Amelia Ruffatti1 Marta Tonello1 Ariela Hoxha1 Savino Sciascia2 Maria J. Cuadrado2 José O. Latino3 Sebastian Udry3 Tatiana Reshetnyak4 Nathalie Costedoat-Chalumeau5,6,7 Nathalie Morel5,6 Luca Marozio8 Angela Tincani9 Laura Andreoli9 Ewa Haladyj10 Pier L. Meroni11,12,13 Maria Gerosa11,12,13 Jaume Alijotas-Reig14,15 Sara Tenti16 Karoline Mayer-Pickel17 Michal J. Simchen18 Maria T. Bertero19 Sara De Carolis20 Véronique Ramoni21 Arsène Mekinian22 Elvira Grandone23 Aldo Maina24 Fátima Serrano25 Vittorio Pengo1,26 Munther A. Khamashta2,27,28
1Rheumatology Unit, Department of Medicine, University of Padua, Padua, Italy
2 Louise Coote Lupus Unit, Guy’s and St Thomas’ NHS Foundation Trust, St Thomas’ Hospital, London, United Kingdom
3Autoimmune,Thrombophilic Diseases and Pregnancy Division, Dr. Carlos G Durand Hospital, Buenos Aires, Argentina
4Department of Systemic Rheumatic Disease, V.A. Nasonova Research Institute of Rheumatology, Moscow, Russia
5AP-HP, Cochin Hospital, Internal Medicine Department, Centre de Référence Maladies Auto-immunes et Systémiques Rares, Paris, France
6Université Paris Descartes, Sorbonne Paris Cité, Paris, France
7 INSERM U 1153, Centre for Epidemiology and Statistics, Sorbonne Paris Cité (CRESS), Paris, France
8Department of Obstetrics and Gynaecology, Università di Torino, Torino, Italy
9Rheumatology and Clinical Immunology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Spedali Civili, Brescia, Italy
10Department of Connective Tissue Diseases, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland
11Division of Rheumatology, G. Pini Institute, Milan
12Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
13 Istituto Auxologico IRCCS, Milan, Italy
14 Systemic Autoimmune Diseases Unit, Department of Medicine, Vall
d’Hebron University Hospital, Barcelona, Spain
15Department of Medicine, Faculty of Medicine, Universitat
Autònoma, Barcelona, Spain
16Department of Medicine, Surgery and Neuroscience,
Rheumatology Unit, University of Siena, Siena, Italy
17Department of Obstetrics, Medical University Graz, Graz, Austria
18Maternal-Fetal Medicine, Department of Obstetrics and
Gynecology, Sheba Medical Centre, Tel Hashomer, Israel
19Clinical Immunology, AO Ordine Mauriziano, Torino, Italy
20Department of Obstetrics and Gynecology, Catholic University of Sacred Heart, Rome, Italy
21Division of Rheumatology, IRCCS Policlinico S. Matteo, Pavia, Italy
22 Service de Médecine Interne et l’inflammation-(DHU i2B), Hôpital Saint-Antoine, Université Paris 06, Paris, France
23Atherosclerosis and Thrombosis Unit, I.R.C.C.S. Casa Sollievo della Sofferenza, S. Giovanni Rotondo, Foggia, Italy
24 Servizio di Medicina Interna, Ospedale Sant’Anna, Torino, Italy
25Department of Obstetrics and Gynecology, Centro Hospitalar de Lisboa Central, NOVA Medical School, Universidade Nova de Lisboa, Lisbon, Portugal
26Cardiology Clinic, Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy
27 Lupus Research Unit, The Rayne Institute, Division of Women’s Health, St Thomas Hospital, London, United Kingdom
28Department of Rheumatology, Dubai Hospital, Dubai, United Arab Emirates Thromb Haemost Address for correspondence Prof. Amelia Ruffatti, Reumatologia, Palasanità, Via Giustiniani, 2 – 35128 Padova, Italy
(e-mail: amelia.ruffatti@unipd.it). received
August 23, 2017
accepted after revision
January 5, 2018
Copyright © Schattauer DOI https://doi.org/
10.1055/s-0038-1632388.
ISSN 0340-6245.
Coagulation and Fibrinolysis
Introduction
A heparin–aspirin combination constitutes the conventional treatment protocol for pregnant women affected with antiphospholipid syndrome (APS). As these strategies fail in approximately 20 to 30% of cases,1 uncovering other options for women refractory to conventional treatment or at high risk of pregnancy complications has become an urgent undertaking.
High-risk antiphospholipid antibody (aPL) profiles seem to be linked to specific serological markers such as multiple aPL positivity2–4 and, in particular, to contemporaneous positivity to all three aPL assays,5–8 to lupus nticoagulant
(LAC) activity9 or to high aPL titers.10,11 Moreover, some well-defined clinical features such as a history of
thromboembolism3,5,7,12–14 and/or the presence of a systemic autoimmune disease7,9,15,16 have been found to be associated with severe maternal–foetal complications in pregnant APS women receiving conventional therapy. Several experts are convinced that in association with conventional therapy, these
high-risk APS patients should also be prescribed additional treatments before/during pregnancy in the effort to improve live birth rates and/or reduce pregnancy complications which often occur despite conventional treatment.14 Treatments prescribed in addition to conventional therapy, which currently include intravenous immunoglobulins (IVIGs), lowdose steroids, plasma exchange or hydroxychloroquine (HCQ), have produced variable results.17,18
A retrospective, multicentre study recently reported that pregnant APS patients with previous thrombosis and triple aPL positivity treated with additional therapy had significantly higher live birth rates with respect to those receiving conventional therapy alone.18A variety of additional therapies including IVIG infusions, plasma exchange and low-dose steroids, alone or combined, were evaluated in that study, but it was impossible to analyse each therapy singularly, as the number of patients studied was insufficient to draw any significant conclusions.18 The current, large, multicentre, observational,
retrospective study set out in that study’s footsteps to investigate the effect of various additional treatments on pregnancy
outcomes in primary APS (PAPS) women refractory to conventional
therapy and/or with risk factors for pregnancy
complications to identify the most efficacious ones.
Materials and Methods
Study Population
Only patients who fulfilled—at the time they were diagnosed
with PAPS—the clinical and laboratory classification criteria
established by the International Consensus in 200419 were
retrospectively enrolled in the study.
Patients fulfilling both the laboratory and clinical criteria
were enrolled: (1) Laboratory criteria referred to laboratory
risk factors, that is a positivity to LAC alone or associated
with IgG/IgM anticardiolipin (aCL) and/or with IgG/IgM antiβ2-glycoprotein
I (anti-β2GPI) antibodies. In accordance with
data in the literature, the following types of aPL profiles were
considered laboratory risk factors: triple aPL positivity5–8
and double/single aPL positivity always including the presence
of LAC.9 At least two consecutive positive antibody
results more than 12 weeks apart were needed to meet this
Keywords
► antiphospholipid
syndrome
► hydroxychloroquine
► low-dose steroids
► intravenous
immunoglobulins
► plasma exchange
Abstract The effect of additional treatments combined with conventional therapy on pregnancy
outcomes was examined in high-risk primary antiphospholipid syndrome (PAPS)
patients to identify the most effective treatment strategy. The study’s inclusion criteria
were (1) positivity to lupus anticoagulant alone or associated with anticardiolipin and/
or anti-β2 glycoprotein I antibodies; (2) a history of severe maternal–foetal complications
(Group I) or a history of one or more pregnancies refractory to conventional
therapy leading to unexplained foetal deaths not associated with severe maternal–
foetal complications (Group II). Two different additional treatments were considered:
oral—low-dose steroids (10–20 mg prednisone daily) and/or 200 to 400 mg daily doses
of hydroxychloroquine and parenteral—intravenous immunoglobulins at 2 g/kg per
month and/or plasma exchange. The study’s primary outcomes were live birth rates
and pregnancy complications. A total of 194 pregnant PAPS patients attending 20
tertiary centres were retrospectively enrolled. Hydroxychloroquine was found to be
linked to a significantly higher live birth rate with respect to the other oral treatments in
the Group II patients. The high (400 mg) versus low (200 mg) doses of hydroxychloroquine
(p ¼ 0.036) and its administration before versus during pregnancy (p ¼ 0.021)
were associated with a significantly higher live birth rate. Hydroxychloroquine therapy
appeared particularly efficacious in the PAPS patients without previous thrombosis.
Parenteral treatments were associated with a significantly higher live birth rate with
respect to the oral ones (p ¼ 0.037), particularly in the Group I patients. In conclusion,
some additional treatments were found to be safe and efficacious in high-risk PAPS
pregnant women.
Thrombosis and Haemostasis
Additional Therapy in High-Risk APS Pregnancies Ruffatti et al.
requirement. (2) Clinical criteria referred to one or more of
the following: a history of maternal thrombosis and/or
previous severe pregnancy complications including eclampsia,
severe preeclampsia (arterial pressure 160/110 and
proteinuria 5 g in a 24-hour urine sample), haemolysis,
elevated liver enzymes, low platelets (HELLP) syndrome,
intrauterine growth restriction (IUGR—a postnatal birth
weight less than the 10th percentile for the gestational
age) and/or a previous pregnancy refractory to conventional
therapy leading to an unexplained foetal death at or beyond
the 10th week of gestation not associated with severe
pregnancy complications.
Patients with any of the following criteria were excluded:
(1) a previous conventionally treated pregnancy that led to a
live birth; (2) the presence of a well-defined associated
autoimmune systemic disease including systemic lupus
erythematosus; (3) age 45 years; (4) single or multiple
organ failure; (5) severe pulmonary hypertension; (6) other
known causes of pregnancy failure.
In addition to conventional therapy (prophylactic or
therapeutic doses of heparin þ low-dose aspirin), the following
treatments were administered: oral treatments such
as low-dose steroids (10–20 mg prednisone daily) and/or a
200 to 400 mg dose of HCQ daily or parenteral treatments
such as IVIG (2 g/kg per month) and/or plasma exchange
administered following a defined timetable. As no controlled
clinical trials have as yet confirmed the efficacy of any
additional therapy, treatment decisions tended to be based
on the opinion and personal experience of the attending
physician, and the patient’s clinical history in this context
could seem more important than a particular aPL profile.
To facilitate statistical analysis, the patients studied were
arbitrarily classified into two groups depending exclusively
on their clinical features: 154 patients (79.4%) who presented
more severe clinical features such as a history of
thrombosis and/or severe pregnancy complications including
eclampsia, severe preeclampsia, HELLP syndrome and
IUGR were assigned to Group 1; 40 patients (20.6%) who
presented less severe clinical features such as a history of one
or more pregnancies refractory to conventional treatment
leading to unexplained foetal deaths not associated with
severe pregnancy complications were assigned to Group II.
The study’s primary outcomes were the live birth rate
(i.e., the number of live newborns surviving the first 27 days
after birth) and severe pregnancy complications. The mean
week of gestation at delivery, the mean birth weight in
percentiles and the number of neonatal complications
were the secondary outcomes.
The Institutional Review Board for Observational Studies
and the Audit Committee of the University of Padua’s Medical
Centre approved the study design. Patients who fulfilled the
inclusion requirements were contacted and asked to sign
informed consent forms. Their medical records were then
retrieved and reviewed.
Antibody Detection
Five of the participating centres used a home-made enzymelinked
immunosorbent assay (ELISA) in accordance with the
minimal requirements proposed by the European Forum on
Antiphospholipid Antibodies to determine aCL and antiβ2GPI
antibodies of IgG and IgM isotypes.20,21 The other 15
centres that determined IgG/IgM aCL and anti-β2GPI antibodies
using commercial kits were recommended to follow
the manufacturers’ directions in particular with regard to the
less than 10% inter- and intra-run coefficient of variability.
LAC was assessed by multiple coagulation tests using platelet-poor
plasma samples, following internationally accepted
guidelines.22,23
Statistical Analysis
The effects of each additional treatment were analysed separately
in the two groups. The associations between the treatments
and the primary outcomes were analysed using
Pearson’s chi square test and Fisher’s exact test. The Kruskal–Wallis
test with multiple pairwise comparisons was used
to analyse the continuous secondary outcomes. The Bonferroni
correction was used in all the multiple comparisons in which
the contingency table was larger than 2 rows 2 columns.
Multiple comparisons of the primary and secondary outcomes
in relation to the additional treatments were performed
correcting the p-value using the Bonferroni adjustment. Backward
conditional logistic regression analysis that was adjusted
for confounding factors including disease duration, maternal
age 35 years, congenital risk factors (factor V Leiden, prothrombin
G20210A mutation, decrease in C and S protein
antigens and activities, antithrombin III deficiency and
increased activated protein C resistance), hypertension (blood
pressure >140/90 mm Hg or use of antihypertensive drugs),
body mass index 30 kg/m2
, aCL, anti-β2GPI and other autoantibodies
was performed to evaluate the independent role of
the additional treatments on the primary outcomes. A p-value
<0.05 was considered significant. Statistical analysis was
performed using the SPSS Statistics version 24 software.
Results
Between 1999 and 2016, a total of 194 pregnant PAPS
patients (mean age ¼ 32.05 years 5.02 SD, range ¼ 17–
44, mean disease duration ¼ 5.01 years 4.5 SD, range
¼ 0–16) attending 20 international centres belonging to
the European Forum on Antiphospholipid Antibodies network
were retrospectively assessed. For 44 of the women
(22.7%), it was the first pregnancy. One hundred fifty (77.3%)
had a history of pregnancy morbidity; in 81 cases (54%), the
pregnancy ended in foetal death, 45 (30%) premature birth
and 14 (9.3%) early miscarriage, and for 10 (6.6%) in a
combination of these. The precedent pregnancy had been
untreated in 18 cases (12%), and it was refractory to conventional
therapy in 132 cases (88%).
One hundred twenty-seven of the PAPS patients (65.5%)
had triple aPL positivity (IgG/IgM aCL plus IgG/IgM antiβ2GPI
antibodies plus LAC) and 67 (34.5%) had LAC alone or
associated with IgG/IgM aCL or IgG/IgM anti-β2GPI antibodies.
Group I comprised 154 patients (79.4%): 76 (49.3%) had
a history of thrombosis, 44 (28.6%) had previous severe
pregnancy complications and 34 (22.1%) suffered from
Thrombosis and Haemostasis
Additional Therapy in High-Risk APS Pregnancies Ruffatti et al.
both complications. Group II comprised 40 patients (20.6%):
all had a previous foetal death refractory to conventional
therapy not associated with severe obstetrical complications.
All 194 pregnant PAPS patients were administered other
treatments in addition to conventional therapy. One hundred
forty-nine (76.8%) received oral additional treatments: 94
HCQ (63.1%), 36 low-dose steroids (24.2%) and 19 both
(12.7%). Forty-five (23.2%) were prescribed parenteral treatments:
16 IVIG (35.5%), 8 plasma exchange (17.7%), and 21
both (46.6%). Additional treatments were initiated before
pregnancy in 112 cases (57.7%) and during pregnancy in 82
(42.3%). Although no major side-effects were registered in
association with the various types of treatments, one patient
discontinued HCQ at the 12th week of gestation due to
diffuse dermatitis.
One hundred sixty-three pregnancies (84%) ended favourably
producing 164 live infants including one set of twins, all
born between the 24 and 41 weeks of gestation (mean
35.7 3.3 SD). There were 115 (70.5%) caesarean deliveries
and 48 (29.4%) vaginal ones. Thirty-five infants (21.3%) were
born in less than 34 weeks of gestation and 91 (55.5%) infants
were born in 37weeks of gestation. The infants (84 males
and 80 females) had a mean birth weight of 2,638.2 g 733.9
SD (range: 600–3,950) and a mean of 42.2 percentiles 28.1
SD (range: 2–99). The infants’ mean Apgar score at 5 minutes
was 8.8 1.2 SD (range: 3–10). Thirty-one (15.9%) of the
pregnancies had negative outcomes: 19 foetal deaths
(61.3%), 7 earlymiscarriages (22.6%) and 5 premature neonates
(16.1%) who died during the perinatal period.
There were 59 cases (30.4%) of severe pregnancy complications:
16 (27.1%) had eclampsia or severe preeclampsia, 16
(27.1%) had IUGR, 6 (10.2%) had HELLP syndrome, 3 (5.1%)
had vascular thrombosis and 2 (3.4%) had catastrophic APS
during puerperium. There were multiple complications in 16
cases (27.1%). There were 43 out of 149 (28.9%) pregnancy
complications during oral treatment and 16 out of 45 (35.5%)
during parenteral treatment; the difference was not signifi-
cant (p ¼ 0.502). There was also no significant difference in
the two patient groups in the frequency of each type of
pregnancy complication.
Neonatal complications were recorded in 19 cases
(11.6%): 12 had respiratory distress (63.2%), 4 had infections
(21.0%), 1 had West’s syndrome (5.3%; in this case, the
mother had received low-dose steroid), 1 had multiple
malformations (5.3%; in this case, the mother had received
low-dose steroid) and 1 had intra-lobar pulmonary sequestration
(5.3%), which was excised without complications
9 months after birth (in this case, the mother had been
prescribed plasma exchange and IVIG).
The Effect of the Different Additional Treatments
The live birth rate and severe pregnancy complications (the
primary outcomes) were first analysed in relation to the oral
and parenteral treatments (►Table 1). Parenteral therapies
produced a significantly higher live birth rate with respect to
oral treatments (p ¼ 0.037), but only when the patients were
considered together. The level of significance was higher in the
group I patients (Group I: p ¼ 0.083 vs. Group II: p ¼ 0.596).
As far as the primary outcomes linked to the different oral
treatments (►Table 2) were concerned, HCQ therapy administered
alone was associated with a significantly higher live
birth rate with respect to both low-dose steroid alone and
HCQ þ low-dose steroid treatments in all the patients considered
together (p ¼ 0.027) as well as in the Group II
patients considered separately (p ¼ 0.017). Severe pregnancy
complications were significantly less frequent in the
HCQ-treated patients (p ¼ 0.008) with respect to the other
oral therapies-treated patients. This latter HCQ’s effect was
more evident in the Group II (p ¼ 0.008) than in the Group I
(p ¼ 0.042) patients. Four hundred milligram daily doses of
HCQ versus 200 mg doses (p ¼ 0.036) and its administration
before versus during pregnancy (p ¼ 0.021) were associated
with a significant increase in the live birth rate (►Table 3).
When drug dosage was not considered, no statistically significant
differences were found in the live birth rate between
the patients who started HCQ before or during pregnancy
Table 1 Live birth rate and pregnancy complications in PAPS patients receiving additional oral and parenteral treatments
Pregnant PAPS
patients
Oral treatments Parenteral treatments p
No. % No. %
Live birth rate
All patients: 194 121/149 81.2 42/45 93.3 0.037a
Group I: 154 92/111 82.9 40/43 93.0 0.083
Group II: 40 29/38 76.3 2/2 100 0.596
Pregnancy complications
All patients: 194 45/149 30.2 14/45 31.1 0.522
Group I: 154 37/111 33.3 12/43 27.9 0.327
Group II: 40 8/38 21.1 2/2 100 0.058
Abbreviation: PAPS, primary antiphospholipid syndrome.
Notes: Group I, PAPS patients with a history of thrombosis and/or severe pregnancy complications. Group II, PAPS patients with a history of refractory
to conventional treatment foetal death occurring without any severe pregnancy complication.
a
Statistical significance.
Thrombosis and Haemostasis
Additional Therapy in High-Risk APS Pregnancies Ruffatti et al.
(p ¼ 0.462). It should be noted that HCQ taken before pregnancy,
which was administered at the time the pregnancy
was being planned, led to a mean pregnancy duration of 37.1
weeks 2.4 SD; HCQ taken during pregnancy, which was
administered at a mean gestational age of 9.5 weeks 7.3
SD, was linked to a mean pregnancy duration of 35.2 weeks
3.3 SD.
Unsuccessful pregnancies during HCQ treatment were significantly
associated with previous thrombosis (p ¼ 0.025). In
fact, 10 out of the 12 women (83.3%) receiving HCQ and
suffering from a pregnancy failure had a history of thrombosis.
Pregnancy losses in the other additional treatment patients
were not, instead, significantly associated with a history of
thrombosis. Six out of the 12 pregnancy losses (50%) occurring
in the HCQ-treated women took place early in the pregnancy
(before the 10th week of gestation), but only 1 out of the 19
(5.3%) pregnancy losses associated with other additional
therapies occurred early. Spontaneous abortions were, thus,
significantly more frequent in the women administered HCQ
treatment with respect to the other additional treatment
patients (p ¼ 0.0034). Five out of the six women (83.3%)
suffering from early pregnancy loss during HCQ therapy
were taking 200 mg daily doses.
When the primary outcomes in the different parenteral
treatment groups were compared (►Table 4), no significant
differences were foundin thelive birth rates. Severe pregnancy
complications were significantly less frequent in the patients
treated with plasma exchange plus IVIG with respect to those
treated with the other parenteral therapies both when the
patients were considered together (p ¼ 0.034) as well as in the
Group I (p ¼ 0.035) women analysed separately.
The findings regarding the secondary outcomes in the
different additional therapies–treated patients are outlined
in ►Table 5. According to the Kruskal–Wallis test, the
patients receiving HCQ had significantly later mean weeks
of pregnancy, while those treated with plasma exchange
alone had earlier ones (p < 0.001).
According to logistic regression analysis, IVIG administered
alone (odds ratio [OR] ¼ 0.123, 95% confidence interval
[CI] ¼ 0.038–0.403, p ¼ 0.001), IVIG plus plasma
exchange (OR ¼ 0.135, 95% CI ¼ 0.033–0.550, p ¼ 0.005)
and HCQ (OR ¼ 0.450, 95% CI ¼ 0.207–0.978, p ¼ 0.044)
alone had protective effects on severe pregnancy complications
in the Group I patients. Moreover, congenital risk
factors (p ¼ 0.004) and body mass index 30 kg/m2
(p ¼ 0.019) were found to be independent risk factors for
pregnancy complications in the Group II patients.
No statistical differences were found between the patients
with triple aPL positivity and those with LAC alone or associated
with IgG/IgM aCL or IgG/IgM anti-β2GPI antibodies.
Table 2 Live birth rate and pregnancy complications linked to the three types of oral additional treatments
Pregnant PAPS
patients
HCQ LDS HCQ þ LDS p
No. % No. % No. %
Live birth rate
All patients: 149 82/94 87.2 27/36 75.0 12/19 63.1 0.027a
Group I: 111 63/74 85.1 22/27 81.5 7/10 70.0 0.479
Group II: 38 19/20 95.0 5/9 55.5 5/9 55.5 0.017a
Pregnancy complications
All patients: 149 19/94 20.2 16/36 44.4 9/19 47.4 0.008a
Group I: 111 19/74 25.7 14/27 51.8 4/10 40.0 0.042a
Group II: 38 1/20 5 2/9 22.2 5/9 55.5 0.008a
Abbreviations: HCQ, hydroxychloroquine; HCQ þ LDS, hydroxychloroquine plus low-dose steroid; LDS, low-dose steroid; PAPS, primary antiphospholipid
syndrome.
Notes: Group I, PAPS patients with a history of thrombosis and/or severe pregnancy complications. Group II, PAPS patients with a history of refractory
to conventional treatment foetal death occurring without any severe pregnancy complication.
a
Statistical significance.
Table 3 Effect on live birth rate linked to two dosages of HCQ (200 or 400 mg) and the timing of its administration (before or
during)
Live birth rate
HCQ dose Before pregnancy During pregnancy
400 mg 200 mg p 400 mg 200 mg p 400 mg 200 mg p
No. % No. % No. % No. % No. % No. %
47 94 35 79.5 0.036a 34 97.1 31 79.5 0.021a 13 86.7 3 75 0.530
Abbreviation: HCQ, hydroxychloroquine.
a
Statistical significance.
Thrombosis and Haemostasis
Additional Therapy in High-Risk APS Pregnancies Ruffatti et al.
Discussion
This is the first study comparing the effect of different treatments
administered in addition to conventional therapy to a
large cohort of pregnant PAPS patients refractory to conventional
therapy and/or at high risk of pregnancy complications.
The patients studied were considered at high risk of pregnancy-related
complications on the basis of a clinical history of
maternal–foetal complications and an aPL profile characterized
by the presence of LAC alone or associatedwith aCL and/or
anti-β2GPI antibodies. The study’s most interesting findings
concerned HCQ therapy which produced, mainly in the Group
II patients, a significantly higher birth rate and significantly
fewer severe pregnancy complications with respect to the
other oral additional treatments. HCQ was found to be the
most efficacious oral treatment used in association with
conventional therapy in the PAPS patients with a previous
foetal death refractory to conventional therapy.
These findings are in agreement with those reported by
two clinical studies examining the effect of HCQ in pregnant
APS women that reported fewer pregnancy losses in the
treated than in the untreated patients.24,25 The novelty of the
current study regards the dosage and timing of HCQ treatment.
In fact, the 400 mg dose of HCQ versus the 200 mg and
its administration before but not during pregnancy were the
two features that were associated with a significant increase
in the live birth rate. HCQ therapy appeared particularly
beneficial in the PAPS patients without previous thrombosis.
In fact, the 10 out of the 12 unsuccessful pregnancies
receiving HCQ treatment were significantly associated
with a history of maternal thrombosis.
While it is true that only a few number of cases (45 cases)
were treated with parenteral additional treatments, that
therapy led to a significantly higher live birth rate with
respect to the oral medications, but only when all of the
patients were considered together. As this result was mainly
due to the contribution of the Group I patients, the more
severe clinical subset, it suggests that these treatments
should be reserved for PAPS patients with a history of severe
maternal–foetal complications and/or in those refractory to
HCQ additional treatment. In addition, logistic regression
analysis showed that both IVIG þ plasma exchange and IVIG
alone had a significant protective effect against severe pregnancy
complications in the Group I patients.
Table 4 Live birth rate and pregnancy complications related to the three parenteral additional treatments
Pregnant PAPS
patients
PE IVIG PE þ IVIG p
No. % No. % No. %
Live birth rate
All patients: 45 7/8 87.5 15/16 93.7 20/21 95.2 0.754
Group I: 43 7/8 87.5 13/14 92.8 20/21 95.2 0.765
Group II: 2 – 2/2 100 – n.a.
Pregnancy complications
All patients: 45 5/8 62.5 6/16 37.5 3/21 14.3 0.034a
Group I: 43 5/8 62.5 4/14 28.6 3/21 14.3 0.035a
Group II: 2 – 2/2 100 – n.a.
Abbreviations: IVIG, intravenous immunoglobulins; n.a., not applicable; PAPS, primary antiphospholipid syndrome; PE, plasma exchange; PE þ IVIG,
plasma exchange plus intravenous immunoglobulins.
Notes: Group I, PAPS patients with a history of thrombosis and/or severe pregnancy complications. Group II, PAPS patients with a history of refractory
to conventional treatment foetal death occurring without any severe pregnancy complication.
a
Statistical significance.
Table 5 Secondary outcomes related to the six additional treatments
Secondary outcomes HCQ LDS HCQ þ LDS PE IVIG PE þ IVIG p
Week at delivery,
mean SD
36.8 2.8 35.7 3 36.3 2.7 31.1 4.7 35.3 2.5 33.7 2.9 < 0.001a
Weight percentiles,
mean SD
49.3 29.7 36.3 3 33.2 20.5 32.4 25.7 36.7 20.4 36.7 23.8 0.121
Neonatal complication,
no. (%)
6 (7.3%) 5 (14%) 2 (16.7%) 3 (43%) 1 (6.7%) 2 (9.5%) 0.092
Abbreviations: HCQ, hydroxychloroquine; HCQ þ LDS, hydroxychloroquine plus low-dose steroid; IVIG, intravenous immunoglobulins; LDS, lowdose
steroid; PE, plasma exchange; PE þ IVIG, plasma exchange plus intravenous immunoglobulins. a
Statistical significance.
Thrombosis and Haemostasis
Additional Therapy in High-Risk APS Pregnancies Ruffatti et al.
There were no major side effects correlated to the various
types of treatments neither in the mothers nor in the
children. As far as HCQ safety is concerned, our data are in
accordance with those of a systematic review and a metaanalysis26
that recently reported that its use during pregnancy
was not associated with a relevant increase in congenital
malformations. In view of the fact that only a few
studies have focused on HCQ treatment during PAPS pregnancies,
data from future investigations examining the longterm
follow-up of mothers and children will provide more
precise information about its safety in these patients. It is
especially important to evaluate any side effects that could
be linked to high dosage (400 mg daily) and/or long-term
duration (before pregnancy).
While it is true that IVIG infusions and plasma exchange
are indeed costly, the current study confirmed that they are
safe and lead to a high live birth rate in women who have
little hope of having successful pregnancies.27–29 As this
particular patient subset is quite rare, the expense of additional
parenteral treatments could be justified by the small
number requiring such treatment.
One of the study’s limitations is its retrospective nature,
but the rarity of these types of PAPS patients complicates
performing prospective studies or clinical trials on additional
treatments. The fact that the study did not have a
core reference laboratory could be considered another
limitation of this study. LAC was nevertheless homogeneously
identified by each attending centre following
international guidelines.22,23 As explained, homemade
ELISA procedures and a variety of commercial kits were
utilized by the various participating centres to determine
aCL and anti-β2GPI antibodies. Despite many efforts to
standardize the assays for these antibodies, methodological
problems continue to persist and there are significant
inter-assay and interlaboratory variations in results even in
connection to commercial kits.30–32 It was thus impossible
to compare all the methods used in the study in a
standardized way to determine if they had any effect on
the laboratory results. The strengths of the study could be
its large number and the homogeneity of the study population
composed only of PAPS patients refractory to conventional
therapy and/or at high risk of pregnancy
complications.
Our results will hopefully help point the direction of
future clinical trials investigating the effect of additional
treatments on refractory and high-risk PAPS patients with
severe clinical history and LAC positivity. For the time being,
the conclusion that can be drawn is that some additional
treatments seem to be safe and efficacious in refractory/
high-risk PAPS pregnant women. Four hundred milligram
daily HCQ therapy begun before pregnancy may be a good
option especially for PAPS patients with a previous pregnancy
refractory to conventional therapy leading to a foetal
death not associated with severe pregnancy complications.
IVIG combined with plasma exchange or alone could be used
in very high-risk pregnant PAPS women and particularly in
those with a history of thrombosis and/or refractory to
previous HCQ additional treatment.
What is known about this topic?
• Since conventional therapeutic strategies fail in
approximately 20 to 30% of pregnant patients affected
with antiphospholipid syndrome (APS), there is an
urgent need to define other therapeutic options to
be used in addition to conventional treatment.
• The most efficacious additional treatment to be combined
with conventional therapy for high-risk APS
pregnant women has not yet been established.
What does this paper add?
• Four hundred milligram daily hydroxychloroquine
therapy begun before pregnancy may be a good option
especially in APS patients with a previous, uncomplicated,
refractory to conventional therapy foetal death.
• Intravenous immunoglobulins combined with plasma
exchange or alone could be used in pregnant APSwomen
with previous severe pregnancy complications.
Conflict of Interest
None.
Funding
None.
Acknowledgements
The authors would like to thank the following investigators
involved in the study: Brucato A., Cutolo M., Favaro
M., Fioravanti A., Le Guern V., Meroni M., Montecucco C.,
Salvan E., Tabacco S., Villani M. and Inverso Moretti L. for
editing the English version.
Finally, the authors would like to thank Dr. Branch D.W.
for his critical review of the manuscript.
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