Antiphospholipid syndrome in pregnancy: A comprehensive review

Abstract

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by the presence of antiphospholipid antibodies and is associated with thrombotic events and pregnancy complications. The classification and management of APS has evolved over time. The classification criteria for APS include laboratory, macrovascular, microvascular, obstetric, cardiac, and hematologic domains. Management focuses on prevention of thrombotic events and/or anticoagulation as the primary treatment for thrombosis. Postpartum and long-term thromboprophylaxis after delivery are recommended to reduce the risk of thrombotic events. Despite these recommendations, optimal anticoagulation agents and intensity of treatment are still topics of debate. Further research is needed to understand the pathophysiology of APS and improve its management during pregnancy. In this review, we discuss the classification and pathophysiology of APS. Current treatment options and clinical trials are also discussed.

Key Words: Antiphospholipid syndrome; Pregnancy complications; Thrombosis; Anticoagulation; Autoimmune disorder

Core Tip: Antiphospholipid Syndrome (APS) is a systemic autoimmune disorder associated with pregnancy complications primarily due to thrombotic events. The diagnosis of APS involves criteria in laboratory, macrovascular, microvascular, obstetric, cardiac, and hematological domains. The cardinal goal of management during pregnancy focuses on prevention of thrombotic events and pregnancy complications.

INTRODUCTION

Antiphospholipid syndrome (APS) has a rich historical background dating back to the early 20^th century when the identification of antiphospholipid antibodies (aPL) was linked to syphilis testing[1]. APS is a systemic autoimmune disorder whose diagnostic criteria were revised in 2006 at the Sydney workshop in Australia. Briefly, APS is characterized by persistent positivity for aPL [including lupus anticoagulant (LA), anti-cardiolipin antibody (aCL) and anti-β2-glycoprotein-1 antibodies (anti-β2GP1)], thrombotic events, and severe pregnancy morbidity. APS significantly impacts pregnancy by causing complications such as recurrent pregnancy losses, early miscarriage, intrauterine growth restriction (IUGR), placental insufficiency, premature labor, and preeclampsia[2,3].

The syndrome's association with thromboembolic events and pregnancy losses led to its recognition as a distinct autoimmune disease[4]. In addition to thrombotic events and pregnancy-related issues, APS is linked to various other clinical conditions. These include skin manifestations like livedo reticularis and cutaneous ulcers, blood disorders such as thrombocytopenia and hemolytic anemia, heart-related problems such as cardiac valvular disease, as well as kidney and neurological complications[5,6]. In this review, we discuss the details regarding the epidemiology, pathogenesis, and management of APS.

Epidemiology

The global annual incidence of APS in pregnancy is estimated at approximately 5 de novo cases per 100000 individuals per year, with a prevalence of 40-50 cases per 100000 individuals[2,5]. Epidemiological data has been limited regarding APS. This is mainly secondary to the characterization of APS in the general population and the changes in the diagnostic criteria. After finalization of the 2006 Sydney criteria, the incidence was estimated to be 2.6 cases per 100000 with an overall prevalence rate of 40.5 per 100000[7].

APS in pregnancy presents a significant risk, with pregnant and postpartum women already being in a prothrombotic state due to physiological changes in anatomy and circulating hormones and coagulation proteases. The risk of thrombosis during pregnancy varies from 1% to 12%. Higher titers of aPL confer a higher risk of developing thrombosis[8]. Pregnant women with APS have been shown to have a 5% risk of thrombosis compared to 0.025%–0.10% in the general population. Thrombosis has also been shown to be more prevalent in the first trimester[9].

In a study by Amikam et al[10], the prevalence of aPL in women with preeclampsia with severe features was 3.3% and 13% in those with placental abruption, with the overall prevalence of aPL in women with placenta-mediated complications being 4.9%. In women with APS, previous thromboses were associated with an increased risk of neonatal mortality, preterm birth, and preeclampsia. APS was shown to contribute to approximately 15% of recurrent pregnancy losses[6].

