Paediatric Respiratory Reviews 44 (2022) 19–30

Contents lists available at ScienceDirect

Paediatric Respiratory Reviews

Mini-symposium: What’s New in the NICU in 2022 (Part 2)

Fetal growth restriction and neonatal-pediatric lung diseases: Vascular

mechanistic links and therapeutic directions
Arvind Sehgal a,b,⇑, Theodore Dassios c,d, Marcel F. Nold a,b,e, Claudia A. Nold-Petry b,e, Anne Greenough c,f
a
Monash Newborn, Monash Children’s Hospital, Melbourne, Australia
b
Department of Pediatrics, Monash University, Melbourne, Australia
c
Department of Women and Children’s Health, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
d
Neonatal Intensive Care Centre, King’s College Hospital NHS Foundation Trust, London, United Kingdom
e
Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria, Australia
f
NIHR Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, United Kingdom

Educational aims

The reader will come to appreciate that:

An overview of the burden of disease for FGR and BPD.

Vascular involvement in the placenta in FGR and BPD cohorts.

Data from human FGR infants, and AGA infants with severe BPD, using high resolution vascular ultrasound.

Therapeutic relevance of the overlapping vascular pathophysiology.

The role of perinatal vascular insults in predisposition to pediatric age-group lung diseases.

a r t i c l e i n f o a b s t r a c t

Keywords: Bronchopulmonary dysplasia (BPD) is the most common respiratory sequela of prematurity, and infants
Fetal growth restriction born with fetal growth restriction (FGR) are disproportionately represented in BPD statistics, as factors
Bronchopulmonary dysplasia which affect somatic growth may also affect pulmonary growth. Effects of in-utero hypoxia underlying
Arterial stiffness FGR on lung parenchymal architecture predisposing to BPD are well documented, but the pulmonary vas-
Mechanisms
cular constructs are not well appreciated. Disruption of angiogenesis during critical periods of lung
Placenta
growth impairs alveolarization, contributing to BPD pathogenesis. Pulmonary artery thickness/stiffness
has been noted in FGR in the initial postnatal weeks, and also in well-grown infants with established
BPD. The lack of waveform cushioning by the major arteries exposes the pulmonary resistance vessels
to higher pulsatile stress, thereby accelerating microvascular disease. Reactive oxygen species, increased
sympathetic activity and endothelial dysfunction are common mediators in FGR and BPD; each putative
targets for prevention and/or therapeutics using interleukin (IL)-1 receptor antagonist (IL-1Ra), mela-
tonin or inhibition of renin–angiotensin–aldosterone system. While BPD is the archetypal respiratory dis-
ease of infancy, effects of FGR on pulmonary function are long-term, extending well into childhood. This
narrative links FGR in very/extremely preterm infants with BPD through the vascular affliction as a mech-
anistic and potentially, therapeutic pathway. Our objectives were to depict the burden of disease for FGR
and BPD amongst preterm infants, portray vascular involvement in the placenta in FGR and BPD cohorts,
provide high resolution vascular ultrasound information in both cohorts with a view to address therapeu-
tic relevance, and lastly, link this information with paediatric age-group lung diseases.
Ó 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

⇑ Corresponding author at: Neonatal Cardiovascular Research, Monash Children’s
Hospital, Adjunct Professor of Paediatrics, Monash University, 246, Clayton Road,
Clayton, Melbourne, VIC 3168, Australia.
E-mail address: Arvind.Sehgal@monash.edu (A. Sehgal).
INTRODUCTION
Bronchopulmonary dysplasia (BPD) remains the most common
respiratory sequela of prematurity. For infants born <32 weeks

