Beyond Critical Congenital Heart Disease: Newborn Screening Using Pulse Oximetry for Neonatal Sepsis and Respiratory Diseases in a Middle-Income Country

Abstract

Background:
Studies on pulse oximetry screening for neonatal sepsis and respiratory disease in a middle-income country are lacking. Newborn screening for critical congenital heart disease (CCHD) using pulse oximetry is an effective and life-saving strategy in developed countries. While most studies have reported false-positive results during CCHD screening, they have not elaborated on the detected disease types. We studied the effectiveness and outcomes of pulse oximetry newborn screening for non-cardiac hypoxemic diseases such as neonatal sepsis, respiratory diseases, and CCHD in a middle-income country.

Methods and findings:
In a pilot study performed at the University Malaya Medical Centre (UMMC), Malaysia, all apparently healthy term newborns, delivered at UMMC were screened pre-discharge using pulse oximetry. Echocardiography was performed for newborns that had positive screening results on two separate occasions, 1-h apart. Newborns with normal echocardiograms were evaluated and treated for other non-cardiac diseases. Fifteen of 5247 term newborns had positive screening results. The median age at screening was 20 h. Thirteen newborns (0.24%) had significant non-cardiac diseases: sepsis (n = 2) and respiratory diseases (n = 11) that required hospitalization and treatment. The remaining two newborns with normal antenatal ultrasonograms had positive screening test and confirmed to have CCHD. Another 18 newborns with negative screening test were later admitted for treatment of sepsis (n = 16) and penumonia (n = 2). All newborns were treated and alive at the end of the study. The sensitivity and specificity of pulse oximetry screening for non-cardiac diseases were 42% and 99.9% respectively, and 100% and 99.7% for CCHD, respectively.

Conclusions:
Routine pulse oximetry screening test was effective in identifying newborns with CCHD and other hypoxemia illnesses, which may led to potential life-threatening condition. This study showed that the expanded use of pulse oximetry has immediate implications for low- and middle-income countries contemplating strategies to reduce neonatal mortality and morbidity.

Abbreviations:
ASD, atrial septal defect; CCHD, critical congenital heart disease; CRP, C-reactive protein; CXR, chest radiographs; NDI, neurodevelopment impairment; PPHN, persistent pulmonary hypertension of the newborn; PDA, patent ductus arteriosus; PFO, patent foramen ovale; TGA, transposition of great artery; TTN, transient tachypnoea of the newborn; VSD, ventricular septal defect.

Full text

RESEARCH ARTICLE
Beyond Critical Congenital Heart Disease:
Newborn Screening Using Pulse Oximetry for
Neonatal Sepsis and Respiratory Diseases in
a Middle-Income Country
Vida Jawin
☯
, Hak-Lee Ang
‡
, Asma Omar
‡
, Meow-Keong Thong
☯
*
Department of Paediatrics, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
☯These authors contributed equally to this work.
‡These authors also contributed equally to this work.
*thongmk@um.edu.my
Abstract
Background
Studies on pulse oximetry screening for neonatal sepsis and respiratory disease in a mid-
dle-income country are lacking. Newborn screening for critical congenital heart disease
(CCHD) using pulse oximetry is an effective and life-saving strategy in developed countries.
While most studies have reported false-positive results during CCHD screening, they have
not elaborated on the detected disease types. We studied the effectiveness and outcomes
of pulse oximetry newborn screening for non-cardiac hypoxemic diseases such as neonatal
sepsis, respiratory diseases, and CCHD in a middle-income country.
Methods and Findings
In a pilot study performed at the University Malaya Medical Centre (UMMC), Malaysia, all
apparently healthy term newborns, delivered at UMMC were screened pre-discharge
using pulse oximetry. Echocardiography was performed for newborns that had positive
screening results on two separate occasions, 1-h apart. Newborns with normal echocar-
diograms were evaluated and treated for other non-cardiac diseases. Fifteen of 5247 term
newborns had positive screening results. The median age at screening was 20 h. Thirteen
newborns (0.24%) had significant non-cardiac diseases: sepsis (n = 2) and respiratory
diseases (n = 11) that required hospitalization and treatment. The remaining two new-
borns with normal antenatal ultrasonograms had positive screening test and confirmed to
have CCHD. Another 18 newborns with negative screening test were later admitted for
treatment of sepsis (n = 16) and penumonia (n = 2). All newborns were treated and alive at
the end of the study. The sensitivity and specificity of pulse oximetry screening for non-
cardiac diseases were 42% and 99.9% respectively, and 100% and 99.7% for CCHD,
respectively.
