1. Fetal and Maternal Medicine Review 2011; 22:4 265–286 C Cambridge University Press 2011
doi:10.1017/S0965539511000131 First published online 3 November 2011
OBSTETRIC ANTIPHOSPHOLIPID SYNDROME - A REVIEW
K SCHREIBER, O ATEKA-BARRUTIA, MA KHAMASHTA AND GRV HUGHES
St Thomas Hospital Lupus Research Unit, The Rayne Institute, King’s College London School of Medicine,
London, United Kingdom.
INTRODUCTION
The Antiphospholipid syndrome (APS) is one of the current hot topics embracing
rheumatology and obstetrics.
The first clinical description of APS was in 1983.1 Venous or arterial thrombosis,
abortion and cerebral manifestations along with circulating antibodies were the first
described hallmarks of the syndrome. In the following years other clinical features,
which include pregnancy complications, such as recurrent miscarriages (RM), pre-
eclampsia or severe placental insufficiency were described.
The first classification criteria of APS were not defined until 1998. Apart
from laboratory criteria they included pregnancy morbidity, such as one or more
unexplained deaths of a morphologically normal fetus at or beyond 10 weeks gestation,
one or more premature births before 34 weeks of gestation due to severe pre-eclampsia,
eclampsia, placental insufficiency or recurrent early miscarriages. In 2006 the criteria
were updated including changes of the laboratory criteria, while the obstetric clinical
criteria remained unchanged.2 (Table 1)
Due to its preponderance for women in their reproductive age (3.5:1 in primary APS
and 7:1 in secondary APS) and the pregnancy morbidity, pregnancy management plays
a central role and is of enormous importance in this syndrome.3 Untreated women
are likely to develop adverse pregnancy outcomes, such as pre-eclampsia, and the live
birth rate without intervention may be as low as 10%.4,5
Successful pregnancy management of APS patients combines pre-conception
counselling, monitoring during pregnancy, consequent education of the patient and
subsequently a post partum follow-up, ideally in a multidisciplinary set-up. An
improvement in monitoring and treating these patients allows more than 70% of
women with APS to deliver a viable live infant.6
In our review we aim to focus on the obstetric antiphospholipid syndrome (OAPS),
the pathogenesis, its clinical manifestations and complications. In order to keep our
review as clinically useful as possible, the entity of OAPS is divided by its serological
Munther A Khamashta, Lupus Research Unit, The Rayne Institute, St Thomas Hospital, London SE1 7EH,
UK. E-mail address: munther.khamashta@kcl.ac.uk

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Table 1 Adapted from the revised classification criteria (Sapporo Criteria) for antiphospholipid
syndrome.
• Vascular thrombosis: ≥ 1 clinical episode of arterial, venous or small vessel thrombosis.
Thrombosis must be objectively confirmed. For histopathological confirmation, thrombosis must be
present without inflammation of the vessel wall.
• Pregnancy morbidity:
• ≥ 1 unexplained deaths of a morphologically normal fetus ≥ 10 weeks of gestation.
• ≥ 1 premature delivery of a morphologically normal fetus < 34 weeks gestation because of:
(i) severe pre-eclampsia or eclampsia defined according to standard definitions.
(ii) recognised features of placental insufficiency.
• Laboratory criteria:
• The presence of antiphospholipid antibodies (aPL), on two or more occasions at least 12 weeks apart
and no more than five years prior to clinical manifestations, as demonstrated by ≥ 1 of the following.
• Presence of lupus anticoagulant in plasma
• Medium to high-titre anticardiolipin antibodies (> 40GPL or MPL, or > 99th percentile) of IgG or IgM
isoforms
• anti-β2 glycoprotein-I antibody (anti- β2GP I) of IgG or IgM present in plasma.
APS classification criteria. Classification criteria for APS have recently been updated in 2006 in Sydney, but were
first proposed in 1998 (Sapporo, Japan). At least one clinical manifestation such as vascular thrombosis or
pregnancy morbidity, together with positive laboratory tests, currently including LA, anticardiolipin (aCL) and
anti-β2-glycoprotein I antibodies (anti-β2GPI), detected at least twice12 weeks apart, are necessary to fulfil
the classification criteria.
and clinical phenotypes. For each subgroup we will address the current treatment
recommendations.
