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The association between patterns of early respiratory disease

and diastolic dysfunction in preterm infants
1,2 ✉
Koert de Waal , Edward Crendal1,3, Amy Chin-Yu Poon2, Mariyam Shaya Latheef2, Elias Sachawars4, Thomas MacDougall4 and
Nilkant Phad1,2

© Crown 2023

BACKGROUND: This study aims to determine the association between clinical patterns of early respiratory disease and diastolic
dysfunction in preterm infants.
METHODS: Preterm infants <29 weeks’ gestation underwent cardiac ultrasounds around day 7 and 14–21. Respiratory dysfunction
patterns were classified as stable (ST), respiratory deterioration (RD) or early persistent respiratory dysfunction (EPRD) according to
oxygen need. Diastolic dysfunction was diagnosed using a multi-parameter approach including left atrial strain (LASR) to help
differentiate between cardiac or pulmonary pathophysiology.
RESULTS: 98 infants (mean 27 weeks) were included. The prevalence of ST, RD and EPRD was 53%, 21% and 26% respectively.
Diastolic dysfunction was more prevalent in the RD and EPRD groups with patent ductus arteriosus and significant growth
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restriction as risk factors. Not all infants with a PDA developed diastolic dysfunction. LASR was lower in the EPDR group.
CONCLUSION: Respiratory dysfunction patterns are associated with diastolic dysfunction in preterm infants.
Journal of Perinatology; https://doi.org/10.1038/s41372-023-01608-5

BACKGROUND Heart failure is defined as an inability of the heart to pump

Most very preterm infants require respiratory support early after
birth and in the first few postnatal weeks [1]. Three distinct
patterns of oxygen requirement and need of respiratory support
have been described in this age group [2]. Infants considered
stable (ST) require little respiratory support and stabilize quickly,
and remain in low fraction of inspired oxygen (FiO2) for weeks
until they come off respiratory support. Others have higher FiO2 at
birth and remain oxygen dependent for several weeks, referred to
as early and persistent respiratory dysfunction (EPRD). A third
group recover from their initial respiratory disease, only to
deteriorate in the second week of life, described as a group with
respiratory deterioration (RD). The RD or persistent dysfunction
has mostly been attributed to pulmonary parenchymal disease
with abnormal lung development due to preterm birth. However,
some preterm infants have been shown to have early respiratory
morbidity due to diastolic dysfunction from immature myocardial
development [3, 4].
Clinical trials have targeted very preterm infants with EPRD and
RD in the second or third week of life with systemic steroids
targeting lung inflammation to prevent further lung disease [5–7].
The results of these trials have only been moderately successful
(dexamethasone) or unsuccessful (hydrocortisone), suggesting
that some of the infants with EPRD or RD might have an
alternative diagnosis. Other pathophysiology that can lead to
greater respiratory support requirements in preterm infants in this
particular timeframe includes the patent ductus arteriosus (PDA),
late onset sepsis and diastolic heart failure (DHF).
blood to the body at a rate matching its needs, or to do so only at
the cost of high ventricular filling pressures [8]. When heart failure
presents with normal systolic function, it is classified as DHF. In
adults, DHF is characterized by a stiff left ventricle (LV) with
decreased compliance and impaired relaxation, which leads to
increased end diastolic pressure [9, 10]. Signs and symptoms of
DHF are similar to those of heart failure with systolic dysfunction
and are created by manifestation of pulmonary edema (RD,
exercise intolerance) or systemic oedema. The diagnosis of DHF is
supported by identifying diastolic dysfunction with Doppler
echocardiography and excluding non-cardiac causes of these
signs and symptoms [11].
Up to 1 in 5 very preterm infants develop diastolic dysfunction on
cardiac ultrasound in the first weeks after birth [12]. About 10% of
those infants continue to develop clinical signs and symptoms that
would support the diagnosis of DHF (e.g., RD, systemic oedema), but
the clinical signs and symptoms overlap with what we know
clinically as RD or EPRD. It is possible that cardiac pathophysiology
plays an important role in the development of clinical respiratory
dysfunction. The aim of this study is to determine the association
between patterns of early respiratory disease and diastolic
dysfunction on cardiac ultrasound in very preterm infants.
METHODS
Patients
This single centre prospective observational study approached all preterm
infants <29 weeks’ gestation. Exclusion criteria were significant cardiac or

