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Thrombosis Research 181S1 (2019) S41–S46

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Thrombosis Research
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Review Article

Managing antiphospholipid syndrome in pregnancy

Karen Schreibera,b, Beverley J. Hunta,*
a
The Thrombosis & Haemophilia Centre, Guy’s & St Thomas’ NHS Foundation Trust, London SE1 7EH, UK
b
Copenhagen Lupus and Vasculitis Clinic, Center for Rheumatology and Spine Diseases, Copenhagen, Denmark

ARTICLE INFO ABSTRACT

Keywords: Antiphospholipid syndrome (APS) is an autoimmune disease characterised by the presence of antiphospholipid
Antiphospholipid syndrome antibodies (aPL). The antibodies currently included in the classification criteria include lupus anticoagulant
Antiphospholipid antibodies (LA), anticardiolipin antibodies (aCL) and anti-β2-glycoprotein 1 antibodies (β2GPI). APS can present with a
Aps
variety of clinical phenotypes, including thrombosis in the veins, arteries and microvasculature and obstetrical
Lupus anticoagulant
Anticardiolipin antibodies
complications. Pregnancy complications in obstetric APS (OAPS) include unexplained recurrent early pregnancy
Anti-beta2-glycoprotein 1 antibodies loss, fetal death, or premature birth due to severe preeclampsia, eclampsia, intrauterine growth restriction or
Obstetric morbidity other consequences of placental insufficiency. Careful, well monitored obstetric care with the use of aspirin
and heparin has likely improved the pregnancy outcome in obstetric APS and currently approximately 70–80%
of pregnant women with APS have a successful pregnancy outcome. However, the current standard of care
does not prevent all pregnancy complications as the current treatment fails in 20–30% of APS pregnancies.
Other treatments options are currently being explored and retrospective studies suggest that trials with
hydroxychloroquine and possibly pravastatin are warranted in pregnant women with aPL. In this review will
focus on the current treatment of OAPS.

1. Introduction birth due to intrauterine growth restriction (IUGR) preeclampsia

Antiphospholipid syndrome (APS) is an autoimmune disease charac-
terised by the presence of antiphospholipid antibodies (aPL), such as
lupus anticoagulant (LA), anticardiolipin antibodies (aCL) and anti-
β2-glycoprotein 1 antibodies (β2GPI) [1]. Patients can test positive for
one, two or all three autoantibody subtypes. It is important that all
antibodies are assessed in each patient. The number of positive antibody
tests are consequently referred to as ‘single’, ‘double’ or ‘triple positive’.
The classification criteria for APS, which often also guide diagnosis,
were originally outlined in the Sapporo criteria and were updated in
2006 and are now referred to as the Sydney criteria [1,2].
The association of circulating LA and aCL, thrombosis, pregnancy
loss and thrombocytopenia was initially described in women suffering
from systemic lupus erythematosus (SLE) [3]. Patients with SLE has
been referred to as ‘secondary’, but it is now widely accepted that
APS is an autoimmune entity of its own [4] and the term secondary
is discouraged.
The presence of aPL is a major acquired thrombophilia and pre-
disposes to venous thrombosis, arterial thrombosis and microvascular
thrombosis.
A hallmark of APS is pregnancy complications, which include
unexplained recurrent early pregnancy loss, fetal death or premature
toxaemia (PET), eclampsia or other consequences of placental
insufficiency [1,5]. aPL is a common cause of recurrent first trimester
loss [6]; data from a retrospective single centre cohort of 500 women
with a history of recurrent first trimester pregnancy loss suggested
that 26.4% are associated with the presence of aPL [6]. aPL is not an
uncommon cause of severe PET and stillbirth, accounting for 12% of
women with severe PET [7] and in 11% of women with stillbirth [7].
The current standard of preventative treatment for APS relies on
anticoagulation and antiplatelet treatment [8]. The combination of
heparin (unfractionated heparin (UF) or low molecular weight heparin
(LMWH)) and low-dose aspirin (LDA) has resulted in a live birth rate
of 70–80% [9] but some trials have shown no improvements in live
birth rates with LMWH.
More recent data suggest a role for novel drugs including the
antimalarial hydroxychloroquine [10,11] and pravastatin [12], and
prospective randomised controlled trials are therefore needed to
confirm this observation [13]. Lefkou et al. highlighted a potential
beneficial role of pravastatin in a retrospective single centre case
control study on women with aPL-related PET and/or IUGR receiving
standard of care treatment including LDA and LMWH [12]. Moreover,
the antimalarial hydroxychloroquine (HCQ) is currently the centre
of attention in both obstetric and thrombotic APS, and the European

