MOLECULAR MEDICINE REPORTS 13: 2457-2466, 2016

Clinical features and survival in individuals with trisomy 18:
A retrospective one-center study of 44 patients
who received intensive care treatments
GEORGE IMATAKA, HIROSHI SUZUMURA and OSAMU ARISAKA
Department of Pediatrics, Dokkyo Medical University School of Medicine, Shimotsuga, Tocihgi 321‑0293, Japan
Received November 10, 2015; Accepted January 21, 2016
DOI: 10.3892/mmr.2016.4806
Abstract. Trisomy 18 syndrome is a common autosomal
aneuploidy chromosomal abnormality caused by the presenceof extra chromosome 18 that leads to malformations of various
parts of the body. In this study, we retrospectively investigated the effect of the medical progression and prognosis of
44 cases of trisomy 18, admitted to our neonatal intensive careunit between 1992 and 2013. The patients were divided into
group A (n=20, 1992‑2002) and group B (n=24, 2003‑2012).
Following delivery, karyotype, gender, gestational weeks,birth place, cesarean section, Apgar score and birth weight
were analyzed using the Fisher's exact test, unpaired t‑testand Mann‑Whitney U test. Based on the statistical results, acomparison was made of the two groups and no significant
differences were observed. Clinical data of major complications, mechanical ventilation, discharge from hospital andsurvival days were reviewed for the cases of trisomy 18. Of
the 44 patients, 42 had cardiac anomaly, 16 had esophageal
atresia, and 3 patients had brain anomaly. Ventilation treatment was performed in 29 cases (65.9%) and an increased
percentage was identified in group B patients. The percentage
survival was estimated using Kaplan‑Meier curves and thetwo groups were analyzed using the generalized Wilcoxon
test. Improvement in life prognosis was observed in group B
as compared to group A. The log‑rank test was used to assess
survey periods of 180 days, 1 year, and the entire observation period. Although significant differences were observed
for the prognosis of trisomy 18 at 180 days after birth, after
1 year and the entire survey period after birth, the significant differences were not confirmed. In conclusion, resultsof the present study provide information concerning genetic

Correspondence to: Dr George Imataka, Department of Pediatrics,
Dokkyo Medical University School of Medicine, 880 Kitakobayashi,
Shimotsuga, Tocihgi 321‑0293, JapanE‑mail: geo@dokkyomed.ac.jp

Key words: prognosis, natural history, trisomy 13, neonatal
intensive care unit, Edwards syndrome

counseling for parents/guardians and life prognosis, prior toapplying intensive management to newborns with trisomy 18.
Introduction
The treatment strategy of trisomy 18 is controversial as the
prognosis is lethal. Approximately 50% of newborns survive>1 week while >90% do not survive beyond 1 years of age.
The medical progression of neonatal intensive care management in Japan has been previously established and the firstdescribed trisomy 18 infants were reported in 1960 (1,2).
The definition of the trisomy 18 syndrome, also known ascommon autosomal aneuploidy chromosomal abnormality
due to the presence of an extra chromosome 18, using thestandard G‑banded karyotype allows for confirmation of
the clinical diagnosis of multiple anomalies (3). It is clinically associated with various major and minor multisystemanomalies, including cardiovascular, brain with neurological,
renal, gastrointestinal, respiratory, and skeletal malformations (4,5). Trisomy 18 is clinically associated with ≥50%of anomalies including craniofacial abnormalities such as
prominent occiput, narrow bifrontal diameter, low‑set andmalformed auricles and micrognathia; hand and feet anomalies including clenched hand, overlapping of index finger
and hypoplasia of nails; thorax deformities; inguinal hernia;
small pelvis; male with cryptorchidism; cardiac and circulatory system, in particular ventricular septal defect (VSD),
patent ductus arteriosus (PDA) and auricular septal defect.
In addition, 10‑50% of cases showed other craniofacial, hand,feet and thorax anomalies, cardiac with pulmonic stenosis,
coarctation of aorta, renal anomaly with horseshoe defect,
double ureter, hydronephrosis and polycystic kidney, while≥50% of cases exhibited central nervous system anomaly
with cerebellar hypoplasia, agenesis of corpus callosum,hydrocephalus, meningomyelocele and Dandy‑walker
malformation (6,7). All the cases had severe mental andpsychomotor disorders.
Epidemiologically, previously conducted studies havefocused on trisomy 18 (4,8‑23). Root and Carey (9) reported
that the incidence of trisomy 18 syndrome is as low as
1 in 8,000 births; however, this is the second highest incidence of chromosomal aberrations in live‑born infants
following trisomy 21. Findings of prevalence studies by2458

