Thrombosis Research 130 (2012) 3237

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Thrombosis Research
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Regular Article

The association of antiphospholipid antibodies with intrauterine fetal death: A

casecontrol study
Linda Bjrk Helgadottir a, b, c,, Finn Egil Skjeldestad a, d, Anne Flem Jacobsen b,
Per Morten Sandset a, c, Eva-Marie Jacobsen a, c
a

Department of Haematology, Oslo University Hospital Ullevl, Oslo, Norway

Department of Obstetrics and Gynaecology, Oslo University Hospital Ullevl, Oslo, Norway
Institute of Clinical Medicine, University of Oslo, Oslo, Norway
d
Department of Gynaecology and Obstetrics, Department of Clinical Medicine, University of Troms, Troms, Norway
b
c

a r t i c l e

i n f o

Article history:
Received 22 August 2011
Received in revised form 4 October 2011
Accepted 16 November 2011
Available online 16 December 2011
Keywords:
antiphospholipid antibodies
fetal death
pregnancy complications
stillbirth
thrombophilia

a b s t r a c t
Introduction: Over the past few decades it has been recognized that antiphospholipid antibodies are associated with pregnancy loss. Other placenta-mediated pregnancy complications have also been associated with
the presence of antiphospholipid antibodies. Most studies have measured antiphospholipid antibodies near
the time of the event investigated.
Objectives: To investigate the association of antiphospholipid antibodies and a history of intrauterine fetal
death (IUFD) in a casecontrol design.
Materials and methods: A casecontrol study of 105 women with a history of IUFD after 22 gestational weeks
and 262 controls with live births. The prevalence of lupus anticoagulant, anticardiolipin- and anti-2glycoprotein 1 antibodies were measured 318 years after the event of IUFD.
Results: Total 9.5% of women with a history of IUFD and 5.0% of controls had at least one positive test for antiphospholipid antibodies (OR 2.0; 95% condence interval (CI) 0.9-4.8). Women with a history of IUFD were
signicantly more often positive for lupus anticoagulant compared to controls (OR 4.3; 95% CI 1.0-18.4). The
association of lupus anticoagulant with a history of IUFD was conned to women positive for other antiphospholipid antibodies in addition to lupus anticoagulant. Being positive for anti-2-glycoprotein 1 or anticardiolipin antibodies alone was not signicantly associated with a history of IUFD.
Conclusions: Women with a history of IUFD after 22 gestational weeks were more often lupus anticoagulant
positive. The association was conned to women with multiple positivity for antiphospholipid antibodies,
although rm conclusions on the importance of multiple positivity cannot be made from this study.
2011 Elsevier Ltd. All rights reserved.

Introduction
Antiphospholipid antibodies (APAs) are heterogeneous autoantibodies that may be associated with increased risk of thrombotic
and vascular complications [1]. Over the past few decades it has

Abbreviations: APAs, antiphospholipid antibodies; PMPC, placenta mediated pregnancy complications; aCL, anticardiolipin antibodies; IgG, immunoglobulin G isotype;
LA, lupus anticoagulant; IUFD, intrauterine fetal death; VIP, the Venous Thromboembolism In Pregnancy study; anti-2GP1, anti-2-glycoprotein 1 antibodies; LR, lupus
ratio; APTT, activated partial thromboplastin time; RVVT, Russell viper venom time;
IgM, immunoglobulin M isotype; ELISA, enzyme-linked immunosorbent assay; OR,
odds ratio; CI, condence interval; ACCP, American College of Chest Physicians.
Corresponding author at: Oslo University Hospital Ullevl, Department of Obstetrics and Gynaecology, P.O.B. 4956 Nydalen, 0424 Oslo, Norway. Tel.: + 47 93429980;
fax: + 47 23016211.
E-mail address: linda_bjork_helgadottir@hotmail.com (L.B. Helgadottir).
0049-3848/$ see front matter 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.thromres.2011.11.029

been recognized that APAs may be associated with pregnancy loss

and other placenta mediated pregnancy complications (PMPC), such
as intrauterine growth restriction, preeclampsia, placental abruption,
as well as pregnancy loss in all trimesters [24]. PMPC affect more
than one in six pregnancies, are major causes of maternal and fetal
morbidity and mortality, and have been attributed to uteroplacental
vascular insufciency [5,6]. The pathophysiology of PMPC related to
APAs probably does not only involve thrombosis of placental vessels,
but also impaired conceptus implantation by damage to decidual or
chorionic vessels or reduction of trophoblast invasiveness, which
can lead to early pregnancy loss, or later in pregnancy, placental
insufciency and PMPC [7].
Previous studies have demonstrated an association of both inherited and acquired thrombophilia with PMPC, and it has been reported
that up to 65% of women with PMPC have some form of acquired or
inherited thrombophilia [8,9]. Both casecontrol and prospective
cohort studies have found increased risk of PMPC in APA positive

