Pediatrics and Neonatology (2017) 58, 236e244

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ORIGINAL ARTICLE

Maternal and Placental Factors Associated

with Congenital Hearing Loss in Very
Preterm Neonates
Shin Hye Kim a,c, Byung Yoon Choi a,c, Jaehong Park a,
Eun Young Jung b, Soo-Hyun Cho b, Kyo Hoon Park b,*

a
Department of OtorhinolaryngologydHead and Neck Surgery, Seoul National University College of
Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
b
Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul
National University Bundang Hospital, Seongnam, South Korea

Received Feb 3, 2016; received in revised form Apr 21, 2016; accepted May 1, 2016
Available online 9 August 2016

Key Words Background: Sensorineural hearing loss (SNHL) is a multifactorial disease that more frequently
antenatal affects preterm newborns. Although a number of maternal conditions have been reported to
corticosteroids; be associated with preterm birth, little information is available concerning maternal risk fac-
funisitis; tors for the development of SNHL. We aimed to identify maternal and placental risk factors
newborn hearing associated with a “refer” result on the newborn hearing screening (NHS) test and subsequently
screening test; confirmed SNHL in very preterm neonates.
preterm; Methods: This retrospective cohort study included 267 singleton neonates who were born alive
refer after  32 weeks. Histopathologic examination of the placenta was performed, and clinical
data were retrieved from a computerized perinatal database. Cases with two abnormal find-
ings, “refer” on the NHS test, and presence of SNHL on the confirmation test were retrospec-
tively reviewed based on electronic medical records.
Results: Forty-two neonates (15.7%) showed a “refer” result, and, on the confirmation test,
permanent SNHL was identified in 1.87% (5/267) of all neonates. Multivariate regression anal-
ysis revealed that the presence of funisitis was independently associated with a “refer” on the
NHS test, whereas use of antenatal corticosteroids was statistically significantly associated
with a reduced incidence of “refer” on the screening test. Neither histologic chorioamnionitis
nor prematurity (as defined by low gestational age and birth weight) was associated with a
“refer” on the NHS test. By contrast, multivariate analysis with occurrence of SNHL as a depen-
dent variable identified no significant associations with the parameters studied, probably
owing to the small total number of neonates with permanent SNHL.

* Corresponding author. Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, 82, Gumi-ro 173 Beon-gil,
Bundang-gu, Seongnam 463-707, South Korea.
E-mail address: pkh0419@snubh.org (K.H. Park).
c
These authors contributed equally to this work.

http://dx.doi.org/10.1016/j.pedneo.2016.05.003
1875-9572/Copyright ª 2016, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-
NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Maternal and placental factors of hearing loss 237

Conclusion: Presence of funisitis was significantly and independently associated with increased
risk of abnormal NHS results, while administration of antenatal corticosteroids was related to a
normal NHS result. These findings support the hypothesis that a systemic fetal inflammatory
response, manifested as funisitis, might play a role in the pathogenesis of SNHL in preterm ne-
onates.
Copyright ª 2016, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/).