PLOS ONE | DOI:10.1371/journal.pone.0137580 September 11, 2015 1/13
OPEN ACCESS
Citation: Jawin V, Ang H-L, Omar A, Thong M-K
(2015) Beyond Critical Congenital Heart Disease:
Newborn Screening Using Pulse Oximetry for
Neonatal Sepsis and Respiratory Diseases in a
Middle-Income Country. PLoS ONE 10(9): e0137580.
doi:10.1371/journal.pone.0137580
Editor: Tonse Raju, NIH, UNITED STATES
Received: May 24, 2015
Accepted: August 18, 2015
Published: September 11, 2015
Copyright: © 2015 Jawin et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any
medium, provided the original author and source are
credited.
Data Availability Statement: All relevant data are
within the paper and its Supporting Information files.
Funding: H-LA received funding for clinical research
from the University of Malaya. This research was
funded by the University of Malaya Research Grant
(RG435/12HTM), URL: umresearch.um.edu.my. VJ
received a fund from The Malaysian Rare Disorders
Society. This is a personal private fund. URL: www.
mrds.org.my. The funders have played a role in the
data collection and analysis by providing the material
needed for the study.

Conclusions
Routine pulse oximetry screening test was effective in identifying newborns with CCHD and
other hypoxemia illnesses, which may led to potential life-threatening condition. This study
showed that the expanded use of pulse oximetry has immediate implications for low- and
middle-income countries contemplating strategies to reduce neonatal mortality and
morbidity.
Abbreviations
ASD, atrial septal defect; CCHD, critical congenital heart disease; CRP, C-reactive protein;
CXR, chest radiographs; NDI, neurodevelopment impairment; PPHN, persistent pulmonary
hypertension of the newborn; PDA, patent ductus arteriosus; PFO, patent foramen ovale;
TGA, transposition of great artery; TTN, transient tachypnoea of the newborn; VSD, ventric-
ular septal defect.
Introduction
Newborn screening for critical congenital heart disease (CCHD) using pulse oximetry is recog-
nized as a highly specific, moderately sensitive, and cost-effective test that meets the criteria for
universal screening. It has been endorsed in the United States and various developed countries
as part of the recommended uniform screening panel for newborns [1,2]. Congenital heart dis-
ease occurs in 8–10 per 1000 live births and accounts for 3% of all infant mortalities and 46%
of deaths from congenital malformations, with most deaths occurring in the first year of life
[3–6]. Approximately one quarter of congenital heart disease children will have critical congen-
ital heart disease (CCHD), which by definition requires surgery or catheter intervention in the
first year of life [7,8]. Current screening methods include prenatal screening and routine new-
born examination [9,10]. However, with routine fetal cardiac ultrasound during pregnancy,
fewer than 50% of the CCHD cases were identified and routine newborn examinations also
failed to detect 75–80% of CCHD as many newborns with CCHD have no signs that can be
detected by clinical examination [11–14]. As congenital cardiac diseases and CCHD are the
main cause of congenital anomalies, early detection of these non-communicable diseases will
lead to improvements in neonatal mortality and morbidity in low- and middle-income
countries.
Granelli et al. reported that depending on the cut-off criteria, the false positive rates of pulse
oximetry screening programs vary between 0.009% and 5% with large studies reporting 0.17%
and 0.3% [15,16]. Between 30% to 70% of the false positives were attributed to detection of sec-
ondary targets but details on these non-CCHD or serious non-cardiac illness were lacking or
not reported as the primary objective of the studies [17,18]. Recent studies have validated the
routine use of pulse oximetry in developed countries and areas of moderate altitude and the rel-
ative ease of program implementation [19–23]. However, data regarding pulse oximetry
screening for CCHD, neonatal sepsis, and respiratory disorders in low- and middle-income
countries is limited [24,25].
