Pulmonary Hypoplasia Caused by Fetal Ascites in Congenital Cytomegalovirus Infection Despite Fetal Therapy

Abstract

We report two cases of pulmonary hypoplasia due to fetal ascites in symptomatic congenital cytomegalovirus (CMV) infections despite fetal therapy. The patients died soon after birth. The pathogenesis of pulmonary hypoplasia in our cases might be thoracic compression due to massive fetal ascites as a result of liver insufficiency. Despite aggressive fetal treatment, including multiple immunoglobulin administration, which was supposed to diminish the pathogenic effects of CMV either by neutralization or immunomodulatory effects, the fetal ascites was uncontrollable. To prevent development of pulmonary hypoplasia in symptomatic congenital CMV infections, further fetal intervention to reduce ascites should be considered.

Full text

November 2017 | Volume 5 | Article 2411
CASE REPORT
published: 06 November 2017
doi: 10.3389/fped.2017.00241
Frontiers in Pediatrics | www.frontiersin.org
Edited by:
Heber C. Nielsen,
Tufts Medical Center,
United States
Reviewed by:
MaryAnn Volpe,
Tufts University School of Medicine,
United States
Flore Rozenberg,
Université Paris Descartes, France
*Correspondence:
Kazumichi Fujioka
fujiokak@med.kobe-u.ac.jp
†These authors have contributed
equally to this work.
Specialty section:
This article was submitted
to Neonatology,
a section of the journal
Frontiers in Pediatrics
Received: 01September2017
Accepted: 24October2017
Published: 06November2017
Citation:
FujiokaK, MoriokaI, NishidaK,
MorizaneM, TanimuraK, DeguchiM,
IijimaK and YamadaH (2017)
Pulmonary Hypoplasia Caused
by Fetal Ascites in Congenital
Cytomegalovirus Infection
Despite Fetal Therapy.
Front. Pediatr. 5:241.
doi: 10.3389/fped.2017.00241
Pulmonary Hypoplasia Caused by
Fetal Ascites in Congenital
Cytomegalovirus Infection Despite
Fetal Therapy
Kazumichi Fujioka1*†, Ichiro Morioka1†, Kosuke Nishida1, Mayumi Morizane2,
Kenji Tanimura2, Masashi Deguchi2, Kazumoto Iijima1 and Hideto Yamada2
1 Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan, 2 Department of Obstetrics and
Gynecology, Kobe University Graduate School of Medicine, Kobe, Japan
We report two cases of pulmonary hypoplasia due to fetal ascites in symptomatic con-
genital cytomegalovirus (CMV) infections despite fetal therapy. The patients died soon
after birth. The pathogenesis of pulmonary hypoplasia in our cases might be thoracic
compression due to massive fetal ascites as a result of liver insufficiency. Despite
aggressive fetal treatment, including multiple immunoglobulin administration, which
was supposed to diminish the pathogenic effects of CMV either by neutralization or
immunomodulatory effects, the fetal ascites was uncontrollable. To prevent development
of pulmonary hypoplasia in symptomatic congenital CMV infections, further fetal inter-
vention to reduce ascites should be considered.
Keywords: congenital cytomegalovirus infection, pulmonary hypoplasia, fetal ascites, fetal therapy, newborn
INTRODUCTION
Pulmonary hypoplasia is a rare and devastating morbidity among newborns, resulting in mortality
up to 70% (1, 2). A pathological feature is an arrest in bronchial growth during fetal growth (3). e
pathogenesis of pulmonary hypoplasia is generally categorized into three mechanisms, including
thoracic compression, lack of fetal breathing movement, and loss of lung uid (4). Many causal
factors might lead to pulmonary hypoplasia, including intrathoracic masses, oligohydramnios,
skeletal malformations, neuromuscular malformations, pleural eusion, cardiac lesions, abdominal
wall defects, and chromosomal aberrations (2). Congenital cytomegalovirus (CMV) infection
occurs in 0.2–2.0% of live-born infants (5), and is a major non-genetic cause of deafness and
childhood neurodevelopmental disabilities (6). erefore, aiming at improvement of fetal/infantile
prognosis, Yamada and collaborators organized Japanese Congenital Cytomegalovirus Infection
Immunoglobulin Fetal erapy Study Group, and commenced multicenterded fetal therapy trial of
hype-immunoglobulin injection into the peritoneal cavity for symptomatic congenital CMV infec-
tions since 2005. And, we have reported a promising results that 41.7% of symptomatic congenital
CMV infections infants whose mothers received fetal therapies had no or minimal sequelae (7). us,
recently, we have actively performed fetal therapy to prenatally diagnosed symptomatic congenital
CMV infections with parental informed consent under approval of the institutional ethics boards of
the Kobe University Hospital.
Symptomatic cases manifest various features at birth, including small-for-gestational age, micro-
cephaly, thrombocytopenia, liver dysfunction, retinopathy, abnormal brain images, and abnormal
auditory brainstem responses (6–10). However, lung complications are uncommon in congenital
CMV infections (11).

