Version July 2025
INTRODUCTION —
Antiphospholipid syndrome (APS) is a clinical and laboratory diagnosis characterized by both persistent antiphospholipid antibodies (aPL) and specific complications. These complications may include venous and/or arterial thrombosis (called thrombotic APS), adverse pregnancy outcomes often associated with placental insufficiency (called obstetric APS [OAPS]), and certain nonthrombotic abnormalities (eg, livedo reticularis). The aPL of concern are lupus anticoagulants (LAs), anticardiolipin antibodies (aCL), and anti-beta2 glycoprotein I antibodies (anti-beta2GPI). APS may occur as a primary condition or in the setting of an underlying disease, usually systemic lupus erythematosus (SLE). Treatment during pregnancy likely reduces both the frequency of thrombosis and the risk of adverse pregnancy outcomes.
Of note, some healthy individuals have aPL and never develop APS-related complications. An example is people who transiently develop aPL after an infection. Identification of these individuals is important to avoid unnecessary treatment.
This topic will discuss the diagnosis of OAPS and management of pregnant patients with thrombotic APS and/or OAPS who are pregnant, postpartum, or attempting to conceive using assisted reproductive technology (ART); their potential pregnancy outcomes will also be discussed. Other important issues related to APS are reviewed separately:
●Clinical manifestations – (See "Clinical manifestations of antiphospholipid syndrome".)
●When to suspect the diagnosis, diagnostic evaluation, diagnosis, and differential diagnosis – (See "Antiphospholipid syndrome: Diagnosis".)
●Management of nonpregnant patients – (See "Antiphospholipid syndrome: Management".)
●Specific issues in pregnant patients with systemic lupus erythematosus – (See "Pregnancy in women with systemic lupus erythematosus".)
PATHOGENESIS OF APS-RELATED PREGNANCY MORBIDITY —
While the pathogenesis of pregnancy morbidity in APS is incompletely understood, antiphospholipid antibodies (aPL) appear to affect a variety of cellular processes including blastocyst implantation in the endometrium; subsequent trophoblast proliferation, migration, and differentiation; complement activation and uterine spiral arterial vasculopathy; and, ultimately, antiangiogenic factor and prothrombotic activation, which impair fetal growth [1,2]. The following table is a detailed summary of proposed pathogenic mechanisms in APS (table 1), which are discussed in detail separately (see "Antiphospholipid syndrome: Pathogenesis"). In addition, a 2024 monograph on thrombotic and obstetric APS provides a detailed quantitative review of mechanisms, phenotypes, specificity, and many algorithms for evaluating all aspects of APS and discusses the strengths and weaknesses of data [3].
CLASSIFICATION —
In 2023, the American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) published new APS classification criteria, which are intended for use in research studies (table 2) [4]. The criteria can be helpful when considering a diagnosis of APS; however, they are not diagnostic criteria and should not be the sole basis for making or excluding the clinical diagnosis.
The 2023 system relies on a weighted point system, with requirements for three points from clinical domains and three points from laboratory domains. It has higher specificity than the 2006 Sapporo APS classification system (99 versus 86 percent) but lower sensitivity (84 versus 99 percent). The updated definitions of pregnancy morbidity include more rigorous criteria for gestational age and placental insufficiency.
Various classification criteria for APS are discussed in detail elsewhere. (See "Antiphospholipid syndrome: Diagnosis", section on 'Classification criteria'.)
WHEN TO SUSPECT OBSTETRIC APS —
OAPS should be suspected in patients with a history of specific pregnancy morbidities, which may be defined by domain 4 of the table (table 2).
Among those with typical pregnancy morbidity, other factors suggestive of associated APS include underlying systemic lupus erythematosus (SLE), clinical manifestations of thrombosis, valvular heart disease, livedo reticularis/ racemosa, or laboratory abnormalities such as unexplained impaired kidney function, mild thrombocytopenia, elevated activated partial thromboplastin time (aPTT), or a biologic false-positive serologic test for syphilis (Venereal Disease Research Laboratory [VDRL] or rapid plasma reagin [RPR] tests). Positive antinuclear antibodies and/or low levels of complement (C3 and C4) are present in some patients with APS, including OAPS, who do not have underlying SLE.