1. Introduction significant SNHL.3,13 However, although a number of

It has been estimated that bilateral sensorineural hearing
loss (SNHL) occurs in approximately 1.86 of 1000 new-
borns.1 The prevalence of bilateral severe SNHL was pre-
viously reported to be 9.7% in neonates who survived with a
very low birth weight ( 1500 g) and 16.7% in neonates who
survived after neonatal seizure.2 Although the prevalence
of severe SNHL in very low birth weight or preterm neo-
nates has decreased in the past decade, it still remains
significant, ranging from 0% to 4%.3 The observed decline in
these numbers is due to the improvement in control of risk
factors such as infection and implementation of oxygen
supply monitoring at neonatal intensive care units (NICUs).
Many studies have addressed the causes of neonatal
SNHL. Morton and Nance1 reported that Mendelian genetic
causes accounted for at least 50e60% of cases of neonatal
SNHL. Furutate et al4 and Park et al5 reported that cyto-
megalovirus infection also accounted for 10e30% of
neonatal SNHL cases. In addition to genetic causes and
cytomegalovirus infection, Swigonski et al6 identified
exposure to ototoxic drugs as one of the most common risk
factors of neonatal SNHL. According to Borradori and col-
leagues,7 dopamine and furosemide are especially
dangerous ototoxic drugs associated with neonatal SNHL.
There have been reports suggesting that prematurity
itself is a cause of neonatal SNHL. Ari-Even Roth et al8
published the incidence of SNHL in neonates with
extremely low birth weight. Ten (3.0%) out of 337 such
neonates were documented to have a hearing impairment.
Of these, one infant (0.3%) showed bilateral moderate-to-
severe SNHL, while the other nine infants (2.7%) turned
out to have conductive hearing loss. Pereira et al9 sug-
gested that low gestational age (GA) and low birth weight
resulted in a higher rate of no response to transient-evoked
otoacoustic emission: the odds ratios for an abnormal
transient-evoked otoacoustic emission result were 1.76 and
1.58, respectively, in neonates with < 30 weeks of gesta-
tion and birth weight < 1500 g. Finally, a statistically sig-
nificant difference in the prevalence of SNHL was observed
between normal full-term neonates and premature neo-
nates (0.82% vs. 3.1%).9
In light of this higher prevalence of SNHL among pre-
mature neonates, several researchers tried to delineate
factors related to prematurity that contributed to the
increased risk of SNHL. Of neonatal factors, hyper-
bilirubinemia,10,11 surgical ligation of patent ductus arte-
riosus,12 and respiratory status (duration of ventilation and
oxygen treatment) appeared to be associated with
maternal conditions have been reported to be associated
with preterm birth (e.g., intrauterine infection and pre-
eclampsia), little information is available concerning
maternal risk factors for the development of SNHL. In
particular, several reports provided somewhat contradic-
tory results with regard to the role of histological cho-
rioamnionitis in the development of SNHL.12,14,15
In recent years, the technology and protocols of the
newborn hearing screening (NHS) test have been signifi-
cantly improved, which has made the NHS test the main
modality for early detection of SNHL. Accordingly, this
study aimed to identify maternal and placental risk factors
associated with abnormal NHS results and subsequently
confirmed SNHL in very preterm neonates.
2. Methods
This was a single-center retrospective cohort study of ne-
onates admitted to the NICU at Seoul National University
Bundang Hospital (Seongnam, Korea) from January 2004 to
January 2013. Since 2003, we have routinely performed
pathological examinations of the placenta for all cases of
preterm delivery at our institution and maintained a data-
base that prospectively collects clinical data on all ob-
stetric women and their neonates admitted to the NICU.
From this database, we retrospectively identified all
singleton infants born alive at  32.0 weeks of gestation
who: (1) survived for at least 90 days after birth; (2) un-
derwent hearing screening examinations; and (3) did not
have major congenital anomalies. We excluded neonates
without histologic examination of the placenta, twins or
higher-order multiple births, and out-born infants. GA was
calculated based on the last menstrual period and
confirmed by the first or second trimester ultrasound ex-
amination. The study was approved by the Institutional
Review Board (IRB) of the Seoul National University Bun-
dang Hospital (IRB number: B-1006/103-102). The require-
ment to obtain informed consent was waived by the IRB.
Electronic medical records regarding hearing loss in one
or both ears of the included preterm singleton neonates
were reviewed twice by two audiologists (S.H.K and J.H.P.)
who were blinded to the maternal and neonatal details and
results of placental pathological examination. Either auto-
mated auditory brainstem response (ABR) or automated
otoacoustic emission (OAE) test was performed as an NHS
test, and the results were recorded as either “refer”
(further confirmatory tests needed) or “pass” (normal). As a
confirmatory test, auditory brainstem response threshold
238
was measured at the age of 3 months, and hearing
thresholds of  25 dB, 26e40 dB, 41e70 dB, and  71 dB
were regarded as normal, mild, moderate, and severe-to-
profound SNHL, respectively. Whereas the results of the
NHS test and final hearing status were expressed as the
number of ears and number of neonates; risk factors asso-
ciated with abnormal NHS results and SNHL were analyzed
individually. The primary outcome measure was a refer
result from one or both ears before hospital discharge,
whereas secondary outcome measure included SNHL
because its incidence has been reported to be rare in
literature.13,16
The following maternal factors were stored in the
database: (1) maternal age; (2) parity; (3) GA at admission;
(4) causes of preterm birth; (5) mode of delivery; (6)
antenatal use of medications; and (7) clinical diagnosis of
chorioamnionitis. Perinatal/neonatal characteristics
retrieved from the database included GA at birth, birth
weight, sex, Apgar scores at 1 minute and 5 minutes, um-
bilical artery pH, pathologic diagnoses of the placenta, use
of surfactant, use of mechanical ventilation, early-onset
