Rheumatology 2013;52:16351641

doi:10.1093/rheumatology/ket167
Advance Access publication 15 May 2013

RHEUMATOLOGY

Original article
Catastrophic antiphospholipid syndrome and
pregnancy: an experience of 13 cases
Guillaume Hanouna1,*, Nathalie Morel1,*, Du Le Thi Huong1, Laurence Josselin2,
Danie`le Vauthier-Brouzes3, David Saadoun1, Adrien Kettaneh2,
Kateri Levesque1, Veronique Le Guern4, Francois Goffinet5, Bruno Carbonne6,
Zahir Amoura1, Jean-Charles Piette1, Jacky Nizard3 and
Nathalie Costedoat-Chalumeau1

Methods. Retrospective series of 13 patients with pregnancy-related CAPS with special focus on the
follow-up.
Results. Eleven patients had known APS and had been treated with low-molecular-weight heparin (n = 10),
aspirin (n = 8), oral anticoagulants (n = 1), HCQ (n = 3) and/or steroids (n = 1) during pregnancy. The most
frequent manifestations of CAPS were cutaneous (n = 11), hepatic (n = 11), renal (n = 10), cardiac (n = 8) and
neurological (n = 5). CAPS usually followed haemolysis, elevated liver enzymes and low platelet count
(HELLP) syndrome (n = 12), which was associated with pre-eclampsia (n = 6) or with eclampsia (n = 3).
No maternal death was observed. The perinatal mortality of 54% was related to prematurity with a
mean gestational age of 26.6 weeks at onset of CAPS or HELLP syndrome. During a mean follow-up
of 4.8 years (range 28 years), seven new pregnancies occurred in five patients and led to one miscarriage, four successful pregnancies and two HELLP syndrome with pre-eclampsia or eclampsia that
occurred at 28 weeks gestation in both cases despite optimal treatment. No relapse of CAPS was
observed. Two mothers suddenly died 2.5 and 6 years after CAPS.
Conclusion. The occurrence of HELLP syndrome in a patient with APS should raise the suspicion of
CAPS in the following days, and anticoagulation should be maintained post-partum or post-abortum.
Subsequent pregnancies are at very high risk.
Key words: antiphospholipid
pregnancy.

syndrome,

catastrophic

antiphospholipid

syndrome,

lupus,

thrombosis,

Introduction
1

Universite Pierre et Marie Curie-Paris 6, Assistance PubliqueHopitaux de Paris, Hopital Pitie-Salpetrie`re, Centre de reference
national pour le Lupus Systemique et le syndrome des
Antiphospholipides, service de medecine interne, Paris, 2Assistance
Publique-Hopitaux de Paris, Hopital Saint Antoine, service de medecine interne, Paris, 3Assistance Publique-Hopitaux de Paris, Service de
Chirurgie Gynecologique et Obstetrique, Centre Hospitalier
Universitaire Pitie-Salpetrie`re, Paris, 4Assistance Publique-Hopitaux
de Paris, Centre de reference maladies auto-immunes et systemiques
rares, Service de medecine interne Pole medecine, Hopital Cochin,
AP-HP, Paris, 5Universite Paris 5, Assistance Publique-Hopitaux
de Paris, Service de gynecologie-obstetrique, Maternite Port-Royal,
Paris and 6Universite Pierre et Marie Curie-Paris 6, Assistance
Publique-Hopitaux de Paris, Service de gynecologie-obstetrique,
Hopital Trousseau, Paris, France.

APS is defined by a combination of arterial and/or venous

thrombosis, pregnancy morbidity and persistent aPLs,
namely LA, aCLs and/or anti-B2GP1 antibodies [1].
Submitted 29 October 2012; revised version accepted 19 March 2013.
Correspondence to: Nathalie Costedoat-Chalumeau, AP-HP, Service
de Medecine Interne 2, Centre de reference national pour le Lupus
Systemique et le syndrome des Antiphospholipides, Centre Hospitalier
Universitaire Pitie-Salpetrie`re, 47-83 Boulevard de lHopital, 75651
Paris Cedex 13, France. E-mail: nathalie.costedoat@gmail.com
*Guillaume Hanouna and Nathalie Morel contributed equally to this
study.

! The Author 2013. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

CLINICAL
SCIENCE

Objective. Catastrophic antiphospholipid syndrome (CAPS) is a life-threatening disease caused by the

onset of rapidly progressive and widespread small-vessel thromboses in the presence of aPLs. The aim of
this study was to examine pregnancy-related CAPS.

Downloaded from http://rheumatology.oxfordjournals.org/ by guest on July 23, 2015

Abstract

Guillaume Hanouna et al.

