J. Perinat. Med.

2018; 46(1): 97–101

Hiroko Takita, Junichi Hasegawa*, Masamitsu Nakamura, Tatsuya Arakaki, Tomohiro Oba,
Ryu Matsuoka and Akihiko Sekizawa

Causes of intrauterine fetal death are changing

in recent years
DOI 10.1515/jpm-2016-0337 Keywords: Chromosome abnormality; fetal anomaly;
Received October 21, 2016. Accepted January 23, 2017. Previously hypercoiled cord; intrauterine fetal death (IUFD); umbili-
­published online February 25, 2017.
cal cord; velamentous cord insertion.
Abstract

Objective: To investigate, how causes of intrauterine

fetal death (IUFD) have changed in recent years with the
advancement of prenatal diagnosis at a single perinatal
center in Japan.
Methods: Medical records were retrospectively reviewed
for all cases of IUFDs that occurred between 2001 and
2014. The most commonly associated causes of fetal deaths
were compared between 2001–2007 and 2008–2014.
Results: The number of IUFD after 20 weeks’ gestation/
all deliveries in our center was 38/6878 cases (0.53%)
in 2001–2007 and 35/7326 (0.48%) in 2008–2014. The
leading cause of IUFD in 2001–2007  was fetal abnor-
malities (43.2%), the prevalence of which was only
8.6% in 2008–2014 (P < 0.01). Meanwhile, the preva-
lence of umbilical cord abnormalities was relatively
increased from 30.0% in 2001–2007 to 54.5% in 2008–
2014 (P = 0.06). In 2001–2007, chromosomal abnormali-
ties were frequently observed (56% of IUFDs due to fetal
abnormalities). Hyper-coiled cord (HCC) and umbilical
ring constrictions were the most frequent cause of IUFD
in both periods. The relatively decreased prevalence of
IUFD due to velamentous cord insertion and umbilical
cord entanglement, HCC and umbilical cord constriction
was increased.
Conclusions: The prevalence of IUFD due to fetal abnor-
malities was reduced, but IUFD associated with umbilical
cord abnormalities tended to increase relatively.
*Corresponding author: Dr. Junichi Hasegawa, Department of
Obstetrics and Gynecology, Showa University School of Medicine,
1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan,
Tel.: + 81-3-3784-8551, Fax: + 81-3-3784-8355,
E-mail: hasejun@oak.dti.ne.jp; and Department of Obstetrics and
Gynecology, St. Marianna University School of Medicine, Kanagawa,
Japan
Hiroko Takita, Masamitsu Nakamura, Tatsuya Arakaki, Tomohiro
Oba, Ryu Matsuoka and Akihiko Sekizawa: Department of
Obstetrics and Gynecology, Showa University School of Medicine,
Tokyo, Japan
Introduction
One in every 200 pregnant women in developed countries
was reported to have a stillborn baby after 20 weeks’ ges-
tation [1, 2]. To reduce the global incidence of stillbirth,
issues of childbirth complications; maternal infections in
pregnancy; maternal conditions, especially hypertension;
fetal growth restriction; and congenital abnormalities
should be addressed [2]. Though the perinatal mortality
rate in Japan is the lowest in the world estimating 2.5 per
1000 live births [3], for further reduction of the perinatal
mortality rate we should comprehend recent causations of
intrauterine fetal death (IUFD). It is hypothesized that the
causations of IUFD have been changing along with the pro-
gress of prenatal diagnosis and perinatal managements.
The objective of the present study was to investigate
how causes of IUFD have changed in recent years with the
advancement of prenatal diagnoses and management at
our single perinatal center in Japan.
Patients and methods
A retrospective study was performed at the Showa University Hos-
pital in Japan. Medical records were retrospectively reviewed for all
cases of IUFD that occurred between 2001 and 2014. The most com-
monly associated causes of fetal deaths were compared between
2001–2007 and 2008–2014. Patients referred to our hospital because
of IUFD were excluded from the present study.
The causes of the fetal deaths were determined by perform-
ing clinical or pathological examinations, based on findings from
external pathological examinations or autopsies of stillbirth infants,
results of pathological examinations of the placenta and umbilical
cord, antemortem ultrasonographic findings of the fetus and pla-
centa, results from karyotyping in the villous tissue or amniotic fluid
and maternal examination results. Each cause of deaths was deter-
mined according to discussion among obstetricians, neonatologists
and pathologists, occasionally with disease specific doctors.
Hyper-coiled cord (HCC) was determined based on crite-
ria of previous report by Strong [4]. The umbilical coiling index is

