Clinic Rev Allerg Immunol
DOI 10.1007/s12016-016-8571-6
Additional Treatments for High-Risk Obstetric Antiphospholipid
Syndrome: a Comprehensive Review
Amelia Ruffatti 1,2 & Ariela Hoxha 1 & Maria Favaro 1 & Marta Tonello 1 & Anna Colpo 3 &
Umberto Cucchini 4 & Alessandra Banzato 4 & Vittorio Pengo 4
# Springer Science+Business Media New York 2016
Abstract Most investigators currently advocate prophylactic-
dose heparin plus low-dose aspirin as the preferred treatment
of otherwise healthy women with obstetric antiphospholipid
syndrome, whilst women with a history of vascular thrombo-
sis alone or associated with pregnancy morbidity are usually
treated with therapeutic heparin doses in association with low-
dose aspirin in an attempt to prevent both thrombosis and
pregnancy morbidity. However, the protocols outlined above
fail in about 20 % of pregnant women with antiphospholipid
syndrome. Identifying risk factors associated with pregnancy
failure when conventional therapies are utilized is an impor-
tant step in establishing guidelines to manage these high-risk
patients. Some clinical and laboratory risk factors have been
found to be related to maternal–foetal complications in preg-
nant women on conventional therapy. However, the most effi-
cacious treatments to administer to high-risk antiphospholipid
syndrome women in addition to conventional therapy in order
to avoid pregnancy complications are as yet unestablished. This
is a comprehensive review on this topic and an invitation to
participate in a multicentre study in order to identify the best
additional treatments to be used in this subset of antiphospholipid
syndrome patients.
* Amelia Ruffatti
amelia.ruffatti@unipd.it
1
Rheumatology Unit, Department of Medicine, University of Padua,
Padua, Italy
2
Reumatologia, Policlinico Universitario, Via Giustiniani,
2-35128 Padova, Italy
3
Blood Transfusion Unit, University-Hospital of Padua, Padua, Italy
4
Cardiology Unit, Department of Cardio-Thoracic and Vascular
Sciences, University of Padua, Padua, Italy
Keywords Obstetric antiphospholipid syndrome .
Treatment . Risk factor . Additional treatment
Introduction
In 1983, the connection between pregnancy loss and the pres-
ence in the blood of anticardiolipin (aCL) antibodies was
made by Graham Hughes [1]. Since then, recurrent pregnancy
loss has been considered as a clinical manifestation of
antiphospholipid syndrome (APS), and the Sydney update of
the preliminary classification criteria of APS confirmed preg-
nancy morbidity as a valuable clinical criterion for APS clas-
sification [2]. More specifically, APS pregnancy morbidity
includes three types of pregnancy complications: (a) one or
more unexplained deaths of a morphologically normal foetus
at or beyond the 10th week of gestation; or (b) one or more
premature births of a morphologically normal neonate before
the 34th week of gestation because of eclampsia or severe
preeclampsia, or recognized features of placental insufficien-
cy; or (c) three or more unexplained consecutive spontaneous
abortions before the 10th week of gestation, with maternal
anatomic or hormonal abnormalities and paternal and mater-
nal chromosomal causes excluded.
The hypotheses on the pathogenesis of lesions in APS
pregnancy morbidity include the thrombogenic effect of
antiphospholipid antibodies which may cause slow progres-
sive thrombosis and infarction of the placenta. Since
antiphospholipid antibodies are associated with systemic
thrombosis, obstetric complications in patients with
antiphospholipid antibodies were first attributed to thrombosis
and infarction at the maternal–foetal interface; indeed, early
reports of placenta from women with the lupus anticoagulant
(LAC) exhibited ischemic infarcts [3]. However, large-scale
histological studies have then revealed that neither thrombosis

