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OBSTETRICS

Evaluation of 1025 fetal deaths: proposed diagnostic workup

Fleurisca J. Korteweg, MD, PhD; Jan Jaap H. M. Erwich, MD, PhD; Albertus Timmer, MD, PhD;
Jan van der Meer, MD, PhD; Joke M. Ravis; Nic J. G. M. Veeger, PhD; Jozien P. Holm, MD, PhD
OBJECTIVE: We sought to evaluate the contribution of different diag-

nostic tests for determining cause of fetal death. Our goal was to propose a workup guideline.
STUDY DESIGN: In a multicenter prospective cohort study from 2002
through 2008, for 1025 couples with fetal death 20 weeks gestation, an
extensive nonselective diagnostic workup was performed. A panel classified cause and determined contribution of diagnostics for allocating cause.
RESULTS: A Kleihauer-Betke, autopsy, placental examination, and cy-

togenetic analysis were abnormal in 11.9% (95% confidence interval

[CI], 9.8 14.2), 51.5% (95% CI, 47.4 55.2), 89.2% (95% CI, 87.2

91.1), and 11.9% (95% CI, 8.715.7), respectively. The most valuable
tests for determination of cause were placental examination (95.7%;
95% CI, 94.296.8), autopsy (72.6%; 95% CI, 69.275.9), and cytogenetic analysis (29.0%; 95% CI, 24.4 34.0).
CONCLUSION: Autopsy, placental examination, cytogenetic analysis,

and testing for fetal maternal hemorrhage are basic tests for workup
after fetal death. Based on the results of these tests or on specific clinical characteristics, further sequential testing is indicated.
Key words: antepartum stillbirth, cause of death, intrauterine fetal
death, workup

Cite this article as: Korteweg FJ, Erwich JJHM, Timmer A, et al. Evaluation of 1025 fetal deaths: proposed diagnostic workup. Am J Obstet Gynecol
2012;206:53.e1-12.

etal death is a devastating experience

for parents and caregivers. A complex
chain of events often precedes the fetal
death. Health care workers are responsible
for providing support to families and for
investigating the cause of death. This information can give insight into why death occurred, which will aid parents in the
mourning process. Furthermore, it will be
of value in determining recurrence risk,
counseling and prevention for future pregnancies, and audit of the care provided,
and it enables comparison of health care.1

Unfortunately the cause of death is reported as unexplained in up to two thirds

of stillbirths.2,3 Using a systematic and
well-defined approach to evaluate the
cause of death reduces this percentage.4
However, the optimal workup after fetal
death has not yet been established and
local protocols differ and are often extensive. Consequently, there is a debate
on which tests and examinations should
be included in an investigative workup to

From the Departments of Obstetrics and Gynecology (Drs Korteweg, Erwich, and Holm and
Ms Ravis) and Pathology and Medical Biology (Dr Timmer); the Division of Hemostasis,
Thrombosis, and Rheology, Department of Hematology (Dr van der Meer); and the
Department of Epidemiology, Trial Coordination Centre (Dr Veeger), University Medical
Centre Groningen, University of Groningen, Groningen, The Netherlands.
Received March 24, 2011; revised Sept. 12, 2011; accepted Oct. 12, 2011.
Dr van der Meer died on Jan. 14, 2009.
This project was funded by The Netherlands Organization for Health Research and Development,
Zorgonderzoek Nederland en Medische Wetenschappen, grant number 2100.0082.
The authors report no conflict of interest.
Reprints: Fleurisca J. Korteweg, MD, PhD, Department of Obstetrics and Gynecology, University
Medical Centre Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands.
f.j.korteweg@og.umcg.nl.
0002-9378/free 2012 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2011.10.026

For Editors Commentary, see Table of Contents

See related editorial, page 1

ensure an acceptable chance of determination of the cause of fetal death.

Several reviews on the workup after fetal death have been published,3,5,6 however a prospective, systematic evaluation
of a large cohort of fetal deaths has not
yet been performed. Therefore we prospectively analyzed all diagnostic tests of
an extensive protocol in which the contribution of each test was evaluated for
determining the cause of fetal death according to the Tulip classification.7 Our
goal was to propose a guideline for an
optimal workup after fetal death in terms
of a high percentage of explained fetal
deaths in combination with a minimum
of testing.

M ATERIALS AND M ETHODS

In 2002, we initiated the prospective intrauterine fetal death (IUFD) cohort study in
50 Dutch secondary and tertiary referral
hospitals. Inclusion criteria were singleton
IUFD diagnosed antepartum 20 weeks
gestation. Pregnancy terminations and intrapartum deaths were excluded. The
study was approved by the review boards
of all hospitals and informed consent was
obtained from all participants.

Diagnostic protocol
Data included medical and obstetric history and details on pregnancy and delivJANUARY 2012 American Journal of Obstetrics & Gynecology

53.e1

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ery. Before the study started we examined local protocols of participating

hospitals regarding diagnostics after
IUFD. Subsequently the study protocol
was based on these local protocols. Diagnostic tests were included in the study
protocol if 70% of hospitals performed
these tests after IUFD. For the study all
participating hospitals followed the
study protocol (Figure 1) and these tests
were offered to all women with an IUFD
so that each couple with IUFD was managed the same way.
Maternal and fetal blood test results
were compared to local laboratory reference values and if greater, were considered abnormal. Maternal and fetal viral
serology and microbiological cultures
were positive if respectively immunoglobulin levels or culture colonies exceeded the reference values in the local
laboratory.
Maternal plasma levels collected on
induction of labor of antithrombin, protein C activity, total and free protein S
antigen, and Von Willebrand factor
(VWF) were measured and the thrombophilias factor V Leiden, prothrombin
G20210A mutation (PTG20210A), and
lupus anticoagulant were determined in
the central laboratory.8 Presence of maternal anticardiolipin antibodies and a
random maternal plasma homocysteine
(abnormal 18.5 mol/L)9 were tested
in local laboratories.
Autopsy and placental examination
were performed by surgical and perinatal
pathologists in participating hospitals. We
urged pathologists to follow the pathology
study protocol based on the guidelines of
the Royal College of Obstetricians and
Gynecologists, the Royal College of Pathologists, and the College of American
Pathologists.7 Cytogenetic evaluation was
performed in genetic centers10 and radiography and magnetic resonance imaging
(MRI) by local radiologists.