neonatal sepsis, respiratory distress syndrome (RDS),
bronchopulmonary dysplasia, intraventricular hemorrhage
(IVH), periventricular leukomalacia, necrotizing enteroco-
litis, and seizure.
“Small for GA” was defined as having a birth weight
below the 10th percentile for a given GA based on the sex-
specific growth curves of Lee.17 The placental specimens
were processed in the Pathology Department according to
the protocol of the College of American Pathologists.18
Tissue samples of the placenta, which were obtained
from the placental membranes, umbilical cord, and chori-
onic plate, were fixed in 10% neutral-buffered formalin and
embedded in paraffin. Sections of the tissue blocks were
stained with hematoxylin and eosin. Histopathologic ex-
amination was performed by experienced board-certified
pathologists who were blinded to the clinical information.
The presence of acute inflammation was noted and classi-
fied as Grade 1 or 2 (Table 1) according to previously pub-
lished criteria.19 Acute histologic chorioamnionitis was
Table 1 Histological grade for acute intrauterine
inflammation.
Amnion & chorionedecidua
Grade 1: at least one focus of >5 neutrophils
Grade 2: diffuse neutrophilic infiltration
Umbilical cord
Grade 1: neutrophilic infiltration confined to
umbilical vessel wall
Grade 2: extension of neutrophilic infiltration
into Wharton’s jelly
Chorionic plate
Grade 1: >1 focus of at least 10 neutrophilic
collections or diffuse inflammation in subchorionic plate
Grade 2: diffuse & dense inflammation, neutrophilic infil-
tration into connective tissue of placental plate, or
placental vasculitis
S.H. Kim et al
defined as the presence of acute inflammatory change in
any tissue sample (amnion, chorionedecidua, umbilical
cord, or chorionic plate). Funisitis was diagnosed in the
presence of neutrophil infiltration into the umbilical vessel
walls or Wharton’s jelly. Clinical chorioamnionitis was
defined according to the criteria proposed by Gibbs et al.20
Early-onset sepsis, RDS, bronchopulmonary dysplasia, IVH,
bronchopulmonary dysplasia, and necrotizing enterocolitis
were diagnosed according to the definitions previously
described in detail.19,21e25
Data analyses were conducted using SPSS 20.0 for Win-
dows (IBM SPSS Statistics, Chicago, IL, USA). For bivariate
comparison, we used Student t test or the ManneWhitney U
test for continuous variables and the c2 test or Fisher’s
exact test for categorical variables, as appropriate. We also
used the ShapiroeWilk test to assess normality of contin-
uous variables. Multivariate logistic regression analysis was
then used to identify maternal and placental factors
significantly and independently associated with “refer” on
the NHS test and SNHL after controlling for potential
neonatal risk factors. Variables with p values < 0.15 in
bivariate analysis were included in logistic regression
analysis. All reported p values are two-sided, and a p < 0.05
was considered to indicate statistical significance.
3. Results
There were 9641 live singleton births at our tertiary referral
hospital during the study period, and 483 infants were born
at  32 weeks of gestation. Of these 483 infants, 116 died in
the delivery room, 50 died before the hearing screening
test, 13 were transferred to other hospitals prior to hearing
screening, 28 did not undergo hearing screening prior to
discharge, six did not have a record of placental pathology,
and three had major congenital malformations. After
exclusion of these infants, 267 preterm infants (534 ears)
were included in the analysis (Figure 1). The mean GA in the
study cohort was 29.4 weeks (standard deviation:
2.0 weeks, range: 23.6e32.0 weeks), and the mean birth
weight was 1349 g (standard deviation: 520 g, range:
465e2105 g).
Of these 267 preterm neonates (534 ears), 63 ears of 42
neonates [11.8% (63/534) and 15.7% (42/267)] showed
“refer” on the NHS test. With regards to the screening
tests, 32 ears of 21 neonates [7.4% (32/434) and 9.70% (21/
217)] showed “refer” on the automated ABR, and 33 ears of
21 neonates [33% (33/100) and 42% (21/50)] showed “refer”
on the automated OAE. SNHL was detected on the confir-
mation test for eight ears from five neonates [1.5% (8/534)
and 1.9% (5/267)], including four with mild SNHL and one
with moderate SNHL. Three neonates showed bilateral
SNHL and the remaining two neonates showed unilateral
SNHL. All of these five neonates showed “refer” on the
automated ABR (2 neonates) or automated OAE (3
neonates).
Table 2 summarizes the relations of maternal and ob-
stetric characteristics with the risk of abnormal findings on
the NHS test and confirmation test among the 267 neo-
nates. Mothers who delivered neonates that showed “refer”
on the NHS test were less likely to have received antenatal
corticosteroids than mothers who delivered neonates that
Maternal and placental factors of hearing loss
Figure 1 Flow chart of the study population and newborn hearing screening outcomes. ABR Z auditory brainstem response;
GA Z gestational age.
showed normal NHS results. Moreover, mothers who deliv-
ered neonates with SNHL had a lower rate of cesarean
delivery than mothers who delivered neonates with normal
hearing, although this difference did not reach the level of
statistical significance (p Z 0.058).
Table 3 shows placental and other perinatal risk factors
in relation to abnormal findings on the NHS test and
confirmatory test among the 267 preterm neonates. Based
on the bivariate analyses, “small for GA” and Apgar scores
at 1 minute and 5 minutes appeared to be related to
“refer” on the NHS test (p Z 0.062, p Z 0.118, and
p Z 0.057, respectively). Presence of funisitis was
239
associated with “refer” on the NHS test and SNHL, although
without statistical significance (p Z 0.147 and p Z 0.058,
respectively). Neither GA at birth nor birth weight was
associated with abnormal NHS results or SNHL.
Table 4 displays neonatal characteristics and morbidities
in relation to abnormal findings on the NHS test and
confirmatory test among the 267 preterm neonates. Use of
mechanical ventilation and use of surfactant appeared to
be related to “refer” on the NHS test (p Z 0.123 and
p Z 0.092, respectively). Neonatal seizure had a statisti-
cally significant association with “refer” on the NHS test
(p Z 0.024). Although occurrence of early-onset neonatal
240 S.H. Kim et al