L.B. Helgadottir et al. / Thrombosis Research 130 (2012) 3237

women, and a systematic review reported a positive association between fetal death and the presence of both anticardiolipin (aCL) antibodies of immunoglobulin G (IgG) isotype and lupus anticoagulant
(LA) [812].
Studies investigating the association between APAs and intrauterine fetal death (IUFD) have often been of small sample size [13], and
they have differed in selection criteria for cases and controls [14,15].
In addition, laboratory detection of APAs is complicated by the heterogeneity of both the antibodies and the assays used for detection.
All these issues can explain the inconsistent ndings of the association of APAs with IUFD.
Investigators reporting on the association between APAs and IUFD
have usually analyzed the prevalence of APAs in blood samples collected within months after suffering IUFD. To our knowledge the
prevalence of APAs several years after the incident, among women
with a history of IUFD, has not been reported. Our hypothesis was
that women with a history of IUFD were more often APA positive,
compared to women with live births only. The aim of our study was
to investigate this association between APAs and IUFD.

Materials and methods

Ethics statement
The Norwegian South-Eastern Regional Committee for Medical
Research Ethics approved the study. Authorization for the use of information from medical records for research purposes was obtained
from the Norwegian Ministry of Health and Social Affairs. The Norwegian Data Inspectorate approved the use of data comprising sensitive
personal health information, and the merging of clinical and registerdata by using the unique 11-digit personal identication number
given to all Norwegian citizens either by birth or immigration. A written informed consent was obtained from all study participants.
The present study was a part of a larger hospital-based casecontrol study; the Venous Thromboembolism In Pregnancy (VIP) study,
and was registered as a clinical observational study at www.
clinicaltrials.gov, with registration number NCT00856076. Data on
clinical risk factors for IUFD and clinical and biochemical risk factors

33

for venous thrombosis related to pregnancy have been published earlier [1619].
Selection of cases and controls
Women with a diagnosis of IUFD were identied retrospectively
by a search for selected codes of the WHO International Classication
of Diseases versions 9 or 10 that were registered in the patient administrative system of two Norwegian hospitals, that is, Oslo University Hospital Ullevl, Oslo, and Akershus University Hospital,
Nordbyhagen, from January 1990 throughout December 2003. We
identied 436 possible cases of IUFD, dened by fetal death after 22
completed gestational weeks or birth weight >500 g. We excluded
49 cases wrongly diagnosed and 8 with non-retrievable records leaving 379 women identied as cases with a veried diagnosis of IUFD in
singleton or duplex pregnancies (Fig. 1). In 2006, the controls received an invitation to participate in the thrombosis part of the VIPstudy, in which 353/1229 (28.7%) agreed to participate. These 353
controls signed a consent to participate and agreed to receive a new
questionnaire at a later time regarding the present study on IUFD
[17,18].
The medical records for cases and controls were reviewed for validation of the diagnosis of IUFD, and information on demographics,
general health, obstetrical history, details of the index pregnancy,
labor, and delivery. The women's unique personal identication numbers were then merged with census data (Statistics Norway, Oslo,
Norway). Women, who had emigrated, died, or had an invalid or foreign address, were excluded. Nine controls with a history of IUFD
were also excluded. This left us with 346 cases and 326 controls eligible for study participation (Fig. 1).
The participants were approached during 20068 by a letter outlining the purpose of the study. Those interested in participating contacted us by e-mail or telephone to schedule an appointment to
donate a blood sample and to answer a questionnaire regarding
socio-demographic factors, obstetrical history, general and psychological health, and quality of life. One of the cases did not donate a
blood sample and was therefore excluded from the study. After two
reminders the nal study population comprised 105 cases and 262
controls (Fig. 1).

Fig. 1. Flowchart selection of study population.