Adjudication of cause of death

After individual classification of the
cause, mechanism, origin of mechanism,
and determination of contributing factors of fetal death according to the Tulip
classification7 by an experienced multidisciplinary panel (consisting of 2 obstetricians, an obstetric resident, a perinatal
53.e2

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pathologist and, if needed, expertise by
a neonatologist, geneticist, or microbiologist), consensus was reached after
discussion. The cause was defined as
the initial, demonstrable pathophysiological entity initiating the chain of events that
had irreversibly led to death. Contributing
factors such as smoking and obesity were
also identified. In addition, comorbidity
was noted such as: hypertension-related
disease during pregnancy including
chronic hypertension, pregnancy-induced
hypertension, preeclampsia, HELLP syndrome, and superimposed conditions.11
Diabetes-related disease during pregnancy
included types 1 and 2 diabetes mellitus
and gestational diabetes with or without
medication.12

Value of diagnostics
Contribution of each diagnostic test for
determination of cause of death according to the Tulip classification was evaluated by the same multidisciplinary panel
first individually and secondly during
the panel sessions. Diagnostics were adjudicated valuable if establishing cause
of death (an abnormal result of a diagnostic test established a cause) or excluding cause of death (a result excluded a cause of death when there was a
suspected cause of death based on clinical
findings or review of the medical history,
current pregnancy, or antenatal investigations). We also registered if a test was
missing for determination of cause of
death (if there was a suspected cause, the
test exploring that cause was missing).
Statistics
Categorical variables were expressed as
counts and percentages, and continuous
data as means with SD or median and
ranges, with exact 95% confidence intervals (CIs) given when appropriate. Differences between groups were evaluated
by the Fisher exact test or 2 test for categorical data. A 2-tailed P value .05
was considered to indicate statistical significance. Statistical analyses were performed using software (SAS, version 9.1;
SAS Institute Inc, Cary, NC).

R ESULTS
From 2002 through 2008 a total of 1164
couples and their fetal deaths were in-

American Journal of Obstetrics & Gynecology JANUARY 2012

cluded, of which 1025 were studied (Figure 1). Investigation into inclusion rates
by comparison of death registration
yearbooks from participating hospitals
yielded an average inclusion of 75% of all
IUFDs eligible for the study. Reasons for
not including IUFDs were: denied informed consent, a language barrier, logistic problems, and the doctors reluctance to include women because of an
already known cause of IUFD at birth.
This involved deaths with placental abruption, known chromosomal abnormalities,
and major congenital anomalies, which resulted in an underrepresentation of such
deaths in our cohort.
Median age of mothers was 30 years
(range, 1751 years) and median gestational age at determination of IUFD was
32 weeks and 0 days (range, 20 weeks and
0 days 42 weeks and 4 days). The distribution of maternal ethnic origin was
87.1% Caucasian, 4.6% African, 3.8%
Eastern, and 4.5% other. Of these mothers 52.7% were nulliparous. Median fetal
weight was 1528 g (range, 125410 g). Of
these babies 37.2% were small for gestational age (10th growth percentile)
and 10.1% large for gestational age
(90th growth percentile) according to
Dutch Kloosterman13 growth charts.

Diagnostic protocol
How often a test of the study protocol
was performed varied from 98.7% for
placental examination to 3.2% for expert
external fetal examination (Figure 1).
The results of various abnormal maternal
blood tests and the number of women
tested are presented in Table 1. Of the
women with increased glycated hemoglobin (HbA1c) (7.9%), 61.8% were not
known to have diabetes-related disease.
Macrosomia and obesity, known risk factors for diabetes,14 were more prevalent in
this group compared to the group with
normal HbA1c. Fetal blood tests derived
from the umbilical cord were only performed in 10.5% mainly due to the impossibility of drawing (enough) blood after
birth.
We recently published on the contribution of coagulation tests.8 As shown in
Table 1, in women with IUFD we more
often observed decreased plasma levels
of antithrombin (17.1%) and protein C

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FIGURE 1

Enrollment of couples with IUFD and diagnostics performed after fetal death
Inclusion criteria
Singleton IUFD diagnosed antepartum (heart beat ceased before labor) 20 weeks of gestation
Total IUFD included: 1164
Informed consent withdrawn: 14
Did not meet inclusion criteria: 60

Total IUFD studied: 1025

Case record form incomplete due to

majority of test results missing: 65

How often a diagnostic test was performed in 1025 fetal deaths

Prior to delivery after determination of IUFD
Mother
Blood tests: 67.6-98.6% of individual tests performed
Blood type, Rhesus factor, Thrombocytes, Uric Acid, Urea, Creatinine, Aspartate, Alanine, Lactate
dehydrogenase (LDH), Bilirubin, Gamma-glutamyltransferase, C-reactive protein, Thyroid-Stimulating
Hormone, Free thyroxine (T4), random plasma glucose, glycated hemoglobin (HbA1c), Kleihauer-Betke,
Hemoglobin electrophoresis, Anti-nuclear Antibodies, Antibody screening, HIV, random
Homocysteine, Anticardiolipin antibodies
Viral serology: 79.1-94.0% of individual tests performed
Toxoplasmosis, Rubella, Cytomegalovirus, Herpes simplex virus, Parvovirus B19, Syphilis, Hepatitis Bsurface-antigen
Coagulation tests: 81.4-93.7% of individual tests performed
plasma levels of Antithrombin, Protein C, total and free Protein S, von Willebrand factor; inherited
thrombophilias Factor V Leiden, Prothrombin G20210A mutation and lupus anticoagulant
Vaginal-rectal swab: 83.2%
Fetus
Cytogenetic analysis; amniocentesis or chorionic villus biopsy: 26.2%
After delivery
Fetus
Blood tests from umbilical cord: 10.5%
Blood type, Rhesus factor, Hemoglobin, LDH, Bilirubin, Reticulocytes, Creatine phosphokinase
Viral serology: 3.6-4.5% of individual testsperformed
Toxoplasmosis, Rubella, Cytomegalovirus, Herpes simplex virus, Parvovirus B19, Syphilis
Ear throat swab: 72.1%
Autopsy: 68.8%, external fetal examination by expert if no consent for autopsy: 3.2%
Cytogenetic analysis: 42.1%; tissue testing of the fetus (fetal blood, fascia lata, pericard, cartilage, or skin),
umbilical cord or placenta
MRI: 6.0%
Radiography: 39.9%
Placenta
Placental swab between the membranes: 59.7%
Pathological examination including histopathology: 98.7%
IUFD, intrauterine fetal death.
Korteweg. Fetal death workup. Am J Obstet Gynecol 2012.