* Corresponding author at: The Thrombosis & Haemophilia Centre, Guy’s & St Thomas’ NHS Foundation Trust, London, UK.
E-mail address: Beverley.hunt@gstt.nhs.uk (B.J. Hunt).

Received 11 April 2019; Received in revised form 31 May 2019; Accepted 3 June 2019
This article is published as part of a supplement sponsored by the International Symposium on Women’s Health Issues in Thrombosis and Haemostasis and Sanofi
0049-3848/ © 2019 Published by Elsevier Ltd.
K. Schreiber and B.J. Hunt
Medicines Agency (EMA) has licenced HCQ for the treatment of APS
[14]. Retrospective data suggest that HCQ reduces the risk of thrombosis
in APS [15]. In obstetric APS the use of HCQ has been associated with
improved pregnancy outcomes in women with aPL-related pregnancy
complications in two flawed retrospective studies [10,11]. Owing to
its favourable safety profile, HCQ is now internationally recommended
for pregnant women requiring immune-modulation for systemic lupus
erythematosus during pregnancy [16–18]. However, there remains an
urgent need for randomised controlled trials assessing the role of HCQ
in women with aPL and results of HYPATIA, an ongoing randomised
controlled trial in pregnancy, are eagerly awaited [13,19].
2. Pathogenesis
2.1. Thrombosis
aPL have the unique ability to induce thrombus formation in the
arterial and/or venous vasculature and/or the microcirculation [20–
23], but the exact mechanism by which aPL lead to thrombosis remains
as yet fully explained. aPL have the potential to activate several cell
types involved in haemostasis including endothelial cells, platelets
and immune cells such as monocytes [23,24]. Other experiments have
shown that some aPL inhibit fibrinolysis and the protein C pathway
[25].
2.2. Pregnancy complications
The pathogenesis of aPL-related recurrent first trimester pregnancy
loss is different from the pathogenesis of morbidity occurring in late
pregnancy [23,26]. First trimester pregnancy loss has been related
to a direct inhibitory effect of aPL on growth [27], placentation
and apoptosis of trophoblast cells [27,28], but the late obstetrical
manifestations including PET, IUGR and stillbirths have been related
to placental dysfunction due to thrombotic and inflammatory changes
[23,29]. The potential underlying causes of these outcomes include as
in preeclampsia failure of the extravillous spiral arteries development,
leading to a reduced maternal blood flow to the placenta and hypoxic
injury, inadequate delivery of nutrients to the fetus, and high-velocity
and high-pressure blood flow that can damage the placenta [23,29].
The complement system has been shown to play a key role in aPL-
related pregnancy morbidity in murine models. In a pregnant murine
model based on BALB/c mice and FcRy mice, mice infused with aPL
had increased fetal losses and exhibited intrauterine fetal growth
restriction. Mice with complement deficiency or complement blockage
showed protection against aPL-induced pregnancy complications, as
did treatment with heparins (which have an anticomplement effect) as
opposed to fondaparinux which has no anticomplement effect [30,31].
Increased complement deposition was observed in the decidua of
pregnant mice infused with aPL, whereas mice depleted of neutrophils
or mice treated with heparin did not show pregnancy loss or growth
restriction and there was no complement deposition in their decidual
tissue [31]. There are little data on the role of complement in humans
except for a study by Shamonki et al., who showed that placentae of
women with aPL have increased complement deposition [32]. It is a
widely accepted hypothesis that aPL cause placental thrombosis and
activation of complement also occurs probably through the classical
pathway [33].
3. Clinical manifestations
3.1. Thrombotic APS
APS is a unique thrombophilia in that it can cause thrombosis in
any vascular bed [1]. The most frequent arterial manifestations are
neurological manifestations such as stroke or transient ischaemic
attacks (TIA), whereas the most common venous thromboembolic mani-
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festation include deep vein thrombosis (DVT) and pulmonary embolism
(PE) [23,34].
Other manifestations including retinal artery or vein thrombosis,
amaurosis fugax, renal thrombotic microangiopathy, pulmonary hyper-
tension and vascular dementia are less frequent (<10% of patients).
Manifestations such as adrenal thrombosis, avascular necrosis,
pathological bone fractures due to bony infarcts or Budd-Chiari
Syndrome are less common (seen in 1%) [34]. Livedo reticularis,
the most common skin manifestation, is sometimes associated with
occlusive arterial events in the brain (known as Sneddon’s syndrome)
[34,35].