IMATAKA et al: CLINICAL FEATURES AND SURVIVAL IN INDIVIDUALS WITH TRISOMY 18

Goldstein and Nielsen (10) Forrester and Merz (11) focusing on
populations in Hawaii and Denmark, respectively, showed thatlive‑born infants of trisomy 18 had an incidence of 1 in 8,000
to 1 in 10,000. By contrast, Bergin et al (12) reported the incidence of trisomy 18 to be 1 of 555 conceptuses, with the mostrecently recorded frequencies in live‑born infants in Dublin
and Leicester in England being in the range of approximately
1 in 3,000. On the basis of the reported literature, the live birthprevalence of trisomy 18 ranges from 1/3,000 to 1/10,000 andthe estimated average is approximately 1 in 6,000 (3,9‑12).
Gender differences during gestation have been previously
identified, with a 4‑fold higher incidence in female subjects
compared to male subjects (5). By contrast, Kuroki andKurosawa (24) reported no gender differences in trisomy 18,
as indicated by data obtained from the prefecture birth defects
monitoring program in Japan. An increase in the age of theparturient female leads to an increased risk of trisomy 21, as
well as the development of trisomy. The recurrence risk oftrisomy 18 has been analyzed and estimated at <1% (25,26).
The precise mechanism of this syndrome is known to develop
from an error in maternal meiosis, with the chromosomal
abbreviation being due to maternal origin in ~96% of cases oftrisomy 18 (27).
When issues such as the medical treatment of newborns,
genetic counseling and medical ethics arise, management withtreatment strategy for this genetic trisomy syndrome is clinicallyessential (6). The life prognosis of trisomy 18 is controversial
as the outcome is usually lethal. Patients with long‑term
survival of trisomy 18 exhibited severe pschyomotor develop­
mental delay. Thus, any approach to the treatment strategy andpolicy of a third‑trimester fetus and live‑born neonate withtrisomy 18 is complicated, resulting in controversial findings.
The primary issue involves the complexity surrounding thedecision‑making process regarding the treatment strategy
immediately following birth in newborns diagnosed withtrisomy 18. Rasmussen et al (13), Crider et al (18) and
Irving et al (19) reported that the important issues involved in
the parental primary care of live‑born infants with trisomy 18
is associated with a high neonatal and infantile mortality death
rate. When a fetus is known to have trisomy 18, delivery bycesarean section is avoided due to ethics issues, as indicatedby Norup (28) in a study conducted in Denmark. The findings of that study showed consensus for physicians working
in the perinatal and neonatal medical unit until 21 weeks withregard to trisomy 18 (28). Irving et al (19) reported that theprenatal diagnosis of trisomy 18 leads to a decision in supportof pregnancy termination in 86% of cases (19). Sociologically,
the medical treatment for the neonatal to infantile periods withdisabilities was found to be different for various countries
depending on factors such as culture, religion, human rights,
law and views on bioethics. Traditionally, a non‑intervention
approach in the newborn management of trisomy 18 and 13
has been previously utilized. Bos et al (29) summarized these
ethical issues, indicating that early diagnosis was extremely
important for the avoidance of unnecessary surgical treatment.
At present, trisomy 18 and 13 are considered to have a highmortality and survivors suffer from severe mental impairment
and fail to thrive. Consequently, surgical procedures are withheld in the early stages of infancy to determine the outcome
following the first few months (6).