nor infarction is so common in the placenta of patients with
APS [3]. Non-thrombotic mechanisms can be identified on
both the maternal and foetal sides, causing the functional im-
pairment of decidua and trophoblast cells, respectively. In fact,
defective placentation may be mediated by the inhibition of
endometrial angiogenesis and by the reduction of trophoblast
differentiation/invasiveness [4]. Furthermore, treatment of tro-
phoblast with antiphospholipid antibodies decreases the ex-
pression of matrix metalloproteinases and increases the ex-
pression of inhibitors of metalloproteinases [4]. Combined,
these changes are likely to contribute to the decreased inva-
sion observed in trophoblasts treated with antiphospholipid
antibodies. Moreover, it was found that complement-
mediated placental inflammation plays a key role in an exper-
imental model of foetal loss [5]. There is strong evidence from
murine models of APS that complement plays a crucial role in
mediating foetal demise in murine antiphospholipid antibody-
affected pregnancies. The complement proteins C3 and C5
have been reported to be crucial for mediating antiphospholipid
antibody-induced thrombosis in mice. Placenta from women
with APS exhibit increased deposition of C4d and C3b, which
supports the hypothesis that complement activation may be
involved in the pathogenesis of pregnancy complications in
women with antiphospholipid antibodies [5]. However, there
are considerable differences in the control of the complement
system at the maternal–foetal interface between mice and wom-
en, and additional human studies are required before a defini-
tive conclusion regarding the role of complement in obstetric
APS can be made [6].
On the basis of these pathogenetic hypotheses, heparin and
aspirin combination constitutes the most frequently applied
treatment protocol in pregnant APS women. What is the ra-
tionale for the use of these drugs? According to the sugges-
tions in the literature, heparin, in addition to a direct effect on
the coagulation cascade, might protect pregnancy by reducing
the binding of antiphospholipid antibodies to trophoblast, re-
ducing inflammation, facilitating implantation and inhibiting
complement activation [7]. Low-dose aspirin induces throm-
boxane reduction not only at the platelet level but also at the
placental level. In vitro, aspirin suppresses the thromboxane
release of the normal placenta in the presence of LAC-positive
IgG [8]. It increases the production of leukotrienes, which act
in stimulating interleukin-3 production. Interleukin-3 en-
hances placental and foetal development and was found in
low amounts in APS patients. Low-dose aspirin restores
interleukin-3 levels in animal models of APS [9]. Moreover,
its suppression of nitric oxide synthetase activity prevents ox-
idative stress able to induce trophoblast apoptosis. In fact, the
increased apoptosis of a trophoblastic cell line (BeWo), in-
duced by the serum of patients with early miscarriages, is
significantly reduced by aspirin [7].
The treatment of pregnancy morbidity related to
antiphospholipid antibodies is not supported by consistent
Clinic Rev Allerg Immunol
findings from well-designed studies [10]. However, the prog-
nosis of pregnancies in patients with APS has greatly im-
proved over the last two decades. Based on the results of some
trials [11–13] and in line with two meta-analyses [14, 15],
most investigators currently advocate prophylactic-dose low-
molecular-weight heparin plus low-dose aspirin (LDA) as the
preferred treatment of otherwise healthy women with obstetric
APS, even if other authors found in this type of patient no
significant difference between treatment with low-molecular-
weight heparin plus low-dose aspirin and that with low-dose
aspirin alone [16]. Although specific clinical trials are lacking,
women with a history of vascular thrombosis alone or associ-
ated with pregnancy morbidity are usually treated with thera-
peutic low-molecular-weight heparin doses in association
with LDA in an attempt to prevent both thrombosis and preg-
nancy morbidity.
The protocols outlined above fail in about 20 % of pregnant
APS women [17], and additional treatments including intra-
venous immunoglobulins (IVIG) [18–28] (Table 1), low-dose
prednisolone [29], or aphaeresis procedures such as plasma
exchange or immunoadsorption [30–37] have, at times, been
combined with conventional therapies (Table 2). Due to the
low number of treated cases, the efficacy of these protocols is
at present not well established.
High-Risk Obstetric APS
Identifying risk factors associated with pregnancy failure
when conventional therapies are utilized is an important step
in establishing guidelines to manage these high-risk patients.
Logically, the choice of treatment in pregnant patients with
APS should be done on the basis of the degree of obstetric
risk. But actually, maternal–foetal risk in APS pregnant wom-
en has not yet been well defined.
The consensus statement of the classification criteria for
definite APS [2] introduced the concept of stratification of
the risk in APS patients on the basis of laboratory and clinical
characteristics. In particular, patients were allocated to classi-
fication categories on the basis of positivity to more than one
test—category I—or to a single test—categories IIA (LAC
alone), IIB (aCL antibodies alone) and IIC (anti-β2-glycopro-
tein I [anti-β2GPI] antibodies alone).
Concerning obstetric APS, several studies have attempted
to identify variables predictive of complications during con-
ventionally treated pregnancies (Table 3). Some investigators
found a higher risk of maternal and foetal complications in
pregnant APS women with previous thromboembolism [38],
and others reported the association of pregnancy loss with the
presence of multiple antiphospholipid positivity, i.e., for
anti-β2GPI antibodies and LAC [39, 40]. A history of throm-
bosis [41, 42], some particular antiphospholipid antibody pro-
files such as the presence of LAC [43] or high titres of aCL or
anti-β2GPI antibodies [44] and APS associated with systemic
Clinic Rev Allerg Immunol

Table 1 Effect of IVIG administered in addition to conventional therapy in high-risk pregnancies of patients with antiphospholipid syndrome

Authors Year Clinical IVIG protocols Outcome

(reference) reports

Carreras et al. [78] 1988 Case report 400 mg kg−1 day−1 for 5 days started at week 17 and followed by 2-day Favourable
courses at 22 and 27 week
Parke et al. [18] 1989 Case report 300 mg kg−1 month−1 for 6 months (before conception); 4-day induction of Favourable
400 mg kg−1 day−1 (after conception) continued at 600 mg day−1 month−1
Wapner et al. [19] 1989 Case reports Pt 1: 1 g kg−1 month−1 from week 9 to 34 weeks Favourable
Pt 2: 1 g kg−1 month−1 from week 10 to 33 weeks
Ron-El et al. [20] 1993 Case report 400 mg kg−1 month−1 (during the pregnancy) Favourable
Kaaja et al. [21] 1993 Case series 1 g kg−1 month−1 Live birth rate 100 %,
1 case of preeclampsia
Arnout et al. [22] 1994 Case report 400 mg/kg for 5 days with a 4-week interval (during the pregnancy for Live birth and placental
6 months) abruption
Somerset et al. 1998 Case report 500 mg kg−1 day−1 for 4 days at weeks 23 and 27 Favourable
[23]
Branch et al. [24] 2000 Multicenter, Group I: LDA (81 mg/day) and unfractionated heparin (7500 U) every 12 h, Fewer cases of IUGR and
placebo- increased to 10,000 U/12 h in the second trimester + IVIG: 1 g kg−1 day−1 neonatal intensive care
controlled for 2 days every month through 36 weeks unit admissions amongst
pilot study Group II: LDA and heparin as above + placebo the IVIG-treated cases
Stojanovich 2007 Case report 5 g kg−1 month−1 for 9 times during the pregnancy Favourable
et al. [25]
Mar et al. [26] 2014 Case report 0.5 mg kg−1 month−1 from week 8 (7 total doses) Favourable
Watanabe et al. 2014 Case series 400 mg kg−1 day−1 for 5 days from week 6 or 7 Live birth rate 100 %
[27]
Rose et al. [28] 2014 Case report 1 g kg−1 week−1 from week 9 IUGR, stillbirth at
21 weeks