DIAGNOSTIC EVALUATION
●Detailed pregnancy history – This includes a description of all prior pregnancies: pregnancy duration in weeks, fetal outcome (early loss, live birth, stillbirth), and complications (particularly preeclampsia and fetal growth restriction). The diagnostic evaluation of any pregnancy with an abnormal outcome should be reviewed to determine whether a cause or probable cause can be identified and assess diagnostic certainty. It is critically important to rule out other causes of pregnancy morbidity before attributing obstetric complications to OAPS.
If placental histopathology is available, the most common histopathologic features of the placenta in patients with APS are infarction, abnormal spiral artery remodeling, decidual inflammation, increased syncytial knots, decreased vasculosyncytial membranes, and deposition of complement split product C4d [5]. However, these findings are not specific to OAPS.
●Other history – Ask about:
•The nature and frequency of any previous thrombotic events, including risk factors for thrombosis (eg, use of estrogen-containing medications, immobility)
•Any history of thrombocytopenia and its diagnostic evaluation
●Any symptoms associated with systemic lupus erythematosus (SLE), such as arthritis/arthralgias, photosensitivity, oral ulcers, patchy hair loss, and Raynaud phenomenon (see "Systemic lupus erythematosus in adults: Clinical manifestations and diagnosis", section on 'History and physical examination')
●Physical examination – There are no pathognomonic physical findings of APS, but physical examination rarely may reveal an anatomic finding that may be associated with pregnancy loss or preterm birth (eg, uterine abnormality) or findings related to ischemia or infarction of specific organs such as the skin or the central nervous system (eg, livedo reticularis/racemosa, stroke). (See "Clinical manifestations of antiphospholipid syndrome".)
●Laboratory evaluation – Routine laboratory testing includes:
•Complete blood count
•Baseline prothrombin time (PT) and activated partial thromboplastin time (aPTT)
•Serum creatinine, urine protein and sediment
•Antiphospholipid antibody (aPL) testing, specifically lupus anticoagulant (LA), anticardiolipin (aCL), and anti-beta2 glycoprotein I antibodies (anti-beta2GPI) (see "Antiphospholipid syndrome: Diagnosis", section on 'Antiphospholipid antibody testing')
If the patient is pregnant at the time of laboratory testing, it is important to be familiar with changes that may be related to normal pregnancy (eg, mild decrease in platelets, mild increase in urinary protein). (See "Maternal adaptations to pregnancy: Hematologic changes" and "Maternal adaptations to pregnancy: Kidney and urinary tract physiology".)
DIAGNOSIS OF OBSTETRIC APS
Obstetric criteria — We make the diagnosis of OAPS based on the presence of both of the following:
●Pregnancy morbidity, which may be defined by domain 4 of the table (table 2). When considering a potential clinical diagnosis of OAPS and the need for prophylactic treatment during a subsequent pregnancy, we look at the overall clinical and serologic picture to decide whether a single, unexplained loss between 10 and 16 weeks may be due to OAPS, including the type and level of antiphospholipid antibodies (aPL).
●Persistent positive aPL (lupus anticoagulant [LA] and/or moderate to high titers of anticardiolipin [aCL] or anti-beta2 glycoprotein I antibodies [anti-beta2GPI]) within three years of the pregnancy morbidity. Laboratory testing must be positive on two separate occasions at least 12 weeks apart to confirm persistence. (See "Antiphospholipid syndrome: Diagnosis", section on 'Antiphospholipid antibody testing'.)
Our confidence in the diagnosis of OAPS increases when any of the following are present:
●There are no alternative explanations for the pregnancy morbidity.
●There is a highly suggestive pattern of results of aPL testing, including any of the following (see "Antiphospholipid syndrome: Diagnosis", section on 'Clinically relevant antiphospholipid antibody profile'):
•The aCL and/or anti-beta2GPI are immunoglobulin G (IgG), with or without immunoglobulin M (IgM), rather than isolated IgM.