1
John Hunter Children’s Hospital, department of neonatology, Newcastle, NSW, Australia. 2University of Newcastle, Newcastle, NSW, Australia. 3John Hunter Hospital, department
of cardiology, Newcastle, NSW, Australia. 4John Hunter Hospital, department of radiology, Newcastle, NSW, Australia. ✉email: koert.dewaal@hnehealth.nsw.gov.au

Received: 6 October 2022 Revised: 4 January 2023 Accepted: 11 January 2023

 K. de Waal et al.
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other congenital abnormalities and death before 21 days of life. Infants
with a small muscular VSD or small ASD could be included. During the
study period local guidelines suggested early surfactant and nasal
continuous positive airway pressure via a bubble system as main
respiratory support strategy. Management of the PDA was directed by
cardiac ultrasound, usually organized in the first week of life. Ethical
approval for this study was obtained from the Hunter New England human
research ethics committee. After informed consent, all infants received a
cardiac ultrasound as close as possible to day 7 after birth, and again
between day 14 and 21 after birth. Additional cardiac ultrasounds could be
performed at clinicians’ discretion.
Clinical definitions
Respiratory patterns were determined according to Laughon et al [2].
Infants were categorized as ST when they received FiO2 < 0.23 between
days 3 and 7 and FiO2 < 0.25 at day 14–21, as RD when FiO2 < 0.23
between days 3 and 7 and FiO2 ≥ 0.25 at day 14–21, and as early persistent
respiratory dysfunction (EPRD) when FiO2 ≥ 0.23 between days 3 and 7,
and FiO2 ≥ 0.25 at day 14–21. Respiratory support settings, and blood gas
values closest to the cardiac ultrasounds were collected from the patient
notes. Where available, chest X-rays were analyzed by two blinded
radiologist using pattern recognition on an arbitrary 3 point Likert scale as
more likely diffuse or focal neonatal pulmonary disorders, can’t
differentiate, or more likely vascular congestion [13].
Weight Z-scores were determined using the Fenton growth charts [14].
Significant growth restriction was defined as a birth weight below the 10th
percentile or Z-score < 1.30. Late onset sepsis was defined as a clinical
deterioration with a positive blood culture.
Echocardiography
Echocardiography examinations were performed using a GE E90 system
v202 (GE ultrasound, Illinois, USA) with 12 MHz probe. Image acquisition
was triggered to the R wave and followed the recommendations of the
American Society of Echocardiography [15]. Analyses were performed
offline using Tomtec Arena version 4.6 and 2D Cardiac performance
analysis build 1.4.0.44 (Tomtec, Unterschleissheim, Germany). The PDA was
assessed from the high parasternal view and the diameter was taken in 2D
at end systole. Ejection fraction was determined from the apical 4 chamber
view using monoplane method of disk [16].
Ultrasound parameters of diastolic function
We used a combination of pulse wave Doppler, Tissue Doppler, volumetric
changes and speckle tracking imaging to assess diastolic function. Left
atrial volume (LAvol) was determined by method of disks from the apical 4
chamber images by tracing the left atrium (LA) at maximum size, omitting
the pulmonary vein confluence and the LA appendage [17]. The EA ratio
was calculated from the respective early and late diastolic peak velocities
from pulsed wave Doppler. The e’ velocity was determined at the septal
annulus with tissue Doppler imaging. The Ee’ ratio was calculated from the
E wave velocity divided by the e’ velocity.
Peak atrial longitudinal strain was used to help differentiate between
diastolic dysfunction of cardiac origin and pulmonary venous hyperten-
sion as isolated feature. In isolated pulmonary venous hypertension, one
would expect left atrial pressures and function to be normal. Progressive
diastolic dysfunction of cardiac origin would increase pressure in all
pulmonary vessels (venous, capillary, and arterial). Peak left atrial
longitudinal strain was determined at QRS using speckle tracking
analysis [18].
Pulmonary hypertension can be the end-result of progressive diastolic
dysfunction of cardiac origin, and was assessed by exploring tricuspid
regurgitation, moderate to severe septal flattening in systole, or any
bidirectional or right-to-left shunt, and recorded as present or not [19].
Definition of diastolic dysfunction
Diastolic dysfunction was assessed using a multi-parametric approach
which included 6 parameters and diagnosed as present when 3 or more
parameters were outside the normal range for age. Based on previous
work in preterm infants at comparable gestational and postnatal age we
set the cut-points at LAvol > 1.50 ml/kg, EA ratio > 0.90, e’ velocity < 2.7, Ee’
ratio > 18, the presence of pulmonary hypertension, and peak left atrial
strain <25% [12, 17].
Statistical analysis
Parameters were expressed as mean and standard deviation or median
and interquartile range where appropriate. Simple group analyses were