PATHOGENESIS
In the last century, APS was mainly considered as an antibody induced thrombophilia,
while 21st century view of the syndrome is wider as other important pathogenic
mechanisms, such as inflammation, have been revealed.
Antiphospholipid antibodies (aPL) represent a heterogeneous group of antibodies
directed against negatively charged phospholipids and/or phospholipid binding
proteins, with direct or indirect pro-thrombotic effects. Amongst the variety of
these antibodies, current classification criteria include anti-cardiolipin (aCL) and
anti-beta2GP1 (a␤2GP1), along with the lupus anticoagulant (LA) phenomenon in
coagulation tests. (Table 1)
APL have the ability to interact with the coagulation cascade at several stages
by directly binding to thrombin, activated Protein C, plasmin and activated factor
X and thereby promote coagulation7–10 . Other target antigens include prothrombin
or annexin V.11 Anti-annexin V promotes indirect procoagulant activity, as Annexin
V inhibits the activation of prothrombin and has also been shown to be of clinical
relevance in patients with early pregnancy loss.12,13
Taking into account that thrombophilia alone does not explain all obstetric
complications, research in recent years highlights inflammation as an important

3. Obstetric antiphospholipid syndrome - a review 267
Figure 1 Pathogenesis of thrombosis in the antiphospholipid syndrome.
additional mechanism. There is evidence that aPL are able to activate cells playing a
role in inflammation, such as platelets, monocytes and endothelial cells.
Activated platelets increase the expression of Glycoprotein IIb/IIIa and
subsequently the synthesis of thromboxane A2, which among other functions
facilitates the aggregation of thrombocytes and hence plays a key-role in thrombosis.
APL with a␤2GP1 activity generates activation of monocytes and endothelial cells.
Endothelial cells and monocytes in turn express adhesion molecules and upregulate
the production of tissue factor, which in turn initiates the activation of the coagulation
cascade.14,15 (Figure 1)
Additionally, aPL complexes formed by ␤2GPI/anti-␤2GPI are able to activate the
classical and alternative pathway of the complement system. This mechanism seems
important and its pathogenic role in pregnancy is a field of growing interest. It is
shown that complement deficiency or direct inhibition of the complement system
is protective against thrombosis and pregnancy loss.16 Therapeutic agents, such as

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heparin, which inhibit the complement system and hence show anti-inflammatory
capacity in combination with an anti-thrombotic effect, may well have more than one
role in APS.17–21
CLASSIFICATION/CLINICAL MANIFESTATIONS
APS is widely considered as a systemic autoimmune disease and the main acquired
thrombophilia. The syndrome is considered as ’primary antiphospholipid syndrome’
(PAPS) if there is no accompanying connective disease, in particular SLE, and as
‘secondary antiphospholipid syndrome’ (SAPS) if there is evidence for such. Due to
the fact that occasional patients with PAPS develop features of SLE, clinical and
serological monitoring on a regular basis in these patients has been suggested.22
The syndrome contains a variety of clinical manifestations, which include deep vein
thrombosis and pulmonary embolism as the most frequent features.23 In contrast to
other thrombophilia disorders, which mainly affect the venous vascular bed, APS also
causes thrombosis in arterial vessels and is hence responsible for different neurological
manifestations such as stroke or transient ischaemic attacks. Other neurological
features include migraine headaches, memory loss and epilepsy.24
Thrombocytopenia and livedo reticularis are the most important haematological
and dermatological characteristics, respectively, and can be found in over 20% of APS
patients. The former is usually not associated with haemorrhagic events but rather
with thrombosis, while livedo reticularis has been associated with occlusive arterial
events.23,25–27
Pregnancy morbidity, such unexplained fetal death, premature birth before 34
weeks of gestation due to severe pre-eclampsia, eclampsia or placental insufficiency
or recurrent early miscarriages are common features of the syndrome. Pre-eclampsia,
premature birth or fetal loss are the most common manifestations and are seen in
10–20% of the APS cases.23 In women suffering from RM, aPL are found in up to 20%.