Catastrophic antiphospholipid syndrome (CAPS), also

named Ashersons syndrome, is a rare complication that
occurs in <1% of APS [2]. CAPS is characterized by multiorgan failure caused by multiple small vessel thrombosis
associated with thrombotic microangiopathy. Most of our
knowledge of CAPS relies on the international CAPS registry, which includes more than 300 patients [3]. In 50% of
patients CAPS was triggered by an identifiable factor,
mainly infections, trauma or surgery, anticoagulation withdrawal, malignancies, lupus flares and/or pregnancy [2].
A review of 15 cases of pregnancy-related CAPS
(including 3 new cases) was published by another group
in 2007 [4]. We report our experience of 13 similar cases.
This retrospective study allowed us to focus on maternal
follow-up, which was not available in the previous study.
We therefore report for the first time the prognosis of
pregnancies following pregnancy-related CAPS.

Results
We retrospectively analysed 13 cases of pregnancyrelated CAPS (Table 1).

General characteristics and past obstetric history

Patients

Pregnancy description

This study included 13 patients referred to a French national SLE and APS referral centre with a diagnosis of
pregnancy-related CAPS, defined by CAPS occurring
during pregnancy or in the 6 weeks post-partum or postabortum, between 2002 and 2012. Cases 11 and 12 were
followed in Saint Antoine Hospital. Case 11 will be submitted as a case report. Case 12 has been previously reported in French as a case report [5].

During the index pregnancies, patients were treated with

low-molecular-weight heparin (LMWH; n = 10), low-dose
aspirin (n = 8), oral anticoagulant (n = 1), HCQ (n = 3) and/
or steroids (n = 1), whereas the two asymptomatic patients
did not receive any treatment. The oral anticoagulant
treatment (fluindione), which is contraindicated in pregnant patients, was maintained throughout the pregnancy
since the patient did not know that she was pregnant. The
diagnosis of pregnancy was made when she presented
with HELLP and eclampsia at 31 weeks gestation (WG).
International normalized ratios (INRs) were at a mean of
2.9 during pregnancy.
In 12 cases CAPS was preceded by HELLP syndrome
that occurred at a mean gestational age of 26.6 weeks
(range 1337 weeks). The HELLP syndrome was associated
with pre-eclampsia in six cases and with eclampsia in three.
The last patient (case 3) had CAPS at 25 WG without HELLP
syndrome. She had a spontaneous delivery with a severely
premature newborn weighing 690 g who died at birth.

Methods
SLE was defined according to the ACR classification criteria [6]. APS was defined according to the Sydney criteria
[1]. Lupus anticoagulant was diagnosed with both aPTTbased assays and DRVVT. Regarding anti-B2GP1 antibodies, both IgG and IgM isotypes were measured. CAPS
was defined according to the 2005 criteria: (i) involvement
of three or more organs, tissues or systems; (ii) development of manifestations in less than 1 week; (iii) histological
confirmation of small vessel occlusion; (iv) presence of
aPLs (LA and/or aCLs) detected on two or more occasions at least 6 weeks apart [7]. Haemolysis, elevated
liver enzymes and low platelet count (HELLP) syndrome
was defined by biological criteria: aspartate amino transferase >2-fold the normal, platelet count <100 000/mm3
and lactate dehydrogenase >600 U/l [8].
For each patient we retrospectively collected clinical,
biological, ultrasonographic and therapeutic data during
pregnancy and data regarding neonates. Four patients
had routine antenatal care in our centre before diagnosis
of CAPS and nine were referred to us after CAPS. In these
cases we provided medical guidelines for the following
pregnancies. Follow-up focused on new manifestations
of APS and new obstetric events.

Statistical analyses
A 2 test was performed for qualitative variables. The level of
significance was set at 0.05. Statistical analyses were performed with SAS version 9.2 (SAS Institute, Cary, NC, USA).

1636

CAPS description
CAPS occurred during pregnancy in 1 patient and postpartum or post-abortum in 12 patients (with an onset
concomitant with labour in 3 patients). In 9 of these 12
patients there was an initial improvement of the maternal
condition between the HELLP syndrome and CAPS, with
a mean delay of 9.1 days (range 228 days).
The most frequent manifestations of CAPS were cutaneous (n = 11), hepatic (n = 11), renal (n = 10), cardiac
(n = 8) and neurological (n = 5). Cutaneous manifestations
included skin necrosis (n = 5, with ear involvement in 4),
purpura (n = 3), splinter haemorrhage (n = 3) and hand
and/or foot erythema (n = 2). Renal involvement required
dialysis in five cases. Cardiac involvement led to severe
cardiac insufficiency in four patients: one required extracorporeal membrane oxygenation (ECMO) and another
had a cardiac arrest and was successfully resuscitated.
Neurological manifestations included convulsions (n = 3),

www.rheumatology.oxfordjournals.org

Downloaded from http://rheumatology.oxfordjournals.org/ by guest on July 23, 2015