The most serious clinical manifestation is rare and is referred to as
catastrophic APS (CAPS). CAPS is classified by thrombosis in at least
three organs often accompanied by small vessel thrombosis developing
over a short period and is associated with a mortality of over 50%
[36,37].
3.2. Other manifestations of APS
Nonthrombotic APS manifestations can include thrombocytopenia,
which is usually associated with a risk of thrombosis rather than
bleeding complications and cardiac valve abnormalities (minor
thickening and/or incompetence due to valve thrombosis). Pregnancy
is a prothrombotic state and thus, for those with previous thromboses,
thromboprophylaxis is important to prevent recurrent thrombosis. One
of the most surprising features of APS is that thrombosis tends to recur
in the same vascular bed as the original thrombosis, in other words
those with previous stroke have a high risk of recurrent stroke, and
those with previous deep vein thromboses (DVT) have an increased
risk of recurrent DVT.
3.3. Obstetric APS
3.3.1. Recurrent early miscarriages
In Europe, the most widely used definition for early miscarriage is
pregnancy loss within the first 12 completed weeks after conception.
Up to 15% of all clinically recognized pregnancies end in this way
[38]. There are many causes for early miscarriage and recurrent
miscarriages, and they include genetic abnormalities, anatomic
variations, endocrine or immune factors (including thyroid disease),
infections (most commonly caused by ‘TORCH’, i.e. toxoplasmosis,
other, rubella, cytomegalovirus, herpes simplex virus) and aPL [39].
In fact, aPL are known to be the commonest treatable cause of recur-
rent early miscarriages. In a cohort of 500 women with a history of
recurrent miscarriages Rai et al. found 9.6% of women to be persistently
positive for LA, whereas aCL IgG and IgM were found in 3.3% and 2.2%,
respectively [40]. The prevention of recurrent early miscarriages is the
only area in obstetric APS in which treatment is based on several clinical
trials, including randomised controlled trials [23].
3.3.2. Late pregnancy loss
Late pregnancy loss or fetal death is defined as pregnancy loss
after 10 weeks of gestation, whereas stillbirth indicates a loss after
20 weeks by some although the definition recommended by WHO for
international comparison, and used by our unit, is a baby born with no
signs of life at or after 28 weeks gestation. The only population-based
study (the stillbirth collaborative research network) reported the
association of aPL (aCL and anti-β2GPI) with a significant increased
odds of stillbirth (three- to fivefold) in 582 cases of fetal death beyond
20 weeks of gestation. However, the group did not measure LAC, and
aCL were not reassessed after 12 weeks interval to confirm persistency
of the aPL [41].
3.3.3. Placental insufficiency and preeclampsia toxaemia (PET)
Placental insufficiency is the failure of the placental to deliver
sufficient nutrients to the growing fetus. Placental insufficiency can
K. Schreiber and B.J. Hunt
manifest as fetal growth restriction (FGR) and/or PET and/or placental
abruption. FGR occurs in about 2–8% of mainly first pregnancies,
whilst severe PET is found in 0.5% of pregnancies in developed
countries.
Most prospective observational studies support the association of
aPL with PET and placental insufficiency. A recent systematic meta-
analysis showed that moderate to high levels aCL are associated
with PET [42]. Moreover, several prospective and retrospective
studies have shown that the persistent presence of high-titre aPL are
associated with FGR and preterm deliveries [34,43,44]. Data from
case–control studies have shown that amongst patients with a history
of PET or FGR, aPL were found in up to 50%, compared with 7%
or less in healthy pregnant women [43]. There is to date only one
randomised controlled trial assessing the management and prevention
of PET and FGR in women with aPL. The aim of the multicentre study
(FRUIT-RCT) was to examine if combined treatment with LMWH and
aspirin reduces recurrent hypertensive disorders (HD) of pregnancy
(HD: preeclampsia, eclampsia or HELLP syndrome) in women with
aPL with a previous delivery for HD and/or small-for-gestational-age
(SGA) birth weight before 34 weeks gestation [45]. Unfortunately,
the study was terminated due to very low event rates and the final
analysis on 33 (recruitment target was 85 women to detect a 50% risk
reduction) women did not show any significant difference between
aspirin alone or aspirin in combination with LMWH [45].
A recent meta-analysis comparing LMWH versus no LMWH for the
prevention of recurrent placenta-mediated pregnancy complications
in 848 pregnant women with a previous history of placental-mediated
