Taiwanese Journal of Obstetrics & Gynecology 59 (2020) 744e747

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Case Report

Polyhydramnios is associated with postnatal dysphagia determining

short-term prognosis of the newborn with 22q11.2 deletion syndrome
- A case series analysis
Tamae Nabeshima, Tatsuya Fujii*, Takeshi Nagamatsu, Ayako Hashimoto,
Takahiro Seyama, Kaori Kubota, Seisuke Sayama, Toshio Nakayama, Keiichi Kumasawa,
Takayuki Iriyama, Yutaka Osuga, Tomoyuki Fujii
Department of Obstetrics and Gynecology, Faculty of Medicine, Japan

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

Article history: Objective: We experienced a case of 22q11.2 deletion syndrome (22qDS), with severe polyhydramnios,
Accepted 1 April 2020 and dysphagia, which prompted us to review prognosis in neonates with 22qDS, with a focus on
dysphagia.
Keywords: Case report: A patient was referred to our hospital at 35 gestational weeks because of polyhydramnios.
Dysphagia After amniotic fluid reduction, labor was induced at 38 weeks. The neonate had serious dysphagia, and
Prognosis
22qDS was diagnosed postnatally by fluorescent in situ hybridization analysis. This prompted a retro-
Polyhydramnios
spective analysis of 9 cases with 22qDS experienced in our facility. Three out of these nine cases showed
polyhydramnios, and had severe dysphagia postnatally. In total, 4 cases had dysphagia, while mortality
was observed in 2 of these 4 cases. Additionally, 5 cases without dysphagia had normal development and
no major complications.
Conclusion: Polyhydramnios associated with postnatal dysphagia might be a risk factor related to short-
term prognostic outcomes in newborns with 22qDS.
© 2020 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction A previous study has identified cardiac disorders as one of

22q11.2 deletion syndrome (22qDS) is the most frequent
microdeletion disorder, occurring in approximately 1 out of 1000
fetuses [1]. The 22q11.2 region contains about 30 genes, of which
TBX1 has been studied extensively. TBX1 deficiency causes conical
duct malformations, hypoparathyroidism, thymus hypoplasia, and
palatal hypoplasia [2]. Typically, there is a 3 MB deletion in the 11.2
region of the long arm of chromosome 22. However, chromosomal
deletion is not uniform, and can sometimes be as small as 0.7 MB.
Lack of genotypeephenotype correlation makes prognosis difficult
in neonates based on genetic tests alone [3]. This necessitates a
functional evaluation of different organs in neonates with such
chromosomal aberration.
Abbreviation: 22qDS, 22q11.2 deletion syndrome.
* Corresponding author. Department of Obstetrics and Gynecology, Faculty of
Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo Ward, Tokyo, 113-8655,
Japan. Fax: 03 3816 2017.
E-mail address: ta2ya0164@gmail.com (T. Fujii).
prominent factors associated with long-term outcome in the
newborns with 22qDS [4]. However, little is known about short-
term prognosis of this disorder. A case with polyhydramnios and
severe dysphagia that was difficult to manage after birth, although
no obvious intracardiac malformations, was found to be associated
with 22qDS at our hospital. This observation prompted retrospec-
tive analyses of 9 cases with 22qDS previously admitted in our
hospital, with a focus on polyhydramnios and dysphagia.
Case presentation
The patient was 30 years old, gravida two, para one. She had a
normal vaginal delivery five years ago. There were no past medical
history and family history. She got pregnant naturally and visited
our hospital at 35 gestational weeks because of polyhydramnios.
The amniotic fluid index (AFI) was 41 and ultrasonography was
used to monitor the right aortic arch (RAA) and right arterial duct of
the fetus (Fig. 1). Gastric bubbles were confirmed, and there were
no vomiting reflexes during the ultrasound observation. No other

https://doi.org/10.1016/j.tjog.2020.07.021
1028-4559/© 2020 Taiwan Association of Obstetrics & Gynecology. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
 T. Nabeshima et al. / Taiwanese Journal of Obstetrics & Gynecology 59 (2020) 744e747 745

Fig. 1. Transabdominal ultrasound findings at 35 gestational weeks. White arrow indicates right aortic arch.