In Japan, the therapeutic policies for poor long‑term life
prognosis for trisomy 18 and 13 involve two controversial
concepts: i) the provision of thorough affection and care
and avoidance of excessive intensive treatment; or ii) the
provision of active intensive treatment including resuscitation and surgery according to the clinical conditions of an
infant in accordance with the wishes of the affected infant's
parents (14,30). However, there was insufficient evidence
regarding the improvement of prognosis of trisomy 18
patients treated at the Neonatal Intensive Care Unit (NICU)
who underwent surgery. Kosho et al (14,31) studied 24 casesof trisomy 18 treated at the NICU, resulting in improved life
prognosis as compared to previously reported data.
After written informed consent was obtained from thefamily members following genetic counseling, intensive
treatment including resuscitation, intra‑tracheal intubation,
support of artificial ventilation, and surgical procedures
was performed for long‑term survival of trisomy 18 at the
NICU of Dokkyo Medical University School of Medicine.
In addition, active support management in the form of homenursing care in cooperation with the family was provided. In
this study, in order to certify the clinical details and survival
periods of trisomy 18 patients managed at the NICU level, weinvestigated a retrospective single‑center study of 44 patientswith trisomy 18, admitted to the Dokkyo Medical University
School of Medicine over a period of >20 years.
In addition, prior to performing this study, important factors
regarding development of neonatal medicine over a period of>20 years was considered. Thus, whether medical progress
influenced improvement of the life prognosis of trisomy 18
patients over such a long study period was examined. The
patients were divided into two groups and criteria considered
included the general condition and life prognosis immediately
following the delivery. The results provide useful information
concerning genetic counseling for parents/guardians and life
prognosis.
Patients and methods
General. The study comprised 6,183 newborn infants who wereadmitted to the NICU of Dokkyo Medical University Hospital in
Japan, during the period of 1992‑2012. The 21‑year period was
divided into two groups: group A constituted the first 11 years(1992‑2002) and group B the second 10 years (2003‑2012).
Group A and B comprised 2,928 and 3,255 newborn patients,
respectively. The newborn infants manifested minor and/or
major external malformations or organ malformations that wereobserved during the clinical examinations by a neonatologist
and pediatrician. The infants underwent a congenital chromosomal test and peripheral blood cells obtained were analyzed
via the standard method of G‑banding karyotype. A breakdown of the patient numerical autosomal trisomies identified
96 patients (1.55%), with trisomy 21; 44 patients (0.71%) withtrisomy 18 including full trisomy, mosaic type and patientswith an extra chromosome 18; and 17 patients (0.27%) withtrisomy 13 were admitted to the NICU. Other chromosomal
abnormalities exhibited included 2 patients with trisomy 8mosaicism, 3 patients with 5p‑syndrome and 4p‑syndrome.
In this study, a retrospective single‑center study was
conducted using NICU medical records from 44 patientsMOLECULAR MEDICINE REPORTS 13: 2457-2466, 2016

with trisomy 18 obtained at the Dokkyo Medical University
Hospital. Group A comprised 20 patients and group B
comprised 22 patients with trisomy 18. There were no cases ofprenatal diagnostic screening for trisomy 18 prior to birth, thus
all 44 cases were diagnosed after birth.
Statistical analysis. Statistical analysis was performd to determine any significant differences between groups A and B. The
positive effect of the NICU management and treatment wasdetermined when no significant differences were observed forthe two groups at delivery but there was a significant differencein the survival prognosis. The following statistical procedure
was performed as establishment for it.
Continuous data during pregnancy and delivery were
described as mean ± standard deviation, if normally distributed,
or median (interquartile range), if not normally distributed.
Comparisons between groups A and B for continuous variables
were made using the unpaired t-test, if normally distributed, orMann‑Whitney U test, if not normally distributed. Categorical
data were described as number and percentage, and differences were analyzed using Fisher's exact test.
The percentage survival was analyzed using Kaplan‑Meiercurves after establishing the longest survival time at 1 year. The
survival curves were estimated according to the Kaplan‑Meiermethod. The generalized Wilcoxon and log‑rank tests wereused to determine statistically significant differences for the
prognosis of survival time at 180 days, 1 year and the entire
investigated period of patients for groups A and B. The time
periods were analyzed using SPSS version 22.0 for Windows(IBM Japan, Tokyo, Japan). P<0.05 was considered to indicate
a statistically significant difference.
Results
Clinical details at pregnancy and delivery. The statisticalanalysis results for groups A and B are shown in Table I. Noneof the 44 patients with trisomy 18 syndrome had a family
history of chromosomal abnormalities. The karyotypes ofchromosomal abnormalities associated with chromosome 18
were identified in the 44 patients using a G‑banding method.
The result of karyotypes included the full type of trisomy 18
in 42 patients (95%), the mosaic type of trisomy 18 in
1 patient (2%), and the rare isodicentric chromosome 18, i.e.,
46,XX,idic(18)(p11.31) in 1 patient.
Of the 44 patients, 16 were males and 28 females. None ofthe patients underwent a prenatal diagnosis using the amniotic
fluid marker test for trisomy 18. The term of delivery was
29‑42 gestational weeks, with an average of 36.7 gestational
weeks. Thirty-six of the patients were born in the Department
of Gynecology at the Dokkyo Medical University Hospital and8 patients were born at other hospital and transferred immediately after birth. Immediately following the delivery, apgar
scores of 1 and 5 min were 3 and 6, respectively. The averagebirth weight was 1585.5±493.6 g, with a range of 770‑2,946 g.
The breakdown of birth weight included 4 patients weighing<1,000 g, 17 patients weighing 1,001‑1,500 g, 13 patientsweighing 1,501-2,000 g, 9 patients weighing 2,001-2,500 g, and1 patient weighing >2,500 g at delivery. Regarding methods ofdelivery, 19 patients were delivered via cesarean section and19 patients via spontaneous delivery.