Patients and methods

The mean age at CAPS onset was 31 years (range 2337

years). Eleven patients had known APS, primary in nine
cases and associated with SLE in two cases. APS manifestations were venous (n = 8), arterial (n = 5) and/or obstetric (n = 4). Two patients had no known autoimmune
disease before the index pregnancy, and SLE and APS
were diagnosed in both cases at the time of CAPS.
In eight patients, CAPS occurred during the first pregnancy, whereas the five other patients had previously
been pregnant. Only one patient had had a successful
pregnancy (case 3), whereas three had experienced a
fetal death (cases 6, 7 and 10) and one had recurrent
early pregnancy loss (case 2).

www.rheumatology.oxfordjournals.org

1637

aCL, B2GP1

LA, aCL, B2GP1, AT 31

LA, aCL, B2GP1

Nonea

PAPS

Nonea

PAPS

SLE, APS

PAPS

Case 3
(2006)

Case 4
(2008)

Case 5
(2009)

Case 6
(2006)

Case 7
(2004)

Case 8
(2002)

LA, aCL, B2GP1,

AT, VT

LA, aCL, AT, fetal

death,
miscarriage

29

32

LA, aCL, B2GP1, VT, 33

fetal death

37

26

LA, aCL, B2GP1, VT, 32

miscarriages

PAPS

Case 2
(2010)

LA, aCL, B2GP1, VT 30

SLE, APS

Case 1
(2008)

Patients

Known
CTD

LMWH (high dose),

steroids

LMWH (high dose),

aspirin, HCQ

LMWH (high dose),

aspirin

None

LMWH (high dose),

aspirin, HCQ

None

LMWH (high dose),

aspirin

LMWH (high dose),

HCQ, aspirin

Treatment during
pregnancy

+4 weeks

+0

+5 days

+3 days

25 WG

+8 days

+15 days

CAPS
onset (WG or
post-partum)

HELLP, eclampsia +15 days

(25)

HELLP, preeclampsia (23)

HELLP (36.5)

HELLP, eclampsia, abruptio

placenta (22)

HELLP, preeclampsia (24)

No

HELLP, preeclampsia
(30.5)

HELLP, preeclampsia (33)

HELLP/preeclampsia (WG)

CAPS
treatment

Neonates
(weight in
grams)

Heparin, steroids, IVIG,

plasma
exchange,
dialysis
Cardiac, neurological,
Heparin, sterrenal (biopsy +), cutaoids (IVMP),
neous, hepatic, panCYC, plasma
creatic, gastric,
exchange,
ocular, venous thromdialysis
bosis, thrombopenia,
HA

Cardiac, neurological,
pulmonary, renal
(biopsy +), hepatic,
pancreatic, splenic,
ocular, thrombopenia

Adrenal, cutaneous,
Heparin,
hepatic, thrombocytosteroids
penia, HA

6.2

6.2

Deathb (NA)

Deathb (NA)

2.6

Healthy child
(2730)

Deathb (NA)

3.9

Heparin, aspirin, Deathb (600)

steroids
(IVMP), IVIG,
dialysis
Neurological, cutaneous, Heparin
hepatic, thrombocytopenia, HA, placenta
(histology +)

Cardiac, renal, splenic,

cutaneous, hepatic,
thrombocytopenia,
HA

5.8

2.3

3.9

Follow-up
(years)

Deathb (690)

Heparin, aspirin, Healthy twins

steroids
(865 and
(IVMP), IVIG
1260)

Cardiac, neurological,
Heparin, sterrenal (biopsy +), cutaoids (IVMP),
neous, ocular, HA
IVIG, plasma
exchange,
CYC, dialysis

Cardiac, renal, hepatic,

cutaneous, HA,
thrombocytopenia,
schizocytes

Renal, hepatic, cutaHeparin, aspirin, Healthy child

neous (biopsy +), HA,
steroids
(2050)
placenta (histology +)

CAPS features

Downloaded from http://rheumatology.oxfordjournals.org/ by guest on July 23, 2015

Laboratory
findingsa obstetric
or thrombosis
(V or A)
Age, yearsa

TABLE 1 Clinical and biological data of 13 patients with pregnancy-related CAPS

(continued)

Renal insufficiency,
stroke at 4 years
(insufficient anticoagulation), sudden
death at 6 years