34

L.B. Helgadottir et al. / Thrombosis Research 130 (2012) 3237

Blood sampling and analyses

Blood was collected in 5 mL Vacutainer tubes (Becton-Dickinson,
Meylan-Cedex, France) containing 0.5 mL buffered citrate
(0.129 mol/L). The tubes were centrifuged at 2000 g for 15 minutes
within 1 hour, and plasma aliquots were frozen and kept at 70 C
until assayed.
The blood was analysed for LA, aCL, and anti-2-glycoprotein 1
(anti-2GP1) antibodies. The assays were performed at the Hematologic Research Laboratory, Department of Hematology, Oslo University Hospital Ullevl (formerly Ullevl University Hospital) as described
earlier [18]. In short, the presence of LA was identied using validated
in-house lupus ratio (LR) tests, which are automated, quantitative, integrated tests for LA [20,21]. Two LR tests were performed, one based
on the activated partial thromboplastin time (LR-APTT) and the other
based on the Russell viper venom time (LR-RVVT). The LR tests were
performed in 1:1 mixture of patient plasma and pooled normal plasma. For each of the LR tests two coagulation times were measured,
one with a reagent with low and the other with a high phospholipid
concentration. The ratio between the two coagulation times (low
phospholipid/high phospholipid concentration) was divided by the
corresponding ratio obtained with pooled normal plasma. The nal
ratio is dened as the LR of that patient's plasma [21]. The reagents
were made from different concentrations of natural phospholipids
(crude cephalin, generously provided by Dr. Tore Janson, AxisShield PoC AS, Oslo, Norway). In the APTT-based assay, a constant
concentration of ellagic acid (Sigma-Aldrich, St. Louis, Missouri,
USA) was used as activator. In the RVVT-based test, RVV (SigmaAldrich) activates factor X directly. The 99th percentile of the LR of
the control group was chosen as the upper reference limit, and was
1.22 for the APTT-based LR test and 1.19 for the RVVT-based LR test.
aCL IgG and IgM isotypes were analyzed with an in-house
enzyme-linked immunosorbent assay (ELISA) essentially as described
by Gharavi et al. [22]. We used serial dilutions of an in-house control
drawn from a strongly aCL positive patient, which were standardized
against Harris commercial standards (American Diagnostica Inc.,
Stamford, CT, USA). Values for IgG and IgM isotypes of aCL were
reported in GPL units and MPL units, respectively. The cut-off values
for a positive test were dened by the 99th percentile of the values
of the control group, and were 10.7 for aCL IgG and 23.7 for aCL IgM.
Anti-2GP1 IgG and IgM isotypes were assayed with commercial
ELISA kits (QUANTA Lite TM 2 GP1 IgG/IgM, INOVA Diagnostics Inc.,
San Diego, USA) for semi-quantitative determination. Results were
expressed in standard IgG and IgM anti-2GP1 units, that is, SGU
and SMU, respectively. The 99th percentiles of the control group
were used as upper reference limits, and were 6.5 for anti-2GP1
IgG and 30.3 for anti-2GP1 IgM.
Statistical analyses
Data were analyzed by Chi-square tests or Fisher's exact tests. Results were presented as percentages and odds ratios (OR) with 95%
condence intervals (CI). In the case of missing values for sociodemographic or clinical variables women were denoted the reference
group in that particular analysis. Signicance level was set at
p b 0.05. All data was analyzed using the Statistical Package for Social
Science version 16.0 (SPSS Inc, Chicago, Il, USA).
Results
Information from medical records of the eligible participants gave
us the opportunity to compare participating women with the nonparticipating. There were no signicant differences in the demographic and clinical data between the participating and nonparticipating women (data not shown). The maternal characteristics
of cases and controls are displayed in Table 1. At the time of the