APS has also been associated with a broad range of cardiac manifestations, which
however are less common, but still can be found in 10–20% of APS patients. They
include valvular disease, such as verrucus endocarditis and valvular thickening or
insufficiency. A similar percentage suffer occlusive arterial heart disease and aPL have
been implicated in premature coronary artery bypass graft occlusion.28 They have
been described as a significant and independent risk factor for myocardial infarction
or cardiac death in young age.29,30
The more unusual clinical manifestations found in less than 10% include retinal
artery or vein thrombosis, amaurosis fugax, renal thrombotic microangiopahty,
pulmonary hypertension and vascular dementia. Adrenal haemorrhage, avascular
necrosis, pathological bone fractures, transverse myelitis or Budd-Chiari Syndrome
are rare conditions, as they are present in less than 1% of the patients, but deserve to
be mentioned. A rare but lifethreatening condition is the catastrophic APS which can
be found in less than 1% of patients and has a mortality of over 50%.31,32 Frequent
manifestations of APS are illustrated in Table 2.33

5. Obstetric antiphospholipid syndrome - a review 269
Table 2 Frequent clinical manifestations of APS
• Venous and/or arterial thrombosis: VTE, PE, stroke, TIA, coronary artery disease, retinal artery or vein
thrombosis
• Obstetric: RM, stillbirth, pre-eclampsia, eclampsia, premature birth, FGR, HELLP, abruptio placentae
• Thrombocytopenia
• Livedo reticularis
• Thrombotic microangiopathy: nephropathy, leg ulcers
• Other: Heart valve disease, epilepsy, pulmonary hypertension, osteonecrosis
MANAGEMENT OF DIFFERENT PHENOTYPES IN APS
Asymptomatic aPL carriers
APL can be detected in 1–5% the background population, and there is an existing
overlap in a significant number of the patients with SLE and APS; aPL are found in
approximately 30–40% of patients with SLE.23,25
APL carriers have an increased risk of developing pre-eclampsia during pregnancy.
Although specific data of other poor pregnancy outcomes are currently lacking,
antiplatelet therapy for the prevention of pre-eclampsia is suggested in these patients,
based on observational study results.34—40
Early miscarriages (<10) and recurrent early miscarriages
In Europe the most widely used definition for early miscarriage is pregnancy loss
within the first 12 completed weeks of pregnancy. Ten to 15% of all clinically
recognised pregnancies end in miscarriage.41
The fact that there is no standardised definition of early miscarriage results
in a certain controversy regarding the frequency of APS in early RM. The lack
of alignment includes among others the definition of intrauterine pregnancy, the
diagnosis of intrauterine pregnancy (ultrasound or biochemical), the exclusion of
other causes of RM and the number of miscarriages required. However, most authors
in Europe consider three consecutive miscarriages before 12 gestational weeks as
RM. The theoretical estimated risk of three consecutive miscarriages is 0.34%, but
RM affects approximately 1% of all women and is hence greater than expected.42
The most common reasons for early miscarriage and RM are genetic abnormalities,
anatomic variations, cervical weakness, endocrine factors and immune factors, such
as thyroid factors, infective agents i.e. TORCH (Toxoplasmosis, Other, Rubella,
Cytomegalovirus, Herpes simplex virus) and aPL.43
Among all possible causes, APS could be responsible for 2–50% of RM whereas
aPL could be identified in 5–20% of RM women.44—48 Maternal age and previous

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number of miscarriage are two independent risk factors for further miscarriage.41,49
The prevalence of aPL in women with a low risk obstetric history is less than 2%.35,50
Regarding complications, differences between the study designs hamper the
comparison and combination of the data. In a multicenter prospective cohort study of
1,000 APS patients, the most frequent fetal complication was miscarriage, followed by
fetal loss and premature birth, while the most common maternal manifestations were
pre-eclampsia, followed by eclampsia and abruptio placentae.25,51 Of the different aPL
that have been investigated thus far, LA is shown to have the strongest association
with early (and late) miscarriages.
