Autoimmunity Reviews 14 (2015) 387–395

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Autoimmunity Reviews
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Review

The European Registry on Obstetric Antiphospholipid Syndrome

(EUROAPS): A survey of 247 consecutive cases☆
Jaume Alijotas-Reig a,b,⁎,aa, Raquel Ferrer-Oliveras c,aa, Amelia Ruffatti d, Angela Tincani e, Elmina Lefkou f,
Ma. Tiziana Bertero g, Emmanuel Coloma-Bazan h, Sara de Carolis i, Gerard Espinosa h,
Patrizia Rovere-Querini j, Anna Kuzenko g, Enrique E. Valverde k, Angel Robles l, Ricard Cervera h,
Valentina Canti g, Micaela Fredi e, Antonio Gil-Aguado l, Krista Lundelin m,1, Elisa Llurba c, Taisiya Melnychuk c,
Cecilia Nalli e, Elisa Picardo n, Erika Silvestro g, Teresa del Ross d, Inmaculada Farran-Codina c,
(EUROAPS Study Group Collaborators)
a
Systemic Autoimmune Disease Unit, Department of Internal Medicine, Vall d’Hebron University Hospital
b
Department of Medicine, Universitat Autonòma, Barcelona, Spain
c
Obstetric and Gynaecolgy Department, Vall d’Hebron University Hospital, Universitat Autonòma, Barcelona, Spain
d
Rheumatology Unit, Department of Clinical and Experimental Medicine Azienda Ospedaliera, University of Padua, Padua, Italy
e
Rheumatology and Clinical Immunology Unit, Ospedale Civile, Brescia, Italy
f
Haematoly Unit, Hippokrateion Hospital of Thessaloniki, Greece
g
Department of Clinical Immunology, A.O. Mauriziano-Umberto I, Turin, Italy
h
Systemic Autoimmune Diseases Service, Hospital Clinic, Universitat de Barcelona, Barcelona, Spain
i
Department of Gynaecology, Gemmeli Hospital, Catholic University, Roma, Italy
j
Vita-Salute Sant Raffaele University and IRCCS Ospedale San raffaele, Milano, Italy.
k
Internal Medicine Department, Althaia Healthcare Network of Manresa, Barcelona, Spain
l
Internal Medicine Department, Hospital Universitario La Paz, Universidad Autònoma, Madrid, Spain
m
Current workplace: Department of Pediatrics, Turku University Hospital, Turku, Finland
n
Department of Obstetrics and Gynaecology, University of Turin, Turin, Italy

a r t i c l e i n f o a b s t r a c t

Article history: Aim: To analyse the clinical features, laboratory data, foetal–maternal outcomes, and follow-up in a cohort of 247
Received 12 December 2014 women with obstetric antiphospholipid syndrome (OAPS).
Accepted 23 December 2014 Methods: The European Registry on APS became a Registry within the framework of the European Forum on
Available online 31 December 2014 Antiphospholipid Antibody projects and placed on a website in June 2010. Cases with obstetric complaints relat-
ed to aPL who tested positive for aPL prospectively and retrospectively were included. The three-year survey
Keywords:
results are reported.
Antiphospholipid antibody
Laboratory categories
Results: 338 women with 1253 pregnancy episodes were included; 915 were historical and 338 were latest
Obstetric antiphospholipid syndrome episodes. All these women tested positive for aPL. 247 of the 338 fulfilled the Sydney criteria. According to the
Obstetric morbidity laboratory categories, 84/247 were in category I, 42 in IIa, 66 in IIb and 55 in IIc. Obstetric complications other
Registry than foetal losses, appeared in 129 cases (52.2%). 192 (77.7%) had a live birth and 55 (22.3%) did not. The latter
Treatment group of only 38 cases (69%) received adequate treatment and 17 (31%) did not. 177/247 (72%) women were put
on heparin plus LDA. Thrombosis appeared in two during pregnancy and in 14 during the puerperium. 7 (3%)
women evolved to complete SLE.
Conclusions: OAPS shows differential characteristics than classical APS. All laboratory test categories are needed
to avoid false-negative diagnoses. In some cases, complement levels could act as a serological marker. OAPS
has very good foetal–maternal outcomes when treated. Thrombosis and progression to SLE in mothers with
OAPS are scarce compared with “classical APS”, suggesting that they have different aPL-mediated pathogenic
mechanisms.
© 2015 Elsevier B.V. All rights reserved.

☆ This paper has not been previously published nor is currently being under consideration for publication elsewhere.
⁎ Corresponding author at: Systemic Autoimmune Disease Unit, Department of Internal Medicine, Vall d'Hebron University Hospital, Department of Medicine, Universitat Autonoma,
Barcelona, Spain, Josep Ma de Segarra 2-F, 08190 Sant Cugat del Vallés, Barcelona, Spain. Tel.: +34 93 489 41 94.
E-mail addresses: jalijotas@vhebron.net, 16297jar@comb.es (J. Alijotas-Reig).
aa
Jaume Alijotas-Reig and Raquel Ferrer-Oliveras have contributed equally in the realization of this manuscript.
1
Current worplace: Department of Pediatrics, Turku University Hospital, Turku, Finland.

http://dx.doi.org/10.1016/j.autrev.2014.12.010
1568-9972/© 2015 Elsevier B.V. All rights reserved.
388 J. Alijotas-Reig et al. / Autoimmunity Reviews 14 (2015) 387–395

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388
2. Patients and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388
2.1. Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388
2.2. Study design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388
2.2.1. Inclusion clinical criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389
2.2.2. Inclusion laboratory criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389
2.2.3. Exclusion clinical criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389
2.2.4. Exclusion laboratory criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389
2.2.5. Other laboratory analysed parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389
2.2.6. Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389
2.3. Assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389
3. Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389
4. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389
4.1. Patient baseline clinical characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389
4.2. Laboratory characteristics and obstetric-related morbidities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
4.2.1. Laboratory categories . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
4.2.2. Complement pathway results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
4.2.3. Associated inherited clot pathway disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
4.3. Obstetric outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
4.4. Maternal outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
5. Analysis of treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
6. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394
Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394
Conflict of interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394
Funding/financial support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394
IRB approval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394