index pregnancy women with IUFD were younger, smoked more

often at rst visit, had more often placental abruption, their fetuses
were more often small for gestational age and they had more often
inherited thrombophilia. Prevalences of demographic and clinical
risk factors were not signicantly different between APA-positive
and APA-negative women at the time of the index pregnancy
(Table 2). At the time of blood sampling there was not a signicant
difference in the rate of miscarriages 22 gestational weeks between
cases and controls, but the cases had more frequently had placental
abruption (Table 3). The APA-positive women had more often a history of recurrent miscarriages compared to APA-negative women
(Table 3). Mean time difference between index pregnancy and
blood sampling were 8.7 years and 8.6 years for APA positive and
APA negative women, respectively.
The prevalence of APAs and the association of APAs with IUFD are
shown in Table 4. Twenty-three women, 10 (9.5%) with a history of
IUFD and 13 (5.0%) controls, were positive for at least one APA test
(OR 2.0; 95% CI 0.9-4.8). The OR for multiple positivity for APAs
among women with IUFD was 7.9 (95% CI 0.8-76.5) as compared to
controls, using APA-negativity as a reference, were as the OR for having a single positive test was 1.5 (95% CI 0.6-4.0). Women with more
than one positive APA test were all positive for LA. LA was signicantly more often positive among women with a history of IUFD, compared to women with live births only (OR 4.3; 95% CI 1.0-18.4).
Exploring the LA positive women by single/multiple positivity for
APA we found that the risk related to LA was conned to women positive for LA in combination with other APAs. Three cases but no controls were positive for other APA tests in addition to LA. Anti-2GP1,
both IgG and IgM, and aCL IgG and IgM were not signicantly associated with a history of IUFD.
Nineteen women had one APA test positive, that is 7 (6.7%) cases
and 12 (4.6%) controls. One case and one control were positive for
two tests, and one case each was positive for three and four tests.

Table 1
Maternal characteristics at index pregnancy.
Variable

Age (at index pregnancy)

b35 years
35 years
Parity
0
1
2
Multiple pregnancy
Hypertensive disorders (HD)
Preeclampsia
Hypertension
Small for gestational age (SGA)
HD and/or SGA
No HD or SGA
HD, no SGA
HD with SGA
SGA, no HD
Diabetes
Placental abruption
Placenta previa
Smoking (at rst visit)
Inherited thrombophilia*

Cases

Controls

N = 105**

N = 262

p-value

80.0
20.0

68.3
31.7

n.s.
b0.03

52.4
34.3
13.3
3.8

50.4
39.3
10.3
2.7

n.s.
n.s.

5.7
5.7
34.3

7.3
4.6
1.5

59.0
6.7
4.8
29.5
1.0
8.6
2.9
27.6
18.4

87.8
10.7
1.1
0.4
0.4
0.8
0.8
8.4
11.8

n.s.
n.s.
b0.001
Reference
n.s
b0.02
b0.001
n.s.
b0.001
n.s.
b0.001
n.s.

p value - represents results from univariate analysis. n.s.: not signicant.

*Inherited thrombophilia: factor V Leiden, prothrombin G20210A polymorphism,
antithrombin, protein C- or protein S deciency.
**Two women using warfarin were excluded from analyses involving protein C and
protein S.

L.B. Helgadottir et al. / Thrombosis Research 130 (2012) 3237

Table 2
Demographic and clinical risk factors among antiphospholipid antibody (APA) positive
and APA negative women.
Variable

Cases
Controls
Age (at index pregnancy)
b 35 years
35 years
Parity
0
1
2
Multiple pregnancy
Hypertensive disorders (HD)
Preeclampsia
Hypertension
Small for gestational age (SGA)
HD and/or SGA
No HD or SGA
HD, no SGA
HD with SGA
SGA, no HD
Diabetes
Placental abruption
Placenta previa
Smoking (at rst visit)
Inherited thrombophilia*

APA positive

APA negative

N = 23**

N = 344**

p-value

43.5
56.5

27.6
72.4

n.s.
n.s.

78.3
21.7

71.2
28.8

n.s.
n.s.

43.5
34.8
21.7
0

51.5
38.1
10.5
3.2

n.s.
n.s.

4.3
8.7
17.4

7.0
4.7
10.5

n.s.
n.s.
n.s.

73.9
8.7
4.3
13.0
0
0
0
21.7
4.5

79.9
9.6
2.0
8.4
0.6
3.2
1.5
13.4
14.3

Reference
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.

p value - represents results from univariate analysis. n.s.: not signicant.

*Inherited thrombophilia: factor V Leiden, prothrombin G20210A polymorphism,
antithrombin-, protein C- or protein S deciency.
**Two women, one in each group, using warfarin were excluded from analyses
involving protein C and protein S.

Discussion
In the present study, we found that women with a history of IUFD,
as compared with women with live births only, were signicantly
more often positive for LA 318 years after the index pregnancy.
This was attributed to women positive for LA in combination with
other APAs, although this study does not allow rm conclusions on
the importance of multi-positivity.
Our nding of increased prevalence of LA among women with a
history of IUFD is in agreement with other studies. However, most investigators, as summarized in a systematic review [9], have found aCL
to be an even stronger predictor of IUFD than LA [1315,23]. Gonen et
al. studied the prevalence of both inherited and acquired thrombophilia among women with unexplained IUFD after 26 gestational
weeks and found LA and aCL to be signicantly more prevalent
among women with a history of IUFD compared to controls, with
OR 6.1 (95% CI 1.4-36.2) and 8.5 (95% CI 1.6-42.3), respectively [13].
The NOHA-study found, in univariate analysis, LA as well as aCL IgG
and anti-2GP1 IgG to be associated with IUFD after 22 weeks of pregnancy. However, in the multivariate analysis, adjusting for other APAs
and inherited thrombophilia, LA was protective of IUFD, but both aCL
IgG and anti-2GP1 IgG were still positive predictors for IUFD [15].
The cause was found to be that no cases, but two controls, had LA as

35

Table 4
Prevalence of APA and OR with 95% CI for APA among women with IUFD compared to
controls.
Variable

APA positive 1 tests

APA positive 1 test
APA positive >1 tests
LA positive 1 test
LA positive + anti-2GP1/aCL negative
LA positive + anti-2GP1/aCL positive
LR-APTT positive
LR- RVVT positive
Anti- 2GP1 positive
Unique anti- 2GP1 positivity
Anti- 2GP1 + 1 LA/aCL positive test
aCL positive
Unique aCL positivity
aCL + 1 LA/ anti- 2GP1 positive test

Cases
(N = 105)

Controls
(N = 262)

(n)

(n)

9.5
6.7
2.9
4.8
1.9
2.9
4.8
1.9
4.8
2.9
1.9
3.8
1.9
1.9

(10)
(7)
(3)
(5)
(2)
(3)
(5)
(2)
(5)
(3)
(2)
(4)
(2)
(2)

5.0
4.6
0.4
1.1
1.1
0
0.8
0.8
1.5
1.5
0
2.3
2.3
0

(13)
(12)
(1)
(3)
(3)
0
(2)
(2)
(4)
(4)
0
(6)
(6)
0

OR

95% CI

2.0
1.5
7.9
4.3
1.7
6.5
2.5
3.2
1.9
1.7
0.8
-

0.9-4.8
0.6-4.0
0.8-76.5
1.0-18.4
0.3-10.5
1.2-34.0
0.4-18.2
0.8-12.3
0.4-8.8
0.5-6.1
0.2-4.3
-

APA: antiphospholipid antibodies, OR: odds ratio, CI: condence interval, IUFD:
intrauterine fetal death, LA: lupus anticoagulant, LR: lupus ratio, APTT: activated
partial thromboplastin time-based, RVVT: Russell viper venom test-based, aCL: anticardiolipin antibodies, anti-2GP1: anti-2 glycoprotein 1.

a unique APA marker. This is in line with our ndings that the risk
of IUFD related to LA is mainly attributed to women positive for
other APAs as well. In studies on thrombosis, a more consistent association with both arterial and venous thrombosis has been found for
LA than for aCL [24].
Results of studies are largely inuenced by differences in study design; for instance eligibility criteria, laboratory methods, and cut-off
values. In accordance with the recent update on the guidelines for
LA detection, we used two LR tests for LA, one based on the APTT,
the other based on RVVT [25]. The LR tests are automated tests; integrating screening, mixing and conrmatory procedures. The results
are calculated as LA ratios (screen/conrm) and normalized against
values obtained with a pooled normal plasma, as recommended by
the guidelines [25]. The LR tests have proven high reproducibility
and low interlaboratory variation in an international multilaboratory
study and where hence chosen for this study [21].
The majority of studies on APA and IUFD have applied various
exclusion criteria in the attempt to investigate women with unexplained IUFD only. Thus they have excluded women with known
causes of IUFD. In most studies, IUFD explained by congenital malformations, abnormal karyotypes, uterine malformations, fetal
hydrops or infections have been excluded. In some studies, women
with maternal risk factors for IUFD, like diabetes, preeclampsia, placental abruption or intrauterine fetal growth restriction have also
been excluded, as well as women with a history of miscarriages
and known thrombophilia. Such differences in study-design make
comparison of results difcult. Our cases were unselected related
to cause and we did not exclude women with known thrombophilia,
miscarriages or known risk factors for IUFD. By this our ndings are
more applicable to the general obstetric population. In a recent review article, Kist et al. demonstrated that the relationship between
adverse pregnancy outcome and thrombophilia was inuenced by