disorders resulting in polyhydramnios were diagnosed. The cervix
length was maintained at 24 mm while the 75 g oral glucose
tolerance test (OGTT) was negative. The estimated fetal body
weight was around
1.5 standard deviation (SD).
A total of 1625 mL of amniotic fluid was removed trans-
abdominally due to abdominal distention. However, the amount of
amniotic fluid increased gradually after first amniotic fluid
removal, and we decided on a planned delivery at 38 gestational
weeks. We removed 1000 mL of amniotic fluid again and started
induction of labor the next day. However, 12 min of bradycardia
was noticed following the onset of labor. As a result, we performed
an emergency cesarean section for non-reassuring fetal status
(NRFS). The bradycardia most likely resulted from a placental
abruption. The newborn was female, with 2377 g body weight.
One and 5 min Apgar scores were eight and nine points, respec-
tively. The umbilical artery blood pH was 7.1 and there were no
obvious malformations in external observation. The medical con-
dition of the mother after cesarean section was good, but the
neonate needed to admit at the neonatal intensive care unit (NICU)
for further examinations.
After admission, a small ventricular septal defect, along with
right aortic arch and right arterial duct abnormalities were diag-
nosed. The neonate needed treatment for hypocalcemia due to
hypoparathyroidism. On the second day after birth, severe
dysphagia occurred and repeated treatments for pneumonia were
required in the following days. Posterior nasal dysfunction and
gastroesophageal reflux were pointed out as abnormal findings
possibly related the development of those respiratory problems.
Chromosome analysis was performed on day 17. Fluorescent in situ
hybridization (FISH) analysis detected only one allele in the 22q11.2
region, confirming the diagnosis of 22qDS.
She was discharged three months after birth. However, oral
ingestion was difficult and required tube feeding, prophylactic
antimicrobial administration and assisted supply of oxygen.
Case series
We retrospectively analyzed 9 newborns diagnosed with 22qDS
between 2002 and 2019 in our hospital. This study was conducted
under approval of the institutional research ethics committee.
Among these infants, 5 were born in our hospital, and 4 newborns
were transferred from other hospitals. The average age of preg-
nancy was 27.3 years, and eight newborns (89%) resulted from
natural conception. Since the second trimester, fetal heart malfor-
mations had been pointed out in five cases (56%) and poly-
hydramnios in three cases (33%) (Table 1). Eight newborns had de
novo onset of the 22qDS, while one newborn had a maternal in-
heritance of the same. The 22qDS was diagnosed postnatally in all
cases. The average week of labor was 38 weeks and 3 days.
Although the forceps delivery rate was high (56%), umbilical artery
blood pH and the Apgar score were relatively normal. Conotruncal
heart malformations were diagnosed in all cases (Table 2).
Dysphagia occurred postnatally in all three patients with poly-
hydramnios. In contrast, only one among the six patients without
polyhydramnios had nasopharyngeal insufficiency and dysphagia
(Table 2). The newborn shown in this case report required two
amniotic fluid removals as severe polyhydramnios (AFI 41).
Dysphagia was most severe in this case. Two other polyhydramnios

Table 1
Maternal characteristics and pregnancy courses.

Case Age Gz P¶ Mode of Conception Complication Findings Indicated weeks Gestation weeks Delivery method

1 30 2 1 Natural None Polyhydramnios, Fetal heart malformation 32w2d 38w3d emCSy

2 19 1 0 Natural VSDyy, Polyhydramnios, Fetal heart malformation About 30w 35w5d emCSy
Umbilical hernia
3 20 1 0 Natural None Polyhydramnios unknown 36w6d emCSy
4 23 2 0 Natural Unknown None After birth 38w3d NVDjj
5 33 1 0 Natural 22qDS s/o Fetal heart malformation 25w1d 38w3d vacuum extraction
6 30 1 0 Unknown Unknown Unknown Unknown 39w1d NVDjj
7 34 1 0 IVF-ETx None Fetal heart malformation 28w5d 39w2d NVDjj
8 30 1 0 Natural Cervical lipoma Fetal heart malformation 29w2d 39w1d NVDjj
9 27 3 0 Natural None None None 34w4d emCSy