conducted using an independent t-test and ANOVA. Categorical variables
were expressed as counts (percent) and analyzed using the Chi squared or
Fisher’s exact test.
This is an exploratory pilot study with primary outcomes respiratory
disease patterns and diastolic dysfunction. An exact sample size could not
be calculated due to limited published data on diastolic dysfunction in
preterm infants. Assuming that the respiratory patterns are equally divided
and 20% develops diastolic dysfunction, a sample of ~100 infants will be
required. Known co-variates for respiratory dysfunction and/or diastolic
dysfunction include a persistent PDA, mechanical ventilation, late onset
sepsis and significant growth restriction [3, 12, 20, 21]. Depending on their
prevalence in the studied cohort, actual required sample could vary.
Analyses were performed on GraphPad version 6 (Prism, LaJolla, CA, USA)
and SPSS version 21 (IBM, Armonk, NY, USA), and p values < 0.05 were
considered statistically significant.
RESULTS
From June 2020 to June 2022, 124 preterm infants <29 weeks
gestation were admitted in the John Hunter Children’s Hospital
neonatal intensive care. Four infants died before 21 days of life, 1
infant was transferred out, 1 infant had significant cardiac
abnormalities (large VSD), in 18 cases the investigators were not
available and in 2 cases no consent was obtained, leaving 98
infants for analysis. The mean gestational age and birth weight of
the cohort was 27.1 (1.4) weeks and 953 (230) grams respectively.
The respiratory patterns and categories are presented in Table 1.
The rate of ST, RD and EPRD was 53%, 21% and 26% respectively.
Infants with RD or EPRD were generally of lower gestational age
and birth weight, and EPRD infants had a lower weight Z-score at
birth (p < 0.05) and were more likely to be male. Diastolic
dysfunction was significantly more prevalent in both the RD and
EPRD groups. The odds ratio of developing diastolic dysfunction
(when compared to the ST group) was 2.2 (95%CI 0.5–9.2) and 3.0
(95%CI 0.8–10.9) on the first scan, and 25 (95%CI 3–225) and 34
(95%CI 4–287) on the second scan for infants with RD and EPRD
respectively.
The first cardiac ultrasound scan was performed at a median of
7 (5–8) days after birth, and the second scan at 18 (15–20) days.
Figure 1 shows the prevalence of diastolic dysfunction in relation
to respiratory patterns, and Fig. 2 shows its progression over time.
Fifteen infants, all with a PDA, had diastolic dysfunction on the first
scan. Nine of these improved over time, 5 with concurrent PDA
closure. In 12 infants diastolic dysfunction newly appeared at the
second cardiac scan, 5 of those had a persistent PDA.
Table 2 shows hemodynamic and cardiac ultrasound para-
meters for each respiratory group at the second scan. When
compared to the ST group, infants with RD and EPRD had lower
blood pressure and lower early diastolic e’ velocities at the first
scan, but not at the second scan. LAvol and Ee’ ratio was higher at
both cardiac scans, with lower atrial strain in the EPRD group only.
The prevalence of pulmonary hypertension at the second scan
was significantly higher in the RD group (19%) and EPRD group
(24%) when compared to the ST group (2%).
There were no significant differences at the first or second
cardiac scan in sodium, lactate, pH, pCO2 and base excess
between the groups. Hemoglobin was significantly lower in the
RD and EPRD groups at first scan (126(19) and 132(30) versus
147(22) gr/L, p < 0.01) and at the second scan (98(17) and 101(16)
versus 115(18) gr/L, p < 0.01).
Eight infants in the ST group (including the one infant with
diastolic dysfunction) received a chest X-ray which were all scored
as more likely to represent a pulmonary disorder. A total of 73
chest X-rays were taken in the RD and EPRD groups, with only 2
classified as more likely vascular congestion.
Journal of Perinatology
 K. de Waal et al.
3
Table 1. Patient demographics per clinical respiratory course.
Stable Respiratory deterioration Early persistent respiratory p value
dysfunction
n 52 (53) 21 (21) 25 (26)
Antenatal
Pregnancy induced hypertension 14 (27) 3 (14) 9 (36) 0.250
Fetal growth restriction (Z-score < −1.00) 7 (13) 4 (19) 8 (32) 0.156
Gestational diabetes 4 (8) 3 (14) 2 (8) 0.658
Prolonged rupture of membranes 9 (17) 8 (38) 5 (20) 0.147
Antenatal steroids 51 (98) 19 (91) 24 (96) 0.332
Neonatal
Birth asphyxia (APGAR < 5 at 5 min) 3 (6) 1 (5) 4 (16) 0.250
Male 26 (50) 10 (48) 19 (76) 0.067
Gestational age 28.0 (0.8) 26.1 (1.4) 26.2 (1.4) <0.001
Birth weight 1080 (194) 835 (204) 788 (157) <0.001
Weight Z-score −0.14 (0.71) −0.12 (0.83) −0.58 (0.79) 0.017
Small for gestational age (<10th 2 (4) 1 (5) 3 (12) 0.361
percentile)
Mechanical ventilation >10 days 0 (0) 4 (19) 9 (36) <0.001
Patent ductus arteriosus >10 days 5 (10) 8 (38) 13 (52) <0.001
Late onset sepsis 2 (4) 4 (19) 3 (12) 0.107
Diastolic dysfunction on 1st scan 5 (10) 4 (19) 6 (24) 0.225
Diastolic dysfunction on 2nd scan 1 (2) 7 (33) 10 (40) <0.001
Data presented as n(%) or mean(SD).

