Antiphospholipid syndrome (APS), which is characterized by the presence of antiphospholipid antibodies (aPL), is associated with increased risk of thrombosis and obstetric complications, including preterm delivery and recurrent pregnancy losses. APS shows diverse clinical manifestations and the risk of complications varies among clinical subtypes. Although these patients are usually treated with aspirin and anticoagulants, the optimal treatment in various clinical settings is unclear, as the risk of complications vary among clinical subtypes and the management strategy depends on whether the patient is pregnant or not. Also, there are unmet needs for the evidence-based, pregnancy-related treatment of asymptomatic women positive for aPL. This review focuses on the management of positive aPL or APS in pregnant and postpartum women, and in women attempting to become pregnant. For asymptomatic aPL positive women, no treatment, low dose aspirin (LDA) or LDA plus anticoagulants can be considered during antepartum and postpartum. In obstetric APS patients, preconceptional LDA is recommended. LDA plus low molecular weight heparin is administered after confirmation of pregnancy. Vascular APS patients should take frequent pregnancy test and receive heparin instead of warfarin after confirmation of pregnancy. During pregnancy, heparin plus LDA is recommended. Warfarin can be restarted 4 to 6 hours after vaginal delivery and 6 to 12 hours after cesarean delivery. Most importantly, a tailored approach and patient-oriented treatment are mandatory.
Antiphospholipid syndrome (APS) is clinically defined by the presence of antiphospholipid antibodies (aPL) coupled with thrombosis and/or pregnancy-related morbidities.1 Patients with APS have increased risk of thrombosis, preterm delivery, and unexplained fetal loss.2 In a multicenter prospective study of 1,000 APS patients, the survival probability at 10 years was 90.7%, with the most frequent cause of death being severe thrombosis. Of these women, 15.5% became pregnant, but only 72.9% of pregnancies resulted in live births. The most common obstetric complication in women with APS was early fetal loss.3 Treatment with oral anticoagulants is generally recommended for patients who have experienced thrombosis, with low dose aspirin (LDA, 75–100 mg/day), with or without heparin, administered to prevent obstetric complications.
Few randomized controlled studies, however, have been performed in pregnant women with APS, making their management uncertain. In addition, the clinical manifestations of APS can differ, with the risk of complications varying according to clinical subtypes and whether or not a patient is pregnant. For example, a retrospective observational study showing that the incidence of pre-eclampsia was high in women with APS found that the rate of pre-eclampsia was higher in women with a history of thrombotic events than in women with a history of only obstetric complications.4 Furthermore, some patients are persistently positive for aPL but show no clinical signs of APS.
The classification criteria for APS were originally designed to standardize clinical studies on APS, not as diagnostic criteria for clinical practice. Also, it may be more difficult to diagnose obstetric than vascular APS owing to the diversity of clinical presentations of the former. The pathogenesis of APS involves the development of new autoantibodies and antibody complexes. In addition, because decidual cells and syncytiotrophoblasts express high basal levels of β2 glycoprotein I (β2GPI), even low aPL titers may increase the risk of adverse pregnancy outcomes.5 Because pregnancy-related morbidity and mortality, including fetal loss, often results in psychological sequelae for the patient and her family members,6 medical decisions in APS positive women must be made carefully, depending on each patient's individual clinical circumstances. This review focuses on the management of women with aPL or APS who are pregnant or attempting to become pregnant. The recommendations of this review are mainly based on the report of the International Congress on aPL Task Force of the American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines and The American College of Obstetricians and Gynecologists practice bulletin.
SEARCH STRATEGY
We used the MEDLINE/PubMed and KoreaMed using the key words “antiphospholipid syndrome” or “antiphospholipid antibodies” and “pregnancy” or “anticoagulation” or “aspirin”; no time limit was imposed. Papers written in languages other than English or Korean, duplicates and irrelevant articles were excluded.