Mild retinal sequela

Adrenal insufficiency

VT at 2 months, pulmonary embolism at

3 months (before
anticoagulation)

1 child at 37 WG (on
steroids, HCQ,
LMWH, aspirin)

1 child at 34 WG with
SLE flare (on steroids, HCQ,
azathioprine,
LMWH, aspirin)
1 child at 38 WG (on
steroids, HCQ,
azathioprine,
LMWH, aspirin)

1 HELLP + eclampsia +
abruptio placenta at
28 WG: 600 g live
child (on steroids,
LMWH, aspirin)

1 miscarriage at 7 WG
(on steroids, LMWH,
aspirin), 1
HELLP + preeclampsia at 28
WG: 500 g alive girl
(on steroids, LMWH,
aspirin, HCQ)

New events
during FU

Catastrophic antiphospholipid syndrome and pregnancy

www.rheumatology.oxfordjournals.org

PAPS

PAPS

PAPS

PAPS (9),
aCL (13), LA (12),
APS+SLE (2),
B2GP1 (10),
Nonea (2)
Venous (8),
Arterial (5),
Obstetric (4)

Case 11
(2010)

Case 12
(2007)

Case 13
(2007)

Total
(number)
31 (23-37)

23

27

32

36

32

+0

+0

+3 days

+2 days

CAPS
onset (WG or
post-partum)

HELLP, eclampsia +3 days

(31)

HELLP, preeclampsia (13)

HELLP (15)

HELLP, preeclampsia (37)

HELLP (30)

HELLP/preeclampsia (WG)

LMWH (10), oral

HELLP (12), preanticoagulants (1),
eclampsia (6),
aspirin (8), HCQ
eclampsia (3)
(3), steroids (1), no
(26.6 WG)
treatment (2)

Oral
anticoagulantsc

LMWH (low dose)

LMWH (high dose),

aspirin

LMWH (high dose),

aspirin

LMWH (high dose),

aspirin

Treatment during
pregnancy

Heparin,
steroids

Fetal death at
13 WG (NA)

Fetal death at
17 WG (NA)

Healthy child
(2285)

4.5

5.2

Follow-up
(years)

Cutaneous (11), hepatic Heparin (13),

Healthy child (6 4.8 (28)
(11), renal (10), carsteroids (12),
delivery of 7
diac (8), neurological
aspirin (5),
children, at a
(5), pancreatic (3),
IVIG (5),
mean term of
adrenal (3), splenic (2),
plasma
33 WG), Fetal
ocular (3), pulmonary
exchange (5),
death (2),
(1), gastric (1), vesicuCYC (3),
deathb (5)
lar (1), venous (1),
Dialysis (5)
Biopsy/histology + (6),
Thrombopenia (11),
HA (9)

Heparin, aspirin, Child with

steroids
developmen(IVMP),
tal delay
plasma
(1060)
exchange

Cardiac, cutaneous,
Heparin, sterhepatic, placenta (hisoids (IVMP),
tology +),
IVIG
thrombocytopenia
Cardiac, renal,
Cutaneous, thrombocytopenia, HA

Neonates
(weight in
grams)

Heparin, aspirin, Healthy child

steroids
(1300)
(IVMP), CYC

Cutaneous, hepatic,
Heparin, sterrenal, adrenal, thromoids, plasma
bocytopenia, gallbladexchange,
der (histology +)
dialysis

Cardiac, neurological,
renal, hepatic, pancreatic, cutaneous,
thrombocytopenia,
HA

Adrenal, renal, hepatic,

thrombocytopenia

CAPS features

CAPS
treatment

1 miscarriage, 1
HELLP + preeclampsia (28 WG),
1
HELLP + eclampsia
(28 WG), 4 deliveries
of healthy children,
2 maternal deaths

Sudden death at
2.5 years

Renal insufficiency
with proteinuria,
high blood pressure
1 child at 36 WG (on
steroids, HCQ,
LMWH, aspirin and
eculizumab)

Autoimmune hepatitis
and primary biliary
cirrhosis

Adrenal insufficiency

New events
during FU

High dose of LMWH means dose adjusted to have anti-Xa activity at least greater than 0.5 (usually two s.c. injections of enoxaparin adjusted to the patients weight). PAPS: primary
APS; CTD: connective tissue disease; VT: venous thrombosis; AT: arterial thrombosis; HA: haemolytic anaemia. aSLE and APS were diagnosed at the time of CAPS. bElective
termination of pregnancy for maternal reasons. cThe pregnancy was unknown until delivery and the patient was treated with her usual treatment (fluindione with mean INR around 2.9).