RM is the only area of APS for which treatment is based on several trials,
including three randomised trials. Two trials, including one randomized trial, did not
show improvement in pregnancy outcome by using LDA and low molecular weight
heparin (LMWH)52,53 while two randomized trials showed improvement of pregnancy
outcome by combining LDA with unfractionated heparin (UFH).54,55 The newer trials
failed to show any benefit of additional heparin treatment, but a non-consistence in
APS classification criteria and the use of different heparin agents (LMWH and UFH)
limits the direct comparison of these studies. Additionally, a meta-analysis showed
a significant reduction in pregnancy complications in women at high risk for pre-
eclampsia treated with antiplatelet agents. Some observational studies also showed
high pregnancy success rates on aspirin alone.56–58
Interestingly, Girardi et al19 were able to identify the inflammatory aspect of APS
and showed that UFH and LMWH, which are heparins with known anti-inflammatory
effects, were able to prevent aPL induced pregnancy loss. This could not be proven
for agents such as Fondaparinux or Hirudin, which do not have anti-inflammatory
abilities. It is important to note that this has only been proven in a murine model.19
Heparin has been shown to affect aPL binding to trophoblast cells and restores normal
trophoblast invasiveness and differentiation, which is an important mechanism in
preventing pre-eclampsia.59—61
Despite obvious controversies raised by the above-mentioned trials, a Cochrane
systematic review34 recommends that women with RM and APS should be treated
with LDA and heparin, which is consistent with some expert recommendations.62
However, a recent international task force group was not able to define a treatment
for this group due to discrepancies in the literature.63
Summarising, some centres use the combination of LDA and heparin as first line
therapy, while others prefer to start mono-therapy with LDA and add LMWH in case
of failure. Some authors using LDA and LMWH suggest discontinuing LWMH at 20
weeks of gestation provided the uterine artery Doppler is normal.
Late pregnancy loss
Late pregnancy loss or fetal death is defined as pregnancy loss after 10 weeks of
gestation, while the term stillbirth indicates a loss after 20 weeks gestation.

7. Obstetric antiphospholipid syndrome - a review 271
In unselected pregnancies fetal death in the 2nd or 3rd trimester of pregnancy
occurs in up to 5%. Although correlation between this condition and aPL is widely
accepted64–66 no population-based studies have proven APS to be a cause of fetal death.
However, promising data regarding this association will soon be available from the
NIH founded Stillbirth Collaborative Research Network population-based study.
An ideal treatment during pregnancy for women with previous fetal death has not
been defined by randomised trials yet, most experts recommend LDA and prophylactic
heparin from the beginning of pregnancy. This regime has shown to result in good
pregnancy outcomes.6,34,62,63,67 Indeed, LMWH appears to reduce the recurrence of
placental-mediated complications.67
Pre-eclampsia and other pregnancy complications
Pre-eclampsia and/or placental insufficiency can present as fetal growth restriction
(FGR) and occurs in about 5–10% of all pregnancies68 , while severe pre-eclampsia and
eclampsia is found in 0.5% of pregnancies in developed countries.69
The association between aPL and these complications has not been elucidated yet70 ,
although most prospective observational studies support this association.35,36,71–74
A recent systematic meta-analysis showed that moderate to high levels aCL are
associated with pre-eclampsia.75
Several prospective25,76–78 and retrospective79 studies have shown that women with
high levels of aPL and/or more than one positive aPL detected, have a higher risk of
FGR and preterm deliveries; 10–50% of them may develop pre-eclampsia, and about
10% of them will present with FGR. Data from case-control studies have shown that
among patients who previously have suffered pre-eclampsia or have delivered a FGR
child, aPL could be found in around 11–29%, compared to 7% or less in healthy
pregnant women.78
The association between aPL carriers and severe pre-eclampsia and placental
insufficiency is still an area of controversy, mainly based on negative results of several
case-control studies.80–82 However, patients with a diagnosis of APS have a higher risk
of developing these complications in future pregnancies and the past obstetric history
is the best predictor of pregnancy outcome in these patients.78
Regarding treatment, a meta-analysis of 31 randomized trials showed that, among
high risk patients, LDA treatment reduced the risk of pre-eclampsia, prematurity (<34
weeks) and serious adverse pregnancy outcome to 10%.83 Furthermore, in pregnancies
progressing beyond 20 weeks’ gestation, maternal and fetal-neonatal outcomes were
close to those found in the general population.