2459

Three types of statistical analyses were performed forgroups A and B. Significant differences were not identified inany of the general conditions examined with the exception of
caesarean section which was statistically significant (P<0.045).
Thus, there were no differences between the two groups withregard to the general state of neonate during time of delivery.
Organ malformations, use of mechanical ventilation, anddischarge from NICU. Ventilation and surgical treatment aswell as discharge from the NICU and prognosis are shown in
Tables II and III. Disease manifestations including trisomy 21,
18 and 13, were indicated in the ultrasonography examination
during the course of pregnancy, such as intrauterine growth
impairment, brain malformation, and congenital heart anomalies. These anomalies were primarily cardiac and brain, andmechanical ventilation as well as surgical procedures were usedprior to analysis of outcome and survival (Tables II and III).
As for the congenital heart diseases, 42 of 44 patients (95%)
had some types of cardiac disorder. The breakdown include
VSD in 37 patients, PDA in 17 patients, atrial septal defect(ASD) in 14 patients, coarctation of the aorta in 8 patients,
double outlet right ventricle in 6 patients, endocardial cushion
defect in 3 patients, tricuspid atresia in 2 patients and tetralogy
of Fallot (TOF) in 2 patients, mitral valve atresia in 2 patients,
transposition of great arteries and hypoplastic left heart
syndrome in 1 patient with trisomy 18. Although 42 cases had
a cardiac problem, only one case with TOF underwent surgery
following transfer from another hospital. Diuretic medication
was prescribed for the management of the cardiac anomalies.
Among the major central nervous malformations, 3 patientswith trisomy 18 had complicated brain or spinal anomaly.
Two patients had spinal meningocele, 1 patient had holoprosencephaly and 1 patient had Dandy‑Walker malformation.
Sixteen cases of esophageal atresia were also identified, while
4 cases had umbilical hernia. Surgical treatment of gastricfistula was performed in 8 cases of trisomy 18 with complicated severe esophageal atresia with cardiac anomalies.
Mechanical ventilation was performed in 11 cases in
20 samples (55%) obtained from group A and 18 cases in
24 samples (75%) obtained from group B. Thus, treatmentusing mechanical ventilation showed an increasing trend
between group A and B. The primary reason for ventilation
therapy was due to respiratory failure with cardiac failure andmanagement of surgery. In‑hospital death at NICU occurred in
35 cases, with 4 cases being transferred from another hospitalto undergo surgical treatment and 5 cases that were discharged
from the NICU were alive. Alive discharge and hospitaltransfer were increased in group B. The longest survival case
was a female patient who survived >6 years and 4 months.
Prognosis. Kaplan‑Meier survival curves were created(Figs. 1 and 2), based on the data obtained from Table IV.
Vertical and horizontal axes of the two figures are thepercentage survival and survival days, respectively, setting thelongest survival time at 1 year.
Fig. 1 shows the curve for all 44 cases, indicating that one
group survived for 4-6 months and the other group survived
for a longer period of time.
Fig. 2 is a breakdown of the data shown in Fig. 1, showing
the percentage survival curves for groups A and B. The

2460

IMATAKA et al: CLINICAL FEATURES AND SURVIVAL IN INDIVIDUALS WITH TRISOMY 18

Table I. Clinical details at delivery of newborns with trisomy 18 included in this study (n=44).
									Entire investigation		Group A		Group B
Characteristics
No. period (1992-2012) No.
(1992-2002)
No.
(2003-2012)

P-valuegroups
A vs. BNo. of patients

-

6,183

-

2,928

-

3,255

-

Trisomy 18 cases

44

44

20

20

24

24

-

Karyotype44		 20		24		
Full		42		20		22
Others		2		0		
20.493aGender44		 20		24		
Male		
16		7		
9
Female		
28		
13		
15