Pathogenesis

The aPL impact various components of the hemostatic system, with the primary pathogenetic mechanisms including cellular activation (platelets, endothelial cells, immune cells), inhibition of anticoagulant potential, inhibition of fibrinolysis, and activation of the complement system (Figure 1)[11–13]. The aPL interact with anionic determinants, such as phospholipids, on the surfaces of endothelial cells and trophoblasts, as well as polyphosphates of platelets or nucleic acids. This interaction requires β2GP1, which is the main cofactor for aPL that exists in two conformations: (1) Circular; and (2) Open/activated[14].

Figure 1 Pathogenesis of antiphospholipid syndrome. Antiphospholipid antibodies (aPL) impact various components of the hemostatic system. The aPL interacts with β2-glycoprotein-1 antibodies (β2GP1) on the surface of endothelial cells, platelets, and trophoblasts. Nuclear factor kappa B is activated, along with the production of cytokines and adhesion molecules that further inflammation. The aPL also interacts with apolipoprotein E2 receptor to reduce nitric oxide production encouraging platelet adhesion. Anti-β2GP1 antibodies trigger production of tissue factor (TF) but reduces the production of protein C to increase the risk of thrombosis. The aPL prevents the binding of tissue plasminogen activator to its receptor on endothelial cells contributing to hypofunction of the fibrinolytic system. Increased complement activation by aPL increases the risk of thrombosis by increasing TF production and leading to thrombosis. APL: Antiphospholipid antibodies; ApoER2: Apolipoprotein E2 receptor; ENos: Endothelial nitric oxide synthase; NF-κB: Nuclear factor kappa B; TF: Tissue factor; TPA: Tissue plasminogen activator; β2GP1: β2-glycoprotein-1.

In the circular conformation, the epitope of β2GP1 is shielded from the plasma. However, upon interaction with anionic surfaces, the epitope becomes exposed and β2GP1 is activated. The formation of antibodies against these exposed epitopes is crucial in the pathogenesis of APS and thrombogenesis. The distribution of β2GP1 has unique characteristics: It is absent on resting endothelium but appears on vascular endothelium following an inflammatory stimulus. However, it is also present on the endothelium of uterine vessels, trophoblasts, and in placental tissues at the implantation site during a normal pregnancy. The interaction of aPL with surface-bound β2GP1 leads to activation of the cells targets and changes in their functional activity that cause thrombosis[15,16].

As a result of p38 mitogen-activated kinase and transcription factor nuclear factor kappa B activation, a proinflammatory and prothrombotic response occurs. This response is characterized by the expression of adhesion molecules (E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1) and the production of cytokines [tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6]. These cytokines promote lymphocyte adhesion, furthering inflammation. Additionally, aPL leads to decreased activity of endothelial nitric oxide synthase. By interacting with the apolipoprotein E2 receptor, aPL reduces nitric oxide production. This nitric oxide deficiency impairs vasodilation and encourages platelet adhesion[16].

Tissue factor (TF) is the major initiator of the extrinsic coagulation cascade. Exposure of blood to TF initiates the coagulation cascade and the production of large amounts of thrombin, which has several prothrombotic properties. Thrombin activates protein C, a major component of the anticoagulant system. A deficiency of protein C leads to an increased risk of thrombosis. The aPL against protein C have been identified, leading to an abundance of TF and a prothrombotic state[17]. Anti-β2GP1 antibodies circulating in the bloodstream can trigger the activation and heightened production of TF on both endothelial cells and monocytes, again further contributing to the increased risk of thrombosis[18].