https://doi.org/10.1016/j.prrv.2022.09.002
1526-0542/Ó 2022 The Author(s). Published by Elsevier Ltd.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
A. Sehgal, T. Dassios, M.F. Nold et al.
gestational age (GA), BPD is defined as continued need for respira-
tory support at 36 weeks post-menstrual age [1]. The NICHD clas-
sification divides BPD into moderate and severe categories based
on oxygen requirement of </30 % and positive pressure ventila-
tion [2]. A more recently published classification uses additional
parameters such as low-flow/high-flow nasal cannula oxygen,
nasal continuous positive airway pressure/nasal intermittent posi-
tive pressure ventilation and invasive positive pressure ventilation
[3]. A significant proportion of infants with severe BPD are also
affected by BPD associated pulmonary hypertension (PH) [4–6].
The additional complication contributes to a prolonged hospital
stay, recurrent hospitalisations in the first two years as well as
higher mortality.
Fetal growth restriction (FGR) is the inability of the developing
fetus to grow as per potential. In clinical terms, investigators have
defined FGR as birthweight (BW) <10th centile for GA and sex [7].
Abnormal Doppler patterns in fetal systemic arteries identify a
subset with especially poor short and long term outlooks. About
two thirds of the late-onset small fetuses present severe forms of
smallness, i.e. estimated fetal weight <3rd centile, or as abnormal
cerebro-placental ratio [8]. This group has features of vascular
mal-perfusion on placental pathology and poorer perinatal out-
comes [9]. While most FGR infants are born preterm, the adverse
respiratory outcomes such as BPD attributable to the FGR state,
are independent of the degree of prematurity, indicating possible
alignment of pathophysiology between FGR and BPD [10–11]. In
a large multi-centric study on >1200 infants born <28 weeks GA,
within all the antenatal, placental and neonatal strata variables,
preterm infants with FGR were at increased risk for BPD compared
with appropriate for gestational age (AGA) infants [10]. This review
focuses on very/extremely preterm FGR infants who develop BPD.
RATIONALE FOR REVIEW
FGR affects lung structure and function, impacting on both alve-
olar parenchymal and vascular components. The prevalent narra-
tive linking in-utero events such as utero-placental insufficiency
(UPI) with ‘subsequent’ respiratory sequela such as BPD is through
the involvement of pulmonary parenchyma and somatic growth.
While the pathophysiology of BPD is multifactorial, the vascular
hypothesis behind it is increasingly being explored [12–13], The
Barker Hypothesis, or the Developmental Origins of Health and
Disease Hypothesis, in its original proposition, explained fetal/de-
velopmental priming of the cardiovascular system [14–15]. How-
ever, the underlying principles are equally relevant to the
developing pulmonary vasculature [16]. In sheep, undernutrition
during the saccular and alveolar stage of lung development not
only leads to prenatal altered surfactant protein expression and
reduction of the alveolar surface area in relation to lung volume,
but also leads to decreased pulmonary vascular growth [17]. There
are emerging experimental and clinical data linking in-utero events
with BPD via ‘pulmonary vascular’ structural and functional
changes (altered pulmonary vasoreactivity).
Angiogenesis is important for optimum alveolarization, espe-
cially during critical periods of lung growth. Pulmonary alveolar
development is closely intertwined with vascular development to
the extent that specific disruption in alveolar development also
interferes with vascular development. Critical periods can occur
during fetal life where respective organs develop and differentiate
during sometimes-narrow windows of maturation. Impairments in
angiogenic signalling during critical fetal periods can reduce pul-
monary vascular density, making them particularly susceptible to
pulmonary vascular injury [13,18–21]. In essence, early-life vascu-
lar disorders may impact alveolar development [12,22]. A wide
variety of prenatal conditions have been associated with impaired
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Paediatric Respiratory Reviews 44 (2022) 19–30
pulmonary vascular development; these include FGR-fetal hypox-
ia, pre-eclampsia, chorioamnionitis and exposure to intrauterine
toxins produced by maternal smoking. Premature infants are still
at a critical stage of lung maturation, making them particularly
susceptible to pulmonary vascular injury mediated via hypoxic
insults. Impairments in placental vascular perfusion further
increase the risk for development of BPD and pulmonary vascular
disease after birth [23–24]. This is corroborated by FGR sheep data
which noted stunted pulmonary vascular growth, and impaired in-
vitro pulmonary artery endothelial cell migration and nitric oxide
production [25]. This in turn may be compounded by postnatal
experiences such as episodes of hyperoxia, hypoxia, positive pres-
sure ventilation and postnatal infection.
The resulting respiratory morbidities are not limited to BPD, but
also include chronic oxygen dependency, lung function abnormal-
ities at follow-up and rehospitalisation due to respiratory ailments
during childhood. While FGR is the archetypal diagnosis that incor-
porates cardiovascular and respiratory adaptation to chronic in-
utero hypoxia, amongst premature infants, BPD is the archetypal
setting for chronic post-natal hypoxia.
SECTION A: BURDEN OF DISEASE
Data from Australian and New Zealand Neonatal Network noted
that amongst infants <32 weeks in 2020, 668 (21 %) were born with
BW <10th centile for GA and sex; approximately 45 % amongst
them weighed <3rd centile [1]. In the same year, the incidence of
BPD was high amongst infants <27 weeks GA (159/249, 64 %). A
3-year regional centre data in preterm infants <32 weeks GA noted
the incidence of FGR to be 27 % [26]. Table 1 summarises studies
noting the incidence of FGR and the greater odds of developing BPD
in preterm FGR infants [26–33]. Combined, prematurity and FGR
increase the risk of BPD by 10–20 fold [34]. The Optum Neonatal
database analysis of the results of 6708 infants from 717 US hospi-
tals demonstrated that the risk adjusted probability of dying or
developing BPD or other morbidities amongst FGR infants was sim-
ilar to that of non-growth restricted infants who were born
approximately 2–3 weeks more immature [35]. BW <3rd centile
amongst extremely low BW infants increases the risk of developing
BPD by five times [36]. A recent five-year study of all extremely
preterm infants admitted to neonatal intensive care in England
noted that infants that developed BPD had a lower median BW z-
score (-0.44) compared to the ones without BPD (-0.23) (Fig. 1)
[37]. Research performed in singletons can be affected by a certain
level of bias caused by individual differences in genetic constitu-
tion, obstetric and maternal factors. However, recent data compar-
ing the larger and smaller twin in monochorionic twins provided
similar outcomes (Table 1) [33]. Finally, a meta-analysis of 211
studies demonstrated that when placental vascular dysfunction
was accompanied by FGR, it was associated with an increased risk
of developing BPD and PH [38].
SECTION B. OVERLAPPING VASCULAR AFFLICTION IN FGR AND
BPD COHORTS: PLACENTAL STUDIES
Vascular pathology in FGR placentae
Placental abnormalities (reduced feto-placental blood in UPI)
are a major aetiology behind FGR [39–41]. Vascular adaptations
are key in maintaining a healthy pregnancy with advancing gesta-
tion. These include a drop in placental vascular resistance and the
establishment of a high-flow circuit to optimise oxygen and nutri-
ent delivery to the fetus. Angiogenesis and vasodilatation facilitate
this evolution and in severe cases of FGR, these adaptive mecha-
nisms fail, resulting in a persistently high placental vascular resis-
A. Sehgal, T. Dassios, M.F. Nold et al. Paediatric Respiratory Reviews 44 (2022) 19–30

Table 1
Summary of studies noting higher incidence of BPD in FGR cohorts.