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TABLE 1

Abnormal blood tests in 1025 intrauterine fetal deaths

Maternal blood tests %
abnormal (n tested)

95% CI

Thrombocytes 100 x 103/L

3.1 (1011) 2.14.3

Thrombophilic defects %
abnormal (n tested)

95% CI

Prevalence normal
population

Acquired thrombophilias

................................................................................................................................................................................................................................................................................................................................................................................

Uric Acid 0.40 mmol/L

10.6 (956) 8.712.7

Antithrombin

17.1 (952) 14.719.7

................................................................................................................................................................................................................................................................................................................................................................................

Urea 7.5 mmol/L

1.6 (976) 0.92.7

Protein C

Creatinine 100 umol/L

2.4 (1007) 1.53.5

Total protein S

2.9 (960) 2.04.2

Aspartate 40 IU/L

8.6 (1001) 6.910.5

Free protein S

1.0 (952) 0.41.8

Alanine 40 IU/L

7.6 (1006) 6.09.4

VWF

4.2 (834) 2.95.8

................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
a
................................................................................................................................................................................................................................................................................................................................................................................

14.3 (954) 12.116.6

................................................................................................................................................................................................................................................................................................................................................................................

Lactate dehydrogenase 250 IU/L

80.6 (988) 78.083.0 Inherited thrombophilias

................................................................................................................................................................................................................................................................................................................................................................................

Bilirubin 26 umol/L

1.7 (928) 1.02.8

Gamma-glutamyl transferase 40 IU/L

6.5 (914) 5.08.3

Heterozygous

5.6

51.3 (832) 47.954.8

Homozygous

0.2

Factor V Leiden

5.8 (935) 4.47.5

5%

................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................

C-reactive protein 10 mg/L

................................................................................................................................................................................................................................................................................................................................................................................

TSH 0.4 mE/L

1.6 (936) 0.92.6

Prothrombin G20210A

2.4 (937) 1.53.5

3%

................................................................................................................................................................................................................................................................................................................................................................................

TSH 4.0 mE/L

8.9 (936) 7.110.9

Heterozygous

Free thyroxine 10.0 pmol/L

13.2 (902) 11.115.6

Homozygous

Free thyroxine 24.0 pmol/L

0.2 (902) 0.030.8

Lupus anticoagulant

2.4

................................................................................................................................................................................................................................................................................................................................................................................

................................................................................................................................................................................................................................................................................................................................................................................

1.5 (865) 0.82.6

3%

................................................................................................................................................................................................................................................................................................................................................................................

Random plasma glucose 6.111.0 mmol/L 19.8 (881) 17.222.5

Random homocysteine

2.9 (733) 1.84.4

5%

Random plasma glucose 11.1 mmol/L

0.9 (881) 0.41.8

AC antibodies

5.6 (791) 4.17.4

210%

HbA1c (glycated hemoglobin) 6.0%

7.9 (907) 6.39.9

................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................

Kleihauer-Betke positive

11.9 (910) 9.814.2

................................................................................................................................................................................................................................................................................................................................................................................

Hemoglobin electrophoresis abnormal

2.7 (754) 1.64.1

Anti-nuclear antibodies positive

9.4 (693) 7.311.8

Antibody screening positive

3.9 (917) 2.85.4

HIV positive

0.3 (763) 0.030.9

................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................

AC, anticardiolipin; CI, confidence interval; TSH, thyroid-stimulating hormone; VWF, Von Willebrand factor.
a

Free protein S2 but normal total protein S.

Korteweg. Fetal death workup. Am J Obstet Gynecol 2012.

activity (4.2%), and increased levels of

VWF (14.3%), compared to healthy pregnant women (in which 2.5% and 97.5%
were the cutoff points for normal ranges).
Overall, inherited thrombophilias in
mothers with IUFD were not more prevalent than in the normal population. This
was also concluded for hyperhomocysteinemia or presence of anticardiolipin antibodies. Of the 40 women unfamiliar with
the antiphospholipid syndrome before the
index pregnancy with either lupus anticoagulant and/or anticardiolipin antibodies
in this study, the cause of death in 12
IUFDs was placental bed pathology with
origin of mechanism infarction, while 23
had other causes of death and 5 an unknown cause of death.
53.e4

Of the women tested for toxoplasmosis, rubella, cytomegalovirus, herpes

simplex virus (TORCH), parvovirus
B19, syphilis, or hepatitis B surface-antigen, 17.9% (95% CI, 15.6 20.5) had
positive IgM antibody titers to one of
these infectious agents or a positive hepatitis B surface-antigen (Table 2). In
1.8% of the total cohort (n 1025) intrauterine infection was allocated as
cause of death, supported by placental or
autopsy findings. Of the 739 performed
fetal ear/throat and 612 placental swabs,
respectively, 25.3% and 22.8% were positive for 1 microorganism (Table 2). Of
the positive fetal and placental swabs in,
respectively, 74.9% and 71.4% Escherichia coli or group B streptococcus was

American Journal of Obstetrics & Gynecology JANUARY 2012

detected. Of the examined placentas

(n 1011) 12.7% (95% CI, 10.714.9)
showed histological chorioamnionitis
without funisitis and only 21.9% and
25.9% of the fetal and placental swabs in
these cases were positive.
As is also shown in Table 2 abnormal
findings were observed in 51.5% of performed autopsies, 89.2% of placentas,
30.6% of MRI, and 7.3% of radiography.
Abnormal autopsy or placental histological evaluation were defined as abnormal
findings stated in the conclusion of the
pathology report performed by the
pathologist. Minor abnormal findings
stated in the report concerning macroscopic or microscopic examination but
not mentioned in the conclusion of the

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TABLE 2

Abnormal viral serology tests, cultures, and other

diagnostics in 1025 intrauterine fetal deaths
% abnormal (n tested) 95% CI
Positive viral serology

Maternal

Toxoplasmosis IgG

23.4 (964) 20.826.3

Toxoplasmosis IgM

1.4 (946) 0.72.3

Fetal
9.8 (41) 2.723.1

..............................................................................................................................................................................................................................................