Neonatal sepsis is a common serious problem and the diagnosis may be difficult to make
as the clinical manifestations are non-specific and none of the available laboratory tests
could be considered as an ideal marker. However, there are evidence to link sepsis with an
early onset of hypoxia. Microcirculatory dysfunction plays a pivotal role in the pathogenesis of
sepsis and septic shock[26]. It is known that cytopathic hypoxia occurs in the mitochondria
within cells when sepsis occurs[27]. In addition, functional shunting in the microcirculation
Pulse Oximetry for Non-Cardiac Hypoxemic Diseases
PLOS ONE | DOI:10.1371/journal.pone.0137580 September 11, 2015 2/13
Competing Interests: The authors have declared
that no competing interests exist.

and in the mitochondrial which lead to the deficit of oxygen extraction is also observed in sep-
sis and septic shock[26,28]. Therefore, pulse oximetry screening test may be beneficial in allow-
ing an early detection of neonatal sepsis. The World Health Organization and UNICEF
reported that up to three quarters of a million deaths per year worldwide are attributed to
severe neonatal bacterial infections [29]. It has been estimated that in 2010 there were 6.8 mil-
lion (uncertainty range: 5.4–8.1 million) cases of possible severe bacterial infection in neonates
over 32 weeks gestation (or above 1,500 g), which included 1.7 million (1.1–2.4 million) cases
of neonatal sepsis, 200,000 cases (21,000–350,000) of neonatal meningitis, and 510,000 cases
(150,000–930,000) of neonatal pneumonia in South Asia, sub-Saharan Africa, and Latin Amer-
ica. In addition, moderate and severe neurodevelopment impairment (NDI) occurred in survi-
vors of neonatal meningitis with a paucity of data on impairment for neonatal sepsis and
pneumonia [30]. In selected east Asian countries, early neonatal sepsis has been reported in
4.91 per 1000 admissions with Group B Streptococcus as well as Klebsiella spp. the most com-
mon gram-negative organisms causing most deaths [31]. Infections that contributed to neona-
tal deaths in other developing countries ranged from 8% to 80% and accounted for as many as
42% of the deaths in the first week of life [32]. The rate of neonatal sepsis has been reported as
high as 170/1000 live births (clinically diagnosed) and 5.5/1000 live births (blood culture- con-
firmed) [32].
In low resource settings, hand-washing routines, cleaning of the umbilical cord with chlor-
hexidine, clean deliveries, and improved case management using effective antibiotic treatment
regimens have been identified as key steps in reducing neonatal infections [33]. To allow timely
diagnosis and prevent possible NDI, pulse oximetry screening for neonatal sepsis before dis-
charge in low- and moderate-income countries may be effective, but there are limited data
[30]. One feasibility study using pulse oximetry screening for neonatal sepsis in 316 asymptom-
atic newborns in a low-income setting reported acceptability by mothers and healthcare profes-
sionals but cautioned that further studies were needed to assess the accuracy of the test in
detecting sepsis in newborns and its clinical impact on neonatal health [34]. There are no
reports of using pulse oximetry for respiratory diseases in newborns [34].
Malaysia is classified as a middle-income country with a birth rate of 500,000 per annum
and an infant mortality rate of 6/1000 live births in 2009 with conditions originating in the
perinatal period reported as the major cause of childhood death [35]. Currently there are no
routine newborn screening programs for CCHD, neonatal sepsis, or respiratory diseases in the
country. As hypoxemia is a common feature of CCHD and respiratory diseases, pulse oximetry
is helpful to detect early mild cyanosis in newborns. We studied the use of pulse oximetry to
screen for both CCHD and non-cardiac hypoxemic diseases such as neonatal sepsis and respi-
ratory diseases.
Materials and Methods
All apparently healthy term newborns born at the University Malaya Medical Center
(UMMC), Malaysia from September 1, 2012 to December 31, 2013, with the exception of week-
ends and public holidays, were enrolled prospectively in this pilot study before hospital dis-
charge. Those newborns with an antenatal diagnosis of congenital heart disease or did not
complete the study were excluded from the analysis. Institutional-review board approval was
obtained from the University of Malaya Ethics Committee (Ethics Committee Reference num-
ber: 913.13) An educational brochure regarding the purpose of the study was distributed to all
parents after delivery. As this screening test involved a great number of newborns, it was not
feasible to obtain written consent from each legal guardian who agreed to take part in the
study, hence an op-out consent applied. For those parents who agreed to participate in the
Pulse Oximetry for Non-Cardiac Hypoxemic Diseases
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study, a verbal consent was obtained on behalf of the minors and documented in the data col-
lection sheet. For those parents of newborns who refused to participate in the screening test, an
objection written consent was collected. The study was conducted according to a standardized
protocol. (Fig 1). Demographics and clinical data were collected from all Infants. Infants that
Fig 1. Study Protocol and Results.
doi:10.1371/journal.pone.0137580.g001
Pulse Oximetry for Non-Cardiac Hypoxemic Diseases
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were screened positive were provided with immediate counselling and referred for investiga-
tion, including echocardiography within 24 h of screening.