Study Subject Population Results Comment

Sehgal K, et al. 2021. (3 year
[2016–2018] single centre
study)
Groene SG et al. 2021. (2010–
2019,single centre,
retrospective)
Boghossian NS et al. 2018. Data
from 2006 to 2014 on 156,587
infants from 852 American
centres: Vermont Oxford
Network.
Klinger G et al. 2013. Population-
based observational study
from Israel Neonatal Network
for data from 2000 to 2010.
Qiu X et al. 2012. Data from the
Canadian Neonatal Network
Ferdynus C, et al. 2009. (Regional
study-Burgundy, France [2000
to 2006])
Bose C, et al. 2009. (14-center,
observational study [2002–
2004])
Aucott SW et al. 2004.
Retrospective, single centre
(1991to1998)
Garite TJ et al. 2004. (Regional
data, 124 neonatal units [1997
to 2001])
Lal MK et al. 2003. (Regional
observational study-Trent,
United Kingdom [1995–1999])
Reiss et al. 2003. (Regional data,
Hesse, Germany [1990 to
1996])
Bardin C et al. 1997.
Retrospective, single centre
study (1983–1991)
Premature infants <32 weeks gestation.
Of 973 infants, the incidence of FGR
was 206 (27 %). 85 % FGR were born
between 28 and 31+6 weeks.-FGR
(n = 206)-AGA (n = 206)
94 included pregnancies, median
gestation 32.4 (IQR 30.4–34.3) weeks.
Data for preterm infants 23–29 weeks.
FGR incidence/gestation
9.95 % overall
10.1 % at 22 weeks;
9.4 % at 23 weeks;
10.2 % at 24 weeks;
10.2 % at 25 weeks;
9.7 % at 26 weeks;
10.% at 27 weeks;
10.% at 28 weeks;
9.9 % at 29 weeks.
Preterm infants born between 24 and
32 weeks, surviving to 36 weeks.
Incidence of FGR amongst <33 weeks
GA infants: 1249/11,909 (10.5 %).
Premature infants 28–31 weeks
gestation (n = 65).
30.4 % infants were FGR-AGA-
(n = 52) -FGR
(n = 13)
Premature infants <27 weeks gestation
(n = 411)
-No FGR (n = 335)-Moderate FGR*
(n = 55) -Severe FGR^
(n = 21)
Comparison between preterm infants
<32 weeks-FGR
(n = 39) -AGA
(n = 41)
Singleton, inborn infants, 23–34 weeks
gestation.
Compared FGR per 3 definitions: -
antenatally diagnosed FGR
(1451 [4.8 %] of total);
-birthweight <10th centile (2936
[9.8 %] of total); -either of the above
(3,708 [12.3 %] of total).
n = 401 (9.9 % of infants  32 weeks)
Preterm infants <32 weeks of gestation.
<32 weeks gestation.
Analyse differences FGR and AGA. -FGR
(n = 183) -AGA
(n = 1,182)
Comparison between preterm infants
(24–266/7 weeks) -FGR
(n = 37) -AGA
(n = 147)
Greater risk of BPD when born FGR.
BPD: 53 (25.7 %) in FGR vs 28 (13.6 %)
in AGA, (p = 0.002), respectively.
Incidence of BPD higher in the smaller
twin vs larger twin (16.7 % vs 6.7 %,
p = 0.008).
BPD risk was increased with FGR,
starting at GA 23 weeks through
27 weeks GA.
BPD was independently associated
with FGR state.
Greater risk for mortality and BPD.
Greater risk of BPD when born FGR.
Increased risk for BPD when FGR
25 % of infants without FGR
60 % of infants with moderate FGR
90 % of infants with severe FGR
Greater BPD in FGR (29 %) vs AGA
infants (15 %).
Each measure of FGR was associated
with " mortality and greater BPD (need
for respiratory support at 28 days of
age)
FGR infants had higher mortality
<28 days and 36 weeks postmenstrual
age (PMA). Greater risk of developing
BPD compared to reference group.
Mortality and BPD were significantly
higher in FGR.
Higher risk for BPD (defined as a need
for supplementary oxygen at 36 weeks
(65 % for FGR vs 32 % for AGA).
Longer duration of respiratory support:
37 ± 10 in FGR vs 23 ± 5 days in AGA
(p = 0.016), home oxygen: 24 (11.6 %) in FGR
vs 8 (3.8 %) in AGA; (p = 0.005) after adjusting
for postnatal variables such as gestation, sex,
antenatal steroids, patent ductus arteriosus,
surfactant and infection.
Odds ratio to develop BPD in smaller twin 2.5
(95 % CI 1.3–4.9).
At 23 weeks (BPD relative risk: 1.84; 95 % CI:
1.30–2.60); at 27 weeks (BPD relative risk:
3.56; 95 % CI: 3.04–4.18).
Greater odds for BPD when FGR (2.65, 95 % CI,
2.24–3.12).
Adjusted odds for BPD (1.78; 95 % CI, 1.48–
2.13).
FGR associated with a significantly increased
risk of BPD (adjusted odds: 2.6, CI 1.3–5.2).
Among antenatal factors, birthweight
provided the most information about BPD
risk. FGR was the only maternal or antenatal
characteristic which highly predicted BPD,
even after adjusting for other risk factors.
Number of days on ventilator, FGR 12 ± 31 vs
AGA 6 ± 15.
Number of days in oxygen, FGR 34 ± 53 vs
AGA 16 ± 27
Respiratory support at 28 days of life:
-No FGR: 4,068 (17.8 %) -FGR definition 1: 287
(19.8 %) -FGR definition 2: 708
(24.1 %) -Either definition 1 or 2: 831
(22.4 %)
Odds of FGR infants developing BPD at
28 days’ and 36 weeks’ PMA (OR: 1.34, 95 %
CI: 1.03–1.74; and OR: 1.87, 95 % CI: 1.39 –
2.51), respectively.
Mortality (23 % in FGR vs 11 % in AGA), BPD
(28 % in FGR vs 14 % in AGA). BPD odds
ratio = 3.80, 95 % CI 2.11, 6.84).
Prolonged need for oxygen supplementation
and ventilator support (94 days for FGR vs
68 days for AGA, and 58 days for FGR vs
40 days for AGA, respectively).