1. Introduction treatment, foetal and maternal outcomes and long-term follow-up of

The antiphospholipid syndrome (APS) is characterised by an in-
creased risk of vascular thrombosis and/or pregnancy complications,
both related to antiphospholipid/anticofactor antibodies (aPL) [1]. This
classical form is believed to be related to activation of the clot cascade
with further thrombosis. Cases with poor obstetric outcomes, mainly
recurrent first trimester miscarriage, foetal losses, stillbirth, early and
severe pre-eclampsia or prematurity, but without a thrombotic history,
are known to have obstetric antiphospholipid syndrome (OAPS) [2].
Classically, these outcomes have also been attributed to placental
thrombosis and/or infarcts. However, in around 50% of cases decidual
or placental thrombosis cannot be confirmed [3,4]. Foetal loss can be ex-
plained by inflammatory histopathological signs, probably due to com-
plement pathway activation [4–7], tissue factor over-expression in
neutrophils and monocytic cells [8], or through a negative imbalance
of angiogenic factors [9], even in the absence of thrombosis. Although
no complete agreement exists, there is evidence that laboratory
markers, treatment response, maternal complications and long-term
follow-up may differ from those observed in classical APS form [2,
10–14]. Similarly, after years of women being treated and papers
published in this regard, no definitive data exist on the true relationship
between early miscarriage and placental insufficiency and aPL, or on ap-
propriate treatment [14]. Furthermore, in the last decade, a wide array
of “non-criteria” obstetric morbidities and diverse non-classical aPL, or
low titres of accepted aPL — aCL, and antiβ2-GPI antibodies — have
been proposed by an increasing number of colleagues [15–21]. Thus,
the recent 14th International Congress on Antiphospholipid Antibodies
Task Force Report on Obstetric APS concluded that there is a paucity of
data on several OAPS-related concerns, and that new information
should be obtained, mainly through randomised clinical trials and
large series of patients recruited from multicentre registries [14]. In an
attempt to confirm the hypothesis that OAPS exist as a separate form
of “classical” APS, we assessed the clinical features, laboratory data,
247 women with pure OAPS.
2. Patients and methods
2.1. Patients
Given the scarcity of OAPS cases, it was considered useful to have ac-
cess to a single, homogeneous database in a multicentre European Reg-
istry where physicians could send, consult or insert patient data to
facilitate and further understanding of several existing gaps associated
with aPL-related obstetric syndromes.
From June 2010, the ad-hoc website and database have been accessi-
ble and ongoing. Since then, patients have been included systematically,
both retrospectively and prospectively, as stated previously [www.
euroaps.org]. All information regarding this project can also be found
on the website.
2.2. Study design
Ten tertiary referral centres at universities in five European countries
are participating in the Registry. Staff at all centres are experienced in the
management of patients with APS/OAPS. To date, the cohort has
consisted of 338 cases, 91 of which were excluded after a thorough revi-
sion and 247 met the proposed Sydney classification criteria. The women
were treated at the previously-mentioned hospitals on an inpatient or
outpatient basis. Rheumatology, internal medicine, haematology, auto-
immune and obstetrics are the departments attending to these women.
Data will be obtained from a standardised form registered in the data-
base containing several items (www.euroaps.org). A limited “obligatory”
number of items (clinical and laboratory) were suggested. Participants
were encouraged to include both complete (pure OAPS) and incomplete
cases. These incomplete cases (91 women) will be analysed further else-
where. All recruited cases and participating hospitals received a numeric
 J. Alijotas-Reig et al. / Autoimmunity Reviews 14 (2015) 387–395
code to ensure privacy and personal data protection. This centralised
Registry was approved by the Review Board and Ethics Committee of
the Vall d'Hebron University Hospital and the University Departments
of Medicine and Obstetrics of the Universitat Autònoma de Barcelona.
The standardised forms once completed could be returned by post or
e-mail.
2.2.1. Inclusion clinical criteria
Only women with pregnancy morbidity included in the APS Sydney
classification criteria [22] with no history of previous documented
thrombotic events (at least 1 clinical episode of venous, arterial or
small vessel thrombosis, in any tissue or organ except the placenta,
with thrombosis being confirmed by objective validated criteria) or
the evidence of any kind of treatment given previously that could
suppose the existence of a thrombotic event, such as full-dose anticoag-
ulants in at least the previous 5 years before entering this study, were
included.
Each case — woman — may have had one or more episodes. Similarly,
all previous obstetric events suffered by each woman are considered.
This Registry accepts, preferably, women diagnosed of OAPS in the last
five years and at present. Thus, the study is in part retrospective and
prospective.
2.2.2. Inclusion laboratory criteria
Standard laboratory criteria according to Sydney recommendations
(lupus anticoagulant; anticardiolipin antibodies (aCL), IgG and IgM
isotypes and antiβeta2glycoprotein-I antibodies (antiβ2GPI) IgG and
IgM isotypes), tested positive at least twice, were mandatory for inclu-