Randomised trials do not clearly define the treatment for patients with a history
of prematurity (<34 weeks) or fetal death (>10 weeks) due to severe pre-eclampsia or
placental insufficiency. Nonetheless, a retrospective study shows that treatment with
LDA and LMWH significantly decreased the risk of HELLP in future pregnancies.84
Taking into account that most of the studies show good pregnancy outcomes with

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heparin initiated in early first trimester of pregnancy, most experts recommend LDA
and LMWH as the standard treatment for these patients.6,34,62
PRIMARY THROMBOPROPHYLAXIS
The risk of thrombosis for asymptomatic aPL carriers is uncertain, although it seems
to be less than 2% and related to traditional vascular risk factors.85,86 According to
retrospective studies, the risk of developing a thrombotic event among SLE patients
with aPL is around 3–4% per year. Likewise, between 1% and 7% of women with
strictly OAPS will develop thrombosis per year.87–90
The protective effect of LDA in patients with SLE with positive aPL, as well as
in patients with OAPS has been shown in several observational studies.30,87,91—94
In contrast, the authors of a prospective randomized trial concluded that LDA is
ineffective in preventing thrombosis in aPL asymptomatic carriers.95 However, the
study included only 98 patients and 6 thrombotic events. Short follow-up, good control
of vascular risk factors and non-reliable patients’ immunological profile are limiting
factors in this study.
Taking into account the low incidence of side effects and recent data suggesting
benefit in women96 , many experts agree that long term LDA should be considered as
primary thromboprophylaxis in OAPS patients63 . Consequently the same approach
should be considered in SLE patients with aPL antibodies, in combination with
antimalarial agents, such as hydroxychloroquine (HCQ).
Regarding asymptomatic aPL carriers prophylactic treatment should be individually
tailored. Treatment of patients with LA and/or positivity of different aPL is
recommended, as these patients are at highest risk of developing a thrombotic
event.90,97–101
Classic vascular risk factors, such as smoking, hypertension, hyper-
cholesterolaemia, diabetes mellitus, Body Mass Index > 30, should be conscientiously
controlled in all patients with aPL. Oestrogen containing oral contraceptives or
hormone replacement therapy should be avoided in these patients.102
According to two recent prospective studies85,86 primary thromboprophylaxis (with
heparin) in patients with aPL should be limited to high-risk situations, such as surgery,
immobilisation and the puerperium.
SECONDARY THROMBOPROPHYLAXIS
Even though inflammation plays an important role in APS, the current treatment for
APS patients with a previous thrombotic event is long-term anticoagulation rather
than immunosuppression.
In the case of first venous thrombosis, secondary thromboprophylaxis with oral
Vitamin K antagonists (VKA), to a target INR of 2.0–3.0 is indicated. According to

9. Obstetric antiphospholipid syndrome - a review 273
expert recommendations, patients with APS and arterial thrombosis should receive
either VKA targeting an INR >3.0, or standard anticoagulation (INR 2.0–3.0) combined
with antiplatelet agents. With regards to the treatment of recurrent thrombotic events
there is a lack of consensus21 , although intensification of treatment, use of LMWH,
HCQ and/or statins are suggested.101
Although pregnant APS patients with a previous thrombotic event (thrombotic
APS) have not been included in most of the studies, LDA and therapeutic dose heparin
(preferably LMWH) throughout pregnancy is recommended.62
Oral VKA should be avoided between the 6th and 10th week of gestation
due to the risk of fetal malformations during organogenesis, hence women who
receive this treatment should switch to heparin (preferably LMWH) as soon as
pregnancy is confirmed. The use of VKA during pregnancy from 10–12 weeks of
gestation should be restricted to special situations (e.g. mechanic heart valve, heparin
allergy/intolerance).103,104 Table 4 summarises treatment recommendations (Table 4)
PREGNANCY COUNSELLING AND CONTRAINDICATIONS
Preconception counselling represents the ideal scenario where patient’s previous
history can be summarised and important issues regarding a planned pregnancy, such
as risks, visits and treatment highlighted.
Patients with a suspicious obstetric history, such as RM, fetal death, pre-eclampsia,
eclampsia, HELLP, prematurity or FGR, previous thrombosis, or previously diagnosed
SLE, should be tested for aPL. Patients with a previous diagnosis of APS should be
retested for aPL prior to pregnancy.105
All patients should be encouraged to stop smoking and to reduce/cease their alcohol
intake. In certain circumstances it might be indicated to assess a haemoglobinopathy
profile.
Patients with severe pulmonary hypertension should be advised against pregnancy,
because of the high risk of deterioration of such and the risk of maternal death. Patients
with a recent thrombotic event in the last 6 months, especially arterial events, or
uncontrolled hypertension should be encouraged to postpone further pregnancies.106
Ideally, prior to conception, or early in pregnancy, all women should be assessed
regarding risk factors for venous thromboembolism. (Table 3). Recently, the British
Royal College of Obstetricians and Gynaecologists (RCOG) has published an updated
guideline for thromboprophylaxis assessment and management during pregnancy and
postpartum for the general population (Figure 2).107
GENERAL MANAGEMENT
LDA and heparin treatment have improved the live birth rate and reduced the risk
of obstetric complications; however, these pregnancies still remain at high risk.