BPD-bronchopulmonary dysplasia, FGR-fetal growth restriction, *moderate FGR-birthweight <10th centile, ^severe FGR-birthweight.
<3rd centile, CI-confidence interval.

tance [39,42]. In comparison to human AGA placentae, the FGR pla-
centae have significantly higher resistance, endothelial dysfunction
and reduced flow-mediated vasodilatation [43].
Maternal Vascular Under-perfusion (MVU) is a group of histo-
logic lesions seen in births complicated by FGR, and affect flow
dynamics such as high placental vascular resistance (Fig. 2). On
histopathology, vascular remodelling/ obstructed spiral arteries
are pathognomonic features of hypoxia and reperfusion [44–45].
Vascular aetiology (villous hypoplasia, increased syncytial knots)
underlies reduced supply of nutrients and oxygen in human FGR
pregnancies [46]. This is corroborated by data from sheep models
of chronic fetal hypoxia and UPI where vascular remodelling with
small lumens and thick walls have been noted [25]. Chronic fetal
hypoxia owing to UPI, as indicated by the extent/severity of

21
A. Sehgal, T. Dassios, M.F. Nold et al.
Fig. 1. Boxplot of the birthweight z-score in infants that developed BPD compared
to infants that did not. The horizontal lines represent the 5th, 25th, 50th, 75th and
95th centile of the values, outliers are depicted as single points. 11,806 included
infants.
MVU, may explain the associations with adverse infant outcomes
[47–49]. MVU is associated with >4 times higher risk of delivering
an FGR infant [50]. In human data, where placental histopathology
was evaluated in a cohort of 40 preterm infants (20 FGR and 20
Fig. 2. Placental histopathology in fetal growth restriction Fig. 2a. Maternal vascular perfusion: Placental infarct, H and E, original magnification Fig. 2b. Fetal vascular
malperfusion: villous stromal-vascular karyorrhexis (old term hemorrhagic endovasculitis), H and E, original magnification 100 Fig. 2c. Chronic intervillositis, H and E,
original magnification 400 Fig. 2d. Microscopic chorangioma, H and E, original magnification 50 (from, Sehgal A, Dahlstrom J, Chan Y, Allison BJ, Miller S, Polglase GR.
Placental histopathology in preterm fetal growth restriction. J Pediatr Ch Health 2019).
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Paediatric Respiratory Reviews 44 (2022) 19–30
AGA, mean GA 30 weeks in either group) using predefined
histopathological characteristics (Amsterdam Placental Workshop
Group Consensus Statement) [51–52], vascular mal-adaptations
in the FGR cohort included MVU, fetal mal-perfusion and acceler-
ated villous maturation. Of interest to the clinicians, the preterm
FGR cohort in this study had significantly longer duration of respi-
ratory support requirements and BPD, compared to gestation and
sex matched AGA infants [52]. In essence, vasculature was a key
‘organ’ to be affected in pregnancies affected by FGR. Fig. 3 depicts
antenatal and postnatal vascular constructs in FGR and BPD and
their influence on lung disease.
Vascular origins of BPD-clues from placental histopathology and cord
blood biomarkers
Placental histopathology and biomarkers have also been inves-
tigated in BPD for early clues of subsequent neonatal respiratory
events, with significant histopathology overlapping findings with
FGR. A study on 56 preterm AGA infants evaluated specific placen-
tal histopathological changes to assess their relationship with BPD
associated PH. Placental as well as echocardiographic assessments
(latter at 36 weeks post-menstrual age) were done by investigators
masked to the grouping (PH or no PH) [23]. The presence of placen-
tal features consistent with MVU increased the relative risk of sub-
sequent BPD-associated PH by 2.75 (95 % CI 1.56 to 4.85, P = 0.004);
the significance persisting after adjustment for GA. Mestan et al.
[24] noted similar findings in a 5-year retrospective cohort study
of premature infants with mean GA 26 weeks. Amongst the com-
mon complications of prematurity, BPD was the only outcome that
was increased with MVU, persisting after adjustment for perinatal
variables (adjusted odds ratio 2.6; 95 % confidence interval [CI] 1.4,
4.8). The antenatal vascular constructs of BPD were corroborated
A. Sehgal, T. Dassios, M.F. Nold et al.
Fig. 3. Antenatal and postnatal vascular constructs in FGR and BPD and their influence on lung disease.
by the findings of significantly lower cord blood angiogenic factors
in placental MVU [53]. These included placental growth factor and
vascular endothelial growth factor-A. Decreased levels in the pla-
centa were predictive of subsequent BPD-PH. Based on the above
results, placental MVU may identify premature infants with BPD
who were exposed to chronic intrauterine hypoxia–ischemia dur-
ing fetal life.
In summary, placental histopathology and cord blood biomark-
ers indicate vascular origins of respiratory sequelae, and MVU is an
important common finding between FGR and BPD.
SECTION C. ARTERIAL STIFFENING IN FGR AND BPD COHORTS:
POSTNATAL DATA
Vascular cross-sectional area is an important determinant of pul-
monary vascular resistance (PVR). Putatively, a reduction of gas
exchange area because of vascular remodelling may necessitate an
increase in pulmonary artery pressure to maintain pulmonary blood
flow. Arterial stiffening due to remodelling contributes significantly
to increased afterload and is an important index of disease progres-
sion. The role of proximal conduit arteries such as main or branch
pulmonary arteries is to dampen the pressure oscillations originat-
ing from right ventricular ejection force. On vascular ultrasound,
increased thickness, and reduced pulsatility and distensibility may
indicate impaired ability to dampen these waveforms. At the organ
level, this exposes the pulmonary resistance vessels to higher pul-
satile stress, thereby accelerating microvascular disease [54]. Over
a period, this may cause decreased pulmonary compliance and pul-
monary oedema. The resultant increased requirements for ventila-
tor support and baro/volutrauma contribute to a higher incidence
of BPD amongst preterm FGR infants.
Arterial stiffening in preterm FGR cohorts
Recent studies using high-definition vascular ultrasound in human
newborns have evaluated dynamic pulmonary vascular properties in
infants with FGR, as influences on perinatal transition. In a prospective
echocardiographic study, the evolution of cardiac function and pul-
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Paediatric Respiratory Reviews 44 (2022) 19–30
monary dynamics in response to minimally invasive surfactant ther-
apy (administered via a catheter followed by continuous positive
airway pressure) was compared between FGR and AGA infants [55].
In this study on preterm infants (mean GA 28 weeks in either group),
the baseline assessments at median age of 3 h noted higher PVR and
lower right ventricular contractility in FGR infants, compared to
AGA infants. The evolution of flow dynamics after surfactant noted a
significantly lesser reduction in PVR in the FGR cohort, indicating that
FGR infants adapt differently in early postnatal life. Potentially, the
altered pulmonary vascular mechanics reflect maladaptive changes
in response to UPI. A recent prospective study evaluated right pul-
monary artery in 40 preterm infants (mean GA 30 weeks in either
group) using colour flow tissue Doppler imaging, comparing infants
with FGR with GA, gender and age matched AGA infants [13]. Vascular
assessments performed in the second week of life noted significantly
greater pulmonary artery wall thickness and reduced pulsatility in
infants with FGR, compared to AGA infants (Figs. 4 and 5). FGR infants
also had a persistently higher PVR. This high pulsatile stress is trans-
mitted to pulmonary arterioles. As postulated earlier, this may lead
to microvascular leakage and decreased lung compliance. As evidence
of ventriculo-arterial coupling in these preterm infants, right ventric-
ular systolic function was also impaired in FGR infants [13]. This is not
surprising as the cardiac inflow tract, pulmonary vascular smooth
muscle, and proximal vascular endothelium all arise from a common
in-utero multipotent cardiopulmonary mesoderm progenitor. Essen-
tially, insults to the developing pulmonary vasculature could also
affect the right ventricle directly or via back pressure changes [56].
Antenatal hypoxia in particular, results in a cascade of maladaptive
consequences, including altered pulmonary vasoreactivity and pul-
monary artery muscularization [57]. Plausibly, involvement of the
pulmonary vasculature is contributory towards a higher incidence
of BPD in preterm FGR infants.
Arterial stiffening in non-FGR severe BPD cohorts: pulmonary
circulation and right heart
Using Synchrotron micro-CT imaging in a murine model of BPD
and BPD-PH, we recently demonstrated that in addition to
A. Sehgal, T. Dassios, M.F. Nold et al. Paediatric Respiratory Reviews 44 (2022) 19–30