Measurement of oxygen saturation (SpO2) was carried out within 24 h of life or before hos-
pital discharge by a cardiology technician who had undergone an on-site supervision and train-
ing. Once competency in obtaining a reliable and accurate result using the Masimo Radical-
7
TM
SET pulse oximetry unit was achieved, the study was carried out. The M-LNCS
TM
pulse
oximetry probe was cleaned with an alcohol swab before each use to prevent cross infection
and was placed on the left foot for 30 s before the reading was recorded. Newborns with an oxy-
gen saturation reading of more than 95% were considered negative on the screening test. Those
who had oxygen saturation reading less than or equal to 95% in two readings measured at least
an h apart were considered to have a positive screening test and an echocardiography examina-
tion was performed by a cardiologist on the same day. In the absence of CCHD, non-cardiac
hypoxemic diseases such as sepsis and respiratory diseases were identified and treated. If the
repeated oxygen saturation was more than 95% on the second reading, this was also considered
a negative screening test. For those newborns with a low risk test result, parents were notified
and a postnatal clinic appointment was scheduled at 6 weeks of age to review the newborn’s
health status. In addition, hospital admission records were reviewed to include neonates who
were initially screened negative for hypoxemia but subsequently admitted for sepsis and respi-
ratory illnesses into the analysis. During the postnatal check up, if the infants were healthy,
they were discharged from the study. However, for those who did not attend the 6-week post-
natal clinic follow-up, a telephone call was made to ensure their well-being and their medical
records were traced.
Data analysis was performed using the statistical package for the social sciences (SPSS), ver-
sion 21.0. The results and underlying causes for infants with positive tests were evaluated and
studied. Sensitivity, specificity, and predictive values were calculated using standard methods
for proportions.
Results
Study population
A total of 5,299 newborns that fulfilled the inclusion criteria were initially enrolled. Parents of
one newborn declined the pulse oximetry screening test. Five newborns who were diagnosed to
have CCHD antenatally were not included in the analysis. Forty-six newborns did not com-
plete the study process at the end of 6 weeks follow-up were also excluded (Fig 1). Demo-
graphic and clinical characteristics of the remaining 5,247 newborns are described in Table 1.
The median age at the time of the pulse oximetry screening test was 20 h.
Newborns with pulse oximetry screening test
A total of 15 newborns (0.28%) had a positive screening test with an oxygen saturation
reading 95%. Thirteen newborns (0.24%) were found to have significant problems such as
sepsis (n = 2) or respiratory problems (n = 11) and there were two cases of CCHD (0.04%).
(Fig 1).
The remaining 5,232 newborns had negative screening results. 3,174 newborns attended the
6 week postnatal clinic follow-up while a telephone call was made to the remaining 2058 new-
borns parents where their infants attended child health clinic elsewhere. 5,211 newborns were
well but 18 newborns had history of post-natal hospital admission which required intervention
based on medical record tracing or parents’interview: 16 newborns fulfilled the criteria for
delayed diagnosis of neonatal sepsis while another two newborns were diagnosed with congeni-
tal pneumonia and another 3 newborns were diagnosed with acyanotic congenital heart disease
Pulse Oximetry for Non-Cardiac Hypoxemic Diseases
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based on physical examination and confirmed by echocardiography. These asymptomatic
patients presented with cardiac murmurs (two newborns had a ventricular septal defect (VSD)
and the other had a small VSD and a patent ductus arteriosus).
Based on the cohort data of the newborns at discharge, the incidence of non-cardiac hypox-
emic diseases was 2.4 per 1,000 live births. The sensitivity and specificity of pulse oximetry
screening test for non cardiac hypoxemic diseases were 42% and 99.9%, respectively while the
positive and negative predictive values were 86% and 99.6%, respectively. The incidence of
CCHD was 0.4 in 1,000 live births. The sensitivity and specificity of the pulse oximetry screen-
ing test for CCHD were 100% and 997% respectively and the positive and negative predictive
values were 35% and 100%, respectively.
Non-cardiac hypoxemic disease
Our screening process detected 13 positive results due to non-cardiac diseases (Tables 2and 3).
All the newborns were clinically asymptomatic with no positive physical findings during initial
examination. There were two newborns who fulfilled the diagnosis of neonatal sepsis; one new-
born was confirmed to have Streptococcus pneumoniae septicemia with positive risk factors for
sepsis, while the other had positive risk factors associated with significant rise in inflammatory
Table 1. Demographic and clinical characteristics of newborns.
Sex
Male 2556 (49%)
Female 2691 (51%)
Race
Malay 3713 (70%)
Chinese 598 (12%)
Indian 512 (10%)
Others*68 (13%)
Non-citizens 356 (67%)
Gestational age
37–40 weeks (term) 4404 (839%)
>40 weeks (post term) 843 (161%)
Birth weight
<2,500 gram 374 (71%)
2,500–4,000 gram 4791 (913%)
>4,000 gram 82 (16%)
Mode of delivery
Spontaneous vaginal delivery 3482 (663%)
Vacuum assisted delivery 208 (3.9%)
Forceps assisted delivery 8 (01%)
Emergency lower section caesarean 927 (176%)
Elective lower section caesarean 595 (11.3%)
Born before arrival 27 (08%)
Risk of sepsis ^
Positive 38 (07%)
Negative 5209 (993%)
Others*, Kadazan, Iban, Orang Asli; Risk of sepsis
^, rupture of membrane more than 18 hours, maternal fever, group B streptococcus on high vaginal swab.
doi:10.1371/journal.pone.0137580.t001
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markers but had negative blood culture report. Another two newborns fulfilled the criteria for
congenital pneumonia with progressive tachypnoea. Chest radiographs (CXR) of one of the
newborn showed pneumonia changes with a spontaneous pneumothorax of the right lung that
did not require any invasive intervention; the latter had a normal chest radiograph. They were
discharged after oxygen support and antibiotics therapy for 1 week.
The other two newborns were diagnosed with persistent pulmonary hypertension of the
newborn (PPHN), a clinical condition in which pre- and post-ductal oxygen saturation differ-
ences are 10%. One of the newborn with Down syndrome was diagnosed with primary
PPHN, which required invasive ventilation and inhaled nitric oxide therapy. The patient was
subsequently discharged at one month of age. Another newborn had PPHN secondary to poly-
cythemia and a partial exchange transfusion was required at 12 h of age. There were two appar-
ently healthy newborns with a history of meconium stained liquid during delivery–and later
diagnosed with meconium aspiration syndrome. Those newborns had developed respiratory
distress who required oxygen treatment and their chest radiograph showed the radiological
changes. There was no PPHN in these patients and both newborns were healthy and dis-
charged at 1 week of age.
An interesting case was a newborn with a deformity of the right forearm was screened
positive. The patient was initially well but later developed respiratory distress. Investigations
performed, including a computerized tomogram (CT) of the thorax, showed right lung hypo-
plasia. Other findings included a sixth thoracic hemivertebrae and bilateral horseshoe kidneys.
A clinical diagnosis of VACTERL association (vertebral anomalies, anal atresia, cardia defects,
tracheoesophageal fistula and or esophageal atresia, renal and radial anomalies, and limb
defects) was made. The patient required noninvasive ventilatory support and was discharged at
1 month of age with long-term home bilevel positive airway pressure support.
Four newborns were treated as transient tachypnoea of newborn (TTN) which required
oxygen therapy for 1–2 days. Chest X-rays were normal and there was no positive culture or
rise in inflammatory markers. The TTN resolved spontaneously after 48–72 hours.
Four of 13 newborns with other hypoxemia illensses were found to have incidental VSD
(n = 2 apical VSD) and mid muscular VSD (n = 2 muscular VSD) on echocardiography, which
were non-critical congenital heart diseases.The echocardiography of the other newborns
Table 2. Definitions of other significant hypoxemia illnesses.
Congenital pneumonia Raised inflammatory markers (CRP>10mg/dl)±positive culture,
radiological changes on Chest X-ray, oxygen requirement (or
longer than 2 h),antibiotics for 5 days
Meconium aspiration syndrome History of meconium staining of liquor, respiratory distress, oxygen
requirement (for longer than 2 h), radiological changes on Chest X-
ray
Sepsis Raised inflammatory markers (CRP>10mg/dl)±positive culture,
antibiotics for 5 days
Transient tachypnoea of newborn
requiring oxygen
Tachypnoea with radiological changes of fluid retention, oxygen
requirement (for longer than 2 h), no rise in inflammatory markers or
positive culture
Persistent pulmonary hypertension
of newborn
Preductal and postductal difference in saturations with
echocardiogram finding of significant tricuspid regurgitation and
evidence of right to left shunt across the PFO and or PDA
CRP, c-reactive protein; PFO, patent oramen ovale; PDA, patent ductus arteriosus. Table adapted from
source file of:Anju Singh,Shree Vishna Rasiah,Andrew K Ewer.The impact of routine predischarge pulse
oximetry screening in a regional neonatal unit.Arch Dis Child Fetal Neonatal Ed.2014 Jul; 99(4):F297-302
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Table 3. Non-Cardiac Hypoxemia Diseases.
No Diagnosis Risk factor PO1
foot,
PO2
foot
Age of
screening
(hours of
life)
Routine
physical
examination
Echocardiography Investigation Treatment Outcome
1 Neonatal
sepsis
Risk factor
of sepsis +
86%,
84%
16 Normal Small PFO/PDA Streptococcus
pneumonia (blood
culture)
Antibiotics Alive
2 Neonatal
sepsis
Risk factor
of sepsis +
92%,
93%
21 Normal Small muscular VSD Sterile blood culture Antibiotics Alive
3 Down
syndrome with
primary PPHN
Nil 87%,
88%
6 Normal High Tricuspid
regurgitation jet
60mmHg, large PDA
5.7mm
CXR: normal Sterile
blood culture
Ventilated
Inhaled nitric
oxide
Inotropic
support
Antibiotics
Alive
4 PPHN with
polycythemia
Nil 87%,
81%
8 Normal Small PFO/PDA Hematocrite: 08 Partial
exchange at
10 hours of
life
Alive
5 TTN Nil 93%,
95%
22 Normal Small PFO/PDA CXR: normal Oxygen
support
Alive
6 TTN Nil 82%,
83%
20 Normal Small PFO/PDA CXR: normal Oxygen
support
Alive
7 TTN Nil 89%,
86%
24 Normal Small apical VSD,
small PDA
CXR: normal Oxygen
support
Alive
8 TTN Nil 87%,
90%
25 Normal Small PFO/PDA CXR: normal Oxygen
support
Alive
9 Congenital
pneumonia
Risk factor
of sepsis +
86%,
86%
14 Normal Mid muscular VSD
1.5mm
CXR: small
spontaneous
pneumothorax right
lung
Oxygen
support
Antibiotics
Alive
10 Congenital
pneumonia
Risk factor
of sepsis +
82%,
85%
7 Normal Small apical VSD CXR: bilateral diffuse
patchy opacities
Oxygen
support
Antibiotics
Alive
11 Meconium
aspiration
syndrome
Light
meconium
stained
liquor
delivery
92%,
93%
5 Normal Small PFO/PDA. CXR: bilateral diffuse
patchy opacities
Oxygen
support
Antibiotics
Alive
12 Meconium
aspiration
syndrome
meconium
stained
liquor
delivery
84%,
86%
5 Normal Atrial septal defect
(ASD) 4 mm, PDA 3
mm. Tricuspid
regurgitation jet
30mmHg
CXR: bilateral diffuse
patchy opacities
Ventilated at
12 hours of
life Antibiotics
Alive
13 Hypoplastic
right lung with
VACTERL
association
Nil 92%,
94%
13 Right forearm
deformity
Mesocardia, small
PDA
Computerized
tomograms of thorax:
right lung hypoplasia.
Skeletal survey:
absent right radius,
T6 hemivetebra
Ultrasound of kidney:
bilateral horseshoe
kidneys
Continuous
bilevel
positive
airway
pressure
(BIPAP)
Alive
PO1, first pulse oximetry reading; PO2, second pulse oximetry reading; SpO2, oxygen saturation; PFO, patent foramen ovale; PDA, patent ductus
arteriosus; CXR, chest x-ray; VSD, ventricular septal defect; PPHN, persistent pulmonary hypertension of newborn; TTN, transient tacypnoea of newborn;
VACTERL, vertebral anomalies, anal atresia, cardia defects, tracheoesophageal fistula and or esophageal atresia, renal and radial anomalies, and limb
defects
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showed a small patent foramen ovale (PFO) and patent ductus arteriosus (PDA) which were
asymptomatic and considered normal findings in newborns within the first 24 h of life. A
repeat echocardiography at 6 weeks old showed a complete resolution of the defect.
CCHD diagnoses
Two newborns who had normal antenatal and fetal cardiac ultrasonograms were screened
positive using pulse oximetry and later confirmed to have CCHD on postnatal echocardio-
gram. One patient had pulmonary atresia with VSD and another had pulmonary atresia, trans-
position of the great artery (TGA) and double outlet right ventricle. The initial routine
postnatal newborn examinations in these newborns were normal and cyanosis was not
detected. After given an appropriate treatment, all newborns with CCHD were alive at the con-
clusion of this study. (Table 4).
Discussion
The majority of studies on newborn screening using pulse oximetry have been focused on the
detection of CCHD. However, little is known about non-cardiac hypoxemia illnesses, which
are the secondary benefits of pulse oximetry screening test. In this study, we evaluated the out-
come of newborn screening for various non-cardiac hypoxemia diseases using pulse oximetry
and showed that this approach has the potential to reduce neonatal infant mortality and mor-
bidity resulting from neonatal sepsis and various respiratory diseases of the newborn.
Pulse oximetry screening test has detected a number of non-cardiac diseases with hypox-
emia (0.25%) such as neonatal sepsis and respiratory problems which were asymptomatic on
physical examination but required immediate medical attention and treatment. As respiratory
diseases and infections contribute to the highest mortality rate during the neonatal period in
low resources and middle-income countries, pulse oximetry has an additional advantage to
detect these non-CCHD and serious conditions earlier before hospital discharge, so that appro-
priate treatment can be instituted. Whilst some authorities may consider transient tachypnea
of newborns (TTN) and mild meconium aspiration syndrome (MAS) as non-life threatening,
it is unclear whether early hypoxemic state due to TTN and mild MAS or tbeirlate diagnosis
may contribute to long-term morbidity, such as neurologic damage and developmental disabil-
ities. Hence, further studies are required to investigate the effect of persistent mild newborn
hypoxemia.
Table 4. Newborns with CCHD.
No CCHD lesions
(echocardiography)
Antenatal
ultrasonograms
Age of
screening
(hours of life)
PO1
foot,
PO2
foot
SpO2 at
24 hours
of life
Routine
physical
examination
Treatment Outcome
1 Pulmonary atresia with
VSD/ASD
Normal 9 65%,
74%
87–91% Normal Prostaglandin E2 at 14
hours of life. PDA
stenting at 1 week of
life
Alive
2 Double outlet right ventricle/
Pulmonary atresia/TGA
VSD/ASD/ PDA
Normal 6 83%,
86%
89–92% Normal Prostaglandin E2 at 9
hours of life, Blalock-
Taussig shunt at 3
months old.
Alive
PO1, first pulse oximetry reading; PO2, second pulse oximetry reading; SpO2, oxygen saturation; VSD, ventricular septal defect; ASD, atrial septal defect;
TGA, transposition of great artery; PDA, patent ductus arteriosus
doi:10.1371/journal.pone.0137580.t004
Pulse Oximetry for Non-Cardiac Hypoxemic Diseases
PLOS ONE | DOI:10.1371/journal.pone.0137580 September 11, 2015 9/13

As perinatal complications and newborn infection rates are high in developing countries,
pulse oximetry screening for CCHD may be used concurrently to screen for other newborn
non-cardiac hypoxemic conditions. This may help low resource countries to reduce infant
mortality and morbidity rates and to achieve the Millennium Development Goal 4, target 4A.
This has been demonstrated by a feasibility study in Tanzania with 316 newborns, which
detected eight newborns with sepsis, including four were detected before 12 h of life [6]. With
the additional advantage of detecting these non-cardiac neonatal diseases, the percentage of
false positive pulse oximetry screening results will be reduced.