The persistence of aPL can also result in the inhibition of natural anticoagulants like protein C, protein S, prothrombin, and annexin[17]. The aPL interferes with the anticoagulant function of protein C through several mechanisms: (1) The aPL inhibits the assembly of the protein C complex; (2) The aPL reduces the activation of protein C through the thrombomodulin-thrombin complex; (3) The aPL directly suppresses the activity of protein C; and (4) The aPL increases the clearance of prothrombin-antibody complexes required by protein C[17]. Annexin V binds to vascular endothelial cells with high affinity, playing an important role in antithrombosis. The aPL antibodies can disrupt the binding of annexin to cell membranes by competitive displacement. This reduction of annexin has been shown to increase the risk of thrombosis[19].

The aPL can also impact the extrinsic and intrinsic fibrinolysis pathways. In the complex regulatory network of the coagulation system, activators, inhibitors, cofactors, and receptors interact to maintain a balance. Plasminogen is converted to plasmin by tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA). Plasminogen activator inhibitor-1 (PAI-1) inhibits the activity of tPA and uPA. The aPL-induced endothelial activation results in the increased release of tPA and PAI-1. Furthermore, by binding to annexin A2, aPL hinders the binding of tPA to its endothelial receptor. This interference potentially disrupts the normal function of each fibrinolytic protein, contributing to diminished function of the fibrinolytic system[20].

The complement system plays a significant role in the pathogenesis of APS. Complement activation primarily occurs through the classical pathway. The classical pathway is activated by antibody-antigen complexes. C3 convertase divides C3 into C3a and C3b. C3a binds to its receptor on platelet surfaces, inducing platelet activation, aggregation, and adhesion. Meanwhile, C3b facilitates phagocytosis and participates in forming C5 convertase, which splits C5 into C5a and C5b. C3a and C5a trigger the expression of TF in monocytes, neutrophils, and endothelial cells. Complement components then bind to platelets to enhance prothrombinase activity, and activation of C3 leads to platelet activation and fibrin formation. Increased complement activation in patients with APS can further increase the risk for thrombosis by increasing expression of TF and promoting prothrombinase activity[11].

CLINICAL FEATURES OF APS

Diagnostic criteria

Venous and arterial thromboses in the presence of aPL and pregnancy morbidity such as spontaneous abortions, fetal demise, or premature births, defines APS. APS can be defined as primary APS when it is isolated and not associated with other conditions. Secondary APS is when there is an association with other autoimmune diseases, mainly systemic lupus erythematous (SLE), drugs, or malignancy[21].

The classification criteria for APS have been extensively studied and refined. A multidisciplinary initiative between the American College of Rheumatology and the European Alliance of Associations for Rheumatology (EULAR) aimed to develop new APS classification criteria, resulting in the identification of 27 candidate criteria organized into 6 domains: (1) Macrovascular venous thromboembolism (VTE); (2) Macrovascular arterial thrombosis; (3) Microvascular; (4) Obstetric; (5) Cardiac; and (6) Hematologic[22]. The 2023 classification criteria require at least one positive aPL test within 3 years of diagnosis of an aPL-associated clinical criterion, in addition to weighted criteria from the six clinical domains and two laboratory domains (Table 1). At least three points from the clinical domains and at least three points from the laboratory domains confirm the diagnosis of APS[22,23]. A high-risk cardiovascular profile is defined as one or more high cardiovascular disease risk factors or three or more moderate risk factors. A high-risk VTE profile is defined as one or more major or two or more minor VTE risk factors[23].

Table 1 Candidate criteria for the diagnosis of antiphospholipid syndrome.

Clinical domains	Criteria	Points
Macrovascular VTE	VTE with a high-risk VTE profile	1
	VTE without a high-risk VTE profile	3
Macrovascular AT	AT with a high-risk cardiovascular profile	2
	AT without a high-risk cardiovascular profile	4
Microvascular	Suspected (one or more of the following): Livedo racemosa, livedoid vasculopathy, acute/chronic aPL-nephropathy, pulmonary hemorrhage	2
	Established (one or more of the following): Livedoid vasculopathy, acute/chronic aPL-nephropathy, pulmonary hemorrhage, myocardial disease, adrenal hemorrhage	5
Obstetric	Three or more consecutive pre-fetal and/or early fetal demise	1
	Fetal demise in the absence of pre-eclampsia with severe features or PI with severe features	1
	Pre-eclampsia with severe features or PI with severe features with/without fetal demise	3
	Pre-eclampsia with severe features and PI with severe features with/without fetal demise	4
Cardiac	Valve thickening	2
	Valve vegetation	4
Hematology	Thrombocytopenia (20 × 109-130 × 109/L)	2
Laboratory domains
Lupus anticoagulant test	Positive once	1
	Persistent positivity	5
ACL and/or anti-β2GP1	Moderate or high positive (IgM) (aCL and/or anti-β2GP1)	1
	Moderate positive (IgG) (aCL and/or anti-β2GP1)	4
	High positive (IgG) (aCL or anti-β2GP1)	5
	High positive (IgG) (aCL and anti-β2GP1)	7

At least one documented clinical criterion from the listed domains plus a positive antiphospholipid antibody test within three years of diagnosis of the clinical criteria are required for diagnosis. ACL: Anti-cardiolipin antibody; APL: Antiphospholipid antibody; AT: Arterial thrombosis; Ig: Immunoglobulin; PI: Placental insufficiency; VTE: Thromboembolism; β2GP1: β2-glycoprotein-1.

OBSTETRICAL COMPLICATIONS OF APS

Unlike thrombotic complications of APS that are associated with increased titers of aPL, low titers of aPL have been reported in those with obstetrical complications[8]. Pregnancy morbidity is thought to be placenta-mediated due to infarction, impaired spiral artery remodeling, decidual inflammation, or the deposition of complement split products[3,10]. Anti-β2GP1 antibodies have been shown to induce complement-mediated damage to vascular endothelial cells of the placental decidua[8]. This results in poor development of the fetal-placental circulation and impaired development of trophoblasts, thereby playing a role in pregnancy loss[9].

Poor development of the fetal-placental circulation leads to fetal growth retardation. The presence of aPL is associated with low birth weight and preterm delivery. Damage to the utero-placental circulation contributes to complications later in pregnancy. Placental abruption in patients with APS has led to intrauterine death and stillbirths[9].

The role of aPL in preeclampsia is not well understood. Poor utero-placental circulation may play a role in preeclampsia. Preeclampsia occurs earlier in women with APS and is more severe. The presence of aCL has been shown to be associated with the development of preeclampsia. Studies have shown that more than one type of aPL increases the risk of severe preeclampsia. Hemolysis, elevated liver enzymes, low platelet counts (HELLP) syndrome, a severe form of preeclampsia, has been shown to occur more often in women with APS and may also occur much earlier in pregnancy[9].

CATASTROPHIC APS

Catastrophic APS (CAPS), or Asherson’s syndrome, is a rare but often fatal form of APS. It is characterized by disseminated intravascular thrombosis leading to multiorgan failure[9,24,25]. CAPS typically manifests during the final trimester of pregnancy or in the postpartum period[26,27]. It tends to occur at a younger age[28]. Many patients have previously exhibited signs of APS, such as fetal loss or VTE. Distinguishing between CAPS and obstetric complications like HELLP syndrome or acute fatty liver of pregnancy can be challenging due to similar clinical presentations. Consequently, the risk of adverse maternal and perinatal outcomes escalates[24]. The occurrence of preeclampsia, HELLP syndrome, and placental abruption should raise suspicion for CAPS.

Detailed diagnostic guidelines for CAPS exist. The diagnosis of CAPS must include all of the following four criteria: (1) Evidence of involvement of at least three organ systems; (2) Development of clinical manifestations simultaneously or within less than one week; (3) Small vessel occlusion identified on histopathology; and (4) Laboratory confirmation of aPL[24,26]. According to the "two-hit" theory, an additional biological trigger or precipitating factor is believed to contribute to the development of CAPS, particularly in the presence of long-term aPL. CAPS can be precipitated by infections, surgery, trauma, withdrawal of anticoagulation, malignancy, obstetric complications, SLE flares, or can be idiopathic[9,24,25]. These events result in endothelial activation, extensive cytokine release, microvasculopathy, and thrombosis[26].

It has been shown that 60% of patients with CAPS exhibit a greater prevalence of rare germline variants in complement regulatory genes and a higher occurrence of mutations in those genes which lead to cell damage[26]. Molecular mimicry is also a key mechanism in the development of CAPS. Research indicates that certain microorganisms possess genetic sequences that closely resemble those found in the binding site of β2GP1 with phospholipids. This similarity can lead to cross-reactivity, where the immune system mistakenly targets the body's own structures, contributing to the development of CAPS[26,29].

Growing evidence suggests that systemic inflammatory response syndrome (SIRS) plays a crucial role in the development of CAPS. SIRS can arise not only from infections but also from various autoimmune diseases. One common manifestation of SIRS in CAPS patients is respiratory distress syndrome, which occurs in up to 25% of cases. This is supported by the presence of common mediator cascades that are characteristic of both CAPS and sepsis[26,30]. Hemostatic changes in pregnancy result in a hypercoagulable state that leads to an increase in proinflammatory markers and a compensated SIRS. When aPL are present, the disrupted interaction between the inflammatory and coagulation cascades can function as a second hit causing increased thrombosis in CAPS[26,31].

WOMEN WHO DO NOT FULFILL DIAGNOSTIC CRITERIA FOR APS

It is unknown how often it is that women who test positive for aPL but do not exhibit obstetric or thrombotic symptoms of APS will experience obstetric problems. It has been shown that up to 10% of the normal population have aPL. Therefore, the presence of aPL in women with recurrent pregnancy losses does not establish the diagnosis of APS[9]. Soh et al[32], demonstrated that women with persistent aPL, without a diagnosis of APS, had similar obstetric complications as control subjects without aPL. Given the pathogenic role of aPL, risk assessment should be based on similar factors used for definite APS. However, the existing literature on the risk of adverse pregnancy outcomes in these individuals is limited, and drawing definitive conclusions is challenging due to variations in the type and number of aPL examined[32,33].

A subgroup of patients with clinical symptoms suggestive of APS but without classic laboratory criteria also exist. These patients are considered seronegative[18]. There are three theories that explain seronegative APS. First, the diagnosis may be incorrect, and the patient has a different coagulopathy. Another theory suggests that traditional laboratory testing may not pick up cases of antibodies against different phospholipids or protein cofactors. Finally, previously positive aPL tests may have returned to negative[34,35]. As in carriers of aPL, the management of this subset of patients is challenging and is the subject of ongoing research.

MANAGEMENT OF APS

General considerations

Management of obstetric APS entails assessing thrombosis risk, initiating prophylaxis, and delivering personalized care to pregnant individuals[36]. To ascertain past pregnancy difficulties, a history of thrombotic events, other related autoimmune disorders, genetic risk factors, major organ involvement, lifestyle risk factors, or drugs that may impair fetal development, preconception counseling is required. The aPL profile should be used as the basis for risk classification. A multidisciplinary team involving hematologists and rheumatologists with expertise in APS should also be consulted[9].

Patients with APS and a history of thrombosis

A retrospective cohort study compared patients treated with warfarin, warfarin plus low-dose aspirin (LDA), LDA alone, prednisone, or no treatment. Treatment with warfarin with a target international normalized ratio (INR) of 2-3 was the most effective in preventing recurrent arterial and venous thrombosis[37]. Another small randomized controlled trial (RCT) supported the use of vitamin K antagonists (VKAs) plus LDA in preventing recurrent strokes in patients with APS[38]. These studies led to some experts supporting treatment of arterial thrombosis in APS with LDA and VKAs with a target INR of 2-3. High intensity VKAs with a target INR of 3-4 is indicated in high-risk patients[12,39]. In patients with APS and a first venous thrombosis, VKAs should be used with a target INR of 2-3[39]. Those with recurrent thromboses should receive long-term anticoagulation[9].