Fig. 4. Pulmonary artery imaging using 2-dimensional and colour Doppler. A, 2-D image from modified short axis view showing the right pulmonary artery. B, colour Doppler
showing the right pulmonary artery. C, m-mode tissue Doppler of right pulmonary artery (from, Sehgal A, Gwini SM, Menahem S, Allison BJ, Miller S, Polglase GR. Preterm
growth restriction and bronchopulmonary dysplasia: the vascular hypothesis and related physiology. J Physiol. 2019).

Fig. 5. Right pulmonary artery. Scatterplot illustrating thickness of the right pulmonary artery. (from, Sehgal A, Gwini SM, Menahem S, Allison BJ, Miller S, Polglase GR.
Preterm growth restriction and bronchopulmonary dysplasia: the vascular hypothesis and related physiology. J Physiol. 2019).

dramatic rarefaction of pulmonary blood vessels of a small diame-
ter (4–7 lm) the percentage of larger vessels (40–60 lm) was up to
9-fold increased in mice with BPD-PH [58]) (Fig. 6. Whilst this
observation is yet to be explored in the FGR setting, this disease-
related abnormality may contribute to the dynamic components
of changes in the pulmonary circulation, which reflect as raised
PVR. Reduced pulmonary vasculature density, abnormal vascula-
ture architecture and vasoreactivity in infants with BPD set the
tone for the development of higher PVR, and eventually, PH and
right ventricular dysfunction. In a prospective echocardiographic
study on preterm infants with severe BPD compared with those
with no BPD (comparable GA at birth; 26 weeks), infants with
BPD had higher PVR and significantly lower right ventricular sys-
tolic and diastolic function on tissue Doppler imaging [59].

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A. Sehgal, T. Dassios, M.F. Nold et al. Paediatric Respiratory Reviews 44 (2022) 19–30

Fig. 6. Representative reconstructed synchrotron micro-CT image of pulmonary vascular injury in a neonatal murine model bronchopulmonary dysplasia-pulmonary
hypertension. Filament filling is colour coded for diameter size highlighting the rarefaction of small pulmonary vessels and increase in the larger vessels (40–60 lm) in 28 day
old pups housed in either air (A) or hyperoxia (B) (from, Bui CB, Kolodziej M, Lamanna E, Elgass K, Sehgal A, Rudloff I, Schwenke DO, Tsuchimochi H, Kroon MAGM, Cho SX,
Maksimenko A, Cholewa M, Berger PJ, Young MJ, Bourke JE, Pearson JT, Nold MF, Nold-Petry CA. Interleukin-1 Receptor Antagonist Protects Newborn Mice Against Pulmonary
Hypertension. Front Immunol. 2019).

Systemic circulation and left heart
Systemic arteries (carotid/aorta) are similarly affected in FGR
cohorts in the initial weeks of postnatal life [60–63]. In a prospec-
tive echocardiographic study on preterm FGR infants, compared to
AGA infants (GA 30 weeks in either group), aorta intima–media
thickness, wall stiffness and peripheral resistance were noted to
be significantly greater in FGR infants [60]. Similar to the right
heart involvement, left ventricular systolic function was impaired
with significant correlations between vascular mechanics and car-
diac function. There is evidence of similar involvement of the sys-
temic vasculature in preterm infants with severe BPD. A
prospective vascular ultrasound study evaluated aortic dynamic
properties in preterm AGA infants with severe BPD and equally
preterm infants with no BPD (GA 26 weeks in either group) [64].
Both, input impedance and stiffness index were significantly
higher in infants with BPD. The significance persisted after adjust-
ing for GA and BW separately, and GA-BW combined. From the
clinical perspective, both populations have noted higher blood
pressure (BP) recordings [60,65]. In a prospective study on FGR
and AGA infants (mean GA 30 weeks in both cohorts), significantly
higher systolic BP was noted at assessments done in the second
week of life [60]. Data on infants with BPD is limited but has noted
similarly results [65]. Fifty-seven infants with severe BPD were
compared with 114 GA matched infants with no BPD. The inci-
dence of hypertension (systolic BP  95th centile) was higher in
the BPD cohort vs no BPD cohort (40.3 % vs 2.6 %, p < 0.001). Higher
BP was associated with significantly longer duration of respiratory
support.
In essence, vascular properties in the two cohorts (FGR and
BPD) are quite similar, with demonstration of thickening and stiff-
ness. The overlapping vascular pathophysiology indicates a semi-
nal role for arterial remodelling and functional impairments in
disease pathogenesis, making the mechanisms, attractive targets
for pharmacological interventions.
SECTION D. MECHANISTIC LINKS AND THE THERAPEUTIC
RELEVANCE OF OVERLAPPING VASCULAR PATHOPHYSIOLOGY.
Table 2 depicts overlapping mechanistic links between FGR and
BPD; many of them could be potential therapeutic targets. Investi-

Table 2
Vascular mechanistic links between FGR & BPD.