emCSy:emergency caesarean section, Gz:Gravida, IVF-ETx:in vitro fertilization-embryo transfer, NVDjj:normal vaginal delivery, P¶:Para, VSDyy:ventricular septal defect.
746 T. Nabeshima et al. / Taiwanese Journal of Obstetrics & Gynecology 59 (2020) 744e747
Table 2
Fetal and newborn findings and turning points.
Case Findings and Clinical course
Birth weight (g) Dysphagia Polyhydramnios Cardiac anomaly
/ Surgical intervention
1 2377   VSDzzz, RAA¶¶
2 2217   PA/VSDxx, MAPCA¶, RAA¶¶
3 2529   PA/VSDxx, MAPCA¶, RAA¶¶
4 2468  IAAx(typeB), VSDzzz, ASDy
/ PAzz-banding þ Aortic reconstruction
5 3305 TOFyyy
6 2740 TOFyyy, PAzz, lt-PA coarctationjj
/ BT shuntz þ PTPAjjjj
7 3053 PA/VSDxx, MAPCA¶
8 2951 RAA¶¶, PA/VSDxx, MAPCA¶
9 1356 ASDy, VSDzzz
ASDy: atrial septal defect, BT shuntz: Blalock-Taussig shunt, IAAx:interrupted aortic arch, lt-PA coarctationjj: left pulmonary artery coarctation, MAPCA¶: major aortopulmonary
collateral artery, Moyy: months, PAzz: pulmonary atresia, PA/VSDxx:pulmonary atresia with ventricular septal defect, PTPAjjjj:percutaneous transluminal pulmonary angio-
plasty, RAA¶¶:right aortic arch, TOFyyy: tetralogy of Fallot, VSDzzz:ventricular septal defect, Yxxx: years.
cases with AFI 30e35 did not require amniotic fluid removal and
dysphagia after birth were not severe compared to the above case.
These data collectively indicate that AFI index correlates with
severity of dysphagia.
Among the four newborns with dysphagia, two died within 6
years after birth. Neither dysphagia nor cardiac malformations
directly resulted in these mortalities. Of the two surviving new-
borns, one is the case we showed in the case report. While it was
not possible to obtained detailed information on the other
newborn. In cases without dysphagia, oxygen administration was
required in one out of five cases, though all cases showed relatively
normal development (Table 2).
Discussion
A patient in our hospital with 22qDS required multiple amniotic
fluid removals and had severe dysphagia after birth. Prenatal ul-
trasound revealed a RAA, however, no other intracardiac abnor-
malities were observed. The diagnosis of 22qDS was made
postnatally. All nine cases of 22qDS reported in this study were
diagnosed postnatally in our hospital. About 70e80% of 22qDS
cases are generally associated with complicated cardiac structural
abnormalities [5], such as tetralogy of Fallot and aortic arch ab-
normalities. RAA is observed in about 10% of 22qDS cases [6] and
while 22qDS is observed in 6.1% of all RAA cases without intracar-
diac malformations [7]. As such, there is a positive correlation be-
tween these disorders. Additionally, increased nuchal translucency
is a well-known sign for chromosomal aneuploidies. However, not
all fetuses with increased nuchal translucency in early pregnancy
without structural abnormalities are diagnosed with 22qDS [8].
Thymic hypoplasia with congenital heart abnormalities might
provide a clue for prenatal diagnosis of 22qDS. In addition, poly-
hydramnios can be observed in only 33% cases of 22qDS [9].
Therefore, the presence of polyhydramnios along with congenital
heart disorders and thymic hypoplasia might provide robust in-
dications for prenatal diagnosis of 22qDS. Cell-free DNA analysis of
maternal peripheral blood can not only diagnose chromosomal
abnormalities but also microdeletions. With its low positive pre-
dictive value, cell-free DNA analysis targeting 22qDS is not appro-
priate for pregnant women at low risk showing normal fetal
structure under ultrasonography. Thus, cell-free DNA analysis is not
currently recommended for prenatal screening [10]. The advantage
of prenatal diagnosis of 22qDS is that it can prevent seizures
resulting from hypocalcemia, leading to overall better prognosis
and long-term development in affected newborns [11]. As noted
Nasopharyngeal Thymus Specific facial Outcome
insufficiency hypoplasia features
   Alive
   Alive
  Death at 6Yxxx
 Unknown  Death at 6Moyy
  Alive
  Alive
  Alive
Unknown Unknown Alive
  Alive
above, the phenotype of 22qDS is so diverse that genetic testing
alone cannot adequately predict postnatal status. However, a
French cohort study reported that 69% of pregnant women with a
prenatal diagnosis of 22qDS opted for artificial abortion [12].
Therefore, prenatal diagnosis of 22qDS must be accompanied with
sufficient genetic counseling to guide parental decision-making
process.
Our analysis of patients with 22qDS showed that dysphagia
occurs more frequently in patients with polyhydramnios. In addi-
tion, the prognostic outcomes in neonates with dysphagia were
worse than in neonates without dysphagia. Besseau-Ayasse et al.,
reported that 9.2% of 22qDS cases were associated with poly-
hydramnios [12]. Approximately 30% of 22qDS have been reported
to have dysphagia derived from the third and fourth gill arches [13].
Thus, premature dysphagia is estimated to be related to poly-
hydramnios. In the present case, severe nasopharyngeal insuffi-
ciency and gastroesophageal reflux disease were observed related
to dysphasia in the present case, although bronchial structural
abnormality was not detected. Varied types of upper respiratory
and gastrointestinal tract abnormalities could be were underlying
factors developing polyhydramnios in prenatal period. The reports
analyzing the effects of dysphagia and polyhydramnios in deter-
mining prognostic outcomes in newborns are limited. Sacca et al.
found that 71% of 22qDS patients had abnormal airway structure
and dysphagia, and as many as 30% cases required tracheostomy,
which affect overall mortality, morbidity, and developmental out-
comes of neonates [14,15] In this study, we found infant mortality
in 2 out of 4 cases with dysphagia. It has been proposed that
congenital cardiac diseases are determinant factor related to long-
term prognosis in 22qDS. In our case series analysis, dysphagia
rather than cardiac anomaly seemed to be associated with short-
term prognosis of the newborns with 22qDS.
Collectively, these data suggest that polyhydramnios and
dysphagia, as well as heart disease, could be important factors in
determining prognostic outcomes in infants with 22qDS.
Declaration of Competing Interest
All authors have no conflicts of interest.
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