Classification criteria and APS-defining clinical morbidity
The original criteria for classifying APS, the Sapporo criteria, were published in 1999 and later amended in 2006. APS was defined as the presence of at least one clinical criterion and one laboratory criterion met.7 Clinical criteria include vascular thromboses and pregnancy-associated morbidity. Patients can be stratified into those with vascular or obstetric APS, depending on whether they have vascular thrombosis or APS-defining pregnancy morbidities alone. Although APS is associated with high rates of pregnancy-related morbidity and mortality, not all obstetric complications are caused by APS. The Sydney criteria78 classify APS-defining morbidity into three groups. The first group includes women with one or more unexplained deaths of a morphologically normal fetus (documented by ultrasound or by direct examination) at or beyond the tenth week of gestation. The second group includes women with one or more premature births of a morphologically normal neonate before the 34th week of gestation because of i) eclampsia or severe pre-eclampsia or ii) recognized features of placental insufficiency. Generally accepted features of placental insufficiency include abnormal or non-reassuring fetal surveillance tests; abnormal Doppler flow velocimetry waveform analysis suggestive of fetal hypoxemia; oligohydramnios; and a postnatal birth weight below the tenth percentile for gestational age. The third group consists of women who have experienced three or more unexplained consecutive spontaneous abortions before the tenth week of gestation, excluding spontaneous abortions caused by maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes.
Risk factors for thrombosis in pregnant women
The risk of thrombosis increases during pregnancy due to profound hormonal changes and decreased mobility during the period of pregnancy. The risk of thrombosis depends on the stages of pregnancy and delivery methods, being higher during the third than during the first trimester and even higher during the early postpartum period (Fig. 1).910 Delivery by cesarean section is associated with a higher risk of thrombosis than vaginal delivery. Other major risk factors include personal history of thrombosis, thrombophilia, systemic lupus erythematosus, APS, heart disease, obesity, diabetes, smoking, sickle cell disease, immobility during the antepartum period, postpartum hemorrhage ≥ 1,000 mL with surgery, pre-eclampsia with fetal growth restriction, blood transfusion, and postpartum infection.111213
Risk of venous thromboembolism in pregnant or postpartum women. Postpartum indicates first 6 weeks after delivery.
ManagementaPL-positive women
Primary thrombo-prophylaxis is generally not recommended for patients who are positive for aPL but have no history of thrombosis, as relatively little is known about the risk of the first thromboembolism and the protective effects of LDA or anticoagulants in this population. A review reported that the annual risk of thrombosis in patients with aPL but without lupus was less than 1%.14 Although one meta-analysis found that LDA had a protective effect in asymptomatic aPL-positive patients, no significant risk reduction was seen when only those studies of good methodological quality were included.15 A randomized, double-blinded placebo-controlled trial of asymptomatic aPL-positive individuals showed that LDA did not prevent thrombosis16 and a prospective observational study found that continuous thrombo-prophylaxis with LDA did not reduce the risk of thromboembolism in asymptomatic aPL-positive patients.17
In high risk situations, such as during extended immobilization and during post-operation and postpartum periods, thrombo-prophylaxis reduced the risk of thrombosis in aPL carriers.1718 Thrombo-prophylaxis with LDA has also been recommended for patients with other cardiovascular risk factors, an underlying autoimmune disease such as systemic lupus erythematosus (SLE) with aPL or a high risk aPL profile.1920 High risk serological features include positive lupus anticoagulant (LA), triple positivity (LA, anti-cardiolipin [aCL] antibody, anti-β2GPI antibody), and isolated persistently positive aCL antibody at medium to high titers.2122 Low molecular weight heparin (LMWH) should be considered for thrombosis prevention in these patients during high risk situations, such as the postpartum period.2123
Antepartum: It is unclear whether pregnant women with aPL but no history of the clinical features of APS are at increased risk for obstetric morbidity or thrombosis during pregnancy. A retrospective study of 139 pregnancies in aPL-positive women not fulfilling the classification criteria for APS found that treatment with LDA did not significantly alter pregnancy outcomes, including the rate of pregnancy loss.24 Thus, there are no strict treatment guidelines for aPL-positive pregnant women with no clinical history of APS. Treatment options can include no treatment, LDA alone, or LDA and a prophylactic dose of LMWH (Table 1).25 However, aPL is highly predictive of pregnancy loss in animal models26 and human diseases.27 Moreover, LDA was found to stimulate leukocyte-derived interleukin-3 production, supporting normal trophoblast growth and hormone expression.28 Based on these findings, the majority of the Advisory Board of the Tenth aPL Antibodies recommended that pregnant women positive for aPL be treated with LDA,29 and LDA is generally recommended during pregnancy or at the beginning of attempting pregnancy, especially in women at high risk of pre-eclampsia (Table 1).30 More importantly, decisions should be based on discussions with patients and their gynecologists based on individual risk-benefit determinations.
Summary of recommendations for treatment of aPL-positive women and women with APS
Variables
aPL-positive women
Obstetric APSc
Vascular APSd
Primary prophylaxis for thrombosis
• Not recommended
• Generally not recommended
• Warfarin to target INR 2.0–3.0 for secondary prophylaxis for thrombosis
• LDA for patients with other cardiovascular risk factors, systemic lupus erythematosus, or high-risk aPL profilea
• LMWH in high-risk situationsb
Antepartum
• Options include
• Preconceptional LDA
• LDA plus a therapeutic dose of LMWH when pregnancy is confirmed
- No treatment, LDA alone and LDA plus LMWH
• LDA plus a prophylactic dose of LMWH after confirmation of intrauterine pregnancy
• Frequent pregnancy test and switch to heparin from warfarin
• LDA is generally recommended, especially in patients at high risk of preeclampsia
• LDA alone is acceptable in patients with a history of premature birth due to uteroplacental insufficiency and no history of fetal death
Postpartum
• LDA for 6 weeks after vaginal delivery and a prophylactic dose of LMWH and LDA for 6 weeks after cesarean delivery in selected patients
• LDA and a prophylactic dose of LMWH for 6 weeks
• Restart warfarin 4–6 hr after vaginal delivery and 6–12 hr after cesarean delivery
• LDA alone for 6 weeks in women with preterm vaginal deliveries due to placental insufficiency
aPositive lupus anticoagulant (LA), triple positivity (LA, aCL antibody, anti-β2 glycoprotein I antibody), and isolated persistently positive aCL at medium to high titers; bSurgery, prolonged immobilization, and puerperium; cAnti-phospholipid syndrome with obstetric complications only and without vascular complications; dAPS with history of thromboembolism.
Postpartum: There is at present no high-quality evidence for postpartum care in aPL-positive patients without a clinical history of APS. Decisions should be based on other thrombogenic risk factors, family history of thrombosis, and route of delivery. Thrombo-prophylaxis is recommended in high risk situations, with the puerperium being an established risk factor for venous thromboembolism (VTE) and the risk being highest during the first 6 weeks postpartum.31 Also, cesarean section increases the risk of VTE.3233 The ACCP Evidence-Based Clinical Practice Guidelines suggested that women with aPL but no personal or family history of thrombosis would not be at increased risk of VTE after delivery, but suggested postpartum anticoagulation in women with traditional risk factors for thrombosis, a personal history of postpartum VTE, or a family history of thrombosis.1134 Also, the Korean Society of Thrombosis and Hemostasis Evidence-Based Clinical Practice Guidelines recommend antepartum plus postpartum prophylaxis for pregnant women with positive aPL.10 Thus, along with intermittent pneumatic compression while in the hospital followed by compression stockings after release, recommendations in selected high risk patients include LDA for 6 weeks after vaginal delivery and prophylactic dose LMWH and LDA for 6 weeks after cesarean delivery (Table 1).3536
Obstetric APS
Thrombo-prophylaxis in obstetric APS patients with no history of thrombotic events is generally not recommended in usual daily life settings, although LDA can be considered in patients with some evidence supporting its benefits in reducing the risk of thrombosis.3738 However, patients who are attempting to become pregnant should be managed differently.