0 (42) 08.4

..............................................................................................................................................................................................................................................

Rubella IgG

90.5 (944) 88.492.3

Rubella IgM

3.2 (853) 2.14.6

75.7 (37) 58.888.2

..............................................................................................................................................................................................................................................

0 (37) 09.5

..............................................................................................................................................................................................................................................

Cytomegalovirus IgG

46.8 (941) 43.550.0

Cytomegalovirus IgM

2.3 (964) 1.43.4

42.5 (40) 27.059.1

..............................................................................................................................................................................................................................................

0 (46) 07.7

..............................................................................................................................................................................................................................................

Herpes simplex virus IgG

63.3 (811) 59.866.6

Herpes simplex virus IgM

7.9 (826) 6.19.9

50.0 (40) 33.866.2

..............................................................................................................................................................................................................................................

0 (41) 08.6

..............................................................................................................................................................................................................................................

Parvovirus B19 IgG

62.8 (869) 59.566.1

45.0 (40) 29.361.5

Parvovirus B19 IgM

2.1 (892) 1.33.3

2.3 (43) 0.0612.3

Syphilis

0.5 (946) 0.21.2

2.3 (44) 0.0612.0

Hepatitis B surface-antigen

0.5 (934) 0.21.2

..............................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................

Cultures

.....................................................................................................................................................................................................................................

Urinary sediment nitrite

3.8 (771) 2.55.4

.....................................................................................................................................................................................................................................

Chlamydia PCR

1.6 (706) 0.82.8

.....................................................................................................................................................................................................................................

Group B streptococcus

17.9 (853) 15.420.7

Fetal swabs

25.3 (739) 22.228.6

Placental swabs

22.8 (612) 19.626.4

.....................................................................................................................................................................................................................................
.....................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................

Other diagnostics

.....................................................................................................................................................................................................................................

Autopsy

51.5 (705) 47.455.2

Placental examination

89.2 (1012) 87.291.1

Cytogenetic analysis

11.9 (362) 8.715.7

MRI

30.6 (62) 19.643.7

.....................................................................................................................................................................................................................................
.....................................................................................................................................................................................................................................
.....................................................................................................................................................................................................................................
.....................................................................................................................................................................................................................................

Radiography

7.3 (409) 5.010.3

..............................................................................................................................................................................................................................................

CI, confidence interval; MRI, magnetic resonance imaging; PCR, polymerase chain reaction.
Korteweg. Fetal death workup. Am J Obstet Gynecol 2012.

report were not regarded as clinically relevant. Cytogenetic analysis was performed in 700 IUFDs (68.3%) and a successful result was obtained in 362 deaths
(51.7%). The prevalence of a chromosomal abnormality in these 362 IUFDs
was 11.9% (95% CI, 8.715.7). Of these
43 chromosomal abnormalities, 37.2%
was trisomy 21, 23.3% trisomy 18, 16.3%
monosomy (45, X), 4.6% trisomy 13,
and in 18.6% other chromosomal abnormalities were found.

Adjudication of cause of death

The main causes of death in the total
cohort of 1025 deaths were placental

pathology (65.2%), congenital anomaly

(4.8%), infection (1.8%), and other
(5.0%) while in 23.2% the cause remained unknown. Subgroups of causes,
mechanism, and origin of mechanism of
death are presented in Table 3. Deaths
caused by fetal maternal hemorrhage
(FMH) of unknown origin with evidence
of fetal anemia confirmed by placental
examination and/or autopsy (1.3%) were
classified according to the Tulip classification as caused by placental parenchyma pathology (n 10) or placenta
not otherwise specified (n 3), both
with origin of mechanism excessive

Research

bleeding. In 10.6% of the total cohort

FMH was observed as a contributing factor. Diabetes-related disease was cause of
death only twice in which maternal diabetic coma resulted in fetal death. In
4.0% of 1025 deaths diabetes-related disease was a contributing factor. Maternal
hyperthyroidism resulted in fetal death
only once; in 2.1% thyroid-related disease was a contributing factor. Most
deaths in the maternal disease group
other (1.3%) were caused by a known
antiphospholipid syndrome before the
index pregnancy (0.9%). The most frequent observed maternal disease during pregnancy was hypertension-related disease (15.1%); placental bed
pathology was in 65.8% the cause of
these deaths.

Value of diagnostics
After the evaluation of the contribution of each test for adjudication of
cause of death according to the Tulip
classification, the most valuable tests
were placental examination in 95.7%
(95% CI, 94.296.8), autopsy in 72.6%
(95% CI, 69.275.9), and cytogenetic
analysis in 29.0% (95% CI, 24.4 34.0)
(Table 4). The tests not mentioned in
Table 4 including coagulation tests and
radiography were respectively never or
only once allocated as valuable for adjudication of the cause.
On the basis of our findings we derived
the following flowchart for an optimal
workup of basic and selective diagnostics
to determine the cause of fetal death
(Figure 2).