LA, aCL,
B2GP1, VT

LA, aCL, AT

LA, aCL,
B2GP1, VT

LA, aCL, B2GP1,

AT, VT, fetal
death

PAPS

Case 10
(2007)

LA, aCL, VT

PAPS

Case 9
(2005)

Patients

Laboratory
findingsa obstetric
or thrombosis
(V or A)
Age, yearsa

Downloaded from http://rheumatology.oxfordjournals.org/ by guest on July 23, 2015

1638

Known
CTD

TABLE 1 Continued

Guillaume Hanouna et al.

Catastrophic antiphospholipid syndrome and pregnancy

then a pregnancy complicated by HELLP syndrome and

pre-eclampsia at 28 WG while she was treated with a
curative dose of LMWH (two injections per day with
anti-Xa activity >0.8), aspirin, HCQ with optimal blood
concentration [9] and 10 mg/day of prednisone. She delivered a 500 g girl who was healthy at the last follow-up
(10 months old). Another patient (case 2) presented a
pregnancy complicated by HELLP syndrome and eclampsia with abruptio placentae at 28 WG while she was treated with a curative dose of LMWH (two injections per day
with anti-Xa activity >0.8), aspirin and 10 mg/day of prednisone. She delivered a 600 g girl who was healthy at the
last follow-up (9 months old). A third patient (case 3) had
two successful pregnancies: one child at 34 WG with SLE
flare (on steroids, HCQ, AZA, LMWH and aspirin) and one
child at 38 WG (on steroids, HCQ, AZA, LMWH and aspirin). The fourth patient (case 4) had an uneventful pregnancy and delivered a healthy child at 37 WG while she
was treated with a curative dose of LMWH, aspirin, HCQ
and 10 mg/day of prednisone. The last patient (case 11)
was treated with curative LMWH, aspirin, HCQ and 10 mg/
day of prednisone with the addition of eculizumab to prevent CAPS recurrence. If we exclude the early miscarriage, two of the six pregnancies were complicated by
HELLP syndrome and pre-eclampsia or eclampsia with
severe prematurity despite optimal treatment. No relapse
of CAPS was observed, but according to the history and
severity of the maternal condition, cases 1 and 2 were
treated with high-dose steroids, maintenance of curative
anticoagulation and aspirin in the post-partum period.
Regarding thrombosis, during follow-up, one patient
had a stroke while her INR was too low because of improper observance of the anticoagulation prescription.
Another patient had a venous thrombosis before receiving
long-term anticoagulation. Two women died suddenly 2.5
and 6 years after CAPS (the cause of death was unclear
for both).

Maternal and fetal prognosis

Discussion

No mothers died at the time of CAPS. Three had long-term

sequelae with permanent adrenal insufficiency (n = 3) and
chronic renal insufficiency that did not require dialysis (n = 2).
Two patients had a fetal death, at 13 and 17 WG. The
maternal condition (HELLP in nine cases and CAPS in one
case) led to a decision for elective termination of pregnancy
between 22 and 25 WG in five cases and to an induction of
labour at a mean term of 33 WG (range 3037 WG) in six
cases, with the delivery of seven healthy children (one twin
pregnancy) with a mean weight of 1748 g. One premature
child (born to case 13) had developmental delay at 5 years
old that was attributed to prematurity (gestational age at
delivery 31 weeks). To summarize, from a total of 14
fetuses, only 7 were born alive, with prematurity (<35 WG)
in 5 cases and sequelae in 1 case.

Follow-up
The median follow-up after CAPS was 4.8 years (range
28 years). Seven new pregnancies occurred in five patients. One patient (case 1) had a miscarriage at 7 WG and

www.rheumatology.oxfordjournals.org

Pregnancy and the post-partum period are well-known predisposing factors for venous thrombosis due to procoagulation physiological changes. We report our experience of
13 cases of CAPS occurring during this period.
Patients had different clinical features of APS before
CAPS (arterial, venous and obstetric). We found a high
rate (69%) of triple positivity for aPLs (LA, aCL and antib2-glycoprotein I antibodies) and a higher proportion of LA
than expected in APS: 92.3% vs 53.6% in a cohort of
1000 APS patients [10] (P < 0.001). This is not surprising,
for different reasons. First, the triple positivity for aPLs
corresponds to a high-risk anti-phospholipid profile [11];
in the multicentre prospective observational PROMISSE
study, the presence of an LA was the most significant
risk factor for adverse obstetric outcome, with a risk of
39% compared with 3% in its absence (P < 0.0001) [12].
Second, the presence of an LA is >80% in patients with
CAPS [13]. Similar to Gomez-Puerta et al. [4], who reported three new cases and reviewed a total of 15
cases of pregnancy-related CAPS, previous obstetric

