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Published online 26 October 2016 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.16016
ABSTRACT
Objectives There have been several attempts to classify
cause of death (CoD) in stillbirth; however, all such
systems are subjective, allowing for observer bias and
making comparisons between systems challenging. This
study aimed to examine factors relating to determination
of CoD using a large dataset from two specialist
centers in which observer bias had been reduced by
classifying findings objectively and assigning CoD based
on predetermined criteria.
Methods Detailed autopsy reports from intrauterine
deaths in the second and third trimesters during
20052013 were reviewed and findings entered into a
specially designed database, in which CoD was assigned
using predefined objective criteria. Data regarding CoD
categories and factors affecting determination of CoD
were examined.
Results There were 1064 intrauterine deaths, including
246 early intrauterine fetal deaths (IUFD) (< 20 weeks),
179 late IUFDs (2023 weeks) and 639 stillbirths
( 24 weeks gestation). Overall, around 40% (n = 412)
had a clear CoD identified, whilst around 60% (n = 652)
were classified as unexplained, including around half
with identified risk factors or lesions of uncertain
significance, with the remaining half (n = 292 (45%))
being entirely unexplained. A stepwise increase in
the proportion of unexplained deaths was observed
with increasing maceration. Black and Asian women
had significantly greater proportions of deaths due to
ascending infection, whilst women aged over 40 years had
significantly increased placenta-related CoDs. There was
no significant difference in CoD distribution according to
maternal body mass index or with increasing postmortem
interval. Around half of those with an identifiable CoD
INTRODUCTION
The primary aim of postmortem investigation of intrauterine death is determination of cause and mechanism of
death, to facilitate counseling of parents, management
of subsequent pregnancies and future interventions1 4 .
Over the last 50 years there have been many attempts
to classify cause of death in stillbirths, but, according
to which of the more than 30 classification systems5 is
used, a variable but significant proportion (1560%)
of stillbirths remain unexplained, despite postmortem
examinations being undertaken in specialist centers6,7 .
Classification systems include the Aberdeen, based predominantly on obstetric findings and clinical history8,9 ,
the Wigglesworth, which subdivides cases into general
groups6 , the Relevant Condition at Death (ReCoDe),
which records associated risk factors7 , and the Causes
of Death and Associated Conditions (CODAC), which
Correspondence to: Prof. N. J. Sebire, Department of Histopathology, Level 3 Camelia Botnar Laboratories, Great Ormond Street Hospital,
Great Ormond Street, London WC1N 3JH, UK (e-mail: Neil.Sebire@gosh.nhs.uk)
Accepted: 6 July 2016
ORIGINAL PAPER
METHODS
This analysis was part of a larger study examining
autopsy findings in intrauterine deaths, based on an
established Microsoft Access autopsy research database
(Microsoft Corp., Redmond, WA, USA) which includes
details of all autopsies performed from 2005 to 2013
inclusive from Great Ormond Street Hospital and
additional cases of stillbirth autopsies from St Georges
Hospital, London. Clinical details, autopsy findings and
results of ancillary investigations were recorded (> 400
variables per case) based on predefined criteria, as
documented in the Database Manual (Appendix S1).
Intrauterine fetal deaths (IUFDs) occurring 23 weeks
gestation were recorded as second-trimester IUFDs, while
those 24 weeks gestation were classified as stillbirths.
For the purposes of this study, detailed autopsy data
from all intrauterine deaths occurring during the second
and third trimesters were reviewed and analyzed through
queries and statistical tests run using Microsoft Access
and Microsoft Excel (Microsoft Corp.), GraphPad Prism
(GraphPad Software Inc., San Diego, CA, USA) and Stats
Direct (StatsDirect Ltd., Altrincham, UK). P < 0.05 was
considered statistically significant.
Strict predetermined criteria were used to assign an
objective cause of death for each case (Appendix S1).
Cause of death was based on definite documented findings,
including clinical history, macroscopic and microscopic
features and results of ancillary investigations, rather than
567
Man et al.