sion and classified as follows:
Category I (more than one aPL positivity); Category II (only one aPL
positivity); IIa: LA+; IIb: aCL IgG/IgM+; IIc: anti B2 GPI IgG/IgM+.
2.2.3. Exclusion clinical criteria
Women did not have the obstetric morbidity defined in the Sydney
criteria i.e. women with fewer than three miscarriages before
10 weeks of gestation or placental insufficiency with pre-eclampsia be-
yond 34 weeks of gestation.
Women with pregnancy losses explained by infectious, metabolic,
anatomic or hormonal factors or maternal and paternal chromosomal
causes were also excluded.
Women with a history of HBV, HCV, HIV infection as well as those
with non-organ systemic autoimmune diseases were also excluded.
2.2.4. Exclusion laboratory criteria
Non-standard aPL types i.e. aPT/aFS antibodies, isotypes i.e. IgA, and
low aPL titers are according to the Sydney laboratory recommendations.
Women with inherited thrombophilic abnormalities were not excluded
(vide infra).
2.2.5. Other laboratory analysed parameters
Other laboratory items included and analysed in this registry were:
serum protein electrophoresis, C3 and C4 complement levels, antinuclear
antibodies (ANAs), ds-antiDNA antibodies and antithyroid antibodies.
Some women were also analysed for antibodies to extractable nuclear
antigens i.e. Ro/La/RNP/Sm and inherited thrombophilia: protein S,
protein C, antithrombin, resistance to activated C protein, homocysteine
and gene polymorphisms of methylen-tetrahydropholate reductase
(MTHFR), FII G20210A and FV Leiden mutations. Several cases were
also tested for PA1-I mutation.
2.2.6. Miscellaneous
Three different heparin prophylactic dose levels were defined: low,
medium and high prophylactic doses, together with therapeutic doses.
Since almost all women treated with LMWH were put on enoxaparin,
these types of doses were defined as low prophylactic 20 mg/day;
389
medium: 40 mg/day, and high: 1 mg/kg/day. Therapeutic doses mean
the administration of 1 mg/kg/bid.
2.3. Assays
Screening assays were used to detect LA according to the Sydney rec-
ommendations of the ISTH Subcommittee. Plasma aCL-IgG/IgM and
antiβ2GPI IgG/IgM antibody titers were usually determined by com-
mercial ELISA methods. In several cases, an in-house ELISA was used.
The results of aCL were expressed as immunoglobulin G phospholipid
(GPL) or immunoglobulin M phospholipid (MPL) using international
reference material. The results of antiβ2GPI IgG/IgM assays were calcu-
lated arbitrary units using a standard curves obtained from a pool of
positive samples that accurately calibrates.
In accordance with Sapporo recommendations, all plasmas were
analysed for the four-solid-phase aPL antibody by methods based on
calibration curves established using the Sapporo standards [23]. The
cut-off values used for medium/high titres of aCL antibodies were 40
GPL and/or MPL before February 2006. Beginning in February 2006, in
accordance with the Sydney classification criteria, the cut-off values
used for medium/high titres for both aCL and antiβ2GPI antibodies
were calculated using either the Sapporo standards or the 99th percen-
tile obtained by testing age-matched healthy women. aPL positivity
had to have been present at least twice, with a minimum interval of
12 weeks.
Antinuclear antibodies (ANA) were determined by indirect immu-
nofluorescence on mouse liver and HEp-2 cell substrate. AntidsDNA an-
tibodies were determined by ELISA or indirect immunofluorescence on
Crithidia luciliae substrate. Precipitating antibodies to extractable nucle-
ar antigens, including Ro/SSA, La/SSB, U1-RNP, and Sm, were detected
by ELISA and counter-immunoelectrophoresis when necessary. Com-
plement protein levels were analysed by nephelometry.
Proteins (AT, PS, PC), resistance to activated C protein, and FII, FV,
MTHFR, PAI-1 mutations were measured using standard methods.
3. Statistical analysis
Values are expressed as the mean, standard deviation, median, 25th
and 75th percentiles (Q1 and Q3, respectively), sum and extreme values
(minimum and maximum) for continuous variables and number and
percentages for qualitative variables. A Student's t-test was used to com-
pare values following normal distribution, while a Mann–Whitney–
Wilcoxon's test or Kruskal–Wallis test was used for data not following
a normal distribution. A chi-squared (χ2) test and Fisher exact test was
used to compare categorical variables. Univariate logistic regression
analysis was used to estimate the risks of analytical parameters in the
presence of the studied morbidities. The statistical software SAS
(ver. 9.3) was used to analyse the datasets.
4. Results
4.1. Patient baseline clinical characteristics
The general and demographic characteristics of the analysed group
are depicted in Table 1. Briefly, 338 women who had had 1253 obstetric
episodes were included; and 915 episodes were historical. 247 of 338
women (73%) fulfilled the Sydney classification criteria. From then on,
these 247 cases were studied. These women were largely Caucasian
(89%) and, reproductively speaking, tended to be older (mean ± SD:
39.18 ± 6.0 years); 22.7% were smokers. On the other hand, five (2%)
had type I diabetes and 30 (12%) clinical or subclinical autoimmune thy-
roid abnormalities, mainly clinical or subclinical hypothyroidism. Re-
garding their previous obstetric morbidity, 54% had had RM, 31%
foetal loss, 1% stillbirth and 5.2% premature birth. 9% of women suffered
diverse morbidity combinations. Regarding their latest obstetric com-
plications, a list of them is detailed in Table 2.
390 J. Alijotas-Reig et al. / Autoimmunity Reviews 14 (2015) 387–395

4.2. Laboratory characteristics and obstetric-related morbidities Table 2

Detailed current⁎ obstetric complications in this OAPS series (N=247).

4.2.1. Laboratory categories Complications N (%)

Laboratory categories of the latest episodes and their relationship No 118 (47.8)
with the main OAPS-related complications are shown in Tables 3 and Yes 129 (52.2)
4. In brief, 84/247 women (34%) were in category I: 58/84 (69%) showed Prematurity 61 (47.3)
double and 26/84 (31%) triple positivity; and 163/247 (66%) fell into Stillbirth & Fetal Loss 29 (22.5)
Miscarriage (latest) 21 (16.3)
category II. The most frequent category II subset was IIb (aCL) (66/
FGR early onset 18 (14.0)
163; 40.5%). It is also noteworthy that 55/163 (33.7%) fell into category Preeclampsia early onset 17 (13.2)
IIc. Overall, all categories were represented and category II contained al- Preeclampsia late onset 16 (12.4)
most double the number of those in category I, with RM, foetal losses Prematurity & Preeclampsia early onset/HELLP 15 (11.6)
and stillbirths being the most frequent in category I. Table 5 shows in Prematurity & FGR early onset 9 (7.0)
HELLP 7 (5.4)
detail the odds ratio and statistical significances among all the different Abnormal uterine blood flow 7 (5.4)
obstetric complications and the aPL type and isotype panel. Briefly, Cord blood flow restriction 4 (3.1)
when logistic regression was conducted, strong correlations between Abruptio placentae 5 (3.8)
categories I and IIa and practically all the obstetric complications i.e. Prematurity & FGR & Preeclampsia/HELLP 4 (3.1)
Abnormal middle cerebral artery blood flow 4 (3.1)
recurrent miscarriages (OR: 1.22), foetal loss (OR: 6.89), early-onset
FGR late onset 2 (1.6)
PE/HELLP (OR: 2.76), prematurity (OR: 3) and FGR (OR: 2.5) were ob- Placental haematoma 1 (0.8)
tained. By contrast, no associations were observed between categories
⁎ Latest pregnancy. The majority of women were under any treatment.
IIb and IIc and those poor obstetric outcomes.
Although this manuscript did not aim to analyse in depth the histor-
ical poor obstetric complications of this cohort of women, the mean data 4.2.3. Associated inherited clot pathway disorders
related to previous obstetric episodes and their laboratory aPL category We had data in 145 cases. Inherited thrombophilia was positive in
are shown in Table 6. Briefly, recurrent miscarriage before 10 weeks was 39/145 (26.9%) women, including those who tested positive for hetero-
the most prevalent obstetric complication (53.8%), followed by foetal zygosis C677T-MTHFR (4 cases). When this polymorphism was not con-
loss (31.2%). Regarding laboratory categories, class II was overall the sidered, the overall prevalence was 35/145 (24.13%) cases. In all, 20
most prevalent since all three subcategories were represented. women had activated C-protein resistance/Factor V Leyden mutation;
7 PS deficiency, 4 homozygosity for C667T-MTHFR, and 2 FII-G20210A
mutation. One woman had AT deficiency, and another a PAI-1 mutation.
4.2.2. Complement pathway results Interestingly, 3 women had combined (double) inherited thrombophilic
Plasma complement levels were analysed in 201/247 (81.37%) alterations. No women showed PC deficiency in this series.
women, of whom 58/201 (29%) had low C4 levels and 22/201 (10.94%)
low C3 levels. Finally, 18/201 (8.95%) women had low C3 and C4 levels.
Overall, 98/201 (48.75%) women had low values. The relationship 4.3. Obstetric outcomes
between low complement levels, particularly with C4, and aPL laborato-
ry categories is depicted in Table 7. Obstetric and foetal outcomes are detailed in Table 8. In short, live
births were achieved in 192/247 cases (77.7%), and in 55 (22.3%) did
not. Of these 192 successful cases, 174 (89.7%) received treatment and
18 (10.3%) did not. Thirty-eight (69%) of the remaining 55 women
who did not achieve live births received treatment and 17 (31%) did
Table 1
Main demographic characteristics and obstetric background of these 247 women. not. Overall, therapeutic schedules in treated pregnant women with
eventual pregnancy failure were: previous LDA in 14/38 (36.84%);
Age (years) mean ± SD 39.18 ± 6.00
LDA during pregnancy in 100% of cases, and LDA + LMWH in 29/38
Ethnicity n (%)
African 2 (0.8) (76.31%), being non-fractionated in one case. When the relationship be-
Afro American/Caribbean 2 (0.8) tween these treated unsuccessful pregnancies and laboratory categories
American (Latino) 8 (3.2) was analysed, 19 cases (50%) fell into category I, 7 (18.42%) category IIa,
Asian 3 (1.2) 7 (18.42%) category IIb, and 5 (13.15) category IIc.
Caucasian 220 (89)
Semitic/Arab 12 (5)
Obstetric complications appeared in 129/247 (52.2%) cases, al-
Smoking habit n (%) though not all ended in foetal demise or stillbirth. Foetal loss was the
Yes 54 (22.0) most frequent (17.80%) fatal complication followed by miscarriage
No 193 (78.0) (16.27%), with stillbirth being relatively infrequent (4.69%). Prematurity
B.M.I. mean ± SD 24.82 ± 4.12
was the most common non-fatal complication (47.28%). Early and se-
Previous diseases n (%)
Thyroida 30 (12) vere pre-eclampsia together with HELLP syndrome appeared in more
Type I diabetes mellitus 5 (2) than 18% of these women. FGR complicated 15.50% of cases.
Previous poor obstetric outcome n (%)
Recurrent miscarriages b10 weeks 133 (53.8)
Foetal loss 77 (31.2)
4.4. Maternal outcomes
Stillbirth 2 (0.8)
Early pre-eclampsia/prematurity 13 (5.2)
Combination 22 (9.0%) Maternal complications and outcomes are detailed in Table 8.
Inherited thrombophiliab n (%) Maternal deaths and generalised thrombotic diathesis — catastrophic
No 106/145 (73.10)
antiphospholipid syndrome — during pregnancy and puerperium did
Yes 39/145 (26.89)
not occur. Cases of gestational venous thrombosis were scarce (1.21%).
B.M.I.: body mass index. Arterial thromboses were not reported. In the puerperal period, throm-
SD: standard deviation.
OAPS: obstetric antiphospholipid syndrome.
bosis appeared in 14 (8.52%) cases: venous in 11 (6.70%) and arterial in
a
Includes: hypothyroidism, subclinical hypothyroidism, and antithyroid antibodies. 3 (1.82%). Of these three cases, two coincided with abrupt cessation of
b
Inherited thrombophilia was analysed only in 145 women. heparin and aspirin. Affected arterial areas were middle cerebral artery
 J. Alijotas-Reig et al. / Autoimmunity Reviews 14 (2015) 387–395 391

Table 3
Laboratory categories of the Registry of women with OAPS.

Laboratory Category Class and isotype of aPL N N (%)

I⁎ 84 (34)
Triple positivity 26/84(30.95)
LA+ aCL IgG+IgM+anti-β2GPI-IgG+IgM+ 3
LA+ aCL IgG+IgM+anti-β2GPI-IgG+IgM- 2
LA+ aCL IgG+IgM+anti-β2GPI-IgG-IgM+ 4
LA+ aCL IgG+IgM- anti-β2GPI-IgG+IgM + 2
LA+ aCL IgG+IgM-anti-β2GPI-IgG+IgM- 15
LA+ aCL IgG+IgM-anti-β2GPI-IgG-IgM+ 0
LA+ aCL IgG-IgM+anti-β2GPI-IgG+IgM+ 0
LA+ aCL IgG-IgM+anti-β2GPI-IgG+IgM- 0
LA+ aCL IgG-IgM+anti-β2GPI-IgG-IgM+ 0
Double positivity 58/84(69.05)
LA + aCL IgG+IgM- 15
LA + aCL IgG-IgM+ 5
LA + aCL IgG+IgM+ 5
LA+ anti-β2GPI IgG+IgM- 3
LA + anti-β2GPI IgG-IgM+ 4
LA + anti-β2GPI IgG+IgM+ 0
aCL-IgG+IgM+anti-β2GPI IgG+IgM+ 3
aCL-IgG+IgM+anti-β2GPI IgG+IgM- 4
aCL-IgG+IgM+anti-β2GPI IgG-IgM+ 0
aCL-IgG+IgM-anti-β2GPI IgG+IgM+ 5
aCL-IgG+IgM-anti-β2GPI IgG+IgM- 11
aCL-IgG-IgM+anti-β2GPI IgG+IgM+ 1
aCL-IgG-IgM+anti-β2GPI IgG-IgM+ 1
aCL-IgG+IgM-anti-β2GPI IgG-IgM+ 1

Laboratory Category Class and isotype of aPL N(%) N (%)

II 163 (66)
IIa Lupus anticoagulant 42 (25.76)
IIb Anticardiolipin antibodies 66 (40.49)
IgG isotype 31
IgM isotype 12
IgG/IgM 23
IIc Anti-B2GPI antibodies 55 (33.16)
IgG isotype 16
IgM isotype 15
IgG/IgM 24

N: number of cases; OAPS: obstetric antiphospholipid syndrome.

⁎ : double positivity 58/84; triple positivity 26/84; aPL: antiphospholipid syndrome.

(2 cases) and brachial artery (1 case). All deep venous thromboses in-
volved femoral (6 cases) and ilio-femoral (5 cases) areas.
Few women of this cohort developed defined autoimmune diseases.
During follow-up, seven cases evolved to full-blown SLE, and SLE-like
syndrome was diagnosed in a further six cases (overall: 5.77%). Three
cases (1.33%) of autoimmune thrombocytopenia were diagnosed dur-
ing follow-up. No other autoimmune disorders were reported.
5. Analysis of treatment
Treatment data are shown in Table 9. Briefly, 213 of 247 (86.2%)
women were treated and 35 (14%) were not, or no data were available.
Interestingly, only 177 (83%) of the treated women received the LDA
plus heparin combination, and only 74 (34.7%) were put on LDA pre-
conceptionally. Daily LDA doses used were 100 mg in 98.9% of cases,
120 mg in 0.4% and 150 mg in 0.7%. Only two cases were treated with
non-fractionated heparin. LMWH was used in different schedules. Pro-
phylactic doses of LMWH were administered as follows: low-dose 47
(20.3%), medium-dose 143 (61.6%) and high-dose (1 m/kg/day) in 17
(7.3%) cases. Six cases were only treated with hydroxychloroquine or
IVIGs. As mentioned previously, the majority of cases were treated
with LMWH, with enoxaparin being the most selected. No antiFactor
Xa activity was monitored. Other drugs were used on occasions.
Drug-related adverse effects were scarce. Only two cases of
clinically-significant vaginal haemorrhage were possibly related to the
therapeutic schedule. LMWH allergy was reported in four cases. No
significant heparin-induced thrombocytopenia or thrombocytopenia-
thrombosis was reported.
6. Discussion
Between 10 and 50% of unexplained recurrent pregnancy losses are
related to positivity for aPL, with, i.e. the positivity average for LA being
8%, and rises to 30% in cases of foetal loss [23]. Thus, aPL/APS is a leading
cause of pregnancy morbidity.
Although venous and arterial thromboses have classically been re-
ported to be the most common and serious complications associated
with aPL, and the majority of these patients will have thrombotic phe-
nomena [24], complete agreement regarding these concerns is lacking.
Some clinicians and researchers are convinced that certain cases will
have only obstetric complications with no or few thrombotic, other
than placental, episodes over time [2,10–14]. Thus, the data of the
Registry support these observations. The obstetric antiphospholipid
syndrome refers to women with only obstetric aPL-related complaints
and no history of or current thrombotic events at the time of diagnosis
[1,2].
Almost 90% of women included in this Registry were Caucasian as
was to be expected, since all the hospitals referring patients to the
Registry were European. Twelve percent of women had thyroid autoim-
mune disorders, mainly subclinical hypothyroidism, the relationship of
which with recurrent first-trimester miscarriage is a matter of debate,
although the compendium of recent papers advises us to treat them
392 J. Alijotas-Reig et al. / Autoimmunity Reviews 14 (2015) 387–395

Table 4 Table 5
Recurrent miscarriage, foetal loss/stillbirth, early-onset preeclampsia, FGR and prematurity Recurrent miscarriage, foetal loss/stillbirth, early-onset preeclampsia, FGR and prematurity,
and their related laboratory categories (latest epsiodes). according to aPL pannel.

Cat. I Cat. IIa Cat. IIb Cat. IIc Variable OR 95% CI p-Value

Miscarriage Recurrent miscarriage (≥3

Total n 84 42 66 55 miscarriages b 10 weeks)
Yes n (%) 11 (13.1) 3 (7.1) 4 (6.1) 3 (5.5) LA + 0.703 0.365–1.352 0.2904
Recurrent miscarriage aCL IgG+ 1.500 0.827–2.720 0.1817
Total n 84 42 66 55 aCL IgM+ 1.245 0.659–2.355 0.4994
Yes n (%) 22 (26.2) 8 (19.0) 20 (30.3) 11 (20.0) aCL IgG+ aCL IgM+ 1.414 0.693–2.885 0.3412
Foetal loss/stillbirth AntiB2GPIgG+ 0.988 0.503–1.941 0.9725
Total n 84 42 66 55 AntiB2GPIgM+ 0.949 0.453–1.985 0.2631
Yes n (%) 10 (11.9) 6 (14.3) 7 (10.6) 5 (9.1) AntiB2GPI IgG+ IgM+ 0.615 0.255–1.485 0.2800
Early onset preeclampsia/ Double + 1.414 0.703–2.844 0.3308
HELLP Triple + 1.222 1.049–3.382 0.0505
Total n 84 42 66 55 Foetal loss/stillbirth (≥1 loss de ≥ 10 weeks)
Yes n (%) 7 (8.3) 8 (19.0) – 8 (14.5) LA + 1.152 0.683–1.941 0.5957
F.G.R. aCL IgG+ 1.416 0.840–2.387 0.1920
Total n 84 42 66 55 aCL IgM+ 1.104 0.619–1.969 0.7379
Yes n (%) 7 (8.3) 6 (14.3) 5 (7.6) 2 (3.6) aCL IgG+ aCL IgM+ 1.290 0.657–2.534 0.4598
Prematurity AntiB2GPIgG+ 1.336 0.773–2.309 0.2996
Total n 84 42 66 55 AntiB2GPIgM+ 1.500 0.815–2.760 0.1925
Yes n (%) 24 (28.6) 11 (26.2) 16 (24.2) 10 (18.2) AntiB2GPI IgG+ IgM+ 1.542 0.734–3.239 0.2529
Prematurity and F.G.R. Double + 0.874 0.478–1.600 0.6628
Total n 84 42 66 55 Triple + 6.880 1.900–24.914 0.0033
Yes n (%) 3 (3.6) 2 (4.8) 3 (4.5) 1 (1.8) Early onset preeclampsia/HELLP
Prematurity and early onset LA + 2.882 1.496–5.326 0.0016
preeclampsia/HELLP aCL IgG+ 0.344 0.175–0.387 0.0020
Total n 84 42 66 55 aCL IgM+ 0.539 0.245–1.187 0.1250
Yes n (%) 6 (7.1) 5 (11.9) – 4 (7.3) aCL IgG+ aCL IgM+ 0.334 0.113–0.984 0.4660
Prematurity and F.G.R. AntiB2GP IgG+ 0.988 0.503–1.941 0.9725
and early onset AntiB2GP IgM+ 0.949 0.453–1.985 0.8885
preeclampsia/HELLP AntiB2GPI IgG+ IgM+ 0.750 0.348–1.705 0.5494
Total n 84 42 66 55 Double + 0.770 0.348–1.705 0.5199
Yes n (%) 2 (2.4) 1 (2.4) – 1 (1.8) Triple + 1.607 0.628–4.110 0.3224
FGR
Cat: laboratory aPL category; F.G.R.: foetal growth restriction.
LA + 2.538 1.197–5.382 0.0151
aCL IgG+ 0.889 0.422–1.873 0.7568
aCL IgM+ 0.992 0.433–2.271 0.9844
aCL IgG+ aCL IgM+ 0.755 0.274–2.082 0.5869
before a new pregnancy is contemplated [25,26]. We could speculate AntiB2GPIgG+ 0.760 0.338–1.708 0.5059
AntiB2GPIgM+ 0.919 0.386–2.188 0.8486
about the role played by thyroid disorders in the obstetric outcome in
AntiB2GPI IgG+ IgM+ 0.742 0.243–2.265 0.6004
our series. To our knowledge, all women in this Registry were put on Double + 1.804 0.775–4.198 0.1710
levothyroxine when necessary. Triple + 1.600 1.017–1.251 0.0693
From the clinical point of view, the percentages of early recurrent Prematurity
LA + 2.569 1.512–4.365 0.0005
miscarriage, foetal loss, pre-eclampsia, foetal growth restriction or pre-
aCL IgG+ 1.089 0.644–1.841 0.7507
maturity in women with APS vary according to the different published aCL IgM+ 0.915 0.511–1.639 0.7654
series. The Registry data, when referred to obstetric histories, showed aCL IgG+ aCL IgM+ 0.865 0.440–1.701 0.6740
recurrent miscarriage before 10 weeks to be the most prevalent obstet- AntiB2GP IgG+ 1.097 0.635–1.894 0.7401
ric complication (53.8%), followed by foetal loss (31.2%). When data re- AntiB2GP IgM+ 0.705 0.380–1.307 0.2669
AntiB2GPI IgG+ IgM+ 1.219 0.601–2.474 0.5836
lated to the last or current pregnancy were analysed, the percentages
Double + 0.954 0.506–1.796 0.8833
changed markedly. Thus, recurrent miscarriage before 10 weeks
Univariant logístic regression for each laboratory parameter.
complicated 8.5% and foetal losses 9.3% of gestations. Severe early-
*Double+: LA+ aCL IgG and/or IgM/LA+ antiβ2GPI IgG and/or IgM/aCL IgG and/or IgM+
onset PE and related conditions such as HELLP syndrome were more anti β2GPI IgG and/or IgM.
prevalent than in the previous poor outcomes. Thus, recurrent miscar- *Triple+: LA+ aCL IgG and/or IgM+ antiβ2GPI IgG and/or IgM.
riage reflected in the Registry was higher than expected, particularly FGR: foetal growth restriction.
in non-treated women. Considering the novel data from basic science
studies previously mentioned in the Introduction, women with aPL
could have a higher rate of early pregnancy loss. Opatrny et al. [27] re-
ported a positive association between aCL-IgG with recurrent miscar- Table 6
riage before 13 weeks of gestation, including the low-aCL-IgG titres. Laboratory categories related to the historical poor obstetric outcomes (women/episodes).
Interestingly, no association was found with aCL-IgM, antiβ2GPI or LA. Category (N) RM Foetal Stillbirth ePE ePE + FGR + ePE + FGR
Moreover, other studies yielded similar results (reviewed in ref. 14). w/e loss w/e w/e w/e P w/e P w/e + P w/e
However, other authors argue the contrary [28–30]. The differences in I 84* 18/64 30/38 51/69 3/6 3/3 6/8 1/1
results of the commented studies can be partially explained by different II 163
inclusion criteria and the definition of positive laboratory aPL results. It IIa 42 8/27 14/16 18/29 1/1 0 0 0
has also been suggested that pre-embryonic and embryonic losses could IIb 66 20/82 21/29 39/60 1/1 1/1 2/2 0
IIc 55 11/35 12/13 30/40 1/1 0 2/4 0
be poor clinical markers of true aPL-related embryo-placental injury.
However, according to the Sapporo and Sydney criteria, if we are strict N: number; RM: recurrent miscarriage (three or more before 10 weeks of gestation);
ePE: early and severe pre-eclampsia; P: prematurity; FGR: foetal growth retardation;
and only cases of morphologically well-formed embryo loss are includ-
Stb: stillbirth; ePE + FGR + P: combination of all three obstetric complications; w/
ed, the probability of chromosomal abnormalities is minimised; thus, e: women/episodes.
the inclusion of recurrent losses before 10 weeks appears to be *
Double positivity 58/84; triple positivity 26/84.
 J. Alijotas-Reig et al. / Autoimmunity Reviews 14 (2015) 387–395 393

Table 7 Table 9
Relationship between low complement levels and aPL laboratory categories. Treatment schedules in this cohort of women.