Antepartum: Preconception LDA increases the likelihood of pregnancy, embryo implantation, and good fetal outcomes in patients with obstetric APS.3940 Thus, pre-pregnancy counseling is critical in obstetric APS patients who may benefit from preconception LDA. The management of women with obstetric APS who are pregnant or attempting to become pregnant is dependent on previous APS-defining obstetric morbidities. In general, patients with recurrent fetal losses require more intensive thrombo-prophylaxis than those with preterm deliveries due to preeclampsia. Patients who experienced early fetal loss, defined as three or more spontaneous abortions earlier than the tenth week of gestation, or late fetal loss, defined as fetal death after the tenth week of gestation, should be administered LDA when attempting pregnancy and a prophylactic dose of LMWH pregnancy is achieved (Tables 1, 2 and Fig. 2). Women who had premature birth before the 34th week of gestation, due to uteroplacental insufficiency (e.g., eclampsia, pre-eclampsia, or other evidence of placental insufficiency) may benefit from LDA alone.41 Although some clinicians recommend combinations of LDA and LMWH, a recent randomized controlled trial found that, when compared with LDA alone, the combination of LMWH and LDA did not reduce the rate of recurrent early-onset pre-eclampsia in women with aPL compared with LDA alone.42
Dosages of anticoagulation regimens<xref rid="B11-jkms-36-e24" ref-type="bibr">11</xref>
Anticoagulation regimen
Anticoagulation dosage
Prophylactic LMWH
• Enoxaparin, 40 mg SC once daily
• Dalteparin, 5,000 units SC once daily
• Tinzaparin, 4,500 units SC once daily
• Nadroparin, 2,850 units SC once daily
Therapeutic LMWH
• Enoxaparin, 1 mg/kg SC every 12 hr
• Daleparin, 200 units/kg SC once daily
• Dalteparin, 100 units/kg every 12 hours
• Tinzaparin, 175 units/kg once daily (target anti-Xa level in a therapeutic range of 0.6–1.0 units/mL 4 hr after last injection for twice-daily regimen)
Prophylactic UFH
• 5,000–7,000 units SC every 12 hr in the first trimester
• 7,500–10,000 units SC every 12 hr in the second trimester
• 10,000 units SC every 12 hr in the second trimester unless aPTT is elevated
Therapeutic UFH
• 10,000 units or more SC every 12 hr in doses adjusted to target aPTT in the therapeutic range (1.5–2.5 × controls) 6 hr after injection
Management of obstetric antiphospholipid syndrome with recurrent abortion.
LMWH = low molecular weight heparin.
aLow molecular weight heparin can be omitted in patients who have only history of placental insufficiency.
Postpartum: Guidelines suggest that patients with a history of three or more consecutive miscarriages before the tenth week of gestation or one or more fetal deaths beyond the tenth week of gestation be treated with LDA and a prophylactic dose of LMWH for 6 weeks after delivery, regardless of the route of delivery. Patients who deliver preterm due to placental insufficiency are recommended to receive LDA for 6 weeks after vaginal delivery and a combination of LDA and a prophylactic dose of LMWH for 6 weeks after cesarean delivery (Fig. 2).35
Vascular APS
Thrombo-prophylaxis: Non-pregnant APS patients with a history of vascular thrombosis should take lifelong warfarin to target international normalized ratio (INR) 2.0–3.0 for secondary prophylaxis.
Antepartum: During pregnancy, LDA with a therapeutic dose of LMWH or unfractionated heparin is recommended (Tables 1 and 2).34 Because of the teratogenicity of warfarin, the choice of when to substitute warfarin with LMWH is a major clinical issue for women of childbearing age. The 2012 ACCP Evidence-Based Clinical Practice guidelines recommended that these women undergo frequent pregnancy tests and be switched to LMWH as soon as pregnancy is confirmed, rather than switching while preparing for pregnancy (Fig. 3).34
Management of vascular antiphospholipid syndrome with recurrent abortion.
LMWH = low molecular weight heparin.
aTherapeutic dose.