The association between patterns of respiratory disease,

diastolic dysfunction and the prevalence of other pathology is
presented in supplementary table 1. The prevalence of PDA > 10
days, mechanical ventilation >10 days, significant growth restric-
tion and late onset sepsis was 26%, 13%, 6% and 9% respectively.
Diastolic dysfunction in the ST and RD groups was predominantly
related to a PDA, and in the EPRD group it was related to growth
restriction with or without a PDA. The prevalence of diastolic
dysfunction in infants with a persisted PDA > 10 days, mechanical
ventilation >10 days, significant growth restriction and late onset
sepsis was 46%, 53%, 66% and 33% respectively.
Figure 3 shows the relationship between the PDA diameter and
diastolic dysfunction. Infants with diastolic dysfunction had a
significantly larger PDA compared to infants without (2.32 versus
1.56 mm, p < 0.001). Not all infants with a large PDA diameter
developed diastolic dysfunction.
Fig. 1 Relationship between patterns of respiratory disease and
incidence of diastolic dysfunction on cardiac ultrasound.
DISCUSSION
This exploration study found a strong association between clinical
patterns of respiratory dysfunction and the prevalence of diastolic
dysfunction on cardiac ultrasound. We hypothesize that cardiac
pathophysiology plays an important role in the development of
clinical signs and symptoms in a subgroup of preterm infants. Our
data showed a strong association between clinical patterns of
respiratory dysfunction and the prevalence of diastolic dysfunc-
tion on cardiac ultrasound.
Diastolic function of the heart describes the filling of the
ventricles. When the mitral valve opens, blood enters the LV
through suction caused by elastic recoil of myocardial fibers re-
lengthening toward their resting length (restoring forces) and
thereby lowering LV cavity pressure. With further filling and
increase in LV cavity size, and the myocardial fibers expanding
beyond their resting length, stiffness of the myocardial tissues will
slow the rate of filling and increase LV cavity pressure. The final
Fig. 2 Prevalence of diastolic dysfunction and progression over time.
phase of diastolic function is created by atrial contraction,

Journal of Perinatology
 K. de Waal et al.
4
Table 2. Hemodynamic and cardiac ultrasound parameters.
First cardiac scan (day 7) Second cardiac scan (day 14–21)

ST RD EPRD ST RD EPRD
Heart rate (beats/min) 163 (11) 164 (11) 169 (12) 162 (8) 163 (7) 165 (10)
Systolic blood pressure (mmHg) 61 (7) 54 (5)# 53 (8)# 66 (8) 62 (9) 63 (11)
Diastolic blood pressure (mmHg) 36 (6) 29 (6)* 31 (6)* 38 (8) 35 (7) 38 (7)
Ejection fraction (%) 60 (8) 64 (8) 65 (7)* 53 (5) 58 (10) 57 (8)
# # #
Left atrial volume (ml/kg) 0.92 (0.36) 1.41 (0.52) 1.43 (0.70) 1.09 (0.20) 1.53 (0.67) 1.74 (1.22)#
EA ratio 0.75 (0.13) 0.81 (0.14) 0.76 (0.17) 0.82 (0.09) 0.85 (0.14) 0.81 (0.15)
e’ velocity (cm/s) 3.6 (0.6) 3.2 (0.5)* 3.1 (0.7)# 3.9 (0.4) 3.6 (0.7) 3.9 (1.4)
Ee’ ratio 12.7 (4.2) 17.2 (5.7)# 17.3 (8.4)# 14.8 (3.1) 18.2 (4.3)# 17.9 (6.2)#
Peak atrial strain (%) 32 (7) 30 (7) 29 (8) 32 (4) 29 (6) 27 (8)*
Data presented as mean(SD). t-test p value at <0.01 or <0.05 when compared to the ST group.
# *