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98      Takita et al., Recent causes of IUFD

calculated by dividing the total number of coils by the length of the
cord in centimeters after delivery. Hyper-coiled cord was defined in
cases of umbilical coiling index > = 0.3 coils/cm.
Statistical analyses
All statistical analyses were performed using the Statistical Pack-
age for the Social Sciences (SPSS) (Windows version 20.0 J; Chicago,
IL, USA). Categorical variables are reported as frequencies and were
compared using Fisher’s exact test.
Ethics statement
This study was approved by the Ethics Committee of our hospital
(No. 1182). The identities of the patients were treated with confiden-
tiality and protected. No personal data were collected in the present
study. The investigation was conducted according to the principles
expressed in the Declaration of Helsinki.
Results
The number of deliveries in our center was 6878 in
2001–2007 and 7326 in 2008–2014, respectively. IUFD
after 20 weeks’ gestation occurred in 38 cases (0.53%) in
2001–2007 and 35 cases (0.48%) in 2008–2014. The back-
ground of all deliveries and IUFDs are shown in Tables 1
and 2. The background of all deliveries in our institution
did not differ between the two periods, except for rates of
pregnancy after assisted reproduction technology (ART)
and cesarean section rate. These rates increased recently.
However, the background of IUFD did not differ between
the two periods.
The prevalence rates of the causes of IUFD in 2001–
2007 and 2008–2014 are shown in Figure 1. In 2001–2007,
the leading cause of IUFD was fetal factors (43.2%), the
prevalence was only 8.6% in 2008–2014 (P < 0.01). Mean-
while, the prevalence of umbilical cord abnormalities
relatively increased from 30.0% in 2001–2007 to 54.5% in
2008–2014 (P = 0.06).
Details of the fetal abnormalities are demonstrated
in Table 3. In 2001–2007, 56% of IUFDs due to fetal mor-
phological abnormalities, and more than half of the cases
with fetal factors were due to chromosomal abnormalities.
(Trisomy 18 and 21 with fetal morphological abnormalities
were frequently observed.) However, in 2008–2014, only
three cases of IUFD were due to fetal factors which were
Trisomy 21 with a body stalk anomaly, absence of ductus
venosus, and selective IUGR.
The prevalence of cord factors between the two
periods is demonstrated in Figure 2. HCC and umbilical

Table 1: Background of all deliveries.

2001–2007 (n = 6878) 2008–2014 (n = 7326) P-value

Age (mean ± SD) 32.1 ± 3.8 32.8 ± 4.7 0.324

Gravida (median, range) 0 (0–7) 0 (0–8) 0.374
Parity (median, range) 0 (0–5) 0 (0–5) 0.453
Singleton 98.3% (6761) 96.3% (7055) 0.523
ART (IVF-ET, ICSI, egg donation) 5.6% (385) 8.5% (626) 0.030
Delivery at gestational weeks (mean ± SD) 39.3 ± 1.1 39.1 ± 1.3 0.512
Cesarean section 25.8% (1775) 27.9% (2044) 0.005
Pregnancy induced hypertension 5.9% (407) 6.4% (471) 0.300
Intrauterine fetal death 0.53% (37) 0.47% (35) 0.176

Table 2: Background of intrauterine fetal deaths.

  2001–2007 (n = 38)  2008–2014 (n = 35)  P-value

Age (mean ± SD)   31.1 ± 5.0  33.8 ± 4.7  0.348

Gravida (median, range)   0 (0–3)  0 (0–4)  0.454
Parity (median, range)   0 (0–3)  0 (0–4)  0.353
Singleton   89.2% (33)  85.7% (30)  0.054
ART (IVF-ET, ICSI, egg donation)   16.2% (6)  25.7% (9)  0.169
Delivery at gestational weeks (mean ± SD)  30.8 ± 5.0  28.1 ± 5.1  0.627
Cesarean section   5.7% (2)  2.9% (1)  0.240
Pregnancy induced hypertension   13.5% (5)  11.4% (4)  0.080