Maternal vascular under-perfusion on placental histopathology

Chronic hypoxemia induced SMc proliferation and fibroblasts in the adventitia ? muscularization of precapillary ‘resistance vessels’

Low VEGFA and VEGFR2 in PAECs (indicating ; alveolar and vascular growth)

Thickened distal air space walls, ; pulmonary vascular growth ? ; pulmonary compliance and diffusing capacity

; elastin expression and elastin fibre deposition in the thickened ECM and blood gas barrier (replaced with collagen which is 100  stiffer)

; angiogenic signalling through direct inhibition of VEGF activity at birth ? ; lung eNOS protein content

Pulmonary artery endothelial injury/dysfunction? ; production of nitric oxide

Alterations in arterial extracellular matrix (; arterial elastin, " expression of metalloproteases, SMc proliferation) ? Thicker, stiffer arteries with narrow lumen ?
‘Adaptive dysmorphic pattern of vascular organization’

Paucity of capillaries within the walls of the thinned abnormally enlarged alveoli

Deficient endothelial progenitor cells in cord blood of infants who subsequently develop moderate or severe BPD; ; in cord blood of mothers with pre-eclampsia-
FGR

Oxidative damage by reactive oxygen species

FGR-Fetal growth restriction, BPD-Bronchopulmonary dysplasia, SMc-Smooth muscle cell, ECM-Extracellular matrix, eNOS-Endothelial nitric oxide synthase, VEGFA- Vas-
cular endothelial growth factor A, VEGFR2- Vascular endothelial growth factor receptor, PAEC-Pulmonary artery endothelial cell.