>0.999aTerm of delivery (week) 44		
20		
24		
Mean ± SD		
36.7±3.2		
37.3±3.2		
36.3±3.2
Median (IQR)		
37.0 (34.0, 39.0)		
37.5 (35.0, 39.8)		
36.5 (34.0, 39.0)

0.309b
0.374cDelivery place
44		
20		
24		
Our hospital		
36		
15		
21
Other hospital		
8		
5		
3

0.436aDelivery38		 15		23		Cesarean section		
19		
4		
15
Vaginally		
19		
11		
8

0.045aApgar score (point)
1 min
37		
14		
23		
Mean ± SD		
3.4±2.1		
3.2±2.2		
3.6±2.1
Median (IQR)		
3.0 (2.0, 5.0)		
2.5 (1.8, 5.0)		
3.0 (2.0, 5.0)
5 min
35		
13		
22		
Mean ± SD		
6.0±2.0		
5.7±2.0		
6.2±2.0
Median (IQR)		
6.0 (5.0, 7.0)		
5.0 (4.0, 6.5)		
6.0 (5.0, 7.0)
Birth weight (g)
44		
20		
24		
Mean ± SD		
1585.5±493.6		
1654.9±576.8		
1527.8±415.9
Median (IQR)		 1536.0 (1186.5, 1969.5)		 1552.0 (1175.0, 2164.0)		
1519.0 (1186.5, 1851.0)
Categorical data
44		
20		
24		
<1,000		4		
2		
2
1,000-1,500		
17		
7		
10
1,501-2,000		
13		
5		
8
2,001-2,500		
9		
5		
4
<2.500		1		
1		
00.631b0.546c0.492b0.180c0.402b
0.525c0.525cNo., %; mean ± standard deviation (SD); median [interquartile range (IQR)]. P-value; aFisher’s exact test; bunpaired t-test; cMann-Whitney
U test.

difference in the curves between groups A and B are evident.
The generalized Wilcoxon test was employed to determine
the differences between the two curves. The results showeda statistically significant (<0.05) p‑value of 0.029 (95% confidence interval), indicating a better prognosis for group B in theprevious 10 years.

Notably, the two curves showed an increasing tendencyof percentage survival during the first 1‑ to 6‑month period(Fig. 2). Subsequently, however, the difference in the percentage
survival of the two groups indicated a decreasing tendency
in the 6‑month to 1 year period. We analyzed this tendency
using the log‑rank test at 180 days and 1 year (Table IV). The

MOLECULAR MEDICINE REPORTS 13: 2457-2466, 2016

2461

Table II. Organ malformations, use of mechanical ventilation, surgical treatments and discharge from NICU for patients withtrisomy 18 (group A, 1992-2002, n=20).
(Group A)
Patients

Major organ
malformations

Mechanicalventilation

1
2
3

Surgicaltreatment

Discharge from NICU
(D, dead; A, alive; T, transfer)

TOF PDA EA-		ECD IAA EA+		TGA ECD-		
Anal atresia
Defects of both thumb
4
PDA CoA EA-		5
VSD PDA UH+
Repair UH
Urachal remnants
6
VSD EA-		
7
EA+
Gastric fistula
8
VSD ASD PDA EA+		9VSD EA	-	
Gastric fistula
10
VSD CoA+
Colostomy
Cleft lip and palate		
Intestinal segmentectomy
11
VSD ASD EA+		12
VSD PDA+		13
VSD EA+
Gastric fistula
14
ASD PDA CoA UH+		15
VSD ASD PDA UH+		16
VSD ASD
-		
17
EA
-		
18
TA
-		
19
VSD DWM+		20
VSD PDA-		
Total		+:11/-:9		Survival(days)

D
D
D

0
0
0

D
D

2
3

D
D
D
D
D

3
8
17
27
30

D
D
D
D
D
A
D
D
D
A
D:18/A:2

47
53
56
78
83
102
116
202
414
2311

VSD, ventriculoseptal defect; ASD, atrial septal defect; PDA, patent ductus arteriosus; CoA, coarctation of the aorta; DORV, double-outlet
right ventricle; ECD, endocardial cushion defect; TOF, tetralogy of Fallot; IAA, interruption of aortic arch; TGA, transposition of great arteries;
TA, tricuspid atresia; UH, umbilical hernia; EA, esophageal atresia; DWM, Dandy-Walker malformation; NICU, neonatal intensive care unit.

