Antiphospholipid syndrome is an autoimmune disease characterized by the occurrence of vascular thrombosis and/or pregnancy morbidity (three or more miscarriages, fetal loss at ≥ 10 gestational weeks, stillbirth, or preterm delivery due to preeclampsia, fetal growth restriction or placental insufficiency) in the presence of antiphospholipid antibodies (lupus anticoagulant antibody, anticardiolipin antibodies or anti β2glycoprotein-1 antibodies). Cases fulfilling the Sydney criteria for obstetric morbidity with no previous thrombosis are known as obstetric antiphospholipid syndrome (OAPS). OAPS is the most frequent treatable cause of recurrent pregnancy loss and late-pregnancy morbidity related to placental injury. The current standard of care for obstetric APS based on aspirin and low molecular weight heparin improves pregnancy outcomes up to 70-80 %. However, 20-30% of these women still have pregnancy complications despite treatment referred as refractory OAPS. New understanding of OAPS pathogenesis involves inflammatory and thrombotic mechanisms. In refractory cases, the addition of Hydroxychloroquine (HCQ), low dose steroids and intravenous immunoglobulins improved pregnancy outcomes. New therapeutic agents (statins and biologic therapies) have been tried for high-risk and recurrent refractory cases with preliminary good results. Currently, focus is put on HCQ, due to its anti-inflammatory, immunomodulatory and antithrombotic mechanisms. Data from retrospective studies shows that the addition of 400mg HCQ started at least 2 months before conception was associated with increased live birth and less pregnancy complications. Hydroxychloroquine seems to be a very promising approach for refractory OAPS. Results from the ongoing randomized controlled trials are expected before any evidence-based recommendations can be given.

Gerde M, Mac Kenzie R, Heer C, Martin A, Beruti E, Balparda J (2022) Obstetric Antiphospholipid Syndrome: Current Trends in Managing Refractory Cases. Ann Pregnancy Care 4(1): 1009.

• Hydroxychloroquine, Antiphospholipid Syndrome, Refractory Obstetric APS, Pregnancy Complications, Review

APS: Antiphospholipid Syndrome; APL: Antiphospholipid Antibodies; SLE: Systemic lupus Erythematosus ; OAPS: Obstetric Antiphospholipid Syndrome; PE: Preeclampsia; LDA: Low Dose Aspirin; LA: Lupus Anticoagulant; OMAPS: APL-Related Obstetric Morbidity; NC-OAPS: Non- Criteria Obstetric Antiphospholipid Syndrome ; β2GP1: β2glycoprotein-1; LMWH: Low Molecular Weight Heparin ; IVIG: Intravenous Immunoglobulin; HCQ: Hydroxychloroquine; RPL: Recurrent Pregnancy Loss; TNF-α : Tumoral Necrosis Factor -α.

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by the occurrence of vascular thrombosis and/ or pregnancy morbidity in the presence of antiphospholipid antibodies (aPL) [1]. The classification criteria for APS were originally outlined in Sapporo (1998) and updated in Sydney (2006) and is now referred to as the “Sydney criteria” [2]. When no other underlying autoimmune disease exists, the syndrome is defined as primary APS. Otherwise, when associated with other autoimmune disorder, mainly systemic lupus erythematosus (SLE), it is named secondary or associated APS [3]. Women that fulfill the Sydney criteria who did not have previous thrombotic events are identified as obstetric antiphospholipid syndrome (OAPS) patients [4].

APS is the most frequent treatable acquired thrombophilia during pregnancy [5], and its prevalence has increased in the last years. In fact, 10–29% of women with poor obstetric outcomes are carriers of aPL [3]. APS is a common cause of recurrent first trimester loss [6]; data from a retrospective single center cohort of 500 women with a history of recurrent first trimester pregnancy loss suggested that 26.4% are associated with the presence of aPL [7]. aPL is also associated with severe preeclampsia (PE) and stillbirth, accounting for 12% of women with severe PE and 11% of women with stillbirth [8].

Conventional treatment with low dose aspirin (LDA) and unfractionated or low molecular weight heparin has resulted in a live birth rate of 70-80% [4,9,10]. However, 20-30% of these women still have an obstetric complication despite treatment, referred as refractory OAPS [11]. Poor obstetric outcomes are associated with the presence of the following risk factors: a concomitant autoimmune disease, history of thrombosis or the presence of triple (+) antibodies, lupus anticoagulant (LA) activity or complement reduction [12]. Currently, several pharmacological strategies are being used to improve these results: increased heparin dose, steroids, intravenous immunoglobulin, plasma exchange, pravastatin, TNF inhibitors, and hydroxychloroquine [13,14] However, the best pharmacological approach is still debated.