FIGURE 1 | Images of case 1. Fetal magnetic resonance imaging shows massive ascites and compressed lungs (A). Chest X-ray (B) and postmortem chest CT (C)
show pulmonary hypoplasia.
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Fujioka et al. Pulmonary Hypoplasia in Congenital CMV Infections
Frontiers in Pediatrics | www.frontiersin.org November 2017 | Volume 5 | Article 241
We describe two cases of congenital CMV infections in
patients who suered from pulmonary hypoplasia due to massive
fetal ascites despite fetal therapy and died soon aer birth.
CASE HISTORY
Case 1
A 27-year-old woman (gravida 2, para 1) underwent a routine
ultrasound examination at 19 weeks’ gestation and fetal ascites
was observed. She was referred to a tertiary center and her serol-
ogy was positive for CMV-IgM. She was then transferred to our
center for further treatment. She was conrmed as having pri-
mary CMV infection during pregnancy by positive CMV-DNA
(3.4×105copies/ml) of fetal ascites and low CMV-IgG avidity
(16.6%) at 20 weeks’ gestation. Fetal magnetic resonance imag-
ing (MRI) at 27weeks showed massive ascites and compressed
low-intensity lungs (Figure1A). We performed fetal therapies,
including intravenous immunoglobulin to the mother [22, 24,
and 25 gestational weeks (GW)], ascites removal followed by
fetal intraperitoneal injection of immunoglobulin (20, 21, 23, 26,
27, and 29GW) and albumin (22, 26, 28, 30, and 31GW); and
amniotic uid removal for polyhydramnios, which occurred since
28weeks (28, 30, and 31 GW). At 31GW and 0 days, she gave
birth to a female neonate (birth weight of 1,824g; Apgar scores
of 4 and 6 at 1 and 5min, respectively) via emergent cesarean
section because of signs of threatened premature delivery aer
cordocentesis. e neonate was tracheally intubated soon aer
birth, and her heart rate gradually increased. Her abdomen was
massively distended with palpable uctuation, but no petechiae
were detected. A blood test showed mild leukopenia (3,800/μl),
anemia (86g/l), thrombocytopenia (6.1×104/μl), hypogamma-
globulinemia (3.46g/l), and hypoalbuminemia (24g/l). Despite
the normal aspartate aminotransferase (66 IU/l) and alanine
aminotransferase (5IU/l) levels, the level of total protein (29g/l),
brinogen (680 mg/l), and prothrombin time (<10%) were
signicantly decreased, suggesting liver failure from congenital
CMV infections. An X-ray showed marked reduction in lung
volume (Figure1B), with an increase in abdominal volume by
massive ascites. Abdominal echo revealed hepatomegaly and
brain echo revealed periventricular hyperechogenicity but could
not detect ventriculomegaly and calcications.
We removed 300ml of peritoneal uid by peritoneocentesis
to lower the lung compression. However, her respiratory status
gradually deteriorated, despite the highest ventilator settings,
with signs of persistent pulmonary hypertension. erefore, we
started inhaled nitric oxide 6 h aer birth, but she developed
pneumopericardium at 8h. At 14 h aer birth, she eventually
died because of pulmonary hypoplasia. Autopsy imaging showed
ventriculomegaly and intracranial calcication, in addition to a
reduced lung volume (Figure1C). Positive CMV-DNA (blood:
66 copies/106 white blood cells, urine: 1.2×107copies/ml) con-
rmed congenital CMV infection.
Case 2
A 30-year-old woman (gravida 3, para 1) had fetal ascites
detected at 22GW by occasional ultrasound with the complaint
of abdominal distension. Further investigation showed fetal
pericardial eusion and positive CMV-IgM. Because of positive