Table 2 Maternal and obstetric factors in relation to abnormal findings of hearing screening test and confirmation test among
267 neonates.
Variables Abnormal finding in hearing p Hearing loss as documented p
screening test by confirmation test
Absent Present Absent Present
No. of infants 225 42 262 5
Maternal age (y) 31.9  3.9 32.1  4.3 0.690 31.9  4.0 29.8  1.9 0.233
Nulliparity 111 (49.3) 20 (47.6) 0.838 127 (48.5) 4 (80.0) 0.207
Cause of preterm delivery
Preterm labor 86 (38.2) 11 (26.2) 0.522 95 (36.3) 2 (40.0) 0.971
PROM 83 (36.9) 18 (42.9) 99 (37.8) 2 (40.0)
Pre-eclampsia 47 (20.9) 11 (26.2) 57 (21.8) 1 (20.0)
Others 9 (4.0) 2 (4.8) 11 (4.2) 0 (0.0)
Cesarean delivery 145 (64.4) 26 (61.9) 0.753 170 (64.9) 1 (20.0) 0.058
Antenatal corticosteroids 195 (86.7) 30 (71.4) 0.010* 221 (84.3) 4 (80.0) 0.570
Antenatal antibiotics, n (%) 120 (53.3) 25 (59.5) 0.460 142 (54.2) 3 (60.0) >0.99
Antenatal otocolytics, 131 (58.2) 21 (50.0) 0.323 149 (56.9) 3 (60.0) >0.99
Antenatal magnesium 56 (24.9) 11 (26.2) 0.846 65 (24.8) 2 (40.0) 0.599
sulfate
Gestational age at 28.4  2.4 27.9  2.8 0.172 28.3  2.4 27.7  2.1 0.540
admission (wk)
Clinical chorioamnionitis 14 (6.2) 5 (11.9) 0.189 18 (6.9) 1 (20.0) 0.311
Data are presented as mean  standard deviation or n (%).
* p < 0.05.
PROM Z premature rupture of membranes.