The aim of this article is to review the concepts related to the diagnosis, pathogenesis and update the pharmacological strategies for OAPS in refractory cases that can help physicians with the management of this high-risk populations.

Diagnosis

According to Sydney criteria [1], antiphospholipid syndrome is present if at least 1 of the clinical criteria and 1 of the laboratory criteria are met. Positivity of antiphospholipid antibodies (aPL) (lupus anticoagulant antibody, anticardiolipin antibodies or anti β2glycoprotein-1 antibodies) must be present in two occasions at least 12 weeks apart [1,2]. Clinical manifestations include vascular thrombosis (arterial or venous) and /or (three consecutive miscarriages before week 10 of gestation, one or more fetal losses at ≥ 10 gestational weeks and stillbirth or preterm delivery due to eclampsia, preeclampsia, or placental insufficiency before the 34th week of gestation). See Table 1.

Table 1: Sydney Criteria (2006) Antiphospholipid Syndrome.

Clinical criteria

1. Vascular thrombosis One or more clinical episodes of arterial, venous, or small vessel thrombosis, in any tissue or organ. Thrombosis must be confirmed by objective validated criteria (i.e., unequivocal findings of appropriate imaging studies or histopathology).

2. Pregnancy morbidity b. One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with normal fetal morphology documented by ultrasound or          by direct examination of the fetus; or c. One or more premature births of a morphologically normal neonate before the 34th week of gestation because of: (i) eclampsia or severe preeclampsia defined according      to standard definitions, or (ii) recognized features of placental insufficiency; or d. Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and          maternal chromosomal causes excluded.

Laboratory criteria

Lupus anticoagulant present in plasma, on 2 or more occasions at least 12 weeks apart, detected according to the guidelines of the International Society on Thrombosis and Haemostasis.

Anti-Cardiolipin Antibodies of IgG and/or IgM isotype in serum or plasma, present in medium or high titer (ie, >40 GPL or MPL, or >the 99th percentile), on 2 or more occasions, at least 12 weeks apart, measured by a standardized ELISA.

Anti- β2glycoprotein-1 antibody of IgG and/or IgM isotype in serum or plasma (in titer >the 99th percentile), present on 2 or more occasions, at least 12 weeks apart, measured by a standardized ELISA.

 

Non-criteria APS

Many patients fail to completely meet the Sydney clinical criteria. These cases are heterogeneously defined across the literature [14,15]. Recently, Alijotas-Reig et al. [14] classified as aPL-related obstetric morbidity (OMAPS) those women who fulfill laboratory criteria but their obstetric morbidity doesn’t reach Sydney criteria (e.g. Two consecutive unexplained miscarriages of well-formed embryos ; three or more non-consecutive miscarriages of well-formed embryos; PE/eclampsia after week 34 of gestation or at puerperium; placental abruption; late premature birth; premature rupture of membranes; unexplained recurrent implantation failure in in vitro fertilization ) [16]. On the other hand, those who fulfill clinical criteria but have low titers of aPL or only one positive test is classified as non- criteria OAPS (NC-OAPS) [17]. These women could present autoantibodies against other phospholipids, such as phosphatidylserine, prothrombin, annexin A5; IgA aCL or IgA β2GPI [18].

Pathogenesis

For many years, placental thrombosis was thought to be the main pathogenic mechanism [19]. However, recent data suggests three mechanisms for aPL-induced pregnancy morbidity: placental thrombosis, defective placentation, and inflammation [14,20]. The pathogenesis of aPL-related recurrent first trimester pregnancy loss is different from second and third trimester pathogenesis [21]. First trimester pregnancy loss has been related to a direct inhibitory effect of aPL on embryo development, placentation, and apoptosis of trophoblast cells [22]. Late obstetrical complications including preeclampsia, intrauterine growth restriction and stillbirth have been related to placental dysfunction due to thrombotic and inflammatory changes [23].

Treatment

Standard of Care Treatment: Currently, despite limited evidence, the standard of care treatment is low dose aspirin (LDA) given preconceptionally (100 mg/day) combined with low molecular weight heparin (LMWH) at prophylactic doses (0.4–0.6 mg/kg/day) or unfractionated heparin (4000–6000 IU/day) since pregnancy is achieved [24]. In patients with previous thrombotic events, secondary thromboprophylaxis with full unfractionated or LMWH doses therapy should be administered [25]. The efficacy of heparin and LDA together in APS patients with previous pregnancy loss is supported by three meta-analyses [26-28]. There is less evidence for the same approach in manifestations other than pregnancy loss [20]. OAPS is associated with 70-80% of pregnancy complications without treatment. Classical treatment with LDA+ low molecular weight or unfractionated heparin has resulted in a live birth rate of 70- 80% [4,9,10].