IVIG intravenous immunoglobulins, LDA low-dose aspirin, IUGR intrauterine growth restriction

lupus erythematosus or other systemic autoimmune diseases component levels have, moreover, been found to be indepen-
[43, 45] have been found to be related to maternal–foetal dent predictors of lower neonatal birth weight and of birth at
complications in pregnant APS women. The persistence of an earlier gestational age, whilst a false-positive IgM TORCH
uterine artery notching and lower complement C3 and C4 (Toxoplasma, rubella, cytomegalovirus and herpes simplex

Table 2 Effect of apheresis procedures administered in addition to other treatments in high-risk pregnancies of patients with antiphospholipid
syndrome

Authors (reference) Year Clinical reports Treatment protocols Outcome

Frampton et al. [30] 1987 Case report Plasma exchange, low-dose aspirin, dipyridamole and low-dose prednisolone Favourable
Kobayashi et al. 1992 Case reports Immunoadsorption, low-dose aspirin and low-dose prednisolone Favourable
[31]
Nakamura et al. 1999 Case series Immunoadsorption, low-dose aspirin and low-dose prednisolone Live birth rate 7/8
[32] (87.5 %)
El-Haieg et al. [33] 2007 Case series Plasma exchange and low-dose prednisone Live birth rate 18/18
(100 %)
Ruffatti et al. [34] 2007 Case series Plasma exchange, therapeutic heparin ± low-dose aspirin; in two cases + IVIG Live birth rate 5/7
(71.4 %)
Bortolati et al. [35] 2009 Case reports Pt 1: Plasma exchange plus IVIG, therapeutic heparin and low-dose aspirin Favourable
Pt 2: Immunoadsorption plus IVIG, therapeutic heparin and low-dose aspirin
Rose et al. [28] 2014 Case reports Plasma exchange, therapeutic heparin, low-dose aspirin, HCQ, low-dose Live birth, preeclampsia
prednisolone and azathioprine
Mayer-Pickel et al. 2015 Case report Plasma exchange, therapeutic heparin and low-dose aspirin Favourable
[36]
Ruffatti et al. [37] 2016 Case series Plasma exchange plus IVIG, therapeutic heparin and low-dose aspirin Live birth rate 17/18
(94.4 %)

IVIG intravenous immunoglobulins, HCQ hydroxychloroquine

 Clinic Rev Allerg Immunol

Table 3 Risk factors for pregnancy failure on conventional treatment in patients with antiphospholipid syndrome

Authors (reference) Year Risk factors

Lima et al. [38] 1996 Previous thromboembolism

Ruffatti et al. [69] 2006 Previous thromboembolism and/or triple antiphospholipid antibody positivity
Sailer et al. [39] 2006 Multiple antiphospholipid antibody positivity
Danowski et al. [45] 2009 Association with SLE or other SAD
Nodler et al. [53] 2009 High antiphospholipid antibody titres
Ruffatti et al. [70] 2009 Antiphospholipid antibody category I (Sydney criteria) or triple antiphospholipid antibody positivity
Bramham et al. [41] 2010 Previous thrombosis
Ruffatti et al. [71] 2011 Association with SLE or other SAD or previous thrombosis and pregnancy morbidity or triple antiphospholipid positivity
Simchen et al. [44] 2011 High titres of anticardiolipin or anti-β2 glycoprotein I antibodies
Fischer-Betz et al. [42] 2012 Previous ischaemic cerebral events and multiple antiphospholipid antibody tests
Lockshin et al. [43] 2012 Lupus anticoagulant positivity or association with SLE or other SAD
de Jesus et al. [54] 2014 Previous thrombosis
Matsuki Y et al. [40] 2015 Multiple antiphospholipid antibody positivity