sepsis seemed to have some association with SNHL, it was
not significant (p Z 0.057).
Multivariate logistic regression analysis was performed
to identify maternal and placental risk factors that had
significant and independent associations with “refer” on
the NHS test or SNHL after controlling for potential
neonatal risk factors (Table 5). In the multivariable model,
presence of funisitis was independently associated with
“refer” on the NHS test (p Z 0.033), whereas use of
antenatal corticosteroids was statistically significantly
associated with a reduced incidence of “refer” (p Z 0.036).
By contrast, multivariate analysis with SNHL as a dependent
variable revealed no significant associations with the pa-
rameters studied, likely owing to the small total number of
affected patients.
Because of a significant difference in the referral rates
between automated ABR and OAE screen tests, we analyzed
the data separately stratified by the hearing screen tests
employed. In both the subgroup using the automated ABR
and the subgroup using the OAE test as the NHS test,

Table 3 Placental and other perinatal risk factors in relation to abnormal findings of hearing screening test and confirmation
test among 267 neonates.
Variables Abnormal finding in hearing screening test p Hearing loss as documented p
by confirmation test
Absent Present Absent Present
No. of infants 225 42 262 5
Gestational age at birth (wk) 29.3  1.9 28.9  2.1 0.230 29.3  1.9 28.6  2.7 0.421
Birth weight (g) 1289  356 1252  415 0.546 1286  363 1129  497 0.343
Small for gestational 31 (13.8) 11 (26.2) 0.062 40 (15.3) 2 (40) 0.177
age (<10th percentile)
Male sex 117 (52.0) 27 (64.3) 0.178 140 (53.4) 4 (80) 0.378
Apgar score <7
1 min 166 (73.8) 36 (85.7) 0.118 197 (75.2) 5 (100) 0.340
5 min 81 (36.0) 22 (52.4) 0.057 102 (38.9) 1 (20) 0.652
Umbilical artery pH 7.286  0.065 7.276  0.098 0.404 7.284  0.071 7.306  0.057 0.604
(n Z 208) (n Z 36) (n Z 241) (n Z 3)
Histologic chorioamnionitis 107 (47.6) 21 (50.0) 0.771 125 (47.7) 3 (60.0) 0.673
Funisitis 42 (18.7) 12 (28.6) 0.147 51 (19.5) 3 (60.0) 0.058
Data are presented as mean  standard deviation or n (%).
Maternal and placental factors of hearing loss 241

Table 4 Neonatal characteristics and morbidities in relation to abnormal findings of hearing screening test and confirmation
test among 267 neonates.
Variables Abnormal finding in hearing screening test p Hearing loss as documented p
by confirmation test
Absent Present Absent Present
No. of infants 225 42 262 5
Continuous positive 188 (83.6) 34 (81.0) 0.657 218 (83.2) 4 (80) >0.99
airway pressure
Mechanical ventilation 130 (57.8) 30 (71.4) 0.123 157 (59.9) 3 (60) >0.99
Use of surfactant 100 (44.4) 25 (59.5) 0.092 122 (46.6) 3 (60) 0.668
Early-onset neonatal sepsis 54 (24.0) 16 (38.1) 0.057 67 (25.6) 3 (60) 0.115
Respiratory distress syndrome 129 (57.3) 26 (61.9) 0.614 152 (58.0) 3 (60.0) >0.99
Bronchopulmonary dysplasia 94 (41.8) 20 (47.6) 0.482 111 (42.4) 3 (60) 0.654
Intraventricular hemorrhage, 13 (5.8) 2 (4.8) >0.99 15 (5.7) 0 (0) >0.99
Grade 2
Periventricular leukomalacia 35 (15.6) 9 (21.4) 0.346 43 (16.4) 1 (20.0) >0.99
Necrotizing enterocolitis 13 (5.8) 1 (2.4) 0.365 14 (5.3) 0 (0) >0.99
Seizure 0 (0) 2 (4.8) 0.024* 2 (0.8) 0 (0) >0.99
Data are presented as mean  standard deviation or n (%).
*p < 0.05.