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Figure 1: The prevalence rates of the causes of IUFD in 2001–2007
and 2008–2014.
Table 3: Details of fetal factors.
  Fetal abnormalities  
2001–2007 (16)  Trisomy 18  
  Trisomy 21 (2 cases: atrial ventrial defect)  3
  Holopoloencephaly  
  Multiple anomalies (single umbilical  
cord, body stalk anomaly)
  Cardiac anomaly (Ebstein)  
  Splenohepatomegaly  
  Ventriculomegaly  
2008–2014 (3)   Trisomy 21 (body stalk anomaly)  
  Absence of ductus venosus  
  Monochorionic diamniotic twin (severe  
fetal growth restriction)
Figure 2: The prevalence of cord factors in 2001–2007 and
2008–2014.
Takita et al., Recent causes of IUFD      99
ring constrictions were the most frequent causes of IUFD
in both periods. The relatively decreased prevalence of
IUFD associated with velamentous cord insertion (VCI)
and umbilical cord entanglement, HCC and umbilical cord
constriction was increased.
Discussion
In the present analysis of IUFDs, the increase in the preva-
lence of cord factors was higher in the period 2008–2014
than in the period 2001–2007. Conversely, the prevalence
of fetal factors decreased. With the improvements in fetal
ultrasonographic evaluation, various fetal abnormalities
have been detected during pregnancy and appropriate
management and interventions have been provided.
The earlier prenatal diagnosis also has an influence
in this direction. In our institution, morphological fetal
assessment during the second trimester had started to
perform since 2000. Then, more detail assessment was
6
added with the passing of the years. On the other hand,
1
the first trimester morphological assessment had started
3 in our institution since 2008. When we explained abnor-
mal fetal findings to patients in the first trimester, some
1 patients desired to undergo amniocentesis or chorionic
1 villous sampling. In our institution between 2011 and
1 2013, it is demonstrated that about half of the cases found
1 morphological abnormalities during the first trimester
1 ultrasound screening resulted in artificial abortion after
1
results of prenatal diagnosis with genetic counseling [5].
A similar situation was observed in the USA, where the
gestational ages at prenatal diagnosis and the abortion
rate for Down syndrome declining significantly since 2005
have been reported [6]. These changes are likely attribut-
able to the improvements in early screening that lead to
higher rates of chorionic villus sampling [6].
Basically, increased prenatal diagnosis during early
gestation and selection of artificial abortion made the
prevalence of umbilical cord abnormalities associated
with IUFD increase relatively. However, the other reason
might be associated with the increasing incidence of ART
pregnancy because ART pregnancy has been reported to
adversely affect placental and umbilical cord develop-
ment [7, 8]. ART pregnancies are associated with higher
risks of placenta previa (RR 3.71), placental abruption
(RR 1.83), polyhydramnios (RR 1.74), and oligohydram-
nios (RR 2.14) [8]. The incidence of VCI was also reported
to increase along with increases in fertility problems and
maternal obesity [9]. VCI occurs in 1.5% of term singleton
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100      Takita et al., Recent causes of IUFD
placentas; however, its incidence increased to 3.65% in
ART pregnancies [10].
Advanced maternal age was reported as risk factors of
HCC, which is significantly associated with adverse perina-
tal outcome and cesarean delivery [11]. HCC and umbilical
constriction at the umbilical ring are often observed in still-
born fetuses and were addressed in several studies [12, 13].
In the present study, among umbilical cord abnormalities,
HCC and its constriction were the most frequent causes of
IUFD in both study periods. The umbilical ring at the fetal
abdominal wall is considered the weakest point in the
umbilical cord. It is thought that an extremely coiled cord
or its extension is associated with sudden fetal death [14].
Good peripartum outcomes of cord factors are con-
sidered to be dependent on prenatal diagnosis and appro-
priate management during delivery [12, 15]. For example,
vasa previa should be diagnosed prenatally and cesarean
delivery should be performed at 35 weeks of gestation or
earlier before membrane rupture, labor, or significant
bleeding occurs [16]. Thus, we also performed antepartum
systematic ultrasonographic screening to detect umbili-
cal cord and placental abnormalities [15]. Almost all cases
with VCI and vasa previa could be antenatally diagnosed
in our hospital [17]. In fact, no cases of IUFD caused by VCI
occurred in the recent study period.
Meanwhile, many IUFDs due to HCC are supposed to
be unavoidable because IUFD associated with HCC sud-
denly occurred without foreshadow. High venous veloc-
ity and increased venous pulsation at the umbilical ring
were reported as predictive findings of fetal compromise.
However, as IUFD due to HCC often occurred not only in
early pregnancy but also before the onset of labor or mem-
brane rupture even at term, we think that prevention of still-
birth in such conditions is limited [18]. Otherwise, almost all
infants will be born healthy even if they have HCC because
the prevalence of non-reassuring fetal status was not so
high, estimated to be only one-fourth of the cases [19].
Further limitation to reduce the incidence of IUFD is
associated with placental abruption. Although some pla-
cental abruptions occurred after the onset of hypertensive
disorder and fetal growth restriction, 27.1% of the cases of
placental abruption occurred without relationship to any
previous symptoms [20]. Management strategies using
new methods of fetal monitoring are required.
Conclusions
In recent years, with the improvement of prenatal
­diagnosis, the prevalence of IUFD due to fetal anomaly
after 20 weeks’ gestation decreased, whereas that of IUFD
associated with umbilical cord and placental factors
tended to increase. The remaining causes of IUFD that
mostly occurred in the earlier gestation or during the
antepartum period involved umbilical cord abnormali-
ties. The prediction of such conditions and further reduc-
tion in the incidence of IUFD might be difficult even if
precise ultrasonography is performed in all pregnant
women.
Author’s statement
Conflict of interest: Authors state no conflict of interest.
Material and methods: Informed consent: Informed
consent has been obtained from all individuals included
in this study.
Ethical approval: The research related to human subject
use has complied with all the relevant national regula-
tions, and institutional policies, and is in accordance
with the tenets of the Helsinki Declaration, and has been
approved by the authors’ institutional review board or
equivalent committee.
Contribution to authorship: Takita H., Hasegawa J. and
Nakamura M. designed the research. All the authors col-
lected the data. Takita H., Hasegawa J. and Arakaki T.
analyzed and interpreted the data. Takita H., Hasegawa
J. and Sekizawa A. drafted the manuscript. Takita H. and
Hasegawa J. performed the statistical analyses.
Funding: None.
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