C OMMENT
A fetal death workup guideline helps in
elucidating the cause of fetal death but
also aims to prevent unnecessary investigations. There is no international generally accepted diagnostic guideline for
fetal death. This study primarily addressed the contribution of a uniform
extensive nonselective protocol of diagnostic tests for the adjudication of the
cause according to the Tulip classification in 1025 fetal deaths. This resulted in
a proposal for a basic and additional
workup guideline. In the cognitive process of making explicit the complex

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TABLE 3

Cause of death, mechanism and origin of mechanism in 1025 IUFDs according to the Tulip classification7
Mechanism of death and origin of mechanism

Cause of death % (n)

Total

Cardiocirculatory;
Cardiocirculatory; Cardiocirculatory; Placental;
congenital heart
Cardiocirculatory; supraventricular umbilical cord
abruptio
malformation
fetal hydrops
tachycardia
occlusion
placentae

Chromosomal defect; numerical

2.8 (29)

Chromosomal defect; structural

0.1 (1)

50.0 (2)

20.0 (4)

Congenital anomaly: syndrome; monogenic

0.1 (1)

Congenital anomaly: syndrome; other

0.2 (2)

Congenital anomaly: central nervous system

0.1 (1)

5.0 (1)

Congenital anomaly: heart and circulatory system

0.4 (4)

10.0 (2)

Congenital anomaly: digestive system

0.1 (1)

Congenital anomaly: neoplasm

0.3 (3)

Congenital anomaly: other; single organ

0.1 (1)

Congenital anomaly: other; multiple organ

0.6 (6)

................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................

50.0 (1)

................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................

5.0 (1)

................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................

50.0 (2)

................................................................................................................................................................................................................................................................................................................................................................................

Placenta: placental bed pathology

31.4 (322)

Placenta: placental pathology; development

18.8 (193)

Placenta: placental pathology; parenchyma

2.8 (29)

Placenta: placental pathology; localization

0.1 (1)

Placenta: umbilical cord complication

5.7 (58)

Placenta: not otherwise specified

6.4 (66)

Infection: transplancental

1.0 (10)

Infection: ascending

0.8 (8)

Other: fetal hydrops of unknown origin

3.3 (34)

Other: maternal disease; diabetus mellitus

0.2 (2)

Other: maternal disease; hyperthyroidism

0.1 (1)

Other: maternal disease; other

1.3 (13)

Other: out of the ordinary

0.1 (1)

100 (61)

................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................

98.3 (58)

................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................

20.0 (4)

................................................................................................................................................................................................................................................................................................................................................................................

1.7 (1)

................................................................................................................................................................................................................................................................................................................................................................................

35.0 (7)

................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................

50.0 (1)

................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................

Unknown: despite thorough investigation

15.8 (162)

5.0 (1)

................................................................................................................................................................................................................................................................................................................................................................................

Unknown: important information missing

7.4 (76)

................................................................................................................................................................................................................................................................................................................................................................................

Total % (n)

100 (1025)

100 (4)

100 (20)

100 (2)

100 (59)

100 (61)

................................................................................................................................................................................................................................................................................................................................................................................

IUFD, intrauterine fetal death.

Korteweg. Fetal death workup. Am J Obstet Gynecol 2012.

chain of events eventually leading to adjudication of an underlying cause of

death during our panel meetings, we also
assessed risk factors and the clinical setting in which fetal death occurred.7
In accordance with others,15-17 we cannot overemphasize the value of autopsy.
Earlier studies also provided evidence that
after IUFD routine macroscopic and histological examination of the placenta is a
necessary complement to autopsy confirming clinical and/or autopsy findings.18-20
Both tests provide information that is
53.e6

(continued )

pertinent to nearly every potential cause

of fetal death and in the majority of cases
exclude causes if there are no signs. Further selective diagnostic testing may follow after pathology results and/or suspect clinical characteristics.
Although an autopsy is optimal, earlier studies have acknowledged the value
of MRI as an alternative,21 particularly
for cerebral pathology.22 Our low performance rate of MRI (6.0%) is probably
due to our high autopsy rate, clinicians
not being familiar with fetal MRI and

American Journal of Obstetrics & Gynecology JANUARY 2012

unavailability of MRI services. MRI was

adjudicated as valuable in only 2 cases
and radiography even less. This is probably associated with inexperience of
most radiologists with reviewing MRI after fetal death. MRI is generally advised if
there is suspicion of cerebral congenital
anomalies and radiography if there is
suspicion of congenital anomalies and
both in the absence of autopsy.23
We observed chromosomal abnormalities in 11.9% of our successfully
karyotyped IUFDs (n 362). In the

Obstetrics

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Research

TABLE 3

Cause of death, mechanism and origin of mechanism in 1025 IUFDs according to the Tulip classification7 (continued)

Placental;
infarction

Placental;
villus
immaturity

0.7 (2)

Placental;
hypoplasia

Placental;
fetal
thrombotic
vasculopathy

Placental;
massive
perivillous
fibrindeposition

Infection
intrauterine

Other; excessive
bleeding

6.1 (9)

None of the
above
3.0 (3)

Unknown
3.2 (9)

................................................................................................................................................................................................................................................................................................................................................................................

0.4 (1)

................................................................................................................................................................................................................................................................................................................................................................................

1.0 (1)

................................................................................................................................................................................................................................................................................................................................................................................

1.0 (1)

0.4 (1)

................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................

1.0 (1)

................................................................................................................................................................................................................................................................................................................................................................................

0.4 (1)

................................................................................................................................................................................................................................................................................................................................................................................

2.0 (2)

................................................................................................................................................................................................................................................................................................................................................................................

7.1 (1)

................................................................................................................................................................................................................................................................................................................................................................................

1.4 (4)

................................................................................................................................................................................................................................................................................................................................................................................

95.9 (257)

4.0 (4)

................................................................................................................................................................................................................................................................................................................................................................................

100 (42)

93.2 (137)

15.4 (2)

11.9 (12)

76.9 (10)

7.9 (8)

................................................................................................................................................................................................................................................................................................................................................................................

100 (4)

100 (7)

................................................................................................................................................................................................................................................................................................................................................................................

7.7 (1)

................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................

65.3 (66)

................................................................................................................................................................................................................................................................................................................................................................................

42.9 (6)

................................................................................................................................................................................................................................................................................................................................................................................