LDA has been shown not only to prevent placental thrombosis by its well-known anti-platelet effect but also to favor placental development by increasing interleukin-3 [29]. Heparin prevents the activation of the complement system [30], one of the main pathogenic mechanisms of aPL-related endothelial damage [31]. Beyond its anticoagulant effect, heparin prevents aPL binding to trophoblast, to antagonize the aPL-induced interference with trophoblast migration, invasion and apoptosis [32].

Refractory Cases: Conventional approach is associated with 70-80 % of success. However, up to 20–30% of cases will have an obstetric complication despite treatment [11]. These cases are referred as refractory OAPS. In this situation, other pharmacological strategies, mainly HCQ, low-dose prednisone, increasing LMWH dose, intravenous immunoglobulins (IVIG) or plasma exchange, have all been tried with good results [33-35], although the best scheme is still unknown.

Hydroxychloroquine: In the last years, investigations are focused on originally an antimalarial drug that has proved to be effective in Systemic Lupus Erythematosus (SLE) and other autoimmune diseases [36]. HCQ has shown to reduce aPL binding to syncytiotrophoblast, reducing inflammation, and improving trophoblast fusion at the decidua level [37,38]. HCQ also improves Annexin V expression, a natural antithrombotic shield at the placental level [38]. Thus, Hydroxychloroquine could be beneficial in APS due to its anti-inflammatory, immunomodulatory and antithrombotic properties [39].

HCQ has been reported to be safe during pregnancy and breastfeeding [40], serious effects described associated with hydroxychloroquine exposure are very rare and include cardiac and retinal toxicity [41,42]. The European Medicines Agency has licensed its use for the treatment of APS [43]. To date, four retrospective studies have shown better pregnancy outcomes in women with aPL/OAPS treated with the addition of HCQ [44-47].

Mekinian et al. [44] in a multicenter retrospective study, reported that pregnancy losses decreased from 81 to 19% (p <0.05) with the addition of HCQ in obstetric APS patients. They described 78% rate of live-born babies in 14 patients with refractory obstetrical APS treated with the addition of HCQ. HCQ at a higher dose (HCQ 400 mg) was observed to be more efficacious than a lower dose (HCQ 200 mg).

Sciascia et al. [45] in a single center retrospective study, showed that the use of HCQ in women with persistent aPL or APS was associated with an increased rate of live births (67 vs 57% p=0.05), a lower rate of pregnancy complications (47 vs 63% p=0.004) and a longer pregnancy duration. In this study, the 55 patients that received HCQ were mainly women with SLE or APS with Lupus like syndrome; the number of refractory cases was not specified. They are now conducting the prospective randomized controlled trial: HYPATIA [48] (HCQ vs Placebo in pregnant women with antiphospholipid antibodies).

Ruffatti et al [46] in a multicenter retrospective study compared several oral and IV strategies. HCQ was used alone or combined with steroids in addition to conventional therapy. They included high-risk APS patients and refractory APS women with history of fetal death and/or previous thrombosis. HCQ was more efficacious than other oral treatments in improving live birth outcomes specially in 44 pregnancies from refractory APS women with no history of previous thrombosis. HCQ initiated during preconception was associated with an increase in the live birth rate than when started during pregnancy. This study highlighted the importance of the dosage and the timing of HCQ as the high (400 mg) versus low (200 mg) doses of HCQ and its administration before versus during pregnancy were associated with a significantly higher live birth rate.

Recently, Gerde et al. [47] in a retrospective single center, cohort study, assessed pregnancy outcomes in 101 pregnancies out of 87 refractory Obstetric APS patients. They compared two different strategies: enoxaparin 60 mg + LDA vs the addition of Hydroxychloroquine 400mg / day to this scheme. HCQ was initiated 2 months before conception. In this study, the addition of HCQ was associated with a higher rate of live births (97.1% vs 62.5% p<0.001) and a lower frequency of pregnancy complications (8.7% vs 37.5% p<0.001). After statistical analysis to adjust for confounders, the estimated treatment effects of HCQ showed an absolute increase in live births of 31%.

Currently, there are four ongoing randomized controlled trials called “HYPATIA” [48], “HIBISCUS” [49], “HYDROSAPL” [50] and the BBQ STUDY [51] to assess if the addition of HCQ to standard treatment is beneficial in pregnant women with aPL/ refractory OAPS.