•The aCL are moderate to high titer.
•Two or more clinically relevant and persistent aPL laboratory results are present.
●Additional aPL-related manifestations are present, such as otherwise unexplained thrombocytopenia, valvular heart disease documented by echocardiography, or thrombotic microangiopathy affecting the kidney (aPL nephropathy) [6]. (See "Clinical manifestations of antiphospholipid syndrome".)
Diagnosing OAPS can be challenging. The heterogeneity and low quality of available data make an association between pregnancy outcomes and aPL very difficult to prove because studies have often measured different aPL, used different thresholds for positive results, lacked confirmatory testing, and/or been biased in selecting patients and controls [7]. In addition, some adverse pregnancy outcomes that are listed in the classification criteria are relatively common, such as very early pregnancy loss (<10 weeks of gestation). When needed, we advise consultation with APS and maternal-fetal medicine experts.
aPL profiles associated with a higher risk of adverse obstetric outcome — aPL profiles vary widely in terms of the numbers, types, and titers of positive classical aPL tests (LA, aCL, and anti-beta2GPI). High-risk profiles more closely associated with adverse obstetric outcomes include:
●Lupus anticoagulant – In prospective studies, LA appears to be the major predictor of poor pregnancy outcomes in patients with APS [8-10]. As an example, in a prospective cohort study of 144 singleton pregnancies among patients with systemic lupus erythematosus (SLE) or primary APS with moderate to high titer aPL, 39 percent with LA had an adverse outcome [9]. Among patients who did not have LA, the frequency of adverse outcomes was 8 percent for IgG aCL, 0 percent for IgM aCL, 0 percent for IgG anti-beta2GPI, and 13 percent for IgM anti-beta2GPI. In the final multivariate risk model, risk factors for adverse outcome included LA status at screening (relative risk [RR] 12.15, 95% CI 2.92-0.54), history of thrombosis (RR 1.90, 95% CI 1.14-3.17 ), SLE (RR 2.16, 95% CI 1.27-3.68), age (RR 1.56 for every five-year decrease in age, 95% CI 1.18-2.08), and race (white versus nonwhite RR 3.24, 95% CI 1.16-9.07).
●Triple aPL positivity – Multiple studies have demonstrated more adverse obstetric outcomes in the setting of triple aPL positivity (ie, LA, aCL, and anti-beta2GPI) [11-15]. As an example, in a multicenter retrospective cohort study of 750 singleton pregnancies with primary APS treated with low-dose aspirin (LDA) and prophylactic low molecular weight heparin (LMWH) from the first trimester, only 30 percent of patients positive for all three aPLs had a live birth [11]. In comparison, patients positive for a single antibody had live birth rates ranging from 48 to 80 percent, depending on the antibody. A limitation of retrospective studies is that all tests were routinely performed in only some patients. In this study, as an example, only 10 percent of patients with any aPL had LA, which is a low number for most clinics.
Future directions — New biomarkers, such as low C4 complement, are gaining credence as additional predictors of adverse outcome of patients with aPL, but require further study before clinical use can be recommended [1,16,17].
Nonclassical antibodies, including the recently described antiphosphatidylserine/ prothrombin (PS/PT) antibody, are also under study; consensus regarding their utility in clinical diagnosis has not been reached [18-20]. (See "Antiphospholipid syndrome: Pathogenesis", section on 'Non-criteria autoantibodies' and "Antiphospholipid syndrome: Diagnosis", section on 'Specific antiphospholipid antibody tests'.)
PREPREGNANCY COUNSELING AND PLANNING
Patients with thrombotic APS and/or obstetric APS
Risk of thrombosis — Nonpregnant patients with thrombotic APS are at high risk of recurrent thrombosis and are generally treated with warfarin and possibly low-dose aspirin (LDA) for an indefinite period that may be lifelong. A direct oral anticoagulant (DOAC) may be reasonable in selected cases. