Apheresis and intravenous immunoglobulins used in addition to conventional therapy to treat high-risk pregnant antiphospholipid antibody syndrome patients. A prospective study

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Highlights

Abstract

Pregnant women with triple antibody positive antiphospholipid syndrome (APS) who have had thrombosis or a history of early, severe pregnancy complications are generally considered at high risk of pregnancy loss. The objectives of this study were to investigate the efficacy and safety of a relatively new treatment protocol used in addition to conventional therapy in high-risk pregnant patients affected with primary APS. The study’s two inclusion criteria were: (1) the presence of triple antiphospholipid positivity, (2) previous thrombosis and/or a history of one or more early, severe pregnancy complications.

Eighteen pregnancies occurring between 2002 and 2015 in 14 APS patients, (mean age 34.8 ± 3.6 SD) were monitored. All 14 (100%) patients had triple antiphospholipid positivity. In addition, six of them (42.8%) had a history of thrombosis, four (28.6%) had one or more previous early and severe pregnancy complications, and four (30.8%) met both clinical study criteria.

The study protocol included weekly plasmapheresis or immunoadsorption and fortnightly 1 g/kg intravenous immunoglobulins. Seventeen of the pregnancies (94.4%) produced live neonates, all born between the 26th and 37th weeks of gestation (mean 33.1 ± 3.5 SD). One female (5.5%), born prematurely at 24 weeks, died of sepsis a week after birth. There were two cases (11.1%) of severe pregnancy complications. No treatment side effects were registered. Given the high live birth rate and the safety associated to it, the study protocol described here could be taken into consideration by medical teams treating high-risk APS pregnant patients.

Introduction

Since the early eighties, recurrent pregnancy loss has been considered the hallmark of the antiphospholipid antibody syndrome (APS), and it is one of its classification criteria (Miyakis et al., 2006). APS pregnancy morbidity is defined as (a) one or more unexplained deaths of morphologically normal fetuses at or beyond the 10th week of gestation and/or (b) one or more premature births of morphologically normal neonates before the 34th week of gestation due to eclampsia or severe preeclampsia or to recognized features of placental insufficiency and/or (c) three or more unexplained consecutive spontaneous abortions before the 10th week of gestation in cases in which maternal anatomic or hormonal abnormalities and paternal/maternal chromosomal causes have been excluded.

Pregnant APS patients should receive personalised treatment strategies. In accordance with the results of several trials (Kutteh, 1996, Rai et al., 1997, Franklin and Kutteh, 2002) and in line with some meta-analysis research studies (Empson et al., 2002, Mak et al., 2010), most investigators currently advocate treating otherwise healthy pregnant patients affected with obstetric APS with prophylactic heparin plus low dose aspirin (LDA). Although specific clinical trials are lacking, APS women with a history of vascular thrombosis alone or associated with pregnancy morbidity are usually treated with therapeutic heparin doses generally in association with LDA in the attempt to prevent both thrombosis and pregnancy morbidity. Given that about 20% of these women do not benefit from this conventional treatment, identifying the high-risk antiphospholipid antibody (aPL) profiles that characterize this subset and the clinical features that are associated to it will presumably help to define treatment strategies and guide the clinical management of these pregnancies.

According to recent reports, high-risk obstetric profiles seem to be linked to specific serological markers such as positivity to all three aPL assays (Ruffatti et al., 2006), positivity to lupus anticoagulant (LAC) (Lockshin et al., 2012) and/or to clinical features such as a history of thrombosis and the presence of a systemic autoimmune disease (Danowski et al., 2009, Bramham et al., 2010, Ruffatti et al., 2011, Fischer-Betz et al., 2012, Lockshin et al., 2012).

The most efficacious, safest therapeutic options for high-risk pregnant APS patients have not yet been established; low-dose prednisolone (Bramham et al., 2011), intravenous immunoglobulins (IVIG) (Kaaja et al., 1993, Branch et al., 2000, Szodoray et al., 2003, Xiao et al., 2013), and/or apheretic procedures such as plasmapheresis or immunoadsorption (Kobayashi et al., 1992, Nakamura et al., 1999, El-Haieg et al., 2007, Ruffatti et al., 2007) have at times, been prescribed. A retrospective multicentre European 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 (Ruffatti et al., 2014). In the study different types of additional therapies including monthly IVIG infusions, weekly aphaeresis procedures and low-dose prednisolone, alone or combined were considered. However, was impossible to examine the additional therapies singularly as the number of patients studied was so small.

This article outlines a prospective case series study designed to evaluate the efficacy and safety of a relatively new protocol for pregnant women with high-risk APS. The effects of an additional therapy combining fortnightly IVIG infusions and weekly aphaeresis procedures were examined in a group of high-risk APS patients attending our clinic.

Section snippets

Material and methods

The pregnancies of women diagnosed with primary APS on the basis of the criteria of the Sydney International Consensus Statement (Miyakis et al., 2006) were prospectively analysed. The study’s two inclusion criteria: (1) at least two consecutive positive test results for LAC and for IgG and/or IgM anticardiolipin antibodies (aCL), and for IgG and/or IgM anti-β2Glycoprotein I antibodies (a-β2GPI) at medium or high titres carried out more than 12 weeks apart and (2) previous thrombosis and/or a

Study cohort

Fourteen high-risk APS patients who experienced a total of eighteen pregnancies were monitored prospectively between February 2002 and April 2015. The patients’ main clinical and laboratory features are outlined in Table 1. All 14 presented triple aPL positivity (the patients’ aPL profiles are outlined in Table 2). Six (42.8%) had a history of thrombosis, four (28.6%) had one or more severe pregnancy complications during a previous pregnancy, and four (28.6%) had both of these. It was the first

Discussion

The most efficacious additional therapies to treat high risk APS pregnant women have not as yet been established. The current one is the first study reporting on the efficacy and safety of an additional treatment protocol including apheretic procedures and IVIG infusions that were administered to a well defined, prospectively analysed cohort of high-risk pregnant APS patients. The combination therapy described here achieved a very high birth rate (94.4%) and a significantly lower prevalence of

Conflict of interest

The authors declare that they have no conflict of interest.

Acknowledgement

The authors are grateful to Linda Inverso Moretti for her assistance in editing this manuscript.

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