multivariate analyses did not reveal any significant associ-
ation between any of the parameters studied and hearing
screening failure.
4. Discussion
This study clearly demonstrated that presence of funisitis
significantly and independently increased the probability of
abnormal NHS results in very preterm infants, while
administration of antenatal corticosteroids increased the
probability of a normal NHS result. By contrast, neither
presence of histologic chorioamnionitis nor prematurity
(i.e., low GA and birth weight) was associated with an
abnormal NHS result. These findings support the hypothesis
that a systemic fetal inflammatory response, manifested by
funisitis, may play a role in the pathogenesis of hearing loss
and suggest that therapeutic interventions to prevent
hearing loss in preterm neonates may need to begin prior to
delivery.
It is generally accepted that postnatal infection/
inflammation, including sepsis and meningitis, can play a
role in the pathogenesis of hearing loss in neonates.26
However, it remains unclear whether prenatal exposure
to infection/inflammation may adversely affect ear devel-
opment and lead to pathological processes implicated in
hearing loss in preterm neonates. In this regard, our find-
ings confirm the lack of association between histologic
chorioamnionitis and either “refer” on the NHS test or SNHL
shown in other studies.12,15 We also found no association
between clinical chorioamnionitis and abnormal hearing
test results. These findings are consistent with the results
of Pappas et al,16 who demonstrated that infants exposed
to histological and clinical chorioamnionitis were not at a