results of the log‑rank test indicated a statistically significant(<0.05) p‑value of 0.036 at the survival point of 180 days. At
the point of 1 year as well as the entire investigated period,
the difference was not statistically significant (<0.05) with ap‑value of 0.075 and 0.126.
Discussion
In this study, we have examined the prognosis of 44 cases oftrisomy 18 identified in our NICU over the course of 21 years
from 1992 to 2013. Depending on the timing of birth, thesubjects with trisomy 18 were divided into two groups, withgroup A comprising 20 cases, born during the period of
1992‑2002, and group B comprising 24 cases, born during
the period of 1992‑2012. The aim of the present study was toclarify the characteristics and prognosis for each trisomy 18case, and to compare and consider the life prognosis of the twogroups. A comparison of factors such as chromosome typeand gender, as well as gestational age as at the time of birth,
birth place, vaginal delivery or cesarean section as method ofdelivery, and Apgar scores based on the 1‑ and 5-min value,and birth weight was made for groups A and B. Statisticalanalysis was conducted using three methods to verify theexistence of significant differences for groups A and B
regarding trisomy 18 for newborns following birth. The results
for the A and B trisomy 18 groups showed that, a significant
difference was identified only for cesarean section, whereas
no significant difference was identified for other factors withregard to the state of the child at birth. Thus, the two groups
were considered uniform. A comparison of the two groups
using the Kaplan‑Meier curve and generalized Wilcoxon test
showed an improvement in prognosis in group B. Thus, theprogression of medical intervention during the two periods
prior to and following the study period is evident due to thelife prognosis of patients with trisomy 18 having improved.
However, the results of the log‑rank test conducted showed
that, although a significant difference was observed in thetrisomy 18 prognosis at the time of 180 days after birth, at
1 year and the entire survey period after birth, these significant
differences could not be confirmed. Thus, additional studies
should be performed to confirm the life prognosis and medical
intervention of trisomy 18 for neonatal to infantile periods.

2462

IMATAKA et al: CLINICAL FEATURES AND SURVIVAL IN INDIVIDUALS WITH TRISOMY 18

Table III. Organ malformations, use of mechanical ventilation, surgical treatments and discharge from NICU for patients withtrisomy 18 (group B, 2003-2012, n=24).
Group B
Patients

Major organ
malformations

Mechanicalventilation

21
22

Surgicaltreatment

Discharge from NICU
(D, dead; A, alive; T, transfer)

n.d.
+		
VSD ASD PDA IAA EA+		Cleft lip and palate
Spurious meningocele
23
ASD TA+		24
ECD+
Gastric fistula25
VSD PDA-		
Cleft lip and palate
26
VSD ASD DORV UH+		Defects of right radius
27
VSD CoA+		
Holoprosencephaly
28
VSD CoA+		29
VSD ASD PDA EA+
Gastric fistula30
VSD MS EA+
Gastric fistula
31
VSD ASD PDA+		32
VSD PDA CDH+
Biliary duct drainage
Biliary duct dilatation
33
VSD ASD EA+
Gastric fistula
34
TOF
Blalock-Taussig operation
35
VSD ASD CoA-		36
VSD ASD-		
Laryngeal malacia
37
VSD ASD PDA CoA+		38
VSD PDA-		
Pyloric stenosis
39
PDA DORV EA-		40DORV MA HLHS
+		
41
DORV
+		
Spurious meningocele
Defects of radius
42
VSD PDA+		43
VSD DORV+		44
VSD CoA VORV EA+Gastric fistula
Imperforate anus
Total		+:18/-:6		

Survival(days)

D
D

0
1

D
D
D

4
8
25

D

45

A

51

D
D
T
D
D

60
70
92
96
108

D
T
D
A

116
127
132
162

D
D

250
250

A
T
D

263
263
309

D
T
D

420
667
699

D:17/T:4/A:3

VSD, ventriculoseptal defect; ASD, atrial septal defect; PDA, patent ductus arteriosus; CoA, coarctation of the aorta; DORV, double-outlet
right ventricle; ECD, endocardial cushion defect; TOF, tetralogy of Fallot; IAA, interruption of aortic arch; TA, tricuspid atresia; MA, mitralvalve atresia; HLHS, hypoplastic left heart syndrome; UH, umbilical hernia; EA, esophageal atresia; CDH, congenital diaphragmatic hernia;
NICU, neonatal intensive care unit; n.d, no data.