50.0 (7)

................................................................................................................................................................................................................................................................................................................................................................................

0.4 (1)

9.2 (26)

................................................................................................................................................................................................................................................................................................................................................................................

0.7 (1)

1.0 (1)

................................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................

2.6 (7)

2.0 (2)

1.4 (4)

................................................................................................................................................................................................................................................................................................................................................................................

0.4 (1)

................................................................................................................................................................................................................................................................................................................................................................................

56.9 (161)

................................................................................................................................................................................................................................................................................................................................................................................

0.4 (1)

26.5 (75)

................................................................................................................................................................................................................................................................................................................................................................................

100 (268)

100 (42)

100 (147)

100 (4)

100 (7)

100 (14)

100 (13)

100 (101)

100 (283)

................................................................................................................................................................................................................................................................................................................................................................................

adjudication of the cause, cytogenetic

analysis was the third most valuable
test (29.0%) and is advised for all
IUFDs by invasive testing before labor.
If no parental consent for invasive testing is given, an umbilical cord sample
postpartum was second best.10 Newer cytogenetic techniques in which tissue culture is not required such as molecular
karyotyping by array-based analysis results
in a more precise evaluation of submicroscopic cytogenetic imbalances and should
be considered when karyotyping fails.

FMH was attributed as cause if there

was evidence of fetal anemia confirmed
by placental examination and/or autopsy in 1.3%. Others reported 3% of
deaths caused by FMH.24 We observed
FMH however in 11.9% of tested
women, comparable to 8% reported in
stillbirths earlier.25 This 12% frequency
may be an overestimate since many of
these cases could have been related to a
nonpathologic event. We would be inclined to advise investigation of FMH
only in cases with suspicion. However, to

preserve erythrocytes until after pathology results are available is technically impossible. We therefore recommend investigation of FMH in all fetal deaths
before induction of labor, to exclude
FMH caused by labor itself.
The most convincing proof of an infectious cause of death is an autopsy with
evidence of organ involvement with an
organism potentially able to cause stillbirth and/or histological placental examination with infectious findings.26 Chorioamnionitis by itself (12.7%) should

JANUARY 2012 American Journal of Obstetrics & Gynecology

53.e7

Research

Obstetrics

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TABLE 4

Valuable tests in relation to determination of cause in 1025 intrauterine fetal deaths

Value of diagnostics
Diagnostic tests
Cause of death, n
Chromosomal defect; numerical

Kleihauer-Betke
Total

Established

Glucose testing
Excluded

Missed

Established

Hb electro-phoresis
Excluded

Missed

Established

Excluded

Missed

29

.................................................................................................................................................................................................................................................................................................................................................................................................................

Chromosomal defect, structural

.................................................................................................................................................................................................................................................................................................................................................................................................................

Congenital anomaly

19

.................................................................................................................................................................................................................................................................................................................................................................................................................

Placenta: placental bed pathology

322

Placenta: placental pathology; development

193

Placenta: placental pathology; parenchyma

29

10

Placenta: placental pathology; localization

.................................................................................................................................................................................................................................................................................................................................................................................................................

.................................................................................................................................................................................................................................................................................................................................................................................................................

.................................................................................................................................................................................................................................................................................................................................................................................................................
.................................................................................................................................................................................................................................................................................................................................................................................................................

Placenta: umbilical cord complication

58

Placenta: not otherwise specified

66

.................................................................................................................................................................................................................................................................................................................................................................................................................

.................................................................................................................................................................................................................................................................................................................................................................................................................

Infection

18

Other: fetal hydrops of unknown origin

34

.................................................................................................................................................................................................................................................................................................................................................................................................................

33

.................................................................................................................................................................................................................................................................................................................................................................................................................

Other: maternal disease; diabetes mellitus

Other: maternal disease; hyperthyroidism

.................................................................................................................................................................................................................................................................................................................................................................................................................
.................................................................................................................................................................................................................................................................................................................................................................................................................

Other: maternal disease; other

13

.................................................................................................................................................................................................................................................................................................................................................................................................................

Other: out of the ordinary

.................................................................................................................................................................................................................................................................................................................................................................................................................

Unknown: despite thorough investigation

162

Unknown: important information missing

76

.................................................................................................................................................................................................................................................................................................................................................................................................................

.................................................................................................................................................................................................................................................................................................................................................................................................................

Total, n

1025

13

14

33

.................................................................................................................................................................................................................................................................................................................................................................................................................

n tested

910

907

754

.................................................................................................................................................................................................................................................................................................................................................................................................................

n not tested

115

118

271

.................................................................................................................................................................................................................................................................................................................................................................................................................

Total, % valuable

2.0

1.7

2.1

1.7

0.1

12.2

................................................................................................................................................................................................................................................................................................................................................................................

Diagnostics were adjudicated valuable if: establishing cause of death, excluding cause of death or missing for determination of cause of death if there was a suspected cause.
AB, antibodies; MRI, magnetic resonance imaging.
Korteweg. Fetal death workup. Am J Obstet Gynecol 2012.

not be considered a cause of stillbirth.

TORCH serology and cultures are traditionally advised in the evaluation of stillbirth. In our study placental examination and autopsy were able to support an
intrauterine infection as cause in only
1.8% of all fetal deaths. This is supported
by others.16,27 More infections were reported by Petersson et al,4 24% in fetal
deaths 22 weeks of gestation, most
commonly group B streptococcus. Differences could be explained due to our
strict criteria7 and the lack of use of molecular diagnostic technology. Based on
our findings we no longer recommend
routine screening for infections. We advise obtaining and storing blood for maternal virus serology for all IUFDs. This
can be analyzed if there are pathological
infectious findings. If there is clinical
suspicion of infection this should be an53.e8

(continued )

alyzed together with maternal, fetal, and

placental cultures. However, in parts of
the world with a high prevalence of infectious causes such as syphilis and malaria28 testing all deaths may well be
advisable.
We recently concluded after analysis
of 750 fetal deaths that, except for VWF,
acquired and inherited thrombophilic
defects were not associated with fetal
death. Although a group of women with
fetal death had lowered plasma levels of
acquired thrombophilic defects when
compared to healthy pregnant women,
these levels remained within the normal
ranges for nonpregnant women. These
data provided no evidence for routine
testing of inherited or acquired thrombophilic defects after fetal death.8 This
is confirmed by our data of 1025 evaluated fetal deaths. Thrombophilia test-