pregnancy complications (with and without aPL) did not show a
benefit for LMWH [46].
Very recently, results from a multicentre randomised controlled
trial on 150 mg aspirin once daily versus placebo conducted in 1776
pregnant women at high risk for preterm preeclampsia without aPL
has shown to reduce the risk of preterm preeclampsia before week
34 of gestation significantly (1.6% versus 4.3%, odds ratio (OR) 0.38,
95% confidence interval (CI) 0.20–0.74; p=0.004) [47].
4. Management in pregnancy
4.1. Preconception counselling
We aim for all women with known aPL and APS to have pre-
pregnancy counselling with their partner to discuss their future
management in pregnancy management and define their specific risks.
This is in line with the current European League against Rheumatism
(EULAR) recommendations for the management of family planning,
assisted reproduction, pregnancy and menopause in patients with
systemic lupus erythematosus and/or antiphospholipid syndrome
[18]. After the visit, the meeting is summarized in a letter sent to
them and their general practitioner. As the risks of pregnancy in an
individual woman are dependent on previous obstetric and thrombotic
history this results in highly diverse advice. For example, if a woman
has had heathy live births at term in the past in the presence of
persisting aPL then she can be reassured that the outcome of any future
pregnancy would be excellent and requires no extra fetal monitoring.
Conversely, a woman with a history of recurrent stroke running an
INR of 3–4 and who already has had HELLP syndrome at 24 weeks
with a 24-week birth resulting in a baby with long-term problems due
to prematurity, despite the use of aspirin and LMWH is very high risk
in future pregnancies, with 5% risks of recurrent stroke and also a high
likelihood of a further HELLP syndrome in the next pregnancy without
further treatment, which would be experimental.
All women should be encouraged to stop smoking and to reduce/
cease their alcohol intake according to the national pregnancy
guidelines. Patients with a recent thrombotic event in the last 3 months,
particularly arterial, and/or uncontrolled hypertension should be
encouraged to postpone further pregnancies [33,48]. Patients with
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severe pulmonary hypertension should be advised against pregnancy,
because of the high risk of deterioration of such and the high risk of
maternal death, as high as 43% [33,48,49].
A complete history and aPL profile should be available before
conception in order to aid risk stratification. Moreover, the three
different clinical phenotype of APS patients (such as those with
recurrent early pregnancy loss, those with previous ischemic placental
complications and those with previous maternal thromboses) are
associated with differing pregnancy outcomes. In a series of 83
pregnancies in 67 women, Bramham et al. showed that women with a
previous history of thrombosis had less favourable neonatal outcomes,
with higher rates of preterm delivery (26.8% versus 4.7%, p=0.05)
and babies of small gestational size (9.5% versus 4.8%, p=0.003)
compared with those with a previous history of recurrent pregnancy
loss before 10 weeks of gestation [50]. Limited data are available
assessing pregnancy performance in women with a history of stroke. In
one prospectively studied cohort of 23 pregnancies in 20 women with
APS and previous stroke and/or TIA, eight patients developed pre-
eclampsia and three patients had a recurrent stroke despite treatment
with LDA and LMWH [51].
The other goal of a preconceptual visit is to rationalise medication
to ensure all drugs are safe to use during pregnancy; ensure that 400ug
of folic acid is taken, and supply LMWH and aspirin to those women
who require it during pregnancy and provide instruction as how to
self-administer subcutaneous injections, and advice on stopping
warfarin as soon as the pregnancy test is positive. Those with anti-
Ro antibodies can be started on hydroxychloroquine preconceptually
aiming to reduce the risk of complete heart block.
4.2. Antenatal care
The specific objective of antenatal care is close observation for
maternal thrombosis especially renal thrombotic microangiopathy
manifestations, prevention of miscarriage in those with a previous
history, and monitoring of features of preeclampsia and fetal growth.
Overall, there is agreement that pregnant women with obstetric APS
require close education and monitoring of maternal and fetal health by
a multidisciplinary team consisting of obstetricians, rheumatologists
and haematologists with special interest in APS [18,52].
We encourage obstetricians and mothers that all women with APS
who are progressing well in pregnancy should be encouraged to have
a vaginal delivery, which gives a lower risk of postpartum thrombosis
and is better for the baby, unless there are obstetric reasons that
suggest otherwise.
Poor flow on uterine arteries Doppler velocimetry is an indirect
indicator for the development of placental insufficiency and/or
preeclampsia [53]. In APS, normal uterine artery results between
20–24 weeks especially have a high negative predictive value of
poor fetal outcome [54]. Those pregnant women with APS who have
bilateral abnormal UAD between 20–24 weeks should be offered
regular obstetric ultrasonography to assess fetal growth, amniotic
fluid volume and, if necessary, assess end-diastolic umbilical artery
blood flow. In 33 women with APS, the positive predictive value
of abnormal uterine artery Doppler for later intrauterine growth
restriction or preeclampsia was 67% with a negative predictive value
of 93% [55]. Another prospective study of 100 pregnancies confirmed
that second trimester Doppler ultrasonography is the best predictor for
late pregnancy outcome in systemic lupus erythematosus and/or APS
[54]. EULAR has now included recommendations on the use of uterine
artery Dopplers into their guideline [18].
4.3. Preventing recurrent thrombosis
The current mainstay of treatment for the thrombotic manifestations
of APS outside of pregnancy is based on anticoagulation, including
vitamin K antagonist (VKA), or heparin and antiplatelet therapy, such
K. Schreiber and B.J. Hunt
as low-dose aspirin. Preliminary data supporting the use of direct
oral anticoagulant (DOAC) in APS patients with previous venous
thromboembolism is available, but there are now many reports of
high rates of recurrent thrombosis with the use of DOACs in APS and
so their use is discouraged. Very rarely immune-modulating agents,
immunosuppression and anticomplement therapy are used in patients
who do not respond to antithrombotic medication or in particularly
severe conditions such as CAPS, but there is little evidence they have
any efficacy.
Within pregnancy there is reliance on aspirin and LMWH. LMWH
does not cross the placenta unlike vitamin K antagonists and the DOACs.
Mothers with a previous history of thrombosis require intermediate
or full-dose anticoagulation usually with LMWH during pregnancy to
prevent further thrombotic events. Our antithrombotic regime tends
to vary considerably, reflecting the mother’s prior thrombotic history.
As a general rule we use higher dose LMWH in those with previous
arterial events, whereas if a mother has only had a previous provoked
calf DVT then we would only use a thromboprophylactic dose of
LMWH with aspirin. They can be switched back to warfarin soon after
delivery if thrombotic risk is high or stay on LMWH as it is often more
convenient in this busy time for a mother. Both VKA and heparins are
compatible with breastfeeding [16,17].
Of ongoing concern in aPL and APS pregnancies is that a
thrombotic renal microangiopathy may develop. This much feared
event is rare and usually occurs insidiously with mild proteinuria
and/or haematuria, perhaps an increased blood pressure and a slowly
increasing creatinine. This can occur despite the use of LMWH and can
be difficult to discriminate clinically from PET, although the rising
creatinine can give it away.
4.4. Preventing obstetric APS
Current standard of care for patients with obstetric APS due to
recurrent first trimester loss includes treatment with LDA (75–100
mg/day) and small doses of LMWH or unfractionated heparin.
These recommendations are based on results from three randomised
controlled trials comparing LDA alone or in combination therapy with
heparin in women with APS [56–58]. Rai et al. showed a significantly
higher rate of live births with LDA plus unfractionated heparin (5000
units BD) versus LDA alone (71% versus 42%; OR 3.37; 95% CI 1.40–
8.10) [56]. Similarly, Kutteh reported a significant improvement
in the live birth rate with LDA and heparin versus LDA alone (80%
versus 44%; p<0.05) [58]. However, no differences in outcome with
combination therapy versus LDA were found in two other randomised
trials, both using LMWH, with live birth rates approaching 80% in
both arms. The heterogeneity in the conclusions seems attributable
to the relatively poor outcomes in women receiving LDA only in the
two former studies [57,59]. Moreover, data from observational studies
have reported 79–100% pregnancy success rates with LDA alone in
this subgroup of women [60]. The current recommendation for the
treatment of obstetric APS is to start with LDA alone and to escalate
to additional LMWH if LDA alone is associated with pregnancy loss.
Data to support this management have recently been published [9,23].
There are retrospective data from Bramham et al. to show that the use