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K Schreiber et al.
Figure 2 Obstetric thromboprophylaxis risk assessment and management.

11. Obstetric antiphospholipid syndrome - a review 275
Table 3 Risk factors for venous thromboembolism in pregnancy
Timeframe Factors
Pre-existing Previous venous thromboembolism
Thrombophilia:
Heritable:
Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Factor V Leiden
Prothrombin gene G20210A
Acquired (antiphospholipid syndrome):
Persistent lupus anticoagulant
Persistent moderate/high-titre anticardiolipin antibodies or β2 glycoprotein
1 antibodies
Medical comorbidities (e.g. heart or lung disease, SLE, cancer, inflammatory
conditions (inflammatory bowel disease or inflammatory polyarthropathy),
nephrotic syndrome (proteinuria > 3 g/day), sickle cell disease,36 intravenous
drug user
Age > 35 years
Obesity (BMI > 30 kg/m2 ) either prepregnancy or in early pregnancy
Parity ≥ 3
Smoking
Gross varicose veins (symptomatic or above knee or with associated phlebitis,
oedema/skin changes)
Paraplegia
Obstetric Multiple pregnancy, assisted reproductive therapy
Pre-eclampsia
Caesarean section
Prolonged labour, mid-cavity rotational operative delivery
PPH (> 1 litre) requiring transfusion
New-onset transient Surgical procedure in pregnancy or puerperium (e.g. ERPC, appendicectomy,
postpartum sterilisation)
Potentially reversiblea Hyperemesis, dehydration
Ovarian hyperstimulation syndrome
Admission or immobility (≥ 3 days’ bed rest) e.g. symphysis pubis dysfunction
restricting mobility
Systemic infection (requiring antibiotics or admission to hospital) e.g. pneumonia,
pyelonephritis, postpartum wound infection
Long-distance travel (> 4 hours)
BMI = body mass index; ERPC = evacuated PPH = postpartum haemorrhage; evacuation of retained
products of conception; SLE = systemic lupus erythematosus
a
May develop at later stages in gestation than the initial risk assessment or may resolve and therefore
continuing individual risk assessment is important
Hence, APS pregnant women need close antenatal surveillance and should generally
be monitored in a multidisciplinary set-up with experience in the management of this
condition. Early recognition of signs related to APS’ complications (either thrombotic
and/or obstetric) is essential to improve both maternal and fetal-neonatal outcomes.

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Table 4 Summary of treatment recommendations
Scenario Treatment
• Women with aPL but no clinical features of • Pregnancy: LDA
APS, or women with aPL and recurrent early • Puerperium: prophylactic LMWH for 7 days.
miscarriages (RM) (<3)
• Patients with ≥ 3 consecutive RM (< 10 • Pregnancy: LDA +/- prophylactic LMWH (if so,
weeks) but no thrombotic events stop at 20w if uterine artery Doppler normal)
• Puerperium: prophylactic LMWH for 7 days.
• Women with adverse obstetric outcomes • Pregnancy: LDA + prophylactic LMWH
(late pregnancy losses, early onset • Puerperium: prophylactic LMWH for 7 days.
pre-eclampsia, HELLP, previous FGR, preterm
delivery) and no thrombotic event
• Women with thrombotic APS and treated with • Pregnancy: LDA + therapeutic LMWH
long-term VKA • Puerperium: switch to VKA
• Women with APS and acute thrombotic event • Pregnancy: LDA + high therapeutic LMWH
during pregnancy • Puerperium: switch to VKA
Standard of care includes early contact with a midwife and with the medical
and obstetric team who will monitor the patient throughout pregnancy and the
puerperium. The frequency of antenatal visits should be dependent on the past history
and the progress of the current pregnancy; consequently complicated medical or
obstetric background will imply more frequent visits. As a guide, from 16 weeks to 32
weeks of gestation women should usually be reviewed every 4 weeks, and fortnightly
from 32–36 weeks of gestation. Every visit should include maternal assessment, with
special attention to proteinuria, maternal hypertension and other features of pre-
eclampsia, as well as obstetric ultrasound assessment, in order to rule out impairment
of fetal growth/development and/or other signs of placental insufficiency.
Uterine and umbilical artery Doppler scans after 20 weeks of gestation are standard
of care in these patients, due to their high negative predictive value and their
ability to assess the risk of poor obstetric outcome (pre-eclampsia, FGR and placental
insufficiency)108 . If the uterine artery Doppler around the 20th week of gestation is
abnormal, it should be confirmed around the 24th week, and subsequent umbilical
artery Doppler should be carried out with each growth scan.
POSTPARTUM
As mentioned above, all women with aPL should receive thromboprophylaxis during
the postpartum period62,63 , although its duration is still an area of controversy. The
British RCOG suggest in their recent guidelines prophylactic LMWH for 7 days for aPL
healthy carriers as well as for OAPS patients, in the absence of other risk factors.107
Previous American guidelines recommend prolonging prophylactic treatment for 4–8
weeks after delivery.62

13. Obstetric antiphospholipid syndrome - a review 277
Women with previous thrombosis should receive long-term anticoagulation, and
should be switched to VKA when the risk of haemorrhages is low (usually 5–7 days
after delivery). VKA and heparin are safe in breastfeeding.103 Additional obstetric
thromboprophylaxis risk assessment postpartum is implicit (Figure 2).
‘REFRACTORY’ OAPS
The best approach to OAPS patients who have failed to have a successful pregnancy on
LDA and heparin (‘refractory OAPS’) is still uncertain. Although further assessment is
needed, recent data suggest that the additional treatment with low dose prednisolone
during the first trimester109,110 and/or with HCQ111 might be beneficial. Additional
treatment with high doses of steroids increases the risk of maternal morbidity (e.g.
diabetes, hypertension, infections, preterm delivery) without any further benefit to
pregnancy outcomes.112
The role of anti-TNF-␣ drugs in these cases is still not known. Recent data from an
APS murine model have indicated the key importance of TNF-␣ in fetal loss, together
with complement activation.113 Safety-wise, a recent systematic review suggests that
some anti-TNF-␣ are safe in pregnancy114 although it remains as a class B drug in FDA
classification. IVIG was proposed as a possible rescue treatment by some authors, but
data from 3 trials have shown no benefit in obstetric or fetal-neonatal outcomes.115–117
OTHER IMPORTANT ISSUES
Women receiving therapeutic doses of LMWH should discontinue it or swap
to prophylactic doses 24 hours prior to the planned delivery. Women on
prophylactic doses of LMWH should not continue LMWH once labour is established.
Reestablishment of LMWH should be postponed until the placenta is delivered.
Epidural anaesthesia can be safely used 24 hours after the last dose of LMWH
(therapeutic dose), or 12 hours after the last dose of LMWH in prophylactic doses.
LMWH can be restarted 2 hours after the epidural catheter has been removed.118,119
LDA should be continued throughout pregnancy. There is no evidence to
discontinue LDA treatment before labour or due to planned epidural anaesthesia,
as LDA does not significantly increase the risk for spinal haematoma. However, many
anaesthesiologists would recommend withdrawal of LDA 3–7 days prior to labour.118
Albeit data are scarce, 1st and 2nd trimesters of pregnancy and lactation are
considered as high bone resorption periods and hence calcium demands are
increased.120,121 Nevertheless, clinically significant bone mass loss is infrequent, and
usually related to classical risk factors such as genetic background, smoking, lack of
regular exercise, BMI<19, low calcium diet and/or vitamin D deficiency.
The association between bone mass loss during pregnancy and LMWH is
uncertain, and no controlled trials have addressed this question yet. The incidence of
unfractionated heparin induced osteoporosis in pregnancy is around 2.2–5%.122,123
However, a recent systematic review suggests that LMWH does not have a

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negative impact on bone mineral density compared to physiological pregnancy bone
resorption.124 Surprisingly, LMWH-induced osteoporosis has only been evaluated in
pregnancy, which hampers the comparison to non-pregnant situations.
Taking into account the beneficial effects of LMWH in APS patients, its use
in APS is more than justified when indicated. Concomitant prophylactic calcium
supplements (with or without Vitamin D) in order to prevent LMWH’s theoretical
osteoporotic effect is a logical and generalized practice.