25
A. Sehgal, T. Dassios, M.F. Nold et al.
gator interest in vasculature as a focus of therapeutics in the
human FGR cohorts has centred primarily on vasodilators and
vasomodulators. Fig. 7 summarizes various therapeutic
interventions.
Pulmonary circulation/right heart focussed interventions
Vasodilator
Phosphodiesterase-5 is produced in the lungs and breaks down
cyclic guanosine monophosphate. Sildenafil decreases the activity
of Phosphodiesterase-5, thereby increasing the levels of cyclic gua-
nosine monophosphate, which decreases pulmonary pressures by
causing vasodilatation and relaxation. Nitric oxide, released from
fetal trophoblasts, is a potent vasodilator by way of increasing cyc-
lic adenosine monophosphate. However, decreased release is seen
in pregnancies complicated by pre-eclampsia or FGR, which
explains the rationale to use sildenafil as a therapeutic option
[66]. However, a systematic review combining in-vitro studies,
experimental animal studies and human studies on women with
fertility disorders was inconclusive [67]. A recent randomized con-
trolled trial investigating the effect of sildenafil (75 mg/day) com-
pared with placebo in pregnancies with severe FGR showed no
differences on the main outcome of prolongation of pregnancy. A
non-significant 2.3 % increase in BW was noted [68]. However, clin-
ical efficacy of the drug’s primary vasodilatory effect in these situ-
ations has not been systematically evaluated. Trapani et al. further
tested this hypothesis in a trial of 100 women with early-onset
pre-eclampsia who were randomised to 50 mg sildenafil or pla-
cebo, thrice daily. This study demonstrated lower mean BP and
improved utero-placental resistance, although no corresponding
improvement in neonatal outcomes [69].
Fig. 7. Summary of various therapeutic interventions.
26
Paediatric Respiratory Reviews 44 (2022) 19–30
Sildenafil has been used for management of BPD associated PH,
the incidence of which ranges from 17 to 40 % [70–72]). In addition
to its physiological effects detailed above, sildenafil also preserves
lung angiogenesis, and decreases PVR and media wall thickness
[73]. Its property of reducing pulmonary inflammatory response
and fibrin deposition makes it a physiologically very suited to
BPD disease physiology management [74]. Echocardiographic and
clinical efficacy of sildenafil was evaluated in 22 infants (mean
GA 25 weeks) with BPD associated PH. Significant improvement
in echocardiographic parameters of pH were noted, alongside
reduction in respiratory support requirements [72]. Mourani
et al. described 25 subjects (median GA at birth: 28 weeks) with
BPD who were administered with sildenafil at the age of <2 years
[75]. Only approximately half (13 [52 %]) the patients had paired
echocardiographic data which showed significant reduction in pul-
monary pressures. A recent systematic review and meta-analysis
evaluated the effectiveness of chronic use of sildenafil in preterm
infants with BPD-associated PH. Five studies were included, yield-
ing a total of 101 patients, with a pooled mean GA of 26 weeks. Pul-
monary arterial pressure improved by >20 % in majority of cases
within 1–6 months [76]. While physiologically appropriate in both
settings (FGR and BPD), greater refinement of this promising ther-
apeutic intervention is warranted to optimise gestation and dose at
administration, as well as outcomes to be studied.
Other therapies
Antioxidant therapy with Vitamin C and E improves endothelial
function and flow-mediated vasodilatation, and attenuates hypoxic
PH, suggesting a reversible component in dysregulation [77]. Mela-
tonin is a neurohormone with antioxidant and vasodilator proper-
ties which are active at the pulmonary level. Recent data noted that
A. Sehgal, T. Dassios, M.F. Nold et al.
daily administration of melatonin mitigated PH and vascular
remodelling in chronically hypoxic rats. Melatonin treatment also
significantly attenuated right ventricular systolic pressures, thick-
ness of the arteriolar wall, and oxidative and inflammatory mark-
ers in the hypoxic animals [78]. Gonzaléz-Candia recently noted
that postnatal treatment with melatonin during the neonatal per-
iod in lambs with chronic hypoxia decreased pulmonary oxidative
stress by inducing antioxidant enzymes and improved pulmonary
vascular reactivity [79]. In essence, melatonin seems a promising
drug which may stop, or possibly reverse these vascular effects,
and needs further exploration in human studies. Furthermore,
inflammation, and specifically the potent inflammatory cytokine
IL-1, is now recognised as a key pathogenic culprit in BPD and
BPD-PH. Interleukin-1 receptor antagonist (IL-1Ra) is a natural pro-
tein that blocks IL-1, and has been safely used as a drug (Anakinra)
to treat many other diseases. Preclinical studies by us and others
have shown that blocking inflammation, specifically the potent
pro-inflammatory IL-1 with Anakinra, early and effectively, holds
great promise for preventing BPD, BPD-PH and also improving neu-
rodevelopmental outcomes [80–83]. Anakinra is currently being
investigated for safety and feasibility in a Phase I/IIa dose escala-
tion trial. Importantly, there is a growing body of preclinical evi-
dence highlighting the role of IL-1 driven inflammation in
placental insufficiency and FGR. Interleukin-1b is elevated in the
serum from women with FGR during the third trimester of preg-
nancy [84]. Placental levels of IL-1Ra were found to negatively cor-
relate with BW and GA in high risk pregnancies [85].
Systemic circulation/left heart focussed interventions
Vasomodulator
Angiotensin converting enzyme (ACE) inhibitors have pharma-
cological properties beyond being effective anti-hypertensive
agents. By way of improving endothelial function, bradykinin
mediated vasodilatation, endothelial nitric oxide release, and
change in extracellular matrix, they are physiologically very suited
to the proposed FGR-BPD pathophysiology of heightened renin-
angiotensin-aldosterone system activity. The inhibition of renin-
angiotensin-aldosterone system by angiotensin receptor blockers
and ACE inhibitors could modify the inflammatory response in
the arterial wall [86–87].
Recent data has postulated the effect of systemic hypertension
and left heart ventricular dysfunction in BPD pathophysiology
[88–89]. Termed as ‘post-capillary pathophysiology, enough left
ventricular afterload may be generated, leading to back-pressure
cascade, raised end-diastolic left atrial pressure, increased pul-
monary venous pressure leading and pulmonary edema. Address-
ing this mechanism, we administered captopril (ACE inhibition)
to extremely preterm infants with ‘severe’ BPD (GA and weight
at birth, 23–29 weeks and 505–814 g, respectively) [90]. All infants
required mechanical ventilation and had no improvement with
postnatal steroids, sildenafil and diuretics. Captopril was adminis-
tered for systemic hypertension and left heart dysfunction. After a
five-week interval (required to reach steady-state), a significant
reduction in oxygen requirements was noted. This prospective
study of AGA infants also demonstrated a reduction in aorta
intima-media thickness, and improved cardiac function and arte-
rial pulsatility [90]. Interestingly, histopathology review of autop-
sies with diagnosis of BPD over a 10-year period noted that
capillary ACE endothelial staining is largely absent in BPD lungs
[91]. This suggests that the improvements in respiratory support
requirements and cardiovascular parameters (especially PVR) in
our study were primarily mediated via the systemic (rather than
direct pulmonary) effects of ACE inhibition. This data warrants fur-
ther exploration of ACE inhibition in selected cohorts as similar
27
Paediatric Respiratory Reviews 44 (2022) 19–30
thickening and reduced pulsatility of pulmonary and systemic
arteries has been seen in FGR infants [13].
Although the physiological role of ACE inhibition in human FGR
cohorts has not yet been explored, recent work in sheep has
demonstrated proof of concept. This explains the physiological
rationale that ACE inhibition may mitigate hyperfiltration. A sheep
model of a single functioning kidney was administered enalapril
for a period of 5 weeks [92], and compared to a control group.
ACE inhibition prevented albuminuria, resulted in approximately
22 % higher renal blood flow and approximately 35 % lower filtra-
tion fraction compared with vehicle-treated sheep. A greater
recruitment of renal function reserve indicated a reduction in
glomerular hyper-filtration–mediated kidney dysfunction.
Increased urinary nitrite in ACE treated animals indicated elevated
nitric oxide bioavailability, which likely contributed to improve-
ments in kidney function and prevention of albuminuria. In
humans, nephrogenesis is complete before birth, and perinatal pro-