Table 5 Risk factors associated with abnormal findings of hearing screening test and confirmation test according to logistic
regression analysis among 267 neonates.
Risk factors Abnormal finding in hearing screening test Hearing loss as documented by confirmation test
p OR (95% CI) p OR (95% CI)
Cesarean delivery NM 0.121 0.152 (0.014e1.643)
Antenatal corticosteroids 0.025* 0.371 (0.156e0.883) NM
Small for gestational 0.107 2.199 (0.843e5.739) NM
age (<10th percentile)
Apgar score <7 at 1 min 0.250 1.901 (0.636e5.681) NM
Apgar score <7 at 5 min 0.593 1.255 (0.545e2.891) NM
Funisitis 0.017* 2.768 (1.200e6.384) 0.229 3.319 (0.471e23.403)
Mechanical ventilation 0.735 1.204 (0.410e3.536) NM
Use of surfactant 0.810 1.132 (0.412e3.113) NM
Early onset neonatal sepsis 0.820 1.106 (0.465e2.629) 0.061 6.035 (0.922e39.492)
Seizure 0.999 (0.000e7.562  109) NM
CI Z confidence interval; NM Z not modeled; OR Z odds ratio.
*p < 0.05.
242
higher risk of permanent hearing loss compared with those
with no chorioamnionitis or histologic chorioamnionitis
alone. Collectively, these observations suggest that
maternal systemic and local inflammatory response in the
fetoplacental unit may not be implicated in the patho-
physiological mechanism of hearing loss development.
In contrast to chorioamnionitis, we found that funisitis
was independently associated with “refer” on the NHS test
after adjustment for potential confounders. In addition,
funisitis also tended to be associated with increased inci-
dence of SNHL in univariate analysis, although this trend
did not reach the level of statistical significance. These
findings are in line with the results of a previous report15
and are to be expected given the strong association be-
tween severity of fetal vasculitis and multiple neuro-
developmental impairments (including hearing loss), which
can be anticipated to cause significant SNHL, in extremely
preterm infants.27 Similarly, with regards to markers of
systemic inflammation in the fetus other than funisitis,
Leung et al15 reported that elevated interleukin-6 (IL-6)
level in cord blood, but not IL-1b and tumor necrosis factor
level, was significantly associated with an increased risk of
hearing screen failure. Collectively, these findings suggest
that prenatal exposure to inflammation may damage the
immature inner ear when fetal inflammatory response is
present. In contrast to maternal inflammatory response,
fetal inflammatory response, defined as an elevated cord
IL-6 level or fetal vasculitis, has been reported to signifi-
cantly increase the risk of white matter injury, cerebral
palsy, and neuropsychiatric disease in the context of fetal
brain.28
In the literature, low GA at birth and low birth weight as
indicators of prematurity have been reported to be
important risk factors for “refer” on the NHS test or hearing
loss.15,29,30 However, we found that neither GA nor birth
weight was associated with an abnormal NHS result and
SNHL, which is in agreement with results of other studies
that utilized multivariable analyses.12,31 The reason for this
discrepancy is not clear, but it may be related to different
cutoffs for low GA used during the enrollment. In this re-
gard, the effect of prematurity on hearing loss is expected
to be largest in a study that includes both advanced GA and
extremely low GA infants; this effect will be obscured in a
study that involves exclusively extremely immature neo-
nates. Indeed, neonates in our study were delivered at
earlier GA and had lower birth weight than those in the
studies showing a significant association between prema-
turity and hearing loss.15,29,30 Likewise, our finding that low
Apgar scores at 1 minute and 5 minutes were not associated
with “refer” on the NHS test or SNHL differs from the
findings of previous studies.15,29 The same explanation may
apply because 1-minute and 5-minute Apgar scores are
directly inversely related to GA and birth weight.32 Similar
to low Apgar scores, umbilical artery pH, the most objec-
tive parameter reflecting fetal metabolic condition at
birth, was not associated with “refer” on the NHS test or
SNHL. These observations indicate that fetal hypoxia may
not be implicated in the pathogenesis of hearing loss.
Previous studies have demonstrated that antenatal cor-
ticosteroids reduce occurrence of RDS, IVH, neurologic
morbidity, and neonatal mortality.33,34 In the context of
hearing loss, we found that use of antenatal corticosteroids
S.H. Kim et al
was significantly associated with a reduced probability of
“refer” on the NHS test. This observation is consistent with
the outcome of the recent report by Leung et al15 but
contradicts the results of Waters et al,31 who demonstrated
that use of antenatal steroids was not associated with a
positive or negative effect on hearing assessment of very
low birth weight infants. Although we cannot explicitly
explain the discrepancies among the studies, they are likely
related to the corticosteroid type (dexamethasone vs.
betamethasone) and regimen (single vs. multiple courses)
and whether the course was completed. In support of this
view, Lee et al35 found that prenatal betamethasone
administration reduced, while that of dexamethasone
increased the risk of hearing impairment in extremely low
birth weight infants. Church et al36 also found that
repeated antenatal corticosteroids treatments had a
harmful effect on ABR of offspring in an animal (rat) model.
The rates of “refer” on the NHS test and SNHL (15.7% and
1.9%) obtained in the current study are similar to those of
recent large-scale studies.13,15,16,37 In agreement with a
previous study,15 we found that prenatal use of antibiotics
did not affect NHS outcomes. The sensitivity and specificity
of the NHS test have improved significantly since its
implementation. This justifies our use of “refer” rate on the
NHS test as one of the main outcome variables. Indeed,
“refer” on the NHS test has facilitated the implementation
of the hearing confirmatory test and early intervention.
With the advent of the NHS test, the average age at which
hearing loss is confirmed has decreased from 24e30 months
to 2e3 months.38
The current study has several limitations. Firstly, the
study is limited by its retrospective nature, although all the
maternal and placental data were prospectively collected
in a computerized perinatal database. Secondly, the anal-
ysis of placental risk factors was limited to characteristics
of placental inflammation. Other, noninflammatory
placental factors such as placental vascular disorders and
coagulation-related lesions of the placenta (e.g., throm-
botic vasculopathy) might be associated with poor hearing
outcomes in preterm neonates. Thirdly, study patients
were recruited over a 9-year period to accumulate a large
number of cases. Accordingly, improvements in preterm
newborn care achieved during this long study period may
have resulted in better hearing outcomes later in the data
collection phase, possibly leading to certain bias toward/
against the impact of various risk factors on hearing loss.
Fourthly, prenatal risk factors of SNHL could not be pre-
cisely evaluated because of the low prevalence of SNHL,
although it was possible to identify a group at high risk of
SNHL. Fifthly, two screening tests with significantly
different “refer” rates, which is in accordance with the
previous study of Lin et al,39 were conducted during the
study period. However, the higher referral rate of auto-
mated OAE may be partially attributed to the higher inci-
dence of SNHL among neonates that showed “refer” on the
automated OAE [6% (3/50)] compared with the SNHL inci-
dence [0.9% (2/217)] among neonates that showed “refer”
on the automated ABR.
In conclusion, the presence of funisitis significantly and
independently increased the probability of abnormal NHS
results, while use of antenatal corticosteroids reduced this
probability. Future studies are needed to elucidate the
Maternal and placental factors of hearing loss
underlying mechanisms of these associations and to inves-
tigate the impact of prenatal treatment on NHS outcomes
and hearing impairment in neonates.
Conflict of interest
The authors have no conflict of interest to disclose.
Acknowledgments
This research was supported by a grant of the Korea Health
Technology R&D Project through the Korea Health Industry
Development Institute, funded by the Ministry of Health
and Welfare, Republic of Korea (Grant No. HI 14C1798). This
fund did not any influence on study design, data collection,
analysis, or interpretations.
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