Table 3
Obstetrical history, until time of blood sampling.
Variable

Cases (N = 105) %

Controls (N = 262) %

p-value

APA-positive (N = 23) %

APA-negative (N = 344) %

p-value

Miscarriage 22 weeks
Recurrent miscarriage (3) 22 weeks
Abruption in any pregnancy

39.0
5.7
11.4

30.9
2.3
1.1

n.s
n.s.
b0.001

47.8
13.0
0

32.3
2.6
4.4

n.s.
0.03
n.s

p value - represents results from univariate analysis. n.s.: not signicant. APA = antiphospholipid antibodies.

36

L.B. Helgadottir et al. / Thrombosis Research 130 (2012) 3237

confounding factors like ethnicity, methods of testing, and severity

of disease [26].
About 5-7% of healthy pregnant women have been reported to
have positive tests for APAs [27]. The prevalence of APAs depends
on the denition of a positive test. It is recommended by international
consensus to dene the cut-off value by the 99th percentile of a control group. Since by denition 1% of the controls will have a positive
result for each test, the prevalence of APAs in the healthy population
will be inuenced by the number of tests for APAs examined. Thus, if
six different tests are used, up to 6% of the control/normal population
will be APA positive.
Although there is some increased relative risk of IUFD associated
with APAs, the absolute risk for APA positive women without previous clinical events is low, and the probability of a successful pregnancy outcome is high. Thus, the screening for APAs in an unselected
population of pregnant women is not recommended. The 8th Guidelines on Antithrombotic Therapy of the American College of Chest
Physicians (ACCP) from 2008 recommend screening for APAs
among women with a history of PMPC [28]. Low molecular weight
heparin and low dose acetylsalicylic acid are currently recommended
for the prevention of recurrent pregnancy loss in women with APAs
[2831]. Current recommendations on treatment of the APA syndrome may have long-term implications. For example, indenite
treatment is recommended after a rst venous thrombosis if the patient has tested positive for APA twice with three months interval.
This is a more rigorous secondary thromboprophylactic therapy
than usually advised, even though little or no data support such recommendations [32]. This study implies that multiple positivity is
probably important although the nature of the study does not allow
rm conclusion. This is in agreement with other recent studies that
have demonstrated that multiple positivity for APAs is more frequently associated with pregnancy complications than single positivity [33,34].
Collection of blood samples only at a single time point and a long
time after the index pregnancy are limitations of our study. However,
one of the rationales for repeated testing is to avoid false positive
tests due to transiently elevated APAs, which is not a concern in the
present study, when the samples were collected 318 years after
the index pregnancy. Moreover, we can not exclude the possibility
that some women have either turned negative or turned positive for
APAs after the index pregnancy, but there is no reason to believe
that this would differ between cases and controls. Remarkably little
is known about the sustainability of APAs over time. In one study,
Erkan et al. found sustained positivity over time in approximately
75% of tests initially positive, but with a mean follow-up time of
only 2.4, 3.5 and 1.0 years for LA, aCL, and anti-2 GP1, respectively
[35]. Another limitation of our study is that only 29% of the identied
cases participated, which probably reects the burden of this serious
complication. In spite of this our sample size is relatively large compared to other studies in this eld. We had information from medical
records from all the eligible participants and we did not nd signicant differences in sociodemographic and clinical factors between
participating and non-participating women. We therefore do not believe that the low participation applies a selection bias, but it does affect the power of the study.
We conclude that women with a history of IUFD after 22 gestational weeks were more often LA positive, 318 years after the incident, but the risk of IUFD related to LA was conned to women
positive for other APAs in addition to LA. However, there is still
great uncertainty related to the association of APAs and IUFD and
the clinical importance is not easily predicated.

Conict of Interest
No conicts of interest.

Acknowledgments
Financial support was received from the South-Eastern Norway
Regional Health Authority Trust, Hamar, Norway, the Oslo University
Hospital Ulleval Scientic Trust, Oslo, Norway, and the Research
Council of Norway. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the
manuscript.

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