gramming influences reduction of nephron number and increased
renal apoptosis [93]. A poorer renal endowment, accompanied by
systemic arterial thickness in FGR could explain ongoing microal-
buminuria by way of glomerular hyper-filtration [94]. In essence,
ACE aimed at vascular stiffness has therapeutic benefits in FGR
pathology as well. The above preliminary animal and human data
indicates the seminal role of arterial stiffness (and directed thera-
peutic potential) in disease physiology.
In summary, a range of therapeutic options are currently under
investigation. Efficacy of these interventions has the potential to
significantly change the neonatal disease paradigm.
SECTION E: PERINATAL VASCULAR INSULTS AND
PREDISPOSITION TO PEDIATRIC LUNG DISEASES
Earlier in the review we elaborated the range of pulmonary vas-
cular architectural and functional impairments in preterm FGR
infants in response to perinatal insults. However, a significant com-
ponent of pulmonary vascular development occurs after birth,
making postnatal insults during infancy and childhood, important
contributors to abnormal lung development.
Long-term lung development: effects of prenatal factors and
accompanying hypoxia
In a retrospective cohort study of 247 mother-neonatal pairs,
pre-eclampsia was associated with BPD, in part mediated by FGR
[95]. Abnormal vascular endothelial growth factor signalling might
play a critical role as it has been described in the pathogenesis of
pre-eclampsia [96] and in the ‘vascular hypothesis’ of BPD [12–
13,97]. Third trimester fetal blood flow patterns might inform
childhood respiratory health. In a population based prospective
study of 903 children in whom Doppler measurements had been
made at a median GA of 30.3 weeks, persistently higher PVR and
a higher risk of late/persistent wheezing was noted at six years
of age [98]. Fetal inflammation is also implicated in FGR, while
hypoxia itself may give rise to inflammation. In one study, 36
women with FGR fetuses had higher peripheral blood lymphocyte
levels of pro-inflammatory cytokines Interleukin-6, Tumour necro-
sis Factor-a, and Interleukin-12 compared to 22 normal AGA preg-
nancies [99]. Arguably, management of fetal inflammation has the
potential to improve metabolic dysfunction and potentially, lung
developmental impairment.
Maternal smoking during pregnancy is also associated with
FGR; impact on growth trajectories persisting up to six months
after birth [100]. In a study evaluating 90 FGR and 180 AGA sub-
jects, maternal smoking exposure was independently associated
with asymmetric FGR, possibly indicating deleterious effects on
A. Sehgal, T. Dassios, M.F. Nold et al.
placental health [101]. Data from epidemiological and experimen-
tal studies indicates the disruptive effects of intra-uterine toxin
exposure (including tobacco smoke) on pulmonary development
[102–103]. Gonzales-Luis and colleagues performed a systematic
review of studies reporting on tobacco smoking during pregnancy
being a potential risk factor for BPD [104]. A significant association
between tobacco smoking during pregnancy and BPD at 36 weeks
was noted (17 studies, RR 1.126, 95 % CI 1.008–1.259, p = 0.036).
Infants with severe BPD are known to have a high incidence of
PH (39 %) [4]. It is possible that maternal smoking during preg-
nancy might affect pulmonary development and predispose to a
higher incidence of persistent PH. Nicotinic acetylcholine receptors
on cells of the pulmonary vessel walls possibly mediate morpho-
logical alterations in fetal pulmonary vasculature. Experimental
studies in timed pregnant rhesus monkeys treated with nicotine
noted significantly greater thickness of the total wall and tunica
adventitia in airway associated vessels [105]. Nicotine exposure
also increased collagen deposition (100 stiffer than elastin) and
contrastingly, lower levels of elastin. Putatively, smoking during
pregnancy may lead to nicotine being transported across the pla-
centa and directly interacting with nicotinic receptors in pul-
monary vessels and cause vascular structural alterations. Such
experimental data strongly points towards a causal linkage [105].
In summary, infants born FGR already have poor lung reserve
due to lung parenchymal and vascular alterations. Interactions
with antenatal smoking further exacerbated by postnatal expo-
sures, may adversely affect long-term respiratory trajectory.
Long term effects-population data
The above postulations are corroborated by population based
studies. In a twin study examining >500 children, the forced expi-
ratory volume in the first second (FEV1) results post-
bronchodilator therapy were significantly negatively associated
with fetal growth [106]. Approximately 40 % of this cohort was
preterm born; associations for FEV1 and forced vital capacity with
GA were non-significant. However, there was significant associa-
tion between restricted fetal growth and post-bronchodilator
FEV1 and forced vital capacity. In a population based prospective
cohort study of approximately 5000 children in The Netherlands,
school age children who had higher airway resistance had lower
fetal growth and weight gain, and were more likely to have physi-
cian diagnosed asthma [107]). Approximately 5 % of this cohort
was born preterm. Information from studies assessing older
cohorts is consistent with the above findings. Ronkainen and co-
workers studied 88 preterm-born children at a mean age of
11 years and reported that in preterm-born children exposed to
FGR, both FEV1 and diffusing capacity for carbon monoxide were
lower compared to preterm-born children with appropriate in-
utero growth after adjustment for a diagnosis of BPD [108]. In a
cross-sectional study of 74 adolescents who were premature
(<32 weeks GA) and had FGR, lower FEV1 (88.7 % versus 95.9 %)
and lower forced vital capacity (88.2 % versus 95.5 %) in compar-
ison to those well grown at birth was noted [109]. Other investiga-
tors however, have suggested that amongst children born very
preterm, and studied between 8 and 15 years of age, the impact
of FGR may be due to the higher risk of BPD in that group [110].
Harris et al. studied 159 subjects of 16–19 years of age born
<29 weeks of gestation, of whom 37 had FGR. Even at this later
age, the FGR cohort had poorer spirometric indices and exercise
capacity compared with those with adequate fetal growth [111].
In more recent data, the influence of FGR on lung function was
tested in children born very preterm. Twenty-eight preterm infants
born <32 weeks GA were cross-sectionally evaluated and com-
pared with 67 AGA infants at 8–15 years of age. Preterm-FGR chil-
28
Paediatric Respiratory Reviews 44 (2022) 19–30
dren had lower mean FEV1, and FGR state was negatively
associated with FEV1 (B = 0.66; P = 0.004) [112].
In essence, disrupted vascular development in FGR alters pul-
monary function and respiratory outlook trajectory, well into the
childhood. Secondary insults such as smoking and viral infections
can further impact pulmonary vascular endowment, and accentu-
ate early ageing.
CONCLUSIONS
From the cardiovascular perspective, multiple mechanistic links
between FGR and systemic hypertension have been explored.
Increasingly, a longitudinal and close association of lung health
with cardiovascular health in individuals born FGR is being consid-
ered biologically plausible. Epidemiological and pathological link-
ages underscore the biological plausibility of vascular links
between FGR state and BPD. The adverse respiratory outlook attri-
butable to FGR and its independence from degree of prematurity
(and linear trajectory with FGR severity), points towards possible
overlapping pathophysiology between FGR and BPD. Studies
depicting longitudinal and cross-sectional data provide distinctive
evidence for the notion that cardiac/ vascular function and respira-
tory function in these high-risk cohorts may be interlinked, and
affected well into adulthood. Understanding the pathways, and
the consequent therapeutic pointers, can significantly improve
the clinical outlook of this cohort.
DIRECTIONS FOR FUTURE RESEARCH
From the clinical perspective, further longitudinal data from
neonatal networks are better placed in delineating the true impact
of FGR. From an investigation point of view, arterial thickness is
being used in adults as an end-point in clinical trials assessing
the impact of antihypertensive medications on cardiovascular risk
[113–114]. Whether similar end-points could be used for experi-
mental trials using ACE inhibition in human FGR, remains to be
tested. From the therapeutic perspective, choosing the appropriate
intervention and the timeline (in-utero: to prevent disease or after-
birth: to reduce disease severity) needs prospective analysis.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
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