SLE systemic lupus erythematosus, SAD systemic autoimmune diseases

virus tests) was an independent predictor of lower neonatal
birth weight [46]. However, a subsequent study failed to re-
port any association between hypocomplementemia and ob-
stetric complications [47].
Conventional treatment of patients with APS during preg-
nancy can significantly improve live birth rates, so reaching
more than 70 % of live birth rate [48], but other complications
remain high despite treatment. Disorders linked to APS during
pregnancy include thrombotic events as well as specific ob-
stetrical complications. The coexistence of both thrombosis
and miscarriage is estimated at 2.5–5 % of APS pregnancies
[49].
Thrombotic events are major problems during pregnancy
because of the management they implicate and the risk of
complications, such as pulmonary embolism. Interestingly,
the Nimes Obstetricians and Hematologists APS (NOH-
APS) observational study compared the incidence of throm-
botic events in 517 women with purely obstetrical APS to 796
seronegative women with a history of pregnancy loss. The
annual rate of thrombotic complications, defined by deep vein
thrombosis (1.46 %), pulmonary embolism (0.43 %), superfi-
cial vein thrombosis (0.44 %) and cerebrovascular events
(0.32 %), was found to be higher in obstetrical APS women
than in control patients (0.43, 0.12, 0.14 and 0.09 %, respec-
tively) [50]. The most serious thrombotic disorder also affect-
ing APS patients during pregnancy or puerperium is cata-
strophic APS (CAPS). CAPS represents 1 % of APS and
can occur inside or outside of pregnancy. CAPS is defined
as a Bthrombotic storm^ secondary to microangiopathic dif-
fuse thrombosis leading to multi-organ failure. Six per cent of
CAPS seems to be associated with pregnancy and postpartum,
but this is probably underestimated [51]. More specific obstet-
rical manifestations include severe preeclampsia, which gen-
erally affects 2–8 % of pregnancies [52]. A cross-sectional
study conducted in Florida on 141,286 women who delivered
in 2001 showed that women with high antiphospholipid anti-
body titres had an increased risk of preeclampsia or eclampsia
(adjusted odds ratio [AOR] = 2.93), placenta insufficiency
(AOR = 4.58) and prolonged length of stay at hospital
(>3 days, AOR = 3.93) [53]. Moreover, APS patients with
history of cerebral ischemic events are at increased risk of
preeclampsia (34.8 %), especially those positive for multiple
antiphospholipid antibody test, and new cerebral ischemia can
occur if preeclampsia develops (OR = 7.0) [42]. Considering
patients with definite APS, there are no randomized controlled
trials that included patients with exclusively severe pre-
eclampsia or eclampsia and premature birth before the 34th
week, as stated by the classification criteria [2]. Therefore, the
recommended treatment for this group of patients (LDA plus
heparin) is the same as for patients with pregnancy loss; how-
ever, its real efficacy is unknown. In fact, preeclampsia is still
common in patients with APS receiving LDA and heparin,
resulting in significant maternal and foetal morbidity in these
pregnancies. Clinicians should be aware of obstetric APS-
related events even in patients with history of only thrombotic
manifestations of the syndrome [54].
There is another severe pregnancy complication in preg-
nant APS women. It is characterized by hemolysis, elevated
liver enzymes and low platelet count (HELLP syndrome)
[55]. Several case reports have described the association be-
tween antiphospholipid antibodies/APS and HELLP syn-
drome [55]. In two case series, the authors concluded that
antiphospholipid antibodies were associated with increased
prevalence and severity of HELLP syndrome [56, 57].
Moreover, HELLP/CAPS overlap has also been reported in
both case reports [58–60] and case series [51]. HELLP syn-
drome is defined as an endothelium-based disorder [61, 62].
The increased prevalence of HELLP syndrome suggested by
Clinic Rev Allerg Immunol
some authors in the setting of APS can be explained in part by
the interplay between antiphospholipid antibodies and endo-
thelial cells, leading to thrombosis and microangiopathic man-
ifestations [56, 57, 61].
As well as preeclampsia, intrauterine growth restriction
(IUGR) is commonly found in pregnant women with APS,
often associated to oligohydramnios with an amniotic fluid
index of 5 cm or less. Both disorders represent different signs
of placental insufficiency and can be found in the same pa-
tient. Isolated foetal impairment, however, is possible and may
develop with absent or minimal maternal signs, like small
uterine height [63]. Some investigators found almost 40 %
of small for gestational age neonates (below the 10th percen-
tile) in patients with thrombotic APS compared to 16 % of
patients with obstetric APS [41]. Other authors reported
28.6 % of small for gestational age in pregnancies after cere-
bral ischemic events related to antiphospholipid antibodies
[42]. A paper evaluating the efficacy of prophylaxis using
LDA and heparin in the prevention of IUGR in patients with
APS provided negative results; of the APS patients, 32.3 %
had low birth weight newborns (below the 10th percentile)
compared to 2.5 % of the control group [64]. Once again,
treatment for this presentation of APS is disappointing, with
a higher frequency of IUGR in APS patients. Premature birth
is reported in 20–25 % of APS patients (range = 11–66 %
based on different studies) [65–68], mainly caused by preterm
delivery due to preeclampsia, HELLP syndrome or IUGR.
Some authors described higher rates of preterm delivery in
patients with thrombotic APS when compared to women with
history of recurrent abortion only [41].
In an attempt to evaluate the influence of clinical and lab-
oratory maternal features on pregnancy outcome, we studied
the pregnancies of 53 APS women with pregnancy morbidity
during a mean follow-up period of 6.3 years. The study group
included only APS women in laboratory classification catego-
ry I. Obstetric history included foetal loss in 72 % of cases,
spontaneous abortions in 22 % and preeclampsia or eclampsia
in 6 %. Laboratory diagnosis showed double antiphospholipid
antibody positivity in 70 % of cases and triple positivity in
30 %. Previous thromboembolism was found in 30 % of the
women (6 % pulmonary embolism, 9 % deep vein thrombosis
and 15 % stroke). The results of the statistical analysis dem-
onstrated that only previous thromboembolism and triple
antiphospholipid antibody positivity were significantly asso-
ciated with a new unsuccessful pregnancy. Moreover, only the
same two parameters were significantly associated with a new
thromboembolism during the next pregnancy. In this study,
we concluded that in primary APS with pregnancy morbidity
in classification category I, quite different groups of patients
may be identified on the basis of laboratory tests and clinical
characteristics. Triple antibody positivity and/or a history of
thromboembolism predict new unsuccessful pregnancy and
new thromboembolism [69].
In a second study, we related laboratory classification cat-
egories with pregnancy outcome in patients with primary APS
prescribed antithrombotic therapy. Ninety-seven pregnancies
of 79 APS women affected with pregnancy morbidity and/or
thromboembolism were followed from December 1995 to
June 2007. According to their laboratory characteristics, the
patients have been divided into categories I, IIA, IIB and IIC.
The Kaplan–Meier survival curves showed the cumulative
proportion of unsuccessful pregnancies in triple-positive,
double-positive or single-positive women. Triple-positive pa-
tients had a significantly higher cumulative proportion of un-
successful pregnancies than double-positive women (p =
0.03). Thus, we concluded that poor pregnancy outcomes oc-
cur more frequently in category I than in category II primary
APS patients. However, it has been seen that a greater predict-
ability is achieved when category I patients are grouped into
triple and double positivity states. Triple-positive patients
might be a specific and separated category of patients at very
high risk of pregnancy loss [70].
In this context, a case–control study drawing on a large
multicentre cohort of conventionally treated pregnancies was
conducted to verify whether specific laboratory profiles and/or
clinical characteristics are predictive of unsuccessful pregnan-
cy outcome during conventional treatments. We retrospective-
ly considered 410 pregnancies of women diagnosed with
APS. The study focused on 57 unsuccessful pregnancies (the
study population) and 57 successful pregnancies (the control
population) matched for age and therapy. All the pregnant
patients were treated with conventional protocol treatments
including LDA and/or heparin. The clinical and laboratory
features of the two groups of APS women were statistically
compared. The most statistically significant risk factors for
pregnancy failure were: (a) association of APS with systemic
lupus erythematosus or other systemic autoimmune diseases
(OR = 6.9, CI = 2.7–17.8); (b) a history of both thrombosis
and pregnancy morbidity (OR = 12.7, CI = 2.8–57.9); and (c)
triple (LAC plus aCL plus anti-β2GPI antibodies)
antiphospholipid antibody positivity (OR = 9.2, CI = 2.8–
30.9; Fig. 1). The probability of pregnancy failure estimated
by logistic regression analysis was 93 % in APS women with
two or more of these features, 63 % in those with only one
feature and 21 % in those with none. It was seen at univariate
analysis that APS patients diagnosed on the basis of a single-
positive test and/or history of pregnancy morbidity alone gen-
erally had successful pregnancies (Fig. 1). It would seem from
these findings that the risk of pregnancy complications in APS
women planning to conceive can be stratified on the basis of
some specific clinical and laboratory features [71].
Additional Treatments in High-Risk Obstetric APS
For the moment, there are no guidelines on the ideal additional
treatment strategy in APS patients at high risk of pregnancy

Fig. 1 Pregnancy outcome in antiphospholipid syndrome women on
conventional therapy. Stratification of the risk of pregnancy
complications on the basis of some specific clinical and laboratory
failure/complications during conventional treatment, probably
because of the rarity of this disorder.
Whilst steroids and aphaeresis procedures are currently
considered additional therapies [72, 73], data on the useful-
ness of IVIG in obstetric APS are conflicting [18–28, 74–76].
The use of IVIG in pregnant APS women is rare and is gen-
erally considered a second-line treatment when other more
standardized therapies have failed [77]. The first description
of a case of obstetric APS patient treated with IVIG was that
by Carreras et al. in 1988 [78]. Treatment with IVIG at the
standard dose of 400 mg kg−1 day−1 for 5 days started at
week 17 and followed by 2-day courses at 22 and 27 weeks
of gestation in a 28-year-old woman who suffered from nine
early spontaneous abortions, two intrauterine deaths and a
perinatal death at 26 weeks. The patient delivered by caesar-
ean section a healthy girl at week 34. IVIG are blood products
prepared from the serum of a large number of donors, and
their use has rapidly grown to treat a wide variety of autoim-
mune diseases [79]. The mechanisms in which IVIG exert
their immunomodulatory and anti-inflammatory effects re-
main unclear, with many pathways in the innate and adaptive
immune systems being potentially targeted. The many expla-
nations for these actions include modulation of Fc receptor
expression on leukocytes and endothelial cells, interaction
with complement proteins, modulation of the synthesis and
release of cytokines and chemokines, modulation of cell pro-
liferation and apoptosis, remyelinization, neutralization of cir-
culating antibodies, selection of immune repertoires, interac-
tion with other cell surface molecules expressed on lympho-
cytes and monocytes, modulation of dendritic cell maturation
and restoration of idiotypic–anti-idiotypic networks [80, 81].
Particularly in APS, IVIG have been shown to inhibit both
the action of antiphospholipid antibodies and their production
[79]. Indeed, some investigators [82] reported that F(ab′)2
fragments from IVIG can neutralize the binding of aCL anti-
bodies to cardiolipin in a dose-dependent manner and other
authors [83] that the same fragment can also inhibit LAC
activity. The mechanisms responsible for the beneficial effects
Clinic Rev Allerg Immunol
features. aOn the basis of univariate analysis. bOn the basis of logistic
regression analysis. aPL antiphospholipid antibodies, SLE systemic lupus
erythematosus, SAD systemic autoimmune diseases
of IVIG in APS may be due to the presence of anti-idiotypic
antibodies to antiphospholipid antibodies in IVIG or the inac-
tivation of B cell clones, leading to subsequently decreased
autoantibody production [77]. In addition, IVIG infusion was
shown to prevent obstetric complications in APS animal
models, possibly preventing the binding of antiphospholipid
antibodies to the trophoblast [84]. It is interesting that IVIG
resulted beneficial in most cases [18–27, 78] when adminis-
tered in addition to the first-line therapy, but it had only a
slight [74] or no effect at all [75, 76] when used alone as the
first-line treatment. However, as the literature shows hetero-
geneous data with respect to IVIG dosing, timing of adminis-
tration and concomitant treatment used (heparin, aspirin or
steroids), it is difficult to draw well definite conclusions about
IVIG benefits in obstetric APS. In general, IVIG therapy is
well tolerated and adverse reactions are usually mild and re-
versible [85]. The use of IVIG infusion is, in any case, limited
because of its high cost and short supply.
As complement system activation and inflammatory
changes seem to induce disorders in trophoblast invasion
and placentation, it is possible that steroids are beneficial in
APS women with recurrent pregnancy loss [86]. Whilst high
doses of prednisolone (40–60 mg/day) administered in com-
bination with LDA have been associated with too many high
rates of pregnancy complications [86], low doses of prednis-
olone (10 mg/day) combined with heparin/aspirin from the
time a pregnancy test resulted positive until the 14th week of
gestation produced encouraging results in APS women with
previous pregnancy morbidity, but not in those also suffering
from previous thromboembolism and triple antiphospholipid
antibody positivity [29].
The safety of both plasma exchange or immunoadsorption
procedures during pregnancy is well documented [30–37]. In
order to avoid bleeding during plasmapheresis treatment, as
plasmapheresis temporarily removes blood clotting factors, in
heparin-treated patients, it is important that the morning hep-
arin, performed after the session, was halved [37]. Both extra-
corporeal blood purification techniques are known to lower
Clinic Rev Allerg Immunol
antibody levels in APS patients [87, 88]. Their use in pregnant
APS patients has, nevertheless, been circumscribed, and de-
scriptions in the literature are limited to case reports [28, 30,
31, 35, 36] and case series [32–34, 37]. Both aphaeresis pro-
cedures have, in any case, always been administered in addi-
tion to other treatments, including steroids, heparin/LDA or
IVIG, and have been associated to a live birth rate ranging
between 71.4 and 100 % of the treated cases [33, 34, 37].
During the first period in which plasma exchange was used
by us, several questions were raised [34]. More precisely, it has
been seen that the replacement fluid used during therapeutic