Lab. categories OAPS (n:201) Drug Cases

C4 C3 C4/C3 n/N (%)

N% N N No treatment 35/247 (14.17)

Treatment 213/247 (86.20)
I (n = 84) 23/84 (27.38%) 9 10
LDA alone 22/213/247 (10.32) (8.90)
IIa (n = 42) 10/42 (23.30%) 4 4
Heparin alone 7/213/247 (3.28) (2.83)
IIb (n = 66) 13/66 (19.69%) 3 2
LMWH 5
IIc (n = 55) 12/55 (21.81%) 6 2
Unfractionated 2
Lab: laboratory; OAPS: obstetric antiphospholipid syndrome. LDA previous pregnancy 74/213/247 (34.74) (30.0%)
Total OAPS sample: 247 women. We have complement data of 201 (81.37%). 98 of them LDA during pregnancy 213/213/247 (100) (86.20)
have low C3 or C4 or C3/C4. Low C4: 58; Low C3: 22; Low C3/C4: 18. LMWH+ LDA 177/213/247 (83.09) (71.65)
Other drugs (6 cases):
Hydroxychloroquine 4/213/247 (1.87) (1.61)
IVIGs 2/213/247 (0.93) (0.80)
appropriate. Furthermore, the good outcomes of the majority of treated
cases argue in favour of their relationship. LDA: low-dose aspirin.
LMWH: low molecular weight heparin.
The Registry showed that less than one third of the historical cohort
IVIGs. intravenous immunoglobulin.
and less than 10% of the latest gestations have suffered foetal loss. This is
a well-known aPL-related complication [30]. As previously mentioned,
foetal losses were initially thought to be more frequent than early recur-
rent miscarriages. Several papers reviewed by de Jesus et al. [14] argued or not, ranging surprisingly from 12% to 100%. Once again, the timing of
the opposite: that foetal loss is less frequent than recurrent miscar- a foetus being considered a stillbirth was heterogeneous.
riages. Thus, these data concur with those of the present study. Either The relatively few cases of pre-eclampsia included in the Registry
way, it should be taken into account that several methodological gaps may be partially explained by the relatively large number of smokers.
render it difficult, therefore, to draw true conclusions, as explained in It is noteworthy that early and late-onset pre-eclampsia were clearly
the meta-analysis of Abou-Nassar et al. [31]. Sample size and laboratory separated, and only the former were included and discussed. In a previ-
methods apart, the timing of the foetal deaths under study ranged from ous study, we found a 13% antiphospholipid antibody prevalence in
8 to 22 weeks of gestation. In the Registry, foetal losses include cases women with PE-complicated pregnancy. Multipositivity for aPL, IgM-
from 10 to 24 weeks. The few cases of stillbirth observed in the Registry aCL and IgM-antiβ2GPI isotypes revealed an association with severe
ranged from 1 to 5% according to whether historical or current pregnan- and early-onset pre-eclampsia [33]. It is worthy to mention that only
cies were analysed. Recently, a multicentre, prospective study was con- 5 women suffering PE were classified into category IIb in the Registry.
ducted by The Stillbirth Collaborative Research Network [32]. Indeed, Thus the statistical results are not enough to address the risk-correlation
the results varied widely, regardless of whether the groups were treated between PE and aCL.
The Registry showed that more than one obstetric complaint arose
in 9.0% of cases.
All laboratory categories are represented in the OAPS Registry. Clas-
Table 8 sically, triple positivity has been related to clinical manifestations of
Obstetric and maternal outcomes related to this cohort of women.
APS, and aCL are poorly related to them [34]. The debate on this topic
n/N/N(%) is, therefore, ongoing. Clark et al. [35] showed that only 0.3% of
Live births 192/247 (77.74) women with early miscarriage tested positive for LA, thereby suggesting
No live births 55/247 (22.26) that it could be removed from the diagnostic panel of early recurrent
Obstetric complications 129/247 (52.2) miscarriage. However, in a previous study, we found that 1.6% women
Miscarriage 21/129/247 (16.27) (8.5)
with early miscarriage tested positive for LA [36]. In the Registry, 31%
Fetal loss 23/129/247 (17.8) (9.31)
Stillbirth 11/129/247 (8.52) (4.45) of women suffering recurrent, early miscarriage tested positive for LA,
Early-PE 17/129/247 (13.17) (6.88) 18.% were included in category I and 13% in category IIa. In the later
Late-PE 16/ 129/247(12.40) (6.47) subset, only 2 (3%) cases had only a recurrent miscarriage as clinical
HELLP 7/ 129/247(5.46) (2.83) APS-manifestation.
F.G.R 20/129/247 (15.50) (8.00)
Prematurity+PE 15/129/247 (11.60) (6.07)
Galli et al. [37], in an attempt to reduce the possible over-diagnosis
Prematurity+FGR 9/129 (7.0) (3.64) of the syndrome, argued in favour of maintaining antiβ2GPI and also
Prematurity+PE+FGR 4/129/247(3.10) (1.62) suggested that aCL should be dropped from the diagnostic laboratory
Pregnancy thrombosis panel owing to the lack of association with clinical APS-related disor-
Venous 2/164 (1.21)
ders. Similar conclusions were drawn by Lockshin et al. [38], particularly
Arterial 0/164 (-)
Puerperal thrombosis with regard to adverse pregnancy outcomes after 12 weeks' gestation.
Venous 11/164 (6.70) Similarly, IgM isotypes have rarely been detected in APS cohorts [39].
Arterial 3/164 (1.82) However, our results showed the opposite, thus all categories and
Drug-related side effects isotypes of aPL were necessary to ensure a diagnosis and, consequently,
Hemorrhages⁎ 2/164 (1.21)
provide the mother and foetus with the benefit of treatment. Thus, aCL
LMWH allergy 4/225 (1.77)
TTS-related to LMWH 0 / (0) (category IIb) are positive as an isolated marker in nearly 27% of cases.
Evolvement into systemic diseases The same can be said for the value of antiβ2GPI (category IIc) that has
S.L.E. 7/225 (3.11) been strongly debated; however, evidence of the antiβ2GPI-obstetric
S.L.E-like 6/225 (2.66)
morbidity relationship is growing. Similarly, the data Registry shows
I.T.P. 3/225 (1.33)
that 22% of cases have only antiβ2GPI antibodies in a recurrent manner
S.L.E: Systemic lupus Erythematosus; S.L.E-like: women resembling having SLE but do not as an aPL marker. Finally, IgM isotype — aCL or antiβ2GPI — accounts for
fulfill the current classification criteria; I.T.P: immune thrombocytopenic purpura. TTS:
thrombocytopenia-thrombosis syndrome related to heparin.
27 cases as the only and recurrent aPL marker. These observations
⁎ : clinically significant bleeding after delivery (no-spontaneous hemorrhages were concur with the results published by other researchers reporting that