568
Table 1 Overall cause of death, defined objectively based on autopsy findings, in a series of 1064 intrauterine deaths in the second and third
trimesters, and subdivided according to gestational age at death
Overall cause of death
Abruption
Ascending infection
Birth trauma
Congenital abnormality
Fetomaternal hemorrhage
Infection
Known cord accident*
Known IUGR*
Placental lesion
Pre-eclampsia
Preterm birth
Twin complication
Unexplained (all)
Unexplained, diabetes
Unexplained, lesion
Unexplained, maternal obesity
Unexplained, post-term
Unexplained, previous fetal loss
Unexplained, unexplained
All (n = 1064)
Stillbirth (n = 639)
38 (4)
176 (17)
7 (1)
50 (5)
6 (1)
13 (1)
4 (< 1)
17 (2)
60 (6)
16 (2)
4 (< 1)
21 (2)
652 (61)
23 (2)
125 (12)
83 (8)
29 (3)
100 (9)
292 (27)
3 (1)
58 (24)
0 (0)
9 (4)
0 (0)
0 (0)
1 (< 1)
4 (2)
1 (< 1)
0 (0)
0 (0)
8 (3)
162 (66)
4 (2)
19 (8)
27 (11)
0 (0)
43 (17)
69 (28)
5 (3)
59 (33)
0 (0)
5 (3)
0 (0)
1 (1)
1 (1)
5 (3)
4 (2)
0 (0)
3 (2)
4 (2)
92 (51)
3 (1)
10 (6)
9 (5)
0 (0)
16 (9)
54 (30)
30 (5)
59 (9)
7 (1)
36 (6)
6 (1)
12 (2)
2 (< 1)
8 (1)
55 (9)
16 (3)
1 (< 1)
9 (1)
398 (62)
16 (3)
96 (15)
47 (7)
29 (5)
41 (6)
169 (26)
Data are given as n (%). Early intrauterine fetal death (IUFD) was defined as intrauterine death < 20 weeks, late IUFD was death at
2023 weeks and stillbirth was death 24 weeks. *Known to pathologist before placental examination. Diabetes mellitus or gestational
diabetes. Fetal, cord or placental lesion. IUGR, intrauterine growth restriction.
Percentage of cases
50
40
30
20
10
br
ng upt
C
on
in ion
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t ti
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at
a
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en G
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ne pli rth
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ed
(a
ll)
di
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RESULTS
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Cause of death
30
Percentage of cases
25
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15
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sc
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at ta th ct
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Cause of death
569
Man et al.
570
80
Percentage of cases
70
60
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40
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20
10
br
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rt
h
m
pl
U
ic
ne
at
xp
io
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la
in
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(a
ll)
Cause of death
Figure 3 Cause of intrauterine death in 752 cases according to maternal ethnicity: white ( ), mixed/Oriental ( ), Asian ( ) or black ( ).
Black and Asian mothers had a significantly greater proportion of deaths associated with ascending infection than did white mothers.
*Known to pathologist before placental examination. IUGR, intrauterine growth restriction.
70
Percentage of cases
60
50
40
30
20
10
ll)
(a
ed
at
ic
in
pl
la
m
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on
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io
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en
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br
fe
up
ct
tio
Cause of death
Figure 4 Cause of intrauterine death in 1039 cases according to maternal age: 35 years ( ), 3640 years ( ) or 41 years ( ). There were
significantly more placenta-related causes of death in mothers over 40 years of age. *Known to pathologist before placental examination.
IUGR, intrauterine growth restriction.
DISCUSSION
The findings of this study have potentially important
implications for both clinical practice and epidemiological
research studies in stillbirth and IUFD. First, using
objective criteria to classify cause of death, many
intrauterine deaths remain unexplained regardless of
gestational age, despite full autopsy examination by
specialist pathologists. Second, the rate of unexplained
death can vary from around 30% to 60% according
to the interpretation of, and significance attributed to,
features in the clinical history, autopsy and placental
examination, despite objective findings being similar.
Third, the cause of death provided both clinically
and in population-based studies is variable and highly
571
80
Percentage of cases
70
60
50
40
30
20
10
al
ity
or
rh
K
ag
no
e
w
In
n
f
e
co
ct
io
rd
n
ac
ci
de
K
no
nt
*
w
n
IU
Pl
G
ac
R
en
*
ta
ll
e
Pr
sio
en
ec
la
m
ps
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ia
et
er
Tw
m
in
bi
co
rt
h
m
pl
U
ic
ne
at
xp
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n
la
in
ed
(a
ll)
a
m
em
lh
er
na
at
m
Fe
to
on
ge
sc
e
ni
ta
la
bn
or
m
tr
au
tio
Bi
rt
h
in
f
nd
in
g
br
up
ec
tio
Cause of death
Figure 5 Cause of intrauterine death in 466 cases according to maternal body mass index (BMI) category27 : underweight ( ), < 18 kg/m2 ;
normal ( ), 1824 kg/m2 ; overweight ( ), 2529 kg/m2 ; obese ( ), 30 kg/m2 . No association between specific causes of intrauterine death
and maternal BMI was observed. *Known to pathologist before placental examination. IUGR, intrauterine growth restriction.
Percentage of cases
70
60
50
40
30
20
10
ll)
(a
ed
at
ic
in
pl
la
m
U
ne
xp
co
in
Pr
Tw
w
K
no
io
rt
bi
er
et
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ec
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ia
ps
io
es
ll
ta
en
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ac
n
w
no
*
R
*
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de
ci
ac
rd
co
n
nt
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ct
fe
lh
na
er
at
m
Fe
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em
In
or
rh
al
m
bn
la
ta
ni
ag
ity
a
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or
tr
h
rt
Bi
C
on
ge
sc
A
au
io
ct
fe
in
en
di
ng
br
up
tio
Cause of death
Figure 6 Cause of intrauterine death in 1039 cases according to duration of time between delivery and postmortem (postmortem interval
(PMI)): 14 days ( ), 58 days ( ), 912 days ( ), 1316 days ( ) or 17 days ( ). There was no significant effect of PMI on
determination of overall cause of death. *Known to pathologist before placental examination. IUGR, intrauterine growth restriction.
Man et al.
572
80
Percentage of cases
70
20%
60
38%
50
Placental examination
(18%)
40
30
20
39%
10
0
Autopsy
None
Mild
Moderate
Severe
Degree of maceration
100%
Unexplained
n = 652 (61%)
80
70
60
50
40
30
20
10
0
Pathologist
ACKNOWLEDGMENTS
N.J.S. is supported by an NIHR Senior Investigator award
and is partially funded by the Great Ormond Street
Hospital Childrens Charity and the NIHR Biomedical
Research Centre at Great Ormond Street Hospital. J.M.
is funded by a grant from Sands (Stillbirth and neonatal
death charity). A.E.H. is supported by an NIHR Clinician
Scientist fellowship and is partially funded by Tommys.
The views expressed are those of the authors and not
necessarily those of the NHS, the NIHR or the Department
of Health.
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de la causa de
Exitus
fetal y muerte fetal intrauterina: factores que influyen en la determinaci on
la muerte en la autopsia
RESUMEN
Objetivos Ha habido varios intentos de clasificar la causa de la muerte (CM) en e xitus fetal. Sin embargo, todos estos
sistemas son subjetivos, lo cual posibilita sesgos del observador y hace difciles las comparaciones entre sistemas. Este
de la CM mediante un conjunto
estudio tuvo como objetivo examinar los factores relacionados con la determinacion
de datos extensos de dos centros especializados en los que el sesgo del observador se haba reducido mediante la
de los hallazgos de manera objetiva y la asignacion
de la CM con base en criterios predeterminados.
clasificacion
Metodos Se revisaron informes detallados de autopsias de muertes intrauterinas en el segundo y tercer trimestre durante
semanas), 179 MFI tardas (2023 semanas) y 639 e xitus fetales (24 semanas de gestacion).
En general, la CM
se identifico claramente en alrededor del 40% (n=412), mientras que alrededor del 60% (n=652) se clasifico como
sin explicacion,
y entre estas ultimas
alrededor de la mitad con factores de riesgo identificados o lesiones con
Se observo un aumento gradual en la
significado incierto, y la mitad restante (n=292 (45%)) totalmente sin explicacion.
de muertes sin explicacion
con el aumento de la maceracion.
Las mujeres de raza negras y asiaticas
proporcion
tuvieron
de muertes debidas a infeccion
ascendente, mientras que las mujeres mayores
significativamente una mayor proporcion
tuvieron significativamente mas
CM relacionadas con la placenta. No hubo diferencias significativas en la
de 40 anos
de CM de acuerdo con el ndice de masa corporal de la madre o con el aumento del intervalo post mortem.
distribucion
En alrededor de la mitad de los fetos con una CM identificable, la causa se pudo identificar a partir de una revision
clnica y de imagenes
o examen fetal externo, y en la mayora del resto se determino mediante el examen de la placenta.
permanecen sin
Conclusiones Basados en criterios objetivos, muchas muertes intrauterinas durante la gestacion
a pesar de la autopsia. La tasa de muertes sin explicacion
vara en alrededor del 30% al 60%, dependiendo
explicacion
de lo significativo de las observaciones. La determinacion
de la CM depende tanto del sistema
de la interpretacion
utilizado como de la interpretacion
subjetiva, de modo que la variacion
en la proporcion
de casos sin
de clasificacion
se basa en gran medida en especulaciones sobre los mecanismos de la muerte. En el examen post mortem se
explicacion
requieren nuevos metodos para determinar objetivamente el motivo de la muerte.
ORIGINAL PAPER