plasma exchange can be an important factor influencing its
results. By evaluating the pathophysiology of the underlying
disease, it is possible to choose different options, including 4 %
albumin solution and fresh frozen plasma. In one of our patient,
suffering from catastrophic APS soon after delivery, the infu-
sion of fresh frozen plasma containing amounts of coagulation
factors was associated with severe thrombotic microangiopa-
thy. This disorder immediately disappeared when plasma ex-
change was administered using 4 % albumin in saline as the
replacement fluid. The temporary reduction of coagulation pa-
rameters that was observed after albumin infusion may have
benefited this thrombophilic APS patient [89]. On the other
hand, the deficiency in natural anticoagulants related to albu-
min infusion was balanced by the administration of antithrom-
bin III at the end of the plasma exchange session. The best
timing for beginning plasma exchange was an important con-
sideration for us as we treated these women. It has been seen
that plasma exchange was completely ineffective in the first
treated patient, when it was begun in the presence of late
foetal-placental damage. Plasma exchange treatment in high-
risk pregnancies should be initiated in the presence of early
complications including bilateral notching or a gradual platelet
fall (>20 %) occurring during the first trimester, or possibly
when foetal heart rate is documented and before complications
occur, so as to remove the offending antiphospholipid antibod-
ies and thus avoid its injuries. Due to the after delivery maternal
microangiopathy, plasma exchange could be restarted after de-
livery. The high probability of bleeding when plasma exchange
is administered soon after surgery, i.e. caesarean section, was
found by us when we were treating the first patient. In fact,
plasma exchange was begun again in this patient a few hours
after caesarean section, and almost immediately, a life-
threatening subfascial hematoma took place. The other three
patients who instead began plasma exchange again several days
after surgery had no bleeding [34]. The advantage of
immunoadsorption as compared to plasma exchange would
be the more selective removal of large amounts of IgG antibod-
ies without significantly affecting other plasma components
such as hormones, natural anticoagulants, cytokines and pro-
teins whose lack might have bad influence on the course of
pregnancy. Moreover, immunoadsorption actually treats a larg-
er plasma volume than plasma exchange, which might transfer
into a more effective treatment. On the other hand, plasma
exchange removal of activated complement components, coag-
ulation factors and microparticles may also be relevant. The use
of immunoadsorption procedure is, in any case, limited because
of its very high cost and long duration of treatment. Thus,
according to our experience, the use of immunoadsorption
technique could be considered in high-risk APS pregnancies
with IgG antiphospholipid antibody isotype as a treatment
when a previous pregnancy failed on plasma exchange or as
substitutive treatment of plasma exchange at early occurrence
of pregnancy complications [37, 90]. For both plasma ex-
change and immunoadsorption, it is important to use only sub-
cutaneous arm veins as blood access points in order to avoid
catheter-related complications.
Whilst the true relevance of these treatments has still to be
confirmed, other suggestions related to experimental models
are rising. Amongst these, hydroxychloroquine might be the
first drug to be largely administered in addition to convention-
al treatment because of its well-documented safety in pregnant
patients [91]. In vitro studies indicate that hydroxychloroquine
may be beneficial to APS patients. In fact, hydroxychloroquine
was able to reduce TLR4 mRNA and protein expression and
to finally restore trophoblast function, suggesting the use
of this drug in obstetric APS [92]. Some authors [93]
showed that hydroxychloroquine can dissociate IgG
antiphospholipid–β2GP1 complexes and reduce the amount
of IgG antiphospholipid antibodies that binds to phospho-
lipid bilayers trapping annexin A5, a potent natural antico-
agulant with high affinity for anionic phospholipids.
Annexin A5 is required for the maintenance of placental
integrity in mice and plays a thrombomodulatory role at the
maternal–foetal interface within the placentary blood cir-
culation by shielding the apical membrane phospholipids
of placental villous syncytiotrophoblasts. The reversion of
IgG antiphospholipid–β2GPI complexes mediated by
hydroxychloroquine permits more annexin A5 to crystal-
lize and may also ameliorate some of the other proposed
thrombogenic effects. The same authors [93] also found
that hydroxychloroquine promotes the formation of second
layers of annexin A5 crystal Bpatches^ over areas where
the mentioned immune complexes had disrupted crystalli-
zation, thereby further reducing the exposure of
thrombogenic phospholipids. However, to the best of our
knowledge, there is only a retrospective study concerning
the use of hydroxychloroquine in obstetric APS [94].
Prospective randomized trials should be designed to eval-
uate its efficacy in patients with obstetric APS as additional
therapy of the current treatment with heparin and LDA.
Recently, a large multicentre, observational, retrospective
study from a European Forum on antiphospholipid antibody
project was undertaken to investigate the effect of various
treatments on pregnancy outcomes in APS women with di-
verse risk factors for pregnancy failure. Between 1996 and

2011, 196 pregnancies of 156 APS women attending 16
European centres were retrospectively considered. The
study’s inclusion criteria were one or more of the following
risk factors: a history of thrombosis, systemic lupus erythema-
tosus and triple antiphospholipid antibody positivity. The fol-
lowing treatments were considered in the study: LDA alone,
prophylactic dose of heparin + LDA, therapeutic dose of hep-
arin + LDA and additional treatments including IVIG infu-
sions, weekly aphaeresis procedures and low-dose predniso-
lone (10 mg/day), alone or combined. The primary outcome of
the study was the live birth rate. Seventy-six per cent of preg-
nancies ended successfully, producing 150 live infants, in-
cluding one set of twins. Mean week of gestation at delivery,
mean birth weight in percentiles and mean Apgar score at
5 min were quite good. Pregnancy loss took place in 24 %
of cases. Maternal–foetal complications were noted in 25 % of
cases. It is interesting to observe that no important side effects
were recorded during all types of treatments. The primary
outcome, i.e. live birth rate, was analysed in relation to patient
risk profiles and treatment strategies. The only risk profile in
which a significant difference was found between treatments
was the thrombosis plus triple antiphospholipid antibody pos-
itivity group. Backward conditional logistic regression, ad-
justed for potential confounding risk factors, analysed all the
treatments in this profile and found additional treatments as
the only independent factor associated with a favourable out-
come of pregnancy (OR = 9.7, CI = 1.1–88.9, p < 0.05). We
can conclude that APS patients with thrombosis and triple
antiphospholipid antibody positivity could be treated during
pregnancy with a second-line therapy in addition to conven-
tional treatment as a higher live birth rate on additional therapy
rather than on conventional therapy alone has been demon-
strated in this subset of patients. However, in this study, it was
impossible to examine the additional therapies singularly and
to identify the benefits and limits of different additional treat-
ment strategies and indicate which is associated with the best
pregnancy outcome as the number of patients studied was so
small [95].
Future Direction
According to the above-mentioned reports, primary APS pa-
tients with a well-defined antiphospholipid antibody profile
(triple antiphospholipid antibody or LAC positivity) in asso-
ciation with a history of thrombotic events and/or previous
severe maternal–foetal complications develop more pregnan-
cy failure/complications compared to pregnant APS women
exclusively affected by previous miscarriages or foetal loss.
Thus, treatment during pregnancy of this subset of APS pa-
tients should be differentiated because it should improve live
birth rates and reduce obstetric complications such as maternal
thrombosis, eclampsia, severe preeclampsia, HELLP syn-
drome, foetal growth restriction and prematurity, which
Clinic Rev Allerg Immunol
generally occur in high-risk pregnant APS women despite
conventional treatment [41, 42].
Given that the rarity of high-risk APS pregnancies does not
allow performing clinical trials, thus, for the time being, a new
multicentre, retrospective study on the framework of the
European Forum on antiphospholipid antibodies focusing on
the efficacy and safety of the different additional treatments in
high-risk pregnant APS women is ongoing in order to identify
the best treatments to be used in addition to conventional
therapy in this subset of patients.
Study Design
Only pregnant patients who fulfilled—at the time they were
diagnosed with primary APS—the clinical and laboratory
classification criteria established by an International
Consensus in 2004 [2] are retrospectively enrolled in the
study.
Both the following two inclusion criteria have to be present
at the time of the considered pregnancy:
1. Laboratory criteria: (a) positivity to all three antiphospholipid
antibody assays, referred to LAC plus aCL plus a-β2GPI
antibodies, or (b) positivity to LAC alone or associated either
to aCL or to anti-ß2GPI antibodies
2. Clinical criteria: (a) a history of maternal thrombosis and/
or (b) one or more of the following severe obstetric com-
plications: eclampsia, preeclampsia (arterial pressure
≥160/110 and proteinuria ≥5 g in a 24-h urine sample),
HELLP syndrome, intrauterine growth restriction (birth
weight <10th percentile), prematurity (delivery <34th
week of gestation) and/or (c) an unexplained foetal death
at or beyond the 10th week of gestation during conven-
tional treatment
Each patient to be included in the study must have at least
one laboratory criterion in combination with at least one clin-
ical criterion.
All the following exclusion criteria had to be absent at the
time of the considered pregnancy:
1. The previous pregnancy occurred successfully on conven-
tional therapy
2. The presence of a well-defined associated autoimmune
systemic disease
3. Age ≥ 45 years
4. Single- or multiple-organ failure
5. Severe pulmonary hypertension
6. Other known causes of pregnancy failure
All the women have to be treated with conventional plus
additional treatments within the 12th week of gestation.
However, additional treatments can start later due to
Clinic Rev Allerg Immunol
pregnancy complications occurring during conventional ther-
apy alone in patients not included in the study from the begin-
ning of pregnancy. Any additional treatments administered
alone or combined is considered in the study, including: low
dose of steroids, equivalent to 10 mg/daily prednisolone;
hydroxychloroquine between 200 and 400 mg/daily accord-
ing to body weight; IVIG in a systematic way with a total
amount of 2 g/kg per month, divided into two to five doses;
apheresis procedures including plasma exchange or
immunoadsorption administered in a systematic way accord-
ing to a well-defined timetable; other treatments in accordance
with the choice of the physician.
The study’s primary outcome is the live birth rate, i.e. the
number of live newborns surviving for the first 27 days after
birth (perinatal period), whilst maternal thrombosis, eclamp-
sia, severe preeclampsia, HELLP syndrome, intrauterine
growth restriction or prematurity are the secondary outcomes.
The medical records of the pregnant APS patients are
reviewed after an informed consent was obtained from all
women.
Baseline data collected for analysis include: age; disease
duration; history and type of pregnancy morbidity;
antiphospholipid antibody profile; other autoantibodies (anti-
nuclear, anti-double-strand DNA, anti-extractable nuclear an-
tigens and anti-thyroid antibodies); presence of genetic risk
factors for thrombosis (factor V Leiden, prothrombin
G20210A mutation, decrease in C and S protein antigens
and activities, antithrombin III deficiency and increased acti-
vated protein C resistance); acquired risk factors for thrombo-
sis (blood pressure >140/90 mmHg or use of antihypertensive
drugs, total cholesterol ≥ 250 mg/dl, diabetes mellitus, body
mass index ≥30 kg m−2 and cigarette smoking); and low C3
and/or C4 levels (below 80 and 10 mg/dL, respectively).
The collected pregnancy-related data include: the type and
dosage of therapy prescribed; when therapy was begun; low
C3 and/or C4 levels; maternal and foetal complications in-
cluding maternal thrombosis, eclampsia, preeclampsia,
HELLP syndrome, premature rupture of membranes, placenta
abruptio, oligohydramnios, intrauterine growth restriction, ab-
normalities of Doppler waveform of the uterine arteries and/or
umbilical artery; pregnancy outcome (live birth or foetal death
or early miscarriage); the week of gestation when delivery
took place; newborn’s sex; birth weight in grams and in per-
centiles; Apgar score at 5 min; and neonatal complications.
ACL and anti-β2GPI of IgG and IgM isotypes are deter-
mined using a homemade enzyme-linked immunosorbent as-
say following internationally accepted guidelines [96]. The
results of aCL testing were expressed as immunoglobulin G
phospholipid or immunoglobulin M phospholipid units using
international reference material. The results of anti-β2GPI as-
says were calculated as arbitrary units using a standard curve
obtained from a pool of positive samples calibrated to Koike’s
monoclonal antibodies (HCAL for the IgG and EY2C9 for the
IgM anti-β2GPI). In accordance with the Sydney update of the
classification criteria [2], the cutoff values for medium/high
titres for both aCL and anti-β2GPI antibodies will be calculat-
ed using the 99th percentile obtained by testing 120 age-
matched healthy women. Alternatively, centres could assess
IgG and IgM aCL and IgG and IgM anti-β2GPI antibodies
using commercial kits following the manufacturers’ instruc-
tions. LAC is assessed by multiple coagulation tests using
platelet-poor plasma samples following the revised interna-
tionally accepted guidelines [97].
Comparisons of the data will be performed using Pearson’s
chi-square test, Fisher’s exact test and the Mann–Whitney test.
Logistic regression and backward conditional logistic regres-
sion analyses will assess the independent effect of the treat-
ments and yield the odds ratio (OR) for treatments adjusted for
confounding variables. A p value <0.05 is considered signif-
icant. A power analysis will be performed to calculate the
hypothetical number of pregnancies required in each sub-
group and in each treatment group in order to obtain reliable
results. The assumption will be made that women who re-
ceived conventional treatments had a 60–70 % chance of
achieving live births. The analysis will be performed to detect
an absolute increase of 20–30 percentage points in the live
birth rates and a decrease of 20–30 percentage points in the
pregnancy complications during conventional plus different
additional treatments. The power of the statistical test will be
80 % and the significance level 5 %.
The results of the study will be reported and discussed in a
paper.
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflict of
interest.
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