communicated). all aPL markers are necessary for the right APS classification [38,40].
394 J. Alijotas-Reig et al. / Autoimmunity Reviews 14 (2015) 387–395
As previously mentioned, LA and triple aPL positivity have been related
to worse outcomes in APS patients [34,41,42]. Similarly, our data
showed a good statistical significance between LA+ and/or triple aPL-
positivity and all-related obstetric complications. In a large European se-
ries, Cervera et al. [43] failed to find risk correlations among different
aPL markers; however, all aPL markers were also associated with
pregnancy loss.
Although complement data of all included cases were not avail-
able, the value of complement levels in these women with OAPS
merits a mention: almost half the women in the Registry had low
plasma levels, particularly at the expense of C4. Recent data showed
the major role played by complement pathway in the pathogenesis
of OAPS [4,6,11].
Interestingly, 24% of APS cases had inherited thrombophilic disorder
(ITD). All but three showed only one thrombophilic alteration. These re-
sults concur with the general prevalence in Caucasian series, and in
studies performed in APS patients [44]. The role played by the associa-
tion of ITD and aPL/APS is controversial. Diz-Kucukkaya et al. [45] stated
that the presence of FV Leiden may define a small subgroup of APS pa-
tients with a higher thrombotic risk. Similar results have been reported
by other authors [46]. Forastiero et al. [47] demonstrated that patients
with ITD and aPL positivity are prone to developing full-blown APS. By
contrast, Berman et al. [48] were unable to find an increased thrombotic
risk with the association of ITD and aPL positivity. In our series, even
though the prevalence of ITD was relatively high, the number of throm-
botic events was very low. Thus, we are not able to address this concern,
since this registry was not powered to do so. Finally, to our knowledge,
data concerning obstetric outcomes in APS women are lacking.
The Registry data revealed very good maternal and foetal outcomes
when LDA plus LMHW were administered. Almost 78% of pregnancies
ended in live births; however, it is noteworthy that complications oc-
curred in over half even though they were treated. Surprisingly, almost
20% of women in the Registry were treated inappropriately. According
to the recent data on OAPS pathology, we believe that treatment should
be started as early as possible. In our series, only 30% of women were
put on LDA before their next pregnancy. Overall, the therapeutic ap-
proaches clearly need to be improved.
The EUROAPS registry showed a low prevalence of maternal
thrombosis and the progression to autoimmune disease, particularly
SLE, compared with classical APS [2].
The Registry has some weak points. First of all, the inclusion of
methods that merge retrospective and prospective cases could raise
concerns for data analysis and therefore, to avoid them, only the data
of the latest pregnancy of each woman were fully analysed. Secondly,
aPL test results are difficult to interpret in certain cases since different
commercial and home-made methods were used. Conversely, the inclu-
sion of laboratory data from different centres could also avoid a possible
bias attributable to one or few laboratories.
Regarding the strong points, the number of pure obstetric APS cases
studied — 247 — with more than 900 historical episodes represents one
of the largest series in this field. Finally, the inclusion of patients from
multiple centres enriches the Registry and minimises any bias that
may arise when results are provided by a single centre.
7. Conclusion
Recurrent first trimester miscarriage followed by foetal loss was the
most common obstetric morbidities in this cohort. Diverse obstetric
complications appeared in half the cases; fortunately, many of them
did not end in foetal death.
All laboratory categories and isotypes are represented in the registry,
being necessary to avoid false-negative diagnoses. In the same way,
strong correlations between categories I and/or IIa and practically all
the obstetric complications were obtained. By contrast, no correlations
were observed between categories IIb and IIc and those poor obstetric
outcomes. Low complement levels were found in almost 50% of cases,
showing classic complement pathway activation. Maternal and foetal
outcomes were good when the currently accepted treatment was
given; however, no effort should be spared to improve these recom-
mendations. Thrombosis and progression to SLE in mothers with OAPS
are scarce compared with “classical APS”. All in all, these results suggest
that differences between classical APS and OAPS may exist, and these
aPL-related clinical subsets could really be mediated by different
mechanisms.
Nevertheless, more cases should be analysed before new recom-
mendations regarding this topic can be made, particularly regarding
clinical and laboratory classification criteria.
The EUROAPS project is ongoing. We considered that the mainte-
nance of the Registry could be very useful in order to have a unique
and homogeneous data bank where all of us were able to introduce,
send or consult data about patients. These data might facilitate the un-
derstanding of several existing gaps associated with aPL-related obstet-
ric syndromes.
Take-home messages
• Obstetric APS is a specific subset within the APS box. Maternal throm-
bosis and progression to SLE are scarce.
• All obstetric complications are well represented in this series.
• All laboratory test categories are needed to avoid false-negative
diagnoses.
• The stronger laboratory risk markers are: LA and triple positivity.
• LMWH plus LDA achieve 80% of live births, with few maternal
complications.
Conflict of interests
The authors declare that there is no conflict of interest.
Funding/financial support
The authors stated that ONAGRUP (01/2009/298) (Barcelona, Spain)
is supporting the EUROAPS project.
IRB approval
This study (EUROAPS) was approved by the Ethics Committee of the
Vall d'Hebron University Hospital (CEIC-HUVH) as well as by the
University Departments of Medicine and Obstetrics, Gynaecology and
Paediatrics of the Universitat Autònoma de Barcelona, Spain.
Acknowledgements
The authors thank Ms. Christine O'Hara for reviewing and correcting
the English style and grammar of the manuscript.
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