Previously, despite medical treatment the prognosis forpatients with trisomy 18 was lethal reason for chromosomal
aberration. Trisomies 21 (Down syndrome), 18 (Edwards
syndrome) and 13 (Patau syndrome), as well as other chromosomes are associated with various types of severe anomaliesof the mainly brain and viscera, and affected neonate usually
do not survive infantile period (4,5). Additionally, complete
autosomal trisomies frequently resulted in non‑implantation or

miscarriage; thus, chromosomal abnormality cases that survive
following birth are primarily trisomies 21, 18 and 13 (8).
Jenderny (32) conducted a study on a German population, andrevealed that clinically, the majority of trisomies are unborn due
to miscarriage. Pregnancy loss rates ranging from 72 to 87%
for trisomy 18 were demonstrated by Sibiude et al (33)and between 49 and 66% by Lakovschek et al (34) for
trisomy 13, respectively. It has been previously identifieddfp-value

180
365
Observation end
4.381
3.173
2.344
1
1
1
0.036
0.075
0.126

Figure 1. Kaplan‑Meier survival curve for patients with trisomy 18 (n=44).

Figure 2. Kaplan‑Meier survival curve for patients with trisomy 18 (group A,
n=20; group B, n=24).

that trisomy 18 and 13 are the most common trisomies
following trisomy 21 (35), with trisomy 18 being the second
common trisomy after trisomy 21. Baird and Sadovnick (36)and Noble (37) reported that the average life expectancy of
Down syndrome was >50 years old due to medical advancesin medically advanced countries. However, to the best of ourknowledge, the majority of live‑born infants with trisomy 18

Mann-Whitney U test, group A vs. B, p-value 0.033. n.d., no data; median [interquartile range (IQR)].

Author/(Refs.)
Weber (50)CarterGoldstein and Root and Embleton Brewer Rasmussen
Lin
Kosho
Imataka
Our study
Our study
Our study		
et al (51) Nielsen (10) Carey (9) et al (17) et al (16) et al (13) et al (52) et al (14)et al (8)			
Year
1967
1985
1988
1994
1996
2002
2003
2006
2006
2007
(1992-2012)(1992-2002)(2003-2012)
No.
n=192
n=43
n=76
n=64
n=34
n=84
n=114
n=39
n=24
n=179
n=44
n=20
n=24
Survival time
% survival % survival % survival % survival % survival % survival % survival % survival % survival % survival% survival% survival% survival
>24 h
98
60
60
86
70
88
86
95
95.8
85.16
90.9
85
95.8
>7 days
89
35
44
45
n.d.
43
63
46
87.5
68.99
79.5
70
87.5
>1 month
72
11
21
34
15
25
39
16
83.3
43.75
65.9
50
79.2
>2 months
52
8
n.d.
22
n.d.
n.d.
30
11
62.5
35.92
52.3
35
66.7
>6 months
13
5
3
9
n.d.
n.d.
11
3
45.8
17.83
25
15
33.3
1 year <
8
4
n.d.
5
0
2
8
3
25
9.09
11.4
10
12.5
Median survival
n.d.
5
6
4
3
6
14.5
36
152.5
n.d.
74.0 (10.3, 192.0) 38.5 (3.0, 97.3) 112.0 (46.5, 259.8)(days)

Group B

Chi-square distribution

Multi-center Queensland,					 Altanta,				All investigated		
study
Australia
Denmark
Utah, USA England Scotland
USA
TaiwanJapanJapan
periodGroup A

Table IV. The analyzed data of the log-rank test at each observation period (group A vs. B).

Variables

Survival days

Table V. Survival rate and prognosis of trisomy 18 in the present study compared to previously reported data.

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IMATAKA et al: CLINICAL FEATURES AND SURVIVAL IN INDIVIDUALS WITH TRISOMY 18