Postpartum: After delivery, warfarin is recommended indefinitely. To minimize postpartum bleeding, anticoagulation treatment should be started 4–6 hours after vaginal delivery and 6–12 hours after cesarean delivery (Fig. 3).1243
Peri-operative management (labor and delivery)
The delivery options in patients receiving anticoagulation include spontaneous labor, induction of labor, and elective cesarean section. The decision should be made in a multidisciplinary team based on obstetric, hematologic, and anesthetic issues.34 Most guidelines from professional organizations and the United States Food and Drug Administration recommend discontinuing LMWH when spontaneous labor begins or 12–24 hours before scheduled induction of labor, cesarean section, or neuraxial anesthesia (12 hours for prophylactic doses and 24 hours for therapeutic doses).1244 In a retrospective study, therapeutic dose of enoxaparin with the last dose 24 hours before the surgery, no patients had thromboembolic complications through 30 days after the procedure.45 Patients receiving therapeutic doses of LMWH should be switched to unfractionated heparin, which has a shorter half-life, at weeks 36–37 of gestation. However, LMWH can be continued until 38 or 39 weeks in patients regarded as being at very low risk of unpredictable preterm delivery.46 Women can safely take LDA during the second and third trimesters without adverse effects on fetal hemodynamics or premature closure of the ductus arteriosus.4748 LDA can be stopped at any time beyond 36 weeks of gestation in patients with no history of thrombosis.35 Moreover, stopping LDA 7 days before delivery can minimize the risks of even minor bleeding.49 Regarding epidural analgesia or neuraxial anesthesia, single agent of LDA can be continued safely according to the 2018 American Society of Regional Anesthesia and Pain Medicine guidelines, but the combination LDA with other anti-platelets of anticoagulants may cause bleeding complications, such as spinal hematoma and caution is warranted.50
Management of APS with SLE
APS often presents as secondary APS related to other autoimmune disease, especially SLE.51 It is reported that up to 40% of SLE patients have aPL52 and aPL is associated with not only obstetric complications but chronic damage in SLE.53 Since there are no studies focused on APS patients with SLE, management of APS in SLE should be in line with the treatment of primary APS.19 All patients with rheumatic and musculoskeletal disease including SLE should be screened for aPL at diagnosis or before or early in pregnancy.1954. In a recent meta-analysis, subgroup analysis of aPL positive patients with the background of SLE revealed a significant protective effect of LDA.15 However, considering the risk-benefit of LDA, it is unclear whether this should be applied to all aPL positive SLE patients. In current guidelines, SLE patients who are aPL positive, LDA is recommended54 especially in patients with high-risk aPL profile (persistently positive medium/high titers or multiple positivity) and/or with other atherosclerotic/thrombophilic factors.19
Future investigations
There are still many uncertainties in the diagnosis and treatment of APS. For example, the classification and management of patients with extra-criteria clinical manifestations or non-criteria aPL41 should be considered in future investigations. Also, as there are studies reporting of the lower risk of VTE in Asian patients than in Caucasians,10555657 despite the increasing incidence of APS in Korea,58 it could be necessary to establish individualized anticoagulation strategies for different ethnic backgrounds.
CONCLUSION
In summary, primary prevention of thrombosis is generally not recommended in asymptomatic aPL-positive women, although anticoagulation should be considered in high-risk conditions. LDA is recommended before conception and during pregnancy to improve pregnancy outcomes. For selected high risk patients, 6 weeks of LDA is recommended for vaginal delivery, and LDA plus a prophylactic dose of LMWH are recommended for cesarean section during the postpartum period. In patients with obstetric APS, LDA is recommend before pregnancy and LDA plus a prophylactic dose of LMWH during pregnancy and for 6 weeks after delivery. In patients with a history of premature birth due to uteroplacental insufficiency but no history of fetal loss, LDA alone is acceptable. Women of childbearing age with vascular APS should be treated with warfarin with frequent pregnancy tests. These patients should be switched immediately to LDA and a therapeutic dose of LMWH when pregnancy is confirmed. The treatment of APS in women of childbearing age depends on the types of prior obstetric and/or vascular complications. In addition, traditional risk factors for thrombosis should also be considered before deciding medical treatment. Current review has limitations. First, it did not address extra criteria clinical manifestations in the diagnosis of APS. Second, the study suggested a general approach in all races, despite the varying risk of thrombosis among different races. Lastly, the options of direct-acting oral anticoagulants (DOACs) in the selection of anticoagulants were not addressed. However, there are not enough data to judge the safety of DOACs during pregnancy. Although this review outlines treatment guidelines, a tailored approach and patient-oriented treatment are mandatory.
ACKNOWLEDGMENTS
English language editing and review services were supplied by Bioedit (https://www.bioedit.com/).
Disclosure: Lee EB has acted as a consultant to Pfizer, received research grants from GC Pharma and Handok Inc. The other authors have no potential conflicts of interest to disclose.
Author Contributions:
Conceptualization: Lee EE, Lee EB.
Supervision: Lee EB.
Writing - original draft: Lee EE, Lee EB.
Writing - review & editing: Lee EE, Lee EB, Jun JK.
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