1639

Downloaded from http://rheumatology.oxfordjournals.org/ by guest on July 23, 2015

stroke (n = 3) and/or coma (n = 2). The other manifestations

were pancreatic (n = 3), adrenal (n = 3), ocular (n = 3), splenic (n = 2) and pulmonary, gastric and gall bladder ischaemia in one case each. One patient had venous
thrombosis. Thrombocytopenia occurred in 11 cases
and haemolytic anaemia in 9.
aPLs were IgG aCLs (n = 13), lupus anticoagulant (n = 12)
and anti-b2-glycoprotein I antibodies (n = 10). Histological
proof of thrombosis was based on renal biopsy (n = 3), ear
necrosis biopsy (n = 1) and a study of the gall bladder after
cholecystectomy (n = 1). As a result, four patients were
classified as definite CAPS and nine as probable CAPS
due to the absence of histological proof in eight cases
and to a course longer than 1 week in one case.
Placental histological study was performed in five cases
and demonstrated numerous thromboses with recent infarcts in three cases, villositis ischaemia with hypotrophia
in one case and was considered normal in the last case. If
placental infarction was included in the criteria, the number
of definite CAPS cases increased to six.
The triggers of CAPS were multiple and included the
pregnancies, modifications of anticoagulant treatment
due to the delivery, surgical procedures (emergency Csections because of the HELLP syndrome performed in
six cases and cholecystectomy in one case) and a concomitant lupus flare in one patient. No other known factors of CAPS were found.
No predictive factor of HELLP or CAPS was found in our
patients. Specifically, 6 of 8 available second trimester
uterine Doppler assessments were considered normal
and 9 of 11 available C3 levels were normal or high, according to pregnancy normal values.
CAPS was always treated with anticoagulants, 12 patients received corticosteroids, 5 received IVIGs (total
dose 2 g/kg) and 5 received plasma exchanges. Other
treatments included antiplatelet agents (n = 5) and CYC
(n = 3, including one for concomitant LN).

Guillaume Hanouna et al.

1640

delivery, but the difficulty lies in selecting patients at high

risk for CAPS.
In our experience, no maternal death was related to
CAPS. In contrast, in the study by Gomez-Puerta et al.
[4], 46% of the mothers died. This may be explained by
the fact that our cases were all observed after 2001, a
date that corresponds to a clear-cut improvement in the
management and prognosis of CAPS [18]. This may also
be explained by the experience acquired by our highly
specialized tertiary centre, leading to the early recognition
of this condition and to aggressive supportive treatment
offered once the diagnosis is made, including ECMO in
one patient.
Fifty-four percent of the pregnancies ended in fetal
(n = 2) or neonatal death (n = 5). This is similar to the
54% of deaths reported by Gomez-Puerta et al. [4]. This
high neonatal death rate was mainly due to the early onset
of HELLP syndrome, leading to the delivery of non-viable
fetuses. This early occurrence of HELLP syndrome is consistent with our previous report of 16 episodes of HELLP
complicating APS in 15 women: HELLP syndrome
occurred during the second trimester in 7 cases (the earliest at 18 WG) [19].
After a first episode of pregnancy-related CAPS, the risk
of adverse obstetric outcome remained very high, even in
patients with optimal management, including treatment
with high-dose LMWH, aspirin (100 mg/day), steroids
and HCQ with optimal blood concentration [9]. We therefore propose that women with pregnancy-related CAPS
should be counselled against a new pregnancy. If the patient still wants to become pregnant after being counselled on the risks, a close multidisciplinary antenatal
care programme should be organized. Eculizumab, a terminal C5 complement inhibitor, has shown its efficacy in
inducing remission and preventing the recurrence of
CAPS and atypical haemolytic and uraemic syndrome
[2022]. It can also be used in pregnant patients [23]. Its
ability to improve maternal and obstetric outcome in pregnancies complicated with CAPS and to prevent recurrence in new pregnancies should be further explored.
Finally, two maternal deaths were observed during
follow-up, but the causes remain unclear. Such a high
rate of death in young patients is in keeping with previous
data on the long-term outcome of CAPS survivors [24].
The main limitation of our study was its retrospective
nature. However, the events occurring during the followup period were prospectively recorded and are unlikely to
be biased. Given the rarity of this condition, a prospective
study is unlikely to be performed.
To conclude, pregnancy-related CAPS is not exceptional
and represented 6% of the cases included in the CAPS
registry [4]. It may become more common since patients
with SLE and/or APS are usually allowed to become pregnant. Physicians should be very cautious when a patient
with APS presents with HELLP syndrome, and we believe
that anticoagulants should be resumed in the first days of
the post-partum period, even in patients with severe
thrombocytopenia secondary to HELLP syndrome. The
prompt initiation of steroids seems to be indicated in APS