and 13 survive <1 year and do not survive to adulthood. In
our study, only 5 of the 44 patients survived beyond 1 year ofage. Generally, the prognosis of trisomy 18 and 13 are lethal,
but long‑term survival cases of such trisomies have beensporadically observed. Kelly et al (38) described 20‑year‑old
women and Torres Hinojal et al (39) reported a 14‑year‑old
patient with trisomy 18. Another case report of long survivalof cases of trisomy 18 was conducted by Petek et al (40) who
reported on a 19‑year-old female and by Smith et al (41) who
reported on an 11-year-old female patient and a 21-year‑old
female patient (42). A search of the literature yielded ≥10
previously reported cases of affected children with trisomy 18,
aged >10 years (43‑45). In our patient, the oldest individualwith trisomy 18 was a 6‑year and 4‑month-old female patientwith severe intellectual and psychomotor disorder.
Patients with trisomy 18 who show long‑term survival
present severe psychomotor delay (46). For such cases, aggressive medical treatment in the intensive care unit is controversial
as life prognosis is lethal. Only a few studies of patients being
managed at NICU have been previously reported. Of these,
Kosho et al (14,31) demonstrated that restricted and intensive medical treatments in NICU are valuable in the form ofgenetic counseling. Since the 1980's, resuscitation and surgicaltreatments for trisomy 18 have been considered from thestandpoints of medical ethics and consideration of quality oflife for patients as well as parents and their families, medical
economic issues, and medical environment in each countries.
In Japan, Nishida and Sakamoto (30) suggested a policy of ‘notreatments beyond current treatments’ for treatment of newborn
infants in 1992. Paris et al (47) also indicated ambiguous ethicalissues in the use of life‑prolonging interventions for an infant
with trisomy 18 in 1992. However, long survival of individuals
with chromosomal abnormalities including trisomy 18 and 13,
owing to medical progression has since been identified. Notably,
treatment policy has also led to gradually changes in medical,
sociological, and technical progression. The 4th edition ofSmith's textbook in 1988 supports the ‘limitation of all medicalmeans for prolongation of life for trisomy 18’ (48). However,the 7th edition of the same textbook in 2013, supports that‘limitation of extraordinary medical means should be seriously
considered’. In addition, it advocates that the personal feelingsof the parents and the individual circumstances of each infant
be taken into consideration (49).
The survival of patients with trisomy 18 and the survival
rate from several countries for the period 1967‑2010 have beenreported in the present study. A long survival period of over
6 months is difficult for patients with trisomy 18, as indicatedby Lin et al in 2006 (52) and Weber et al (50) in 1967. On theother hand, the recent findings of Kosho et al (14) and thoseof our group (8) for populations of Japan, revealed improved
life outcome of trisomy 18. Studies have been recently
conducted to investigate treatment procedures and outcome
for trisomy 18 (53). Mechanical ventilation treatment was
performed in 29 of 44 patients (65.9%) by in the present study
and the percentage was increased in group B. Paris et al (47)suggested that physicians should be attentive with regard toconcentration treatment including ventilation therapy andlife‑prolonging intervention. Bos et al (29) also report avoidance of emergency surgery in newborns with trisomy 18. In thepresent study, patients underwent ventilation therapy owing

to respiratory failure and general management. Fenton (54)suggested factors such as quality of life for determining treatment for trisomy 18. On the other hand, surgical treatment ispreferred following informed consent with counseling fromthe family support meeting (55). Kosho (31) emphasized careof children with trisomy 18 in Japan. Information such as
cesarean section (56), general condition (57), health care (58),family (59) and neonatal experience (60) care were important in the treatment of cases with trisomy 18. However,no clear guideline regarding treatment policy and strategy
has been established. In Japan, the surgical treatment of avariety of congenital cardiac diseases (61‑65) and esophageal
atresia (66) have been performed in patients with trisomy 18.
In addition, treatment for apnea and epilepsy (67‑69) werealso provided. Graham et al (70) summarized 35 cases ofcardiac surgery with trisomy 18 and 13, with increased
discharge from the hospital. However, prognosis and qualityof life of those patients remain unclear. Janvier et al (71)
discussed the issue of ethics regarding an infant‑associated
VSD. Kaneko et al (62) reported 17 cases of trisomy 18
with cardiac surgery and 14 cases (82%) were discharged
from NICU leading to a conclusion that it was effective indecreasing mortality in NICU due to cardiac failure. NICU
management with ventilation and surgical procedures has
potential to improve the short‑term outcome of <1 year
in trisomy 18. In the present study, an improvement in theoutcome of 6 months from delivery by various treatments
including mechanical ventilation and surgical procedure wasobserved. However, additional studies on a larger number ofcases should be performed concerning treatment strategy
and genetic counseling to the family with a newborn withtrisomy 18.
Although the present study had a small sample size, ourdata provide one of the larger single‑center studies currently
available. The results of the present study provide information
concerning genetic counseling for parents and their families
and life prognosis, prior to applying intensive management to
newborns with trisomy 18
Acknowledgements
We would like to express our gratitude and appreciation to all
the NICU medical staff, Dokkyo Medical University Hospital,
Tochigi, Japan.
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