In this study, the true positive for non-CCHD hypoxemia illnesses and CCHD were 13 and
2 neonates, respectively with no false positive result. Out of 5247, there were 18 false negative
results (0.34%) which included 2 and 16 neonates admitted and treated for pneumonia and
neonatal sepsis, respectively. Be that as it may, pulse oximetry successfully detected early 13 out
of 31 (42%) neonates with life-threatening conditions. The earlier diagnosis and treatment of
respiratory illnesses and neonatal sepsis reduced morbidity and further studies will be required
to ascertain the long term outcome of this cohort of patients. In addition, while there was no
mortality reported resulting from respiratory diseases and neonatal sepsis, it is possible that in
a larger study involving other low or moderate resource countries, infant mortality rates may
be reduced.
Although there was sufficient evidence for CCHD screening using pulse oximetry, this pilot
study indicated an even greater potential advantage of using pulse oximetry to screen for neo-
natal sepsis and respiratory diseases. On a global scale, as these diseases account for a large
number of neonatal mortality and morbidity particularly in low resource settings, there is a
potential for huge gains using pulse oximetry screening for respiratory diseases and neonatal
sepsis.
Parental acceptance of newborn screening in our setting was high as only the parents of one
newborn chose to opt out from the screening program. The study was supported by health pro-
fessionals, and the test was highly accurate. The total amount of time spent for the training of
the cardiology technician for the study was four hours. This included 2 hours for explanation
and familiarisation of the protocol and demonstration of the correct technique of measuring
pulse oximetry readings. This was followed by on-site supervision to ascertain the competency
of the technician in obtaining a reliable and consistent result. On the average, the time required
for pulse oximetry screening test for each newborn was 5 minutes. As the number of positive
screening case detected was 15 cases over 16 months, the number of screening tests which
require further assessment and observation was <1 case/month. This did not require addi-
tional manpower and the time consumed was negligible. On the basis of our finding, pulse
oximetry screening will require no or minimal additional resource in the hospital that had pae-
diatric cardiologist services. However further study will be required to ascertain the resources
needed in the hospital without paediatric cardiologist service. We concluded that pulse oxime-
try screening test was simple, feasible and did not appear to overload clinic services. While
antenatal or fetal cardiac echocardiography may detect those with gross four chamber anoma-
lies, there is a strong likelihood of missing those with outflow tract defects. In addition, other
confounding factors leading to false negative antenatal ultrasound findings were the depen-
dence on the level of expertise of the ultrasonographer, gestational age of the fetus, fetal posi-
tion, and the type of heart defect. The majority of the newborns with CCHD remained
asymptomatic after birth due to the presence of persistent fetal transitional circulation. The
presence of cyanosis may not be apparently visible in newborns with darker skin complexion.
Therefore, these newborns would likely be discharged with undetected CCHD if pulse oximetry
was not performed.
Pulse Oximetry for Non-Cardiac Hypoxemic Diseases
PLOS ONE | DOI:10.1371/journal.pone.0137580 September 11, 2015 10 / 13

This study also showed the importance of post screening follow-up as well as a need to
establish a registry for CCHD and non-CCHD hypoxemic diseases to further evaluate the cost-
effectiveness of this screening strategy before a nation-wide or national program is launched.
Detailed analyses of the types of non-cardiac hypoxemic diseases detected may help in the
appropriate allocation of resources to neonatal care.
We confirmed that the pulse oximetry screening test for newborns had a significant impact
on neonatal health. The test was highly accurate and acceptable to both parents and health pro-
fessionals. This test is able to confer the additional benefit to detect non-cardiac hypoxemic dis-
eases such as neonatal sepsis and respiratory diseases, especially in low- and middle-income
countries. A similar larger multicenter international study in low resource or developing coun-
tries should be done to confirm the above observations as well as to determine the cost-effec-
tiveness of this strategy.
Supporting Information
S1 Table. List of positive pulse oximetry screening result.
(DOCX)
S2 Table. List of false negative pulse oximetry screening result.
(DOCX)
Acknowledgments
We thank Betty S.S, Nur Arina and Lim Su Kwan for their assistance in conducting this
research, all other specialists, medical officers and staff nurses who provided assistance in the
postnatal and paediatric wards and all patients and caregivers who participated in the study.
Author Contributions
Conceived and designed the experiments: M-KT VJ H-LA AO. Performed the experiments: VJ
H-LA. Analyzed the data: VJ M-KT. Contributed reagents/materials/analysis tools: H-LA M-
KT VJ. Wrote the paper: VJ M-KT H-LA AO.
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