The use of direct oral anticoagulants (DOACs) in APS is not without controversy. In a cohort study of 176 APS patients, DOACs were less effective than VKAs in preventing VTE[40]. The Trial of Rivaroxaban in APS (TRAPS study) was prematurely stopped due to increased thromboembolic events in the patients treated with DOACs[41]. A meta-analysis of four RCTs found that there was a significantly increased risk of recurrent arterial thrombosis. These results support international guidelines that advise against the use of DOACs in APS patients with a prior history of arterial thrombosis[42]. DOACs should only be used in those who are not able to maintain a target INR despite adequate adherence or those who have a contraindication to VKAs[39].

Treatment of obstetric complications

The goal of treatment during pregnancy is to reduce the occurrence of adverse maternal and fetal outcomes. Conventional treatment in patients who are currently pregnant without a prior history of thrombosis includes LDA (81-100 mg/day) plus low molecular weight heparin (LMWH). Prophylactic LMWH should be continued for 6 weeks postpartum[12,36].

In those with a prior history of thrombotic APS, treatment includes LDA plus therapeutic LMWH or unfractionated heparin (UFH)[12,36]. Rai et al[43] performed a RCT in pregnant women with recurrent pregnancy loss associated with aPL comparing LDA daily or LDA and 5000 units of UFH twice daily. Treatment with LDA and UFH had a significantly higher rate of live births as compared to the control group[43]. Kutteh et al[44], demonstrated similar findings in a single-center, prospective trial. A systematic review of ten trials demonstrated that combination therapy with LDA and heparin would reduce pregnancy loss by 54% in women with aPL, further supporting the efficacy of LDA combined with heparin[45]. VKAs, which are the standard of care, should be restarted after pregnancy and continued indefinitely[12].

In women experiencing recurrent pregnancy complications despite receiving combination therapy with LDA and heparin, options such as escalating heparin to therapeutic dosing or introducing low-dose prednisolone (10 mg/day), plasma apheresis, intravenous immunoglobulin (IVIG), or a combination of these therapies may be prescribed[39,46]. A multicenter research study and a retrospective case series concentrating on high-risk or refractory obstetric APS demonstrated varying degrees of efficacy in improving pregnancy outcomes with IVIG, apheresis, or a combination of both[47,48]. In a prospective trial comparing prednisone and LDA compared to IVIG alone in pregnant women with a history of recurrent fetal loss, IVIG treatment led to lower pregnancy complication rates compared to prednisone and LDA[49].

Hydroxychloroquine (HCQ) is a known treatment for SLE due to its anti-inflammatory and immunomodulatory properties. It has been shown to reduce the risk of arterial and venous thromboses in patients with SLE[12]. HCQ at a dosage of 5-6 mg/kg/day has been shown to have an impact on the pathophysiological mechanisms of APS. In vitro studies have shown the ability of HCQ to inhibit aPL binding to trophoblasts. Furthermore, by blocking complement activation, HCQ prevented placental insufficiency and aberrant fetal brain development in a murine obstetric APS model. When combined with traditional treatment, HCQ has been shown in three retrospective human studies to improve pregnancy outcomes[50].

Two ongoing RCTs are investigating the use of HCQ in obstetric APS. The HYPATIA study, a multicenter RCT initiated in 2018, aims to evaluate HCQ versus placebo alongside standard of care in women with persistent aPL planning for pregnancy[51]. Furthermore, the effectiveness of HCQ as a supplement to standard treatment during pregnancy in both obstetric and thrombotic APS is being evaluated by a French RCT that started in January 2020[52].