ST stable group, RD respiratory deterioration group, EPRD early progressive respiratory dysfunction group.

associated clinical respiratory signs and symptoms in preterm

Fig. 3 Patent ductus arteriosus (PDA) diameter in relation to
diastolic dysfunction.
increasing the LA pressure above the LV pressure and establishing
the final LV end diastolic volume and pressure before the mitral
valve closes and contraction begins. Diastolic dysfunction is
characterized by an increased pressure at the end of diastole or
abnormal patterns or LV myocardial relaxation.
The preterm heart undergoes significant changes with the
transition from fetus to newborn, and is exposed to higher preload
and afterload than the fetus [22]. The intrinsic differences in
cardiac structure and function of the preterm heart when
compared to the term heart would make it prone to earlier
failure of available compensatory mechanisms. LV afterload might
be modulated by altering systemic vascular resistance and
lowering blood pressure. PDA closure can assist in reducing
preload, but this often does not occur after very preterm birth [23].
Atrial volume and pressure may increase progressively and atrial
dysfunction might appear with prolonged periods of increased
preload and afterload, often without LV systolic dysfunction
[17, 24].
Our current study supports the above-described mechanistic
pathways in the development of diastolic dysfunction and
infants. Blood pressure was lower in the infants with respiratory
signs and/or diastolic dysfunction. Atrial volume and the Ee’ ratio
was increased in infants with respiratory signs, both parameters
associated with raised atrial pressure, and atrial dysfunction was
found in the EPRD group where persistent high atrium volume
was common. Increased LA pressure can lead to pulmonary
venous congestion and a subsequent increase in right ventricle
afterload. To compensate the right ventricular driving pressure has
to increase, which can explain the higher rate of pulmonary
hypertension found in the RD and EPRD groups [4, 25]. Pulmonary
hypertension due to pulmonary vascular disease as seen in
abnormal preterm lung development would not necessarily
increase LA pressure, and thus ultrasound estimates of LA
pressure could be proposed to differentiate between a pulmonary
or cardiac origin of respiratory signs and symptoms. Chest x-ray
was unable to differentiate between respiratory and cardiac
diastolic pathophysiology.
The prevalence of diastolic dysfunction was high in infants with
respiratory signs and a persistent PDA for more than 10 days,
mechanical ventilation for more than 10 days, significant growth
restriction and late onset sepsis. The PDA is a hemodynamic
condition where high volumes of blood pass through an open
shunt into the left side of the heart, leading to progressive
morphological and functional changes in the LA and the LV [26].
Besides PDA closure, limited compensatory mechanisms are
available to the preterm heart to control the rising LA pressure
with a PDA. The foramen ovale is used to offload some of the
raised volume and pressure in the LA, but often fails to do so
completely [27]. This explains why the presence of a PDA has
strong associations with ultrasound parameters of diastolic
dysfunction [12, 28–30]. Somewhat unexpectedly, we found that
not all infants with a PDA developed diastolic dysfunction despite
estimates of high shunt volume. The PDA diameter was not a
good predictor of clinical respiratory dysfunction, and we would
recommend adding the presence of diastolic dysfunction to select
patients for treatment.
Mechanical ventilation and respiratory signs and symptoms are
inherently associated with each other, but the relationship
between mechanical ventilation and diastolic dysfunction is less
well understood. Cyclic changes in intrathoracic pressure can
theoretically enhance early diastolic recoil forces [31]. Some
studies in preterm infants did not find a relationship early after
birth, but Bussmann et al. showed that LV diastolic dysfunction
was independently associated with a higher risk of needing
mechanical ventilation [3, 32, 33]. Studies in adults have shown
that ultrasound parameters of early diastolic function (E wave, e’