of aspirin and LMWH does improve pregnancy outcome in those with
prior second or third trimester loss [50]. Table 1 outlines treatment
recommendations for women with APS in different clinical settings.
4.5. Postpartum
We advise that all women with previous thrombosis should
continue their anticoagulation postpartum either with LMWH or a
VKA. All women without previous thrombotic APS should be assessed
regarding risk factors for thromboembolism and should receive
thromboprophylaxis postpartum if indicated according to local
guidelines. Lefevre et al. showed that patients with obstetric APS have
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a higher thrombotic risk when compared with healthy women (3.3 vs.
0–0.5/100 patient-years), even if treated with LDA [61]. Similarly,
in a 10-year observational study of 1592 women with pure obstetric
APS and no history of thrombosis, Gris et al. [62] showed that LA was
a risk factor for unprovoked proximal and distal deep and superficial
vein thrombosis, and similar results have been seen in other studies
[63]. The Royal College of Gynaecology in the UK, for example,
recommends aPL-positive women without clinical manifestations of
APS receive 7 days of postpartum thromboprophylaxis and for women
with APS this is extended to 6 weeks [64].
5. Perspectives in obstetric APS
The current treatment regimens to prevent obstetric morbidity in
APS have improved pregnancy outcome to a live birth rate of over
70% as mentioned above [50]. As 30% of women continue to have
pregnancy complications, international groups are currently assessing
different options in order to improve pregnancy outcomes in women
with APS. The additional use of low-dose steroids has been assessed
in refractory obstetric APS with recurrent first trimester loss and may
have some benefits [65]. It is our practice to add prednisolone 10 mg
daily from a positive pregnancy test to week 12 in those who have
failed to maintain a pregnancy with aspirin and LMWH. Intravenous
immunoglobulin (IVIG) has caused no significant improvement in
pregnancy outcomes [66].
Interesting data on pravastatin suggest a beneficial role in those
women with established aPL-related PET. In a case series, 11 patients
were treated with 20 mg pravastatin in addition to standard treatment,
whereas the controls continued LDA and LWMH only. In all patients
exposed to pravastatin, signs of preeclampsia, such as blood pressure
and proteinuria, improved and signs of placental perfusion remained
stable without further deterioration compared with the control group
[12].
The immune-modulator HCQ may have beneficial effects not only
in the management of thrombotic APS [15] but also in the prevention
of pregnancy complications [11,67,68]. In retrospective studies of
pregnant patients with aPL and or APS, we and others showed that
HCQ is a candidate for preventing aPL-related adverse pregnancy
outcomes [10,11].
In more detail, Mekinian et al. reported from a retrospective
multicentre cohort study consisting of 30 APS patients (and 35
pregnancies) that HCQ treatment was associated with fewer first
trimester miscarriages (pregnancy losses decreased from 81% to 19%,
p<0.05) and improved live birth rates in refractory obstetric APS to
78% (p<0.05) [11]. In our retrospective observational cohort study of
96 women with 170 pregnancies, we also showed that HCQ treatment
was associated with a higher live births rate (67% in HCQ treated
vs. 57% in untreated patients, p=0.05) and a lower prevalence of
pregnancy morbidity (47% vs. 63%, p=0.004). Pregnancy duration
was longer in patients receiving HCQ compared with those who did
not receive HCQ (median 27.6 weeks (range 6–40) versus 21.5 weeks
(range 6–40); p=0.03) and fetal losses beyond the 10 weeks of
gestation were less frequent in women who were treated with HCQ
(2% vs. 11%, p=0.05). Moreover, ischaemic placental-mediated
complications (preeclampsia, eclampsia and FGR were less prevalent
in HCQ-treated women than in the control group (2% vs 10.9%,
p=0.05). There was a significantly higher rate of women undergoing
spontaneous vaginal labour in HCQ women compared with women
without HCQ treatment (37.3% vs. 14.3%, p=0.01). The association
of HCQ with the absence of aPL-related complications in pregnancy
was confirmed in multivariate analysis (OR 2.2, 95% CI 1.2–136.1;
p=0.04) [10]. In none of the abovementioned studies were any fetal
abnormalities observed [10,11]. Prospective clinical trials are eagerly
awaited [13]. The European randomised controlled multicentre trial
HYPATIA (Hydroxychloroquine to improve Pregnancy outcome in
women with Antiphospholipid Antibodies) will assess the role of HCQ
K. Schreiber and B.J. Hunt Thrombosis Research 181S1 (2019) S41–S46

Table 1
The treatment recommendations at our local unit at St Thomas’ Hospital.
Clinical presentation Treatment Evidence

Persistent presence of aPL during first pregnancy or
before the first pregnancy without previous adverse
pregnancy outcomes
Persistent positivity for aPL and history of recurrent first
trimester pregnancy loss (without previous thrombosis)
History of miscarriage or previous history of ischaemic
placental mediated- complications
Patients with thrombotic APS (venous or arterial)
Postpartum presence of aPL
Close monitoring of fetus and mother during Data support the use of LDA to prevent PET in high-risk
pregnancy with LDA treatment pregnancies [47], but no studies have been done in APS
LDA with or without prophylactic LMWH or Low-quality randomized controlled trials [56–59]
unfractionated heparin
LDA with prophylactic LMWH or unfractionated Low-quality randomized controlled trials [69]
heparin
LDA and low-dose, intermediate-dose or full-dose LMWH Based on one prospective observational study [50]
LMWH thromboprophylaxis for ≥1 week postpartum, Based on case–control studies and cohort studies [64]
to 6 weeks on an individual basis depending on the
presence of additional risk factors for thrombosis.
Women with thrombotic APS can restart anticoagulation
once haemostasis is achieved. VKA are safe in
breastfeeding; no safety data on DOACs are available
[16,17]

The treatment choice is based on the patients’ clinical phenotype assessed at the preconceptual review when patients are seen for pregnancy counselling. Patients are also
made aware that they require regular follow-up during pregnancy
aPL, antiphospholipid antibodies; APS, antiphospholipid syndrome; DOAC, direct oral anticoagulant; LDA, low-dose aspirin; LMWH, low-molecular-weight heparin, PET,
preeclampsia; VKA, vitamin K antagonists
Adapted from GSTT local treatment protocol and Schreiber et al. [23]

versus placebo in pregnant women with aPL and hopefully provide
more robust evidence on the use of HCQ in this setting [13].
6. Summary
APS is the most frequent acquired risk factor for a treatable cause
of recurrent first trimester pregnancy loss. APL are associated with
increased risk of conditions associated with ischaemic placental
dysfunction, including stillbirth, intrauterine death, preeclampsia,
premature birth, and fetal growth restriction and also thrombosis in
pregnancy. The current standard of care for obstetric APS is based
on aspirin and LMWH. New approaches aiming to improve pregnancy
outcomes include the immune-modulator HCQ.
Conflict of interest statement
None declared.
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