Corticosteroids: Steroids impair complement activation both in vitro and in vivo [52]. They have been used in common practice for refractory cases for decades. Use of steroids in refractory cases, in a low dose (10 mg prednisolone/day) during the first trimester was associated with an increased rate of live births and low rate of pregnancy complications [52]. However, high-dose corticosteroids (e.g., prednisolone 40-60 mg/day) are associated with multiple complications during pregnancy (e.g., gestational diabetes, hypertensive disorders, and premature rupture of membranes). Recently, Bramham et al. [53] published their results on a cohort of women with refractory OAPS treated with early low dose prednisolone in addition to LDA and prophylactic heparin who achieved 61% live births.

Intravenous Immunoglobulins: Intravenous immunoglobulins (IVIG) are being used in some autoimmunemediated diseases, with varying degrees of success [54,55]. IVIG may improve recurrent pregnancy loss (RPL) by neutralizing autoantibodies and decreasing NK cell activity. Recently, Ruffatti et al. [56] analyzed high-risk APS, including OAPS patients, and showed that IVIG administration was associated with a significantly higher live birth rate when compared with oral scheduled treatments for refractory cases.

Statins: Preliminary data from the use of pravastatin in preeclamptic patients with APS show interesting results [57]. Statins may improve placental hemodynamics and thus the outcome of pregnancy through a nitric oxide–dependent mechanism. In a case- control study Lefkou et al, [58] described beneficial effects in eleven patients that received pravastatin (20 mg daily) in addition to LMWH/LDA at the onset of pre-eclampsia and/or IUGR. These beneficial effects were observed as early as 10 days after pravastatin treatment onset. However, safety and doses of statins in pregnant woman are not yet established.

Biologic Therapy: TNFα-Targeted Therapies: Tumoral Necrosis Factor -α (TNF-α) is a cytokine that causes inflammation by means of predominantly T-cell-mediated tissue damage [59]. Recently, Alijotas-Reig et al. showed how the treatment with TNF-α inhibitors in 18 patients with refractory aPL/OAPS was accompanied by good obstetric results: 70% were successful, without adverse maternal–fetal effects [60]. Currently, a RCT is ongoing, the IMPACT Study. In this study, the selected TNF-α blocker is Certolizumab, which does not cross the placenta. In his recent review, Alijotas-Reig recommends using Adalimumab or Certolizumab over Infliximab or Etanercept (Table 2) [14].

Treatment of Non-Criteria Patients: No consensus exists for the diagnosis and treatment of non-criteria pregnant patients. However, most physicians, despite the lack of robust evidence, choose to treat these patients during pregnancy based on the presumption that such aPLs may be clinically relevant [61]. Further investigation is needed.

Recently, Alijotas- Reig et al [14] gave a 6 steps recommendation in the management of refractory cases (Table 2).

Table 2: Recommended steps in the treatment of refractory OAPS (Alijotas-Reig et al [24]).

Standard of Care treatment for OAPS	ASA 100 mg started 4 weeks before gestation. Prophylactic LMWH from the time of knowing pregnancy
Refractory cases: Step 1	+ HCQ 200–400 mg/day, according to body weigh
Step 2	+ low-dose prednisone 10 to 15 mg/d (started as soon as pregnancy is known) or increasing LMWH dose
Step 3	+ add IVIGs and/or perform plasma exchange
Step 4	add TNF inhibitors (infliximab, etanercept, but better use adalimumab or certolizumab)
Step 5	Consider adding hydrophilic statins (pravastatin 20–40 mg/day), or eculizumab

 

APS is the most frequent acquired risk factor for a treatable cause of recurrent first trimester pregnancy loss. APL are also associated with an increased risk of conditions associated with placental dysfunction, including stillbirth, preeclampsia, premature birth, and fetal growth restriction. Non-criteria OAPS cases are still challenging for clinicians. The best approach for these patients needs further investigation. New understanding of OAPS shows that inflammation plays a key role in obstetric morbidity. The current standard of care for obstetric APS is based on aspirin and LMWH. In refractory cases, therapy with HCQ and /or low dose steroids (10 mg prednisolone/day) are currently recommended by experts. New therapeutic agents have been tried for high-risk and recurrent refractory cases, IVIGs, plasma exchange, statins, biologic therapies (TNF-α inhibitors) with preliminary good results. HCQ seems to be a very promising approach for refractory Obstetric APS. Results from the ongoing randomized controlled trials are expected before any evidence -based recommendations can be given. In the meantime, retrospective studies have shown that the addition of 400mg HCQ started at least 2 months before conception is associated with improved obstetric outcomes and is considered the first option to treat this high-risk population.

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