FIGURE 2 | Images of case 2. Fetal magnetic resonance imaging shows massive ascites, hepatomegaly, and compressed lungs (A). Postmortem chest (B) and
abdominal CT (C) show pulmonary hypoplasia and massive ascites with hepatomegaly.
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Fujioka et al. Pulmonary Hypoplasia in Congenital CMV Infections
Frontiers in Pediatrics | www.frontiersin.org November 2017 | Volume 5 | Article 241
CMV-DNA in the amniotic uid (3.4×106 copies/ml), she was
transferred to our center for further treatment at 24GW and
4 days. Fetal MRI at 30weeks showed massive ascites, hepa-
tomegaly, pericardial eusion, and compressed low-intensity
lungs (Figure 2A). We performed fetal therapies, including
intravenous immunoglobulin to the mother (24, 25, 26, and
30GW), ascites removal followed by fetal intraperitoneal injec-
tion of immunoglobulin at 28GW and albumin plus packed red
blood cells at 29GW to treat fetal anemia. At 31GW and 2days,
she gave birth to a female neonate (birth weight, 2,236g; Apgar
scores of 1 and 1 at 1 and 5min, respectively) via emergent
cesarean section because of non-reassuring fetal status. e
neonate was heavily edematous and had bradycardia at birth.
Her condition was diagnosed as hydrops fetalis based on the
generalized edema and massive ascites. She was resuscitated
with manual ventilation under inhaled nitric oxide and chest
compression. However, she did not respond to resuscitation
and died 20min aer birth. A blood test showed leukocytosis
(31,300/μl), anemia (41g/l), thrombocytopenia (2.4×104/μl),
hypogammaglobulinemia (1.51g/l), hypoalbuminemia (6.0g/l),
and increased aspartate aminotransferase levels (650 IU/l).
Abdominal echo revealed hepatomegaly with hyperechoic
lesions suggesting hemorrhage in the liver, and brain echo
revealed mild ventriculomegaly and hyperechoic lesions sug-
gesting calcications. Autopsy imaging showed pulmonary
hypoplasia, hepatomegaly, ascites, and intracranial calcication
(Figures 2B,C). Positive CMV-DNA (blood: 1.6 × 103 cop-
ies/106 white blood cells, tracheal aspirates: 4.5× 104 copies/
ml) conrmed congenital CMV infection.
DISCUSSION
Pulmonary hypoplasia is a rare condition, aecting 9–11/10,000
live births (1). e pathophysiology of pulmonary hypoplasia
is a reduction in the number of lung cells, airways, and alveoli,
resulting in a decrease in organ size and weight. ese factors are
highly correlated with insucient gas exchange (4). Diagnosis of
pulmonary hypoplasia is based on clinical ndings of respiratory
distress occurring almost secondary to other fetal anomalies
(1, 10). In addition, low-intensity fetal lung on MRI could be the
clues of pulmonary hypoplasia (12). ere have been no sucient
data regarding its impact on the neurodevelopmental outcome;
however, favorable outcomes at 5 years of ages were reported
in congenital diaphragmatic hernia, which is oen associated
with pulmonary hypoplasia (13). e most feasible pathogenesis
of pulmonary hypoplasia in our cases is thoracic compression
via massive ascites, which occurred from early pregnancy. e
greatest impairment of lung development occurs when compres-
sion occurs in the lungs during the last trimester (4). e fetal
lungs were highly compressed at this time in our cases. Extrinsic
thoracic compression usually occurs in oligohydramnios, where
the maternal uterine wall directly compresses the fetal thorax (4).
Our case 2 suered from hydrops fetalis, and Page and Stocker
reported this as the cause of pulmonary hypoplasia (14); however,
their cases were complicated with large pleural eusions or renal
dysplasia; two main causes of pulmonary hypoplasia via thoracic
compression or loss of lung uid. Our case 2 showed only mild
pericardial eusions but not pleural eusions, and we considered
that those could not aect the lung development signicantly as

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Fujioka et al. Pulmonary Hypoplasia in Congenital CMV Infections
Frontiers in Pediatrics | www.frontiersin.org November 2017 | Volume 5 | Article 241
space occupying lesions of the chest. us, we believe that not
hydrops fetalis itself, but its underlying mechanisms to develop
pulmonary hypoplasia is more important. In our cases, the volume
of ascites was so large that the fetal abdominal wall might not have
been able to extend further, resulting in strong compression of the
fetal thorax. Although fetal ascites is an uncommon complication
of congenital CMV infections, overt systemic disease might occur
as hepatosplenomegaly and ascites in the fetus as a result of liver
insuciency (15).
In lung complications of congenital CMV infections, a few
patients suering from persistent pulmonary hypertension have
been reported (16–18). However, their etiology was hypothesized
to be interstitial pneumonia or vasculitis, and not pulmonary
hypoplasia. Similar to our cases, Stocker reported an autopsy case
of congenital CMV infection presenting as massive ascites (28%
of total body weight) with secondary pulmonary hypoplasia (26%
of expected weight) that was diagnosed at postmortem (19). In
his study, CMV inclusion bodies were detected within the nucleus
and cytoplasm of the epithelial cells of the bile duct. Although we
could not perform the autopsy of the lungs due to unavailability
of parental consents, fetal MRI and autopsy imaging could add
sucient information regarding pulmonary hypoplasia.
Despite aggressive neonatal resuscitation, we could not res-
cue our patients. Additionally, multiple fetal therapies failed to
prevent development of pulmonary hypoplasia. Fetal treatment
with hyper-immunoglobulin was supposed to have neutralizing
eects by inhibiting the replication of CMV, or immunomodula-
tory eects by decreasing the immune cells associated with the
production of inammatory cytokines which can contribute to
immune-mediated fetal damages (20–22). We have previously
reported that (1) immunoglobulin fetal therapy could decrease
CMV DNA copy numbers in fetal ascites and (2) CMV viral
load is weaker in fetal ascites than in amniotic uid in congenital
CMV infections (7). With regard to viral load, CMV-DNA copy
numbers in amniotic uid of our two cases are comparable with
those in previous reports where fetal therapy caused a good
outcome (7). erefore, we believe that fetal treatment modality,
which consisted of ascites removal followed by administration of
immunoglobulin or albumin, was eective in controlling viral
load, but not eective for controlling the volume of fetal ascites.
CONCLUDING REMARKS
Pulmonary hypoplasia due to fetal ascites is a rare, but an
important, cause of neonatal death in congenital CMV infec-
tions. Further fetal intervention to control fetal ascites should be
considered.
ETHICS STATEMENT
Parental written informed consent was given to present cases. e
fetal therapy protocol was approved by the institutional ethics
boards of the Kobe University Hospital.
AUTHOR CONTRIBUTIONS
KF, IM, and KN managed the patients, contributed to the concep-
tion of the study, and draed the manuscripts; MM, KT, and MD
managed the mothers and performed the fetal therapy; and KI
and HY critically reviewed the manuscript. All authors read and
approved the nal manuscript.
FUNDING
is work was partially supported by the JSPS (grant nos:
16H06971 and 17H04341) and a grant for the Research on
Child Development and Diseases from AMED (grant nos:
16gk0110021s0101).
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Conict of Interest Statement: e authors declare that the research was
conducted in the absence of any commercial or nancial relationships that could
be construed as a potential conict of interest.
e reviewer MV and handling editor declared their shared aliation.
Copyright © 2017 Fujioka, Morioka, Nishida, Morizane, Tanimura, Deguchi, Iijima
and Yamada. is is an open-access article distributed under the terms of the Creative
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