American Journal of Obstetrics & Gynecology JANUARY 2012

ing should be considered in women with

IUFD and a family history of hereditary
thrombophilia or a personal history of
venous thromboembolism, to prevent
further maternal thromboembolisms.29
Overall about 10% of fetal deaths are
associated with maternal disease.30 We
observed hypertension and diabetes-related disease during pregnancy in, respectively, 15.1% and 4.0% of the total
cohort. Diabetes-related and thyroid-related disease as cause of death were rare.
However, an increased HbA1c was often
observed illustrating the needs for further scientific investigation into unestablished gestational diabetes. Testing
for maternal disease in asymptomatic
women has been suggested by many6; we
recommend testing selectively if there is
a suspect clinical history or suspect current pregnancy. In cases with fetal hy-

Obstetrics

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Research

TABLE 4

Valuable tests in relation to determination of cause in 1025 intrauterine fetal deaths (continued)
Antibody screening
Established

Excluded

Anticardiolipin AB
Missed

Established

Excluded

Mother viral serology

Missed

Established

Excluded

Mother swabs
Missed

Established

Fetus swabs
Excluded

Missed

Established

Excluded

Missed

.................................................................................................................................................................................................................................................................................................................................................................................................................
.................................................................................................................................................................................................................................................................................................................................................................................................................
.................................................................................................................................................................................................................................................................................................................................................................................................................

.................................................................................................................................................................................................................................................................................................................................................................................................................

.................................................................................................................................................................................................................................................................................................................................................................................................................
.................................................................................................................................................................................................................................................................................................................................................................................................................
.................................................................................................................................................................................................................................................................................................................................................................................................................
.................................................................................................................................................................................................................................................................................................................................................................................................................

.................................................................................................................................................................................................................................................................................................................................................................................................................

.................................................................................................................................................................................................................................................................................................................................................................................................................

30

31

.................................................................................................................................................................................................................................................................................................................................................................................................................
.................................................................................................................................................................................................................................................................................................................................................................................................................
.................................................................................................................................................................................................................................................................................................................................................................................................................

.................................................................................................................................................................................................................................................................................................................................................................................................................
.................................................................................................................................................................................................................................................................................................................................................................................................................

39

.................................................................................................................................................................................................................................................................................................................................................................................................................
.................................................................................................................................................................................................................................................................................................................................................................................................................

31

.................................................................................................................................................................................................................................................................................................................................................................................................................

917

791

964

853

739

.................................................................................................................................................................................................................................................................................................................................................................................................................

108

234

61

172

286

.................................................................................................................................................................................................................................................................................................................................................................................................................

3.4

3.7

1.1

0.0

4.9

11.5

0.8

1.2

1.4

1.4

................................................................................................................................................................................................................................................................................................................................................................................

drops tests to prove red cell alloimmunization, parvovirus B19 serology and
hemoglobin electrophoresis are advised
to exclude other causes of death as these
were considered valuable in these cases.
Obtaining amniotic fluid, which is advised for all fetal deaths, may also provide opportunities for investigation into
metabolic disease.
The value of this nationwide study
with 50 participating hospitals lies in its
size and the approach in which fetal
death was evaluated: a case-by-case evaluation of 1025 IUFDs. For establishing
the cause of death we used the Tulip classification for perinatal mortality that
separates cause, mechanism, and risk
factors that are often mixed in other systems.31 Having strict criteria, the Tulip
classification system itself influenced our
adjudication of causes and judgment as

to whether tests were valuable. Not all

possible tests are needed to classify cause
of death in the Tulip classification. The
distribution of causes of death obviously
also influences the contribution of diagnostic tests.
In general, the occurrence of diagnostic test abnormalities in our study was
low. A comparison of abnormal test results in IUFD vs live born was neither
planned nor performed. Some abnormal
tests may also be relatively common in
live births and therefore it may be difficult
to judge their relevance when found in a
cohort of stillbirths. However in our procedure of classifying the cause, we considered all available information including
the clinical setting in addition to abnormal
test results and other diagnostics.
The clinical implications of our findings are presented in a flowchart for di-

agnostic workup to determine cause of

fetal death according to the Tulip classification (Figure 2). Autopsy, placental
examination and cytogenetic analysis are
the basis for diagnostic workup for all fetal deaths. We recommend further individualized sequential testing to avoid
unnecessary investigations and positive
test results that do not identify the cause
of stillbirth and bring on anxiety. Modifications to the guideline, for example
testing of HbA1c, can be applied in view
of risk factor assessment, declined autopsy consent, endemic differences in
causes of fetal death, local preferences
and different cultures, technology, or financial resources.

Participating hospitals
We thank 50 Dutch hospitals for participating in our national IUFD study: Albert

JANUARY 2012 American Journal of Obstetrics & Gynecology

53.e9

Research

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TABLE 4

Valuable tests in relation to determination of cause in 1025 intrauterine fetal deaths (continued)
Fetus viral serology
Established

Excluded

Cytogenetic analysis
Missed

Established

Excluded

Autopsy
Missed

29

Established
13

Placenta
Excluded
3

Missed
1

Established
13

MRI
Excluded

Missed

Established

Excluded

Missed

.................................................................................................................................................................................................................................................................................................................................................................................................................

.................................................................................................................................................................................................................................................................................................................................................................................................................

15

20

16

155

44

319

59

28

193

28

.................................................................................................................................................................................................................................................................................................................................................................................................................

.................................................................................................................................................................................................................................................................................................................................................................................................................

.................................................................................................................................................................................................................................................................................................................................................................................................................
.................................................................................................................................................................................................................................................................................................................................................................................................................

.................................................................................................................................................................................................................................................................................................................................................................................................................

14

50

22

11

66

.................................................................................................................................................................................................................................................................................................................................................................................................................

