Rheumatology 2008;47:iii23–iii27 doi:10.

1093/rheumatology/ken181

Management of the controversial aspects of the antiphospholipid

syndrome pregnancies: a guide for clinicians and researchers
D. Erkan1, S. Patel1, M. Nuzzo2, M. Gerosa3, P. L. Meroni3, A. Tincani2 and M. D. Lockshin1

Background. Recommendations for the treatment of aPL-positive patients with pregnancy morbidity are based on a limited number of well-
designed clinical trials. However, the management of pregnant aPL-positive women still displays several open questions.
Objective. To determine the practice patterns of experienced physicians in the management of the controversial aspects of aPL pregnancies.

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Methods. A questionnaire reproducing debated conditions was initially sent to the Advisory Board members (ABMs) of the 12th Congress of
aPL and the Fifth Conference on Sex Hormones, Pregnancy and Rheumatic Diseases (Florence, Italy, April 2007), and then the same
questionnaire was posted at the Hospital for Special Surgery (www.hss.edu) website and all attendees (ATS) of the above meetings were
invited to participate via e-mail. Answers have been collected and analysed in a descriptive fashion and responses of the two groups
evaluated by Chi-square or Fisher’s exact test.
Results. As a whole 75 responses from the ABMs and ATS were included in the analysis. In general, there was no significant difference
between the opinions of two groups.
Conclusions. Management recommendations displayed reasonable consistence: (i) for the use of low-dose aspirin and low-molecular
weight heparin during pregnancy and during ovarian stimulation for in vitro fertilization; (ii) against oestrogen-containing oral contraceptives;
and (iii) for the use of anticoagulants in the post-partum period.

KEY WORDS: Antiphospholipid syndrome, Lupus anticoagulant, Pregnancy, In vitro fertilization, Aspirin, Heparin.

Background
APS is diagnosed when thrombosis or pregnancy morbidity
occurs in persistently aPL-positive individuals. Although the
management of aPL-positive pregnant patients is controversial
due to limited well-designed controlled trials, the current
recommendation is: (i) low-dose aspirin (LDA) and prophylactic
dose heparin for patients fulfilling the Updated Sapporo APS
Classification Criteria based on pregnancy morbidity only; (ii)
LDA and therapeutic dose heparin for patients fulfilling the
Updated Sapporo APS Classification Criteria based on a vascular
event; and (iii) no treatment for asymptomatic (no history of
pregnancy and thrombosis) persistently aPL-positive patients
(LDA may be considered although there are no data to support
this strategy) [1].
Despite these recommendations, many open questions without
evidence-based answers remain for the management of pregnant
aPL-positive patients, especially when the initial treatment fails.
Thus, the primary objective of this study was to determine the
practice patterns of experienced physicians in the management
of the controversial aspects of the aPL pregnancies. Detailed
information about the management of APS pregnancies can be
found elsewhere [1].
Methods
We surveyed the Advisory Board members (ABMs) and attendees
(ATS) of the 12th Congress of aPL and the Fifth Conference on
Sex Hormones, Pregnancy and Rheumatic Diseases, which were
held in Florence, Italy (April 2007). In March 2007, during the
first phase of the survey, a close-ended questionnaire with short
patient scenarios was e-mailed to ABMs. In June 2007, during the
second phase of the survey, the same questionnaire was posted at
1
Division of Rheumatology, Hospital for Special Surgery, Weill Medical College
of Cornell University, NY, USA, 2Rheumatology and Clinical Immunology Unit,
University of Brescia, Brescia and 3Department of Infant Medicine, University of
Milan, IRCCS Istituto Auxologico Italiano, Milan, Italy.
Submitted 18 March 2008; accepted 2 April 2008.
Correspondence to: D. Erkan, The Barbara Volcker Center for Women and
Rheumatic Disease, Hospital for Special Surgery, 535 E 70th Street, New York, NY
10021, USA. E-mail: erkand@hss.edu
iii23
ß The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
the Hospital for Special Surgery (www.hss.edu) website and all
ATS of the above meetings were invited to participate via e-mail.
The questions were about responders’ medical background,
experience with APS patients and pregnancies, and controversial
issues in the management of APS pregnancies. Multiple-choice
questions allowed respondents to choose medication combina-
tions as needed.
Although responses were analysed in a descriptive fashion, we
compared the responses of the ABMs to the responses of the ATS
by Chi-square or Fisher’s exact test. Also, a literature review was
performed to determine the clinical relevance of our survey.
Results and Discussion
We received 26/50 (52%) responses from the ABMs and 61/525
(12%) responses from the ATS. Twelve of 61 (20%) of the ATS
who responded preferred not to fill out the questionnaire due to
their limited experience with APS pregnancies; thus, 49 responses
from the ATS were included in the analysis. Table 1 demonstrates
the characteristics of the responders.
Physicians treating APS patients during pregnancy often face
problems that do not have an answer in evidence-based medicine
but that require decisions nonetheless. This survey was performed
to identify the behaviour of physicians (ABMs) who have long
experience with pregnant APS patients; in addition, we explored
the opinions of ATS of the same conferences, to see if they would
make the same decisions. Results show that ABMs and ATS do
not significantly differ in most cases; this allows us to identify a
general behaviour.
Recurrent pregnancy loss despite treatment
Next pregnancy of an APS patient with a late fetal loss on LDA
and prophylactic dose low-molecular weight heparin (LMWH)
(Fig. 1A): almost 80% of all responders increased LMWH dose
to a therapeutic dose, 20% used intravenous immunoglobulin
(IVIG) with or without other medications, and 30% chose to
monitor factor Xa (FXa) levels during the next pregnancy. Next
pregnancy of an APS patient (history of deep vein thrombosis)
with a late fetal loss on LDA and therapeutic dose LMWH
(Fig. 1B): the use of IVIG and FXa monitoring was 37 and 41%,
respectively among all responders. The use of FXa monitoring in
iii24 D. Erkan et al.

TABLE 1. Characteristics of the responders

HELLP syndrome
Board members Attendees Recommendation against pregnancy in a patient with a history of
Specialty (n ¼ 26) (%) (n ¼ 49) (%) HELLP (haemolysis, elevated liver enzymes, low platelet)
Rheumatology 16 (62) 16 (33) syndrome: 68% of responders advised that a future pregnancy is
Obstetrics 5 (19) 14 (29) feasible (ABM: 73% and ATS 64%, P ¼ NS). Recurrence rate of
General internal medicine 3 (12) 7 (14) HELLP syndrome in APS patients: the majority estimated <50%
Haematology 1 (4) 9 (18)
Immunology 0 2 (4)
chance of recurrence (ABM: 81% and ATS: 80%, P ¼ NS).
Other (or unknown
) 1
(4) 1 (2) HELLP syndrome occurs in <1% of normal pregnancies and
Primary responsibility
10–15% of pre-eclamptic patients [6, 7]. In aPL-negative patients,
Patient care 23 (88) 39 (80) HELLP syndrome usually develops between 24 and 32 weeks,
Clinical research 1 (4) 8 (16) only 1% of the patients develop serious liver complications, and it
Basic research 1 (4) 0 usually resolves with delivery [6, 7]. However, in aPL-positive
Administrative 0 1 (2)

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Other (or unknown
) 1
(4) 1 (2) patients, the HELLP syndrome usually occurs during the second
trimester of the pregnancy, almost one-third of the patients
How many aPL-positive patients do you see in a typical week?
1–2 Question was not asked 24 (49) develop hepatic infarcts, and aggressive treatment is needed to
3–5 Question was not asked 9 (18) reverse the syndrome as the majority of the patients develop
6–10 Question was not asked 9 (18) thrombotic complications and rarely catastrophic APS [7].
11–20 Question was not asked 4 (8) Despite this life-threatening nature of HELLP syndrome in
>20 Question was not asked 3 (6)
APS patients (microangiopathic form of APS), the majority of
How many aPL-positive pregnant patients (or those considering pregnancy) responders do not contraindicate a new pregnancy, even if they
do you see in a typical month?
1–2 Question was not asked 24 (49) consider the rate of recurrence high compared with that recorded
3–5 Question was not asked 12 (25) in the general population (2–6%) [8]. Although the recurrence rate
6–10 Question was not asked 7 (14) of HELLP syndrome is unknown in aPL-positive patients, a
11–20 Question was not asked 5 (10) possible interpretation of this unexpected result could be that
>20 Question was not asked 1 (2)
most of the responders underestimate the severity of the problem
How many aPL-pregnancies have they followed within the last 2 years? due to not being involved in the direct management of patients
1–2 1 (4) 1 (2)
3–5 1 (4) 8 (16) suffering form HELLP syndrome.
6–10 4 (15) 10 (20)
11–20 4 (14) 17 (35) LDA during pregnancy
>20 13 (50) 13 (27)
No answer 3 (12) 0 Recommendation of LDA in pregnant, persistently aPL-positive


patients (Fig. 2): the recommendation based on all the responses
Heparin-receiving patients.
was 85, 92, 93 and 89% in asymptomatic aPL-positive patients,
aPL-positive patients with one embryonic loss, aPL-positive
patients with two embryonic losses and aPL-positive patients
heparin-receiving pregnant patients: in general, 55% of the with non-criteria aPL features, respectively. Notably, the use of
responders considered FXa monitoring as a useful tool (ABM: LDA for patients with one or two early (<10 weeks) miscarriages
46% and ATS: 64%, P ¼ NS). was significantly more common among the ATS.
APS patients without previous thrombosis usually receive LDA There are no clear guidelines for the management of pregnant
and prophylactic doses of heparin during subsequent pregnancies, aPL-positive patients who do not fulfill Sapporo criteria for
as therapeutic doses of heparin do not provide additional benefit definite APS. Since pregnancy and aPL can be additive risk
[2]. However, from a practical point of view, when patients fail factors for vascular thrombosis, LDA therapy can be justified as it
prophylactic heparin, almost 80% of responders would increase has minimal maternal or fetal side-effects. However, there are
LMWH to a therapeutic dose (Fig. 1A), although such dosing is no controlled studies demonstrating that LDA affects pregnancy
not proven to be effective by controlled studies. IVIG may be used outcomes in persistently aPL-positive patients without the
for aPL-associated pregnancy losses that are refractory to LDA diagnosis of APS.
and heparin (prophylactic or therapeutic dose); 37% of the
responders suggested the addition of IVIG with or without
Heparin during pregnancy
other medications (Fig. 1B) in APS patients who fail LDA and
therapeutic dose LMWH; however, there are no controlled data Recommendation of heparin in pregnant, persistently aPL-
supporting this approach [3]. positive patients: the recommendation based on all the responses
The physiological changes that occur in pregnancy (increase in was 7, 27, 75 and 63% in asymptomatic aPL-positive patients,
heparin-binding proteins, increased clearance of heparin, and aPL-positive patients with one early miscarriage (embryonic loss),
larger volume of distribution of heparin due to pregnancy- aPL-positive patients with two early miscarriages and aPL-
associated increase in plasma volume) may result in a decrease in positive patients with non-criteria aPL features, respectively.
plasma half-life of heparin [2] resulting in pregnancy failure. The responses were not significantly different between ABM and
According to our survey, about half of the physicians looking ATS.
after pregnant patients with APS consider FXa plasma levels as a Although the risk of pregnancy morbidity can be as high as
useful tool to assess the adequate dose of heparin therapy as 90% in untreated APS patients with a history of pregnancy
suggested by Barbour et al. [2]. These results are in agreement with morbidities, the risk is unknown in asymptomatic, persistently
the available literature, although reports both support [4] and aPL-positive patients or in APS patient with a history of
question the role of anti-FXa level monitoring for heparin [5]. thrombosis. Despite the lack of evidence, when treatment is
Medium/high doses of corticosteroids do not offer advantages considered, aspirin is usually the first choice in persistently aPL-
in comparison with the standard therapy and are known to be positive patients who do not have history of thrombosis or late
associated with important side-effects (pre-term delivery, pre- fetal loss. Heparin is usually added to LDA for highly selected
eclampsia). In our survey, only a small percentage of physicians reasons such as older maternal age, assisted reproduction
suggested the use of low doses of corticosteroids as an additional techniques or in pregnant women with significant aPL profile
treatment for pregnancy loss recurrences despite LDA and (positivity for lupus anticoagulant test and/or high titres of anti-
heparin therapy. cardiolipin/anti-
2-glycoprotein-I antibodies).
 Controversial aspects of APS pregnancies iii25

A
Advisory board members (n = 26) Attendees (n = 49)
90 90
84%
80 80
70%
70 70

60 60
Percentage

Percentage
50 50

40 40

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30 30

20 15% 20
12% 14%
10 10
4% 2% 0
0 0
Increase LMWH Continue the CS Warfarin Increase LMWH Continue the CS Warfarin
to therapeutic same regimen to therapeutic same regimen
dose dose

Total: 18* Total: 4* Total: 3 Total: 1 Total: 41* Total: 7* Total: 1 Total: 0
3 with IVIG 1 with IVIG 1 with IVIG 4 with IVIG 3 with IVIG 1 with IVIG
1 with CS

*FXa monitoring = 3/22 (14%) *FXa monitoring = 19/48 (40%)

B
Advisory board members (n = 26) Attendees (n = 49)

90 90 88%
85%
80 80

70 70

60 60
Percentage

Percentage

50 50

40 40

30 30

20 20
12% 10%
10 10
4%
2%
0 0
Continue the same IVIG Warfarin Continue the same IVIG Plasma exchange
regimen regimen

Total: 22* Total: 3 Total: 1 Total: 43* Total: 5 Total: 1

9 with IVIG 1 with CS 11 with IVIG
4 with further LMWH
2 with CS
1 with IVIG and PE
1 with PE * FXa monitoring = 27/43 (63%)
*FXa monitoring = 4/22 (18%)

FIG. 1. (A) What are your treatment recommendation(s) for a persistent lupus anticoagulant test-positive APS patient with a mid-pregnancy fetal loss (despite treatment
with LDA and prophylactic dose LMWH) when she starts a new pregnancy? The patient has no history of arterial/venous events. The responses were not significantly
different between ABMs and ATS except the choice of FXa monitoring during pregnancy (P ¼ 0.03). (B) What are your treatment recommendation(s) for a persistently lupus
anticoagulant test-positive APS patient with a mid-pregnancy fetal loss (despite treatment with low dose aspirin and therapeutic dose LMWH) when she starts a new
pregnancy? The patient has a history of deep vein thrombosis 5 yrs ago. The responses were not significantly different between ABMs and ATS. CS: corticosteroids;
PE: plasma exchange; IVIG: intravenous immunoglobulin; LMWH: low-molecular-weight heparin; PE: plasma exchange.
iii26
Advisory board members (n = 26)
100
Yes
90
81% 85% 81%
77%
80
70
60
Percentage
50
40
30
20
10
0 0
A B C D
FIG. 2. Do you recommend the use of LDA in a persistently aPL-positive pregnant patient (lupus anticoagulant test positive and/or aCL IgG 80 U tested twice 12 weeks
apart) and A: asymptomatic (no history of vascular or pregnancy events)? B: with only one early (<10 weeks) miscarriage? C: with two early (<10 weeks) miscarriages?
D: asymptomatic but with headache, livedo or heart valve disease? The responses were not significantly different between ABMs and ATS except B (P ¼ 0.02) and
C (P ¼ 0.05).
Our survey shows that patients with non-criteria APS features
and particularly those suffering from two or less early mis-
carriages are treated as classical APS pregnancies. This behaviour
can be attributed to relative safety of heparin therapy in
pregnancy and also to the profound awareness of the pathogenic
potential of aPL.
LDA or heparin during IVF
Recommendation of LDA in pregnant, persistently aPL-positive
patients during in vitro fertilization (IVF): 69–83% said yes
to LDA independent of the APS classification criteria.
Recommendation of heparin in pregnant, persistently aPL-
positive patients during IVF: the recommendation based on all
the responses was 31, 84 and 73% in asymptomatic aPL-positive
patients, APS patients with vascular events and APS patients with
only pregnancy events, respectively. The responses were not
significantly different between ABM and ATS.
Cohort studies demonstrated that aPL positivity does not
predict a successful conception [9]; a meta-analysis of seven
studies found no relationship with infertility and aPL [10]. A
double-blind randomized controlled study demonstrated no
benefit of heparin and LDA (compared with placebo) for aPL-
positive patients undergoing IVF [11]. However, the major
limitation of these studies is the lack of correction for karyotypic
aberrations [9].
Given that IVF is associated with increased oestrogen produc-
tion and, rarely, with ovarian hyperstimulation syndrome
(OHSS), anticoagulation can be considered for thrombosis
prevention in aPL-positive patients [9]. There are no guidelines
about the optimal prevention strategy. Our survey shows that the
majority of responders are keen to use anticoagulation during IVF
in patients with a formal diagnosis of either thrombotic or
obstetric APS, while in asymptomatic aPL-positive carriers LDA
seems to be the treatment of choice.
Oestrogen or oral contraceptives in APS
Recommendation against oestrogen/oral contraceptive use for
APS patients as long as they are anticoagulated: overall 73% of all
the responders recommended against oral contraceptive use
D. Erkan et al.
Attendees (n = 49)
Yes
100
96% 96%
92%
88%
90
80
70
60
Percentage
50
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40
30
20
10
A B C D
(ABM: 73% and ATS: 74%, P ¼ NS). Recommendation against
oestrogen/oral contraceptive use for asymptomatic, persistently
aPL-positive patients if they are on LDA: overall 91% of all the
responders recommended against oral contraceptive use (ABM:
96% and ATS: 86%, P ¼ NS).
Oestrogen-containing contraceptives increase the risk of
thrombosis in general population and, given multiple case reports
of APS patients developing thrombosis on contraception, oral
contraceptives are generally contraindicated in aPL-positive
patients. Approximately 25% of the ABMs and the ATS allowed
oestrogen-containing pills in fully anticoagulated patients, but the
percentage decreased for patients that are on LDA only.
Progesterone-only contraceptives do not increase the thrombosis
risk [12] and thus they can be considered in aPL-positive patients.
However, there are no controlled data supporting this approach.
Post-partum thrombosis prophylaxis
Duration of postpartum thrombosis prophylaxis: the most
commonly recommended postpartum thrombosis prophylaxis
periods among all responders were 4–6 weeks (36%) and 6–8
weeks (27%) (ABM: 19% recommended 2–4 weeks, 58% 4–6
weeks, 19% 6–8 weeks and 4% 8–12 weeks) (ATS: 14%
recommended 1–2 weeks, 14% 2–4 weeks, 24% 4–6 weeks, 30%
6–8 weeks and 18% 8–12 weeks).
Despite the lack of controlled studies regarding duration of
anticoagulation, it is well accepted that persistently aPL-positive
patients require post-partum anticoagulation given that post-
partum period is a risk for thrombosis; the duration recommenda-
tions range from 3–5 days [13] to 6–8 weeks [1] to 12 weeks [14].
In a recent Canadian survey, physicians most frequently selected
long-term post-partum anticoagulation (defined as up to 8 weeks)
independently of the medication chosen [15]. Our survey confirms
the usual choice of long-term post-partum anticoagulation that is
generally prolonged for an average of 6 weeks.
Conclusion
Although evidence-based and experts’ guidelines are available for
the general management of pregnancy loss and complications in
APS women, several common practical aspects have not been
 Controversial aspects of APS pregnancies
addressed in a systemic manner. Our survey was planned in order to
offer suggestions for these problems, to provide practical informa-
tion that may help the everyday management of these patients, and
to identify opportunities for further research questions.
Despite the fact that these opinions are not evidence-based,
there is not a significant difference between ABMs’ and ATS’
suggestions. As a whole, the management recommendations for
aPL-positive patients have a reasonable consistency for: (i) the use
of LDA and LMWH during pregnancy and during ovarian
stimulation for IVF; (ii) oestrogen-containing oral contraceptives
are usually avoided; and (iii) there is agreement in the use of
anticoagulation in post-partum period.
Rheumatology key messages
 Recommendations for the treatment of aPL-positive patients with
pregnancy morbidity are based on a limited number of well-
designed clinical trials.
 Based on the practice patterns of experienced physicians,
management recommendations display reasonable consistency:
(i) for the use of LDA and LMWH during pregnancy and during
ovarian stimulation for IVF; (ii) against oestrogen-containing oral
contraceptives; and (iii) for the use of anticoagulation in the post-
partum period.
Acknowledgements
The authors would like to thank the following physicians for
participating in the survey: A. Alaa Fadhil Alwan, Ales Ambrozic,
Paul Ames, Mary-Carmen Amigo, Laura Andreoli, Jon Arnason,
Francesca Bellisai, Andrea Bendrups, Eduardo Borba, Maria
Bortolati, Ware Branch, Katarina Bremme, Antonio Brucato,
Howard Carp, Ricard Cervera, Laura Contino, Maura Costa,
Claudia Costo, Saabrina Cozzolino, Dorota Darmochwal-Kolarz,
Sara De Carolis, Philippe de Moerloose, Ronald Derksen, Carlos
Dias, Andrea Doria, Alina Laura Dumitrascu, Gerard Espinosa,
Rebecca Fischer-Betz, Claudio Galarza, Inge-Margrethe Gilboe,
Sonia Hammami, Kathryn Hassell, Gili Kenet, Munther
Khamashta, Robert Lahita, Carl Laskin, Roger Levy, Andrea
Lojacono, Aldo Maina, Maria Jose Mattioli, Gale McCarty,
Gentry McIntyre, Federico Mecacci, Mayer Mitter, Jadranka
Morovic-Vergles, Marta Mosca, Jack Murray, Srdan Novak,
iii27
Cecilia Pappalardo, Jose Maria Pego-Reigosa, Vittorio Pengo,
Michelle Petri, T. Flint Porter, Jacob Rand, J. Rauch, Robert
Roubey, Amelia Rufatti, Guillermo Ruiz-Irastorza, Silvia
Sanchez-Ramon, Debra Shepherd, Yehuda Shoenfeld, Mary
Stephenson, Mayumi Sugiura-Ogasawara, Maria Tektonidou,
Maria Bertero Tiziana, Aaron Tomer, Andrea L. Tranquilli, G.
Valesini, Serena Wu and Masahide Yamazaki.
Disclosure statement: The authors have declared no conflicts of
interest.
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