www.rheumatology.oxfordjournals.org

Downloaded from http://rheumatology.oxfordjournals.org/ by guest on July 23, 2015

history was usually unsuccessful, with only one successful

pregnancy among five patients.
We also similarly found that the clinical manifestations
of CAPS were not different from those of CAPS unrelated
to pregnancy [4]. Nine of our cases were probable, and
not definite, mainly because of the lack of histological
proof. This is often the case in CAPS, as emphasized by
analysis of the CAPS registry [7]. In this setting it is not
clear whether the placenta should be included in the
histological criteria of CAPS. We found thrombosis in
three of five analysed placentas, and the inclusion of
this tissue would have increased the number of definite
cases from four to six.
Our series allowed us to study the predictive factors of
CAPS. Different authors, including our team, have stressed
that uterine artery Doppler abnormalities during the second
trimester are highly predictive of adverse obstetric outcome [14, 15], but six of eight patients with available data
had normal uterine artery Doppler before the occurrence of
CAPS. This point is important since second trimester US
examination is often used for the evaluation of obstetric risk
further in pregnancy. Complement activity regulation appears to be involved in the pathology of CAPS [16] and may
be an important prognostic factor for pregnancy outcome
in APS patients [17]. Nevertheless, 9 of 11 patients with
available data had normal levels of C3. Regarding treatment, only 2 of 15 patients reported by Gomez-Puerta
et al. [4] were treated before the occurrence of CAPS. In
contrast, 10 of our 13 patients developed HELLP syndrome
while receiving adequate treatment that always included
high-dose LMWH, associated in eight cases with aspirin,
and an additional patient developed HELLP while being
treated with oral anticoagulants. It is noteworthy that
most of the patients had a suspension of LMWH for a few
days associated with a withdrawal of aspirin. This could
have facilitated the occurrence of CAPS in the post-partum
or post-abortum period.
Finally, HELLP syndrome, which is often associated
with pre-eclampsia or eclampsia, could be considered
the only predictive factor of CAPS, and preceded CAPS
in 12 patients. The frequency of HELLP reported here was
higher than in the study by Gomez-Puerta et al. (92% vs
53%) [4]. CAPS and HELLP syndrome are classified as
microangiopathic disorders. Both conditions share the
same hepatic and haematological manifestations (the
last one being excluded from the three necessary tissue
involvements in the classification criteria of CAPS).
However, in our experience the two conditions are clinically different and are usually separated by a free interval,
with the signs of HELLP syndrome disappearing after delivery and CAPS typically starting a few days or even
weeks after. The clinical consequence is that patients
with APS who develop HELLP syndrome should be very
carefully followed up in the post-partum or post-abortum
period. Specifically in the context of delivery, aspirin is
often stopped and LMWH reduced, especially when
thrombocytopenia is present. Upgrading the treatment in
the peripartum period could be an option in high-risk patients, resuming aspirin and LMWH in the hours following

Catastrophic antiphospholipid syndrome and pregnancy

patients presenting with severe HELLP syndrome.

Interestingly, when HELLP occurred in the general population, there was no clear evidence of any effect of corticosteroids on substantive clinical outcomes, except for an
improvement in platelet counts [25]. Optimal management
is associated with a reduction in maternal mortality, but
fetal and neonatal prognoses depend mostly on the gestational age at the onset of CAPS. Further pregnancies
should probably be discouraged and, if they do occur,
they should be carefully monitored.
Rheumatology key messages
Pregnancy may be a trigger for CAPS in patients
with APS.
. HELLP syndrome in patients with APS indicates a
high risk of CAPS.
.

11 Pengo V, Ruffatti A, Legnani C et al. Incidence of a first

thromboembolic event in asymptomatic carriers of high
risk antiphospholipid antibody profile: a multicenter prospective study. Blood 2011;118:47148.
12 Lockshin MD, Kim M, Laskin CA et al. Lupus anticoagulant, but not anticardiolipin antibody, predicts adverse
pregnancy outcome in patients with antiphospholipid
antibodies. Arthritis Rheum 2012;64:23118.
13 Cervera R, Bucciarelli S, Plasin MA et al. Catastrophic
antiphospholipid syndrome (CAPS): descriptive analysis of
a series of 280 patients from the CAPS Registry.
J Autoimmun 2009;32:2405.
14 Le Thi Huong D, Wechsler B, Vauthier-Brouzes D et al. The
second trimester Doppler ultrasound examination is the
best predictor of late pregnancy outcome in systemic
lupus erythematosus and/or the antiphospholipid syndrome. Rheumatology 2006;45:3328.