Journal of Perinatology

velocity, Ee’ ratio) can predict difficulties with weaning off
mechanical ventilation [34]. This finding would suggest that
diastolic dysfunction drives the need for mechanical ventilation as
opposed to mechanical ventilation causing diastolic dysfunction.
Late onset sepsis was more common in infants who developed
respiratory dysfunction, but we were unable to establish a
significant association with concomitant diastolic dysfunction.
Late onset sepsis in preterm infants is usually linked with high
blood flows, and one would expect similar pathophysiology in
diastolic function as with a PDA [20, 35].
We found that a lower birth weight Z-score contributed to
persistent respiratory problems and diastolic dysfunction. Intrauter-
ine growth restriction is known for abnormalities in cardiac structure
and function that can persist into adulthood [36]. SGA hearts after
birth show signs of cardiac remodeling with hypertrophy and
dilatation. Altered function can be seen in ultrasound parameters
that are associated with myocardial relaxation (low e’ velocity,
prolonged relaxation time) or stiffness (shorter E wave deceleration)
[37–40]. Diastolic dysfunction in SGA infants appears to occur during
relative normal blood flow volumes. This might support the concept
that diastolic dysfunction has different phenotypes in preterm
infants, similar to what is found in adults [11]. In some infants
diastolic dysfunction is created by high volume throughput (PDA,
sepsis), and in others it might be primarily caused by abnormal
cardiac relaxation or increased myocardial stiffness (SGA).
There are several limitations to the findings of our pilot
exploration study. Based on the actual prevalence of some co-
variates in this cohort, we acknowledge that our sample is not large
enough to provide strong associations between all subgroups.
Disparity between patient populations, postnatal age, used ultra-
sound hardware and analysis software can lead to variation in
reference values used to establish diastolic dysfunction. We
recommend establishing local reference values to validate a multi-
parameter approach to diastolic dysfunction. There remains a
significant lack of normative data of ultrasound parameters of
diastolic function in preterm infants at various gestation and
postnatal age. Our data should not be used to infer judgment on the
relationship of diastolic function, treatments for it, and closure
effects in the setting of a PDA. This would require a prospective
study with selection of patients with truly pathologic shunts.
CONCLUSION
Our data showed a strong association between clinical patterns of
respiratory dysfunction and the prevalence of diastolic dysfunction
on cardiac ultrasound. A multi-parameter approach was able to
assess diastolic function and estimate LA pressure. Estimates of high
LA pressure could be used to differentiate between cardiac or
pulmonary pathophysiology of clinical respiratory signs. The findings
in this study can be used to establish the clinical diagnosis of DHF
and help select very preterm infants for future studies that target
possible treatments to the principal pathophysiology.
DATA AVAILABILITY
The datasets generated during and/or analyzed during the current study are not
publicly available due to patient confidentiality of individual cases, but are available
from the corresponding author on reasonable request.
REFERENCES
1. Thébaud B, Goss KN, Laughon M, Whitsett JA, Abman SH, Steinhorn RH, et al.
Bronchopulmonary dysplasia. Nat Rev Dis Prim. 2019;5:78.
2. Laughon M, Allred EN, Bose C, O’Shea TM, Van Marter LJ, Ehrenkranz RA, et al.
Patterns of respiratory disease during the first 2 postnatal weeks in extremely
premature infants. Pediatrics 2009;123:1124–31.
3. Bussmann N, Breatnach C, Levy PT, McCallion N, Franklin O, El-Khuffash A. Early
diastolic dysfunction and respiratory morbidity in premature infants: an obser-
vational study. J Perinatol. 2018;38:1205–11.
Journal of Perinatology
K. de Waal et al.
5
4. Bussmann N, El-Khuffash A, Breatnach CR, McCallion N, Franklin O, Singh GK, et al.
Left ventricular diastolic function influences right ventricular - Pulmonary vas-
cular coupling in premature infants. Early Hum Dev. 2019;128:35–40.
