysis.
Poole, Grace,Harris, Christopher,Greenough, Anne