Bearing in mind that a recent meta-analysis of 13 randomized trials comparing the
intake of at least 1g of calcium daily versus placebo during pregnancy showed a >50%
reduction in the risk of preeclampsia and a 25% reduction in the risk of preterm
delivery, calcium supplementation becomes a cornerstone of management in these
patients.
FUTURE PERSPECTIVE AND FUTURE THERAPIES
Since the first description of the disease extensive interest and research has improved
the basic understanding, diagnosis and treatment of patients with APS. Future
research needs to focus on the investigation of new therapies, the re-definition of
the classification criteria, novel pregnancy outcome markers or research in patients
currently labeled as seronegative APS.
New therapeutic agents for the treatment of APS are widely discussed. As
previously discussed antiplatelet agents, mostly aspirin, different heparin types or
coumadin derivates are used for the treatment of obstetric complications or as
secondary thromboprophylaxis. Other anti-aggregation agents such as dipyridamole
or clopidogrel in combination with aspirin are widely used in patients suffering artrial
fibrillation or stroke. The combination of these agents has been shown to be more
efficient than mono-therapeutic aspirin in selected patient groups126–127 , and could be
an alternative for patients with contraindications for VKA. Though, at present, there
is only limited evidence for the use of antiplatelet agents other than aspirin in patients
suffering APS.
Novel agents such as rivaroxaban or dabigatran are currently licensed for primary
thromboprophylaxis. Dabigatran, an oral direct thrombin inhibitor, administered
at a dose of 150 mg has been shown to be more effective than warfarin in the
prevention of stroke and systemic thrombotic events, while the incidence rate of
major haemorrhages was similar. The study was conducted on patients with atrial
fibrillation.128 Its efficacy in the secondary prevention of thromboembolism is similar
to warfarin when administered at a dose 150 mg twice daily.129 These drugs display an
enormous advantage compared to warfarin treatment, not only regarding warfarin’s
slow onset of action, its very narrow therapeutic window and its numerous dietary and
drug interactions, but also its socio-economic impact and/or resource implications.
However, due to insufficient experience this new generation of anticoagulants will
not be licensed for the use in pregnancy and/or lactation immediately.

15. Obstetric antiphospholipid syndrome - a review 279
Of particular interest is the antimalarial agent HCQ, which has been used in SLE
for many years. HCQ displays a broad spectrum of beneficial effects and is hence
considered as a cornerstone in the treatment of SLE. Given its safety profile, HCQ
is given to most SLE patients and should be continued during pregnancy.130 Studies
suggest a positive effect of HCQ in APS.91,131 However, randomised clinical trials are
needed to confirm this benefit.
The anti-inflammatory effect of statins, is the logical reasoning why these
agents are discussed as adjuvant treatment. Fluvastatin for example has anti-
thrombogenic and anti-inflammatory properties132 and has recently been shown
to reduce vascular endothelial growth factor, serum tissue factor and TNF-␣
significantly.133 Additionally, different types of statins have been shown to have
positive effects on serum activity of markers involved in pre-eclampsia in a murine
model134,135 . The current StAmp trial will hopefully prove the role of statins during
pregnancy and determine effects on pregnancy outcomes.
Rituximab is a monoclonal antibody targeting CD-20 positive B-lymphocytes.
Speculations about the role of Rituximab in APS is a consequence of the fact that
B-cells are involved in the pathogenesis of the syndrome136,137 . The RITAPS study is
underway to elucidate the drug’s safety and effectiveness in persistently aPL positive
patients. Other agents, such as anti-TNF-␣ therapy, have been suggested, as it has
been hypothesised that TNF-alpha plays a role in the pathophysiology of APS induced
thromboses.138 However, a possible clinical usefulness has still to be proved and as
far as safety is concerned, the lack of experience in the use of biological agents during
pregnancy is a major limiting factor.139
In parallel with current research that focuses on the achievement of a better
mechanistic understanding regarding the patho-mechanism of APS, future therapies
might be targeted on anti-inflammatory and/or immunomodulatory aspects. This
might amongst others include targets such as the complement system, tissue factor
activation or the inhibition of specific platelet glycoproteins.140
ACKNOWLEDGEMENT
Karen Schreiber has been supported by ESF BIOLUPUS - European Science
Foundation.
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