5. Doyle LW, Cheong JL, Hay S, Manley BJ, Halliday HL. Late (≥ 7 days) systemic
postnatal corticosteroids for prevention of bronchopulmonary dysplasia in pre-
term infants. Cochrane Database Syst Rev. 2021;11:Cd001145.
6. Onland W, Cools F, Kroon A, Rademaker K, Merkus MP, Dijk PH, et al. Effect of
Hydrocortisone Therapy Initiated 7 to 14 Days After Birth on Mortality or
Bronchopulmonary Dysplasia Among Very Preterm Infants Receiving Mechanical
Ventilation: A Randomized Clinical Trial. Jama 2019;321:354–63.
7. Watterberg KL, Walsh MC, Li L, Chawla S, D’Angio CT, Goldberg RN, et al.
Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia. N Engl
J Med. 2022;386:1121–31.
8. Pfeffer MA, Shah AM, Borlaug BA. Heart Failure With Preserved Ejection Fraction
In Perspective. Circ Res. 2019;124:1598–617.
9. Obokata M, Reddy YNV, Borlaug BA. Diastolic Dysfunction and Heart Failure With
Preserved Ejection Fraction: Understanding Mechanisms by Using Noninvasive
Methods. JACC Cardiovasc Imaging 2020;13:245–57.
10. Nagueh SF. Left Ventricular Diastolic Function: Understanding Pathophysiology,
Diagnosis, and Prognosis With Echocardiography. JACC Cardiovasc Imaging
2020;13:228–44.
11. Parikh KS, Sharma K, Fiuzat M, Surks HK, George JT, Honarpour N, et al. Heart
Failure With Preserved Ejection Fraction Expert Panel Report: Current
Controversies and Implications for Clinical Trials. JACC Heart Fail. 2018;6:
619–32.
12. de Waal K, Costley N, Phad N, Crendal E. Left Ventricular Diastolic Dysfunction
and Diastolic Heart Failure in Preterm Infants. Pediatr Cardiol. 2019;40:1709–15.
13. Liszewski MC, Lee EY. Neonatal Lung Disorders: Pattern Recognition Approach to
Diagnosis. AJR Am J Roentgenol. 2018;210:964–75.
14. Fenton TR, Kim JH. A systematic review and meta-analysis to revise the Fenton
growth chart for preterm infants. BMC Pediatr. 2013;13:59.
15. Lopez L, Colan SD, Frommelt PC, Ensing GJ, Kendall K, Younoszai AK, et al.
Recommendations for quantification methods during the performance of a
pediatric echocardiogram: a report from the Pediatric Measurements Writing
Group of the American Society of Echocardiography Pediatric and Congenital
Heart Disease Council. J Am Soc Echocardiogr. 2010;23:465–95.
16. Phad N, de Waal K. Left ventricular ejection fraction using manual and semi-
automated biplane method of discs in very preterm infants. Echocardiography
2020;37:1265–71.
17. de Waal K, Phad N, Boyle A. Left atrium function and deformation in very preterm
infants with and without volume load. Echocardiography 2018;35:1818–26.
18. Badano LP, Kolias TJ, Muraru D, Abraham TP, Aurigemma G, Edvardsen T, et al.
Standardization of left atrial, right ventricular, and right atrial deformation ima-
ging using two-dimensional speckle tracking echocardiography: a consensus
document of the EACVI/ASE/Industry Task Force to standardize deformation
imaging. Eur Heart J Cardiovasc Imaging. 2018;19:591–600.
19. Mourani PM, Sontag MK, Younoszai A, Miller JI, Kinsella JP, Baker CD, et al. Early
pulmonary vascular disease in preterm infants at risk for bronchopulmonary
dysplasia. Am J Respir Crit Care Med. 2015;191:87–95.
20. Kharrat A, Jain A. Hemodynamic dysfunction in neonatal sepsis. Pediatr Res.
2022;91:413–24.
21. Cohen E, Whatley C, Wong FY, Wallace EM, Mockler JC, Odoi A, et al. Effects of
foetal growth restriction and preterm birth on cardiac morphology and function
during infancy. Acta Paediatr. 2018;107:450–5.
22. Finnemore A, Groves A. Physiology of the fetal and transitional circulation. Semin
Fetal Neonatal Med. 2015;20:210–6.
23. Deshpande P, Baczynski M, McNamara PJ, Jain A. Patent ductus arteriosus: The
physiology of transition. Semin Fetal Neonatal Med. 2018;23:225–31.
24. Sirc J, Dempsey EM, Miletin J. Diastolic ventricular function improves during
the first 48-hours-of-life in infants weighting <1250 g. Acta Paediatr. 2015;104:
e1–6.
25. Mourani PM, Ivy DD, Rosenberg AA, Fagan TE, Abman SH. Left ventricular dia-
stolic dysfunction in bronchopulmonary dysplasia. J Pediatr. 2008;152:291–3.
26. de Waal K, Phad N, Collins N, Boyle A. Cardiac remodeling in preterm infants with
prolonged exposure to a patent ductus arteriosus. Congenit Heart Dis.