Statins are currently contraindicated during pregnancy[53]. Statins inhibit cholesterol synthesis and its inhibition during embryogenesis interferes with sonic hedgehog signal transduction[54]. Congenital anomalies such as central nervous system defects, limb defects and VACTERL association have been reported, particularly with the use of lipophilic statins[54,55]. Pravastatin is water soluble, and there is moderate crossing of the placenta. Pravastatin and fluvastatin have not been shown to cause these congenital defects[54,56], making these agents ideal in the management of preeclampsia. Costantine et al[56], conducted a randomized pilot clinical trial evaluating the safety of 20 mg pravastatin in pregnant women with a previous history of preeclampsia. They demonstrated that pravastatin was safe with favorable pregnancy outcomes.

Due to the shared pathophysiological features between preeclampsia and atherosclerotic cardiovascular disease, there has been consideration for utilizing statins in treatment or prophylaxis against obstetrical complications. The protective effects of pravastatin on the endothelium, coupled with its ability to restore angiogenic balance, may account for reductions in placental and maternal manifestations of preeclampsia. Lefkou et al[57], conducted a small observational trial which demonstrated significant improvement in maternal and fetal/neonatal outcomes among APS-afflicted women administered pravastatin (20 mg/day) in addition to LDA and heparin following the onset of preeclampsia or IUGR, compared to those receiving conventional treatment[57]. Another study demonstrated that fluvastatin decreased prothrombotic and proinflammatory markers in aPL-positive patients[58].

In women with preeclampsia, the use of pravastatin was shown to lead to an improvement in blood pressure and improved pregnancy outcomes. Women treated with pravastatin had reduced rates of preeclampsia and a lower incidence of delivery before 37 weeks of gestation[59]. In the Statins to Ameliorate Pre-Eclampsia trial, prophylactic pravastatin in women at high risk of preeclampsia led to its delay and improvement in the angiogenic profile of these women[53]. Chaiworapongsa et al[54], report the successful use of pravastatin in a patient with a history of four previous pregnancy losses. The patient received heparin and aspirin during her fourth pregnancy but suffered fetal demise at 20 weeks. The patient began receiving pravastatin 20 mg daily at 17 weeks and 4 days gestation during her fifth pregnancy. She was induced at 34 weeks and vaginally delivered a healthy male child without complications[54]. Despite the concerns for teratogenicity from statin use, further studies are needed to determine when its use is indicated and when the benefits outweigh the risks.

Certolizumab is a TNF-α inhibitor that does not cross the placental membrane, suggesting a lack of in utero exposure[60]. Considering the possible role of TNF-α in the development of obstetric complications, the ongoing IMProve Pregnancy in APS with Certolizumab Therapy trial is investigating whether certolizumab pegol, a TNF-α inhibitor, can mitigate the risk of adverse pregnancy outcomes in high-risk APS patients with aPL profiles. To date, there have been no adverse events reported with the use of the certolizumab[61].

Postpartum and long-term prophylaxis after delivery

Maternal hypercoagulation can persist for up to 12 weeks post-delivery. Thus, continuing heparin at a prophylactic dose for 6–12 weeks postpartum is advisable to mitigate the risk of thrombotic events in mothers with obstetric APS[62]. A large retrospective study using the APS ACTION database identified risk factors for thrombotic post-obstetric complications in women with APS. Notably, cardiovascular risk factors, valvular heart disease, superficial venous thrombosis, multiple aPL positivity and a younger age at diagnosis were correlated with thrombosis development[63]. Similarly, a 10-year observational study involving 1592 women with pure obstetric APS and no prior thrombosis history demonstrated that LA positivity was associated with increased risk of unprovoked deep vein thrombosis and other thrombotic events, despite all patients receiving LDA as primary prophylaxis[64].

The efficacy of prophylaxis with LDA in this population remains uncertain, although a small retrospective study suggested a potential benefit. However, it is worth noting that patients treated with empiric LDA had a lower rate of thrombosis compared to those who did not receive LDA[65]. A randomized study comparing LDA alone versus LDA plus warfarin in aPL-positive patients without a thrombosis history demonstrated comparable thrombosis rates between the two groups, with more bleeding events observed in the warfarin group[66]. In terms of long-term management, primary thromboprophylaxis may be prudent for patients with obstetric APS lacking a history of thrombosis, given their elevated thrombotic risk.