References

15 Bats AS, Lejeune V, Cynober E et al. Antiphospholipid

syndrome and second- or third-trimester fetal death:
follow-up in the next pregnancy. Eur J Obstet Gynecol
Reprod Biol 2004;114:1259.

1 Miyakis S, Lockshin MD, Atsumi T et al. International

consensus statement on an update of the classification
criteria for definite antiphospholipid syndrome (APS).
J Thromb Haemost 2006;4:295306.

16 Salmon JE, Heuser C, Triebwasser M et al. Mutations in

complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort.
PLoS Med 2011;8:e1001013.

2 Cervera R. Update on the diagnosis, treatment, and

prognosis of the catastrophic antiphospholipid syndrome.
Curr Rheumatol Rep 2010;12:706.

17 De Carolis S, Botta A, Santucci S et al. Complementemia

and obstetric outcome in pregnancy with antiphospholipid
syndrome. Lupus 2012;21:7768.

3 Cervera R, Group CRP. Catastrophic antiphospholipid

syndrome (CAPS): update from the CAPS Registry.
Lupus 2010;19:4128.

18 Bucciarelli S, Cervera R, Espinosa G et al. Mortality in the

catastrophic antiphospholipid syndrome: causes of death
and prognostic factors. Autoimmun Rev 2006;6:725.

4 Gomez-Puerta JA, Cervera R, Espinosa G et al.

Catastrophic antiphospholipid syndrome during pregnancy and puerperium: maternal and fetal characteristics
of 15 cases. Ann Rheum Dis 2007;66:7406.

19 Le Thi Huong D, Tieulie N, Costedoat N et al. The HELLP

syndrome in the antiphospholipid syndrome: retrospective
study of 16 cases in 15 women. Ann Rheum Dis 2005;64:
2738.

5 dYthurbide G, Rousset P, Carbonne B et al. [Liver infarcts

with early HELLP syndrome and probable catastrophic
antiphospholipid syndrome]. Rev Med Interne 2009;30:
2559.

20 Shapira I, Andrade D, Allen SL et al. Induction of sustained

remission in recurrent catastrophic antiphospholipid syndrome via inhibition of terminal complement with eculizumab. Arthritis Rheum 2012;64:271923.

6 Hochberg MC. Updating the American College of

Rheumatology revised criteria for the classification of
systemic lupus erythematosus. Arthritis Rheum 1997;40:
1725.

21 Hadaya K, Ferrari-Lacraz S, Fumeaux D et al. Eculizumab

in acute recurrence of thrombotic microangiopathy after
renal transplantation. Am J Transplant 2011;11:25237.

7 Cervera R, Font J, Gomez-Puerta JA et al. Validation of the

preliminary criteria for the classification of catastrophic
antiphospholipid syndrome. Ann Rheum Dis 2005;64:
12059.
8 Sibai BM. Diagnosis, controversies, and management of
the syndrome of hemolysis, elevated liver enzymes, and
low platelet count. Obstet Gynecol 2004;103:98191.
9 Costedoat-Chalumeau N, Amoura Z, Hulot JS et al. Low
blood concentration of hydroxychloroquine is a marker for
and predictor of disease exacerbations in patients with
systemic lupus erythematosus. Arthritis Rheum 2006;54:
328490.

www.rheumatology.oxfordjournals.org

22 Lonze BE, Singer AL, Montgomery RA. Eculizumab and

renal transplantation in a patient with CAPS. N Engl J Med
2010;362:17445.
23 Kelly R, Arnold L, Richards S et al. The management of
pregnancy in paroxysmal nocturnal haemoglobinuria on
long term eculizumab. Br J Haematol 2010;149:44650.
24 Erkan D, Asherson RA, Espinosa G et al. Long term outcome of catastrophic antiphospholipid syndrome survivors. Ann Rheum Dis 2003;62:5303.
25 Woudstra DM, Chandra S, Hofmeyr GJ et al.
Corticosteroids for HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome in pregnancy. Cochrane
Database Syst Rev 2010, CD008148.

1641

Downloaded from http://rheumatology.oxfordjournals.org/ by guest on July 23, 2015

Disclosure statement: The authors have declared no conflicts of interest.

10 Cervera R, Khamashta MA, Shoenfeld Y et al. Morbidity

and mortality in the antiphospholipid syndrome during a 5year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis 2009;68:142832.