.................................................................................................................................................................................................................................................................................................................................................................................................................

15

18

.................................................................................................................................................................................................................................................................................................................................................................................................................

32

15

26

34

.................................................................................................................................................................................................................................................................................................................................................................................................................

.................................................................................................................................................................................................................................................................................................................................................................................................................

.................................................................................................................................................................................................................................................................................................................................................................................................................

10

.................................................................................................................................................................................................................................................................................................................................................................................................................

.................................................................................................................................................................................................................................................................................................................................................................................................................

24

19

139

17

153

25

16

59

66

75

87

455

179

266

10

.................................................................................................................................................................................................................................................................................................................................................................................................................

36

.................................................................................................................................................................................................................................................................................................................................................................................................................

30

57

702

.................................................................................................................................................................................................................................................................................................................................................................................................................

46

362

705

1012

62

.................................................................................................................................................................................................................................................................................................................................................................................................................

979

663

320

13

963

.................................................................................................................................................................................................................................................................................................................................................................................................................

17.4

3.7

29.0

13.1

72.6

55.9

95.7

76.9

4.8

0.0

................................................................................................................................................................................................................................................................................................................................................................................

Schweitzer Hospital, Dordrecht; Alysis

Zorggroep Zevenaar; Amphia Hospital,
Breda; Amstelveen Hospital; Antonius
Hospital, Sneek; Atrium Medical Center,
Heerlen; Bronovo Hospital, the Hague;
Bethesda Hospital, Hoogeveen; Deventer
Hospitals; Diaconessenhuis, Utrecht; Erasmus University Hospital Rotterdam; Flevo
Hospital, Almere; Gelre Hospitals, Apeldoorn; Gelre Hospitals, Zutphen; Groene
Hart Hospital, Gouda; Haga Hospital, the
Hague; Isala Klinieken, Zwolle; Kennemer
Gasthuis, Haarlem; Lange Land Hospital,
Zoetermeer; Leids University Medical Cen-

53.e10

ter, Leiden; Maasland Hospital, Sittard; Martini Hospital, Groningen; Meander Medical
Center, Amersfoort; Medical Center Alkmaar; Medical Center Leeuwarden; Medical Center Rijnmond Zuid, Rotterdam;
Medical Spectrum Twente, Enschede;
Medical Center Haaglanden, the Hague;
Nij Smellinghe, Drachten; Rivierenland Hospital, Tiel; Rijnland Hospital, Leiderdorp; Rode Kruis Hospital,
Beverwijk; Ruwaard van Putten Hospital, Spijkenisse; Sint Elisabeth Hospital,
Tilburg; Sint Franciscus Gasthuis, Rotterdam; Sint Lucas Andreas Hospital,

American Journal of Obstetrics & Gynecology JANUARY 2012

Amsterdam; Scheperhospital, Emmen;

Slingeland Hospital, Doetinchem; Streekziekenhuis Midden Twente, Hengelo;
Twee Steden Hospital, Tilburg; University Medical Center Groningen; University Medical Center Utrecht; University
Medical Center Sint Radboud, Nijmegen; VieCuri Medical Center Noord
Limburg, Venlo; Vlietland Hospital,
Vlaardingen; Vrije University Medical
Center, Amsterdam; Walcheren Hospital,
Vlissingen; Westfries Gasthuis, Hoorn;
Wilhelmina Hospital, Assen; Zaans
Medical Center, Zaandam.
f

Obstetrics

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Research

FIGURE 2

Guideline flowchart for diagnostic workup to investigate cause of fetal death

Basic investigation for all intrauterine fetal death antepartum
review previous obstetric history, current pregnancy, antenatal investigations,
maternal and paternal family and personal history
counsel parents on value autopsy, placental examination, and cytogenetic analysis
before induction of labor perform invasive cytogenetic analysis (amniocentesis or chorionic villus biopsy) and
preserve tissue for possible additional future tests
test for fetal maternal hemorrhage
collect and store serum for maternal virus serology; analyze selectively
Basic investigation for all intrauterine fetal death postpartum
external fetal examination preferably by expert: documentation of morphological (ab)normalities and photos
register birthweight and trimmed placental weight
if no informed consent for invasive cytogenetic analysis, sample umbilical cord for cytogenetic analysis
placental examination including histopathology
if antepartum/postpartum suspected cerebral congenital anomalies
MRI
radiography
if antepartum/postpartum suspected congenital anomalies
autopsy
if no autopsy consent discuss selective autopsy
external fetal examination by expert familiar with congenital anomalies including photographs, MRI, and radiography

Selective investigation intrauterine fetal death

if clinical signs and symptoms of maternal disease:
blood tests and test urine for albumen
suspected hypertension-related disease
suspected disturbed thyroid function
thyroid-stimulating hormone, free thyroxine (T4)
suspected diabetes-related disease, macrosomia (history), a strong family history of diabetes, or obesity
glucose screening: such as glycated hemoglobin (HbA1c) or oral glucose tolerance test
if suspected drug use

toxicology screen

if signs of fetal hydrops antibody screening, parvovirus B19 serology and hemoglobin electrophoresis,
amniotic fluid testing for possible investigation into metabolic disease
if clinical signs of infection: collect and analyze vaginal-rectal swab mother, fetal, and placental swabs
and analyze maternal virus serology and amniotic fluid for molecular diagnostic technology
if signs of infection in placenta or at autopsy determine maternal viral serology and amniotic fluid for molecular
diagnostic technology
in women with a family history of hereditary thrombophilia or a personal history of venous thromboembolism
perform thrombophilia work-up several months postpartum
All IUFD: multidisciplinary panel classification meetings for evaluation cause of intrauterine fetal death
IUFD, intrauterine fetal death; MRI, magnetic resonance imagine.
Korteweg. Fetal death workup. Am J Obstet Gynecol 2012.

JANUARY 2012 American Journal of Obstetrics & Gynecology

53.e11

Research

Obstetrics

ACKNOWLEDGMENT
We dedicate this article to Jan van der Meer,
who died unexpectedly on Jan. 14, 2009.

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