CAPS

Early recognition of CAPS is essential for administering appropriate medical interventions and improving patient outcomes[9,26]. Because CAPS only occurs in 1% of patients with APS, the management of CAPS is based on case reports and expert opinion. A CAPS registry has been created with over 500 cases reported. An analysis of these cases has formulated the basis for first-line treatment in CAPS[12,26,36]. First-line therapy for CAPS includes eliminating the source (i.e., termination of pregnancy or treatment of infection), full anticoagulation with LMWH, glucocorticoids, and plasmapheresis[26]. Glucocorticoids are used for their anti-inflammatory properties and the ability to decrease the cytokine storm associated with CAPS. Early administration of high-dose steroids for at least three days is recommended[12,67]. Plasma exchange has been shown to improve mortality. IVIG alone has not been shown to be beneficial[12]. However, IVIG in addition to triple therapy (anticoagulation, plasmapheresis, high-dose steroids) is a component of the international consensus guidelines for the management of CAPS. It is recommended to give IVIG after the last day of plasmapheresis[26]. The risk of recurrent disease in CAPS is not well studied, and women who have had CAPS are advised not to get pregnant again[9].

The aPL carriers who do not fulfill clinical criteria for APS

The risk of obstetric complications in carriers of aPL or women testing positive for aPL without evidence of obstetric or thrombotic manifestations of APS remains uncertain. Given the pathogenic role of aPLs, risk assessment should be based on similar factors used to define obstetric APS. However, the existing literature on the risk of adverse pregnancy outcomes in these individuals is limited, and drawing definitive conclusions is challenging due to variations in the type and number of aPLs examined[32,33].

LDA, commonly employed in women without aPLs to prevent preeclampsia, has not demonstrated effectiveness as primary prophylaxis in reducing adverse pregnancy outcomes in aPL carriers. However, this conclusion is based on a systematic review encompassing only five studies involving 154 pregnancies[68]. Nonetheless, in clinical practice, LDA is often prescribed for managing pregnant aPL carriers, particularly those with a history of one or two fetal losses or those with a high-risk aPL profile. A recent extensive analysis of data from the European Registry on Obstetric Antiphospholipid Antibody Syndrome comprising 1640 cases revealed that women with obstetric morbidity that did not meet APS criteria benefited from combination therapy involving LDA and prophylactic LMWH[69].

HCQ is speculated to be advantageous for pregnant aPL carriers. The HYPATIA study aims to evaluate the role of HCQ in reducing adverse pregnancy outcomes in aPL carriers. Retrospective data demonstrated that HCQ was associated with a higher rate of live births and a lower prevalence of aPL-related pregnancy morbidity. Although other systematic reviews have demonstrated a lack of evidence to support the use of HCQ, the HYPATIA study hopes to demonstrate that HCQ could be considered in selected cases that are refractory to standard therapy[51].

CONCLUSION

APS is an autoimmune disease characterized by aPL and associated with thrombotic events and severe pregnancy complications. APS significantly impacts pregnancy outcomes, leading to recurrent pregnancy losses, early miscarriage, IUGR, placental insufficiency, premature labor, and preeclampsia.

Management of APS in pregnancy involves risk stratification for thrombosis prophylaxis and individualized care. Treatment typically includes aspirin and heparin/LMWH to improve pregnancy outcomes. Additional therapies such as low-dose prednisolone, plasma apheresis, or IVIG might be considered for patients with a history of recurrent pregnancy complications despite standard treatment. Postpartum and long-term thromboprophylaxis after delivery are also recommended to reduce the risk of thrombotic events.

The field of APS continues to evolve, particularly as more cases of CAPS are identified. The EULAR has proposed recommendations for the diagnosis and management of APS. Despite these advances, more research is needed to better understand this complex disease and produce targeted treatment options.