2017;12:364–72.
27. Rios DR, de Freitas Martins F, El-Khuffash A, Weisz DE, Giesinger RE, McNamara PJ.
Early Role of the Atrial Level Communication in Premature Infants with Patent
Ductus Arteriosus. J Am Soc Echocardiogr. 2021;34:423–432.e1.
28. Schmitz L, Stiller B, Koch H, Koehne P, Lange P. Diastolic left ventricular function
in preterm infants with a patent ductus arteriosus: a serial Doppler echocardio-
graphy study. Early Hum Dev. 2004;76:91–100.
29. Parikh R, Negrine RJ, Chikermane A, Rasiah SV, Ewer AK. Assessment of myo-
cardial function in preterm infants with patent ductus arteriosus using tissue
Doppler imaging. Cardiol Young-. 2015;25:70–5.
 K. de Waal et al.
6
30. de Freitas Martins F, Ibarra Rios D, MH FR, Javed H, Weisz D, Jain A, et al. Rela-
tionship of Patent Ductus Arteriosus Size to Echocardiographic Markers of Shunt
Volume. J Pediatr. 2018;202:50–5.e3.
31. Sehgal A, Ruoss JL, Stanford AH, Lakshminrusimha S, McNamara PJ. Hemody-
namic consequences of respiratory interventions in preterm infants. J Perinatol.
2022;42:1153–60.
32. Murase M, Morisawa T, Ishida A. Serial assessment of left-ventricular function
using tissue Doppler imaging in premature infants within 7 days of life. Pediatr
Cardiol. 2013;34:1491–8.
33. James AT, Corcoran JD, Jain A, McNamara PJ, Mertens L, Franklin O, et al.
Assessment of myocardial performance in preterm infants less than 29 weeks
gestation during the transitional period. Early Hum Dev. 2014;90:829–35.
34. Sanfilippo F, Di Falco D, Noto A, Santonocito C, Morelli A, Bignami E, et al.
Association of weaning failure from mechanical ventilation with transthoracic
echocardiography parameters: a systematic review and meta-analysis. Br J
Anaesth. 2021;126:319–30.
35. Sanfilippo F, La Rosa V, Grasso C, Santonocito C, Minardi C, Oliveri F, et al.
Echocardiographic Parameters and Mortality in Pediatric Sepsis: A Systematic
Review and Meta-Analysis. Pediatr Crit Care Med. 2021;22:251–61.
36. Cohen E, Wong FY, Horne RS, Yiallourou SR. Intrauterine growth restriction:
impact on cardiovascular development and function throughout infancy. Pediatr
Res. 2016;79:821–30.
37. Fouzas S, Karatza AA, Davlouros PA, Chrysis D, Alexopoulos D, Mantagos S, et al.
Neonatal cardiac dysfunction in intrauterine growth restriction. Pediatr Res.
2014;75:651–7.
38. Harada K, Suzuki T, Takahashi Y, Ito T, Toyono M, Ishida A, et al. Abnormal left
ventricular diastolic filling patterns in small-for-gestational-age infants. Early Hum
Dev. 1998;51:197–204.
39. Leipälä JA, Boldt T, Turpeinen U, Vuolteenaho O, Fellman V. Cardiac hypertrophy
and altered hemodynamic adaptation in growth-restricted preterm infants.
Pediatr Res. 2003;53:989–93.
40. Rodriguez-Guerineau L, Perez-Cruz M, Gomez Roig MD, Cambra FJ, Carretero J,
Prada F, et al. Cardiovascular adaptation to extrauterine life after intrauterine
growth restriction. Cardiol Young-. 2018;28:284–91.
AUTHOR CONTRIBUTIONS
Dr KdeW had the primary responsibility for protocol development, recruitment,
measurements and data analysis and was the author of the original draft of the
paper. Dr EC participated in recruitment, measurements and contributed to the
writing of the paper. Dr NP, ACP, MSL, ES, and TM helped in data analysis and
contributed to the writing of the paper.
FUNDING
Open Access funding enabled and organized by CAUL and its Member Institutions.
COMPETING INTERESTS
The authors declare no competing interests.
ETHICS APPROVAL
All procedures performed in studies involving human participants were in
accordance with the ethical standards of the institutional and/or national research
committee and with the 1964 Helsinki declaration and its later amendments or
comparable ethical standards. This paper does not contain any studies with animals
performed by any of the authors.
INFORMED CONSENT
Informed consent was obtained from all individual participants included in the study.
ADDITIONAL INFORMATION
Supplementary information The online version contains supplementary material
available at https://doi.org/10.1038/s41372-023-01608-5.
Correspondence and requests for materials should be addressed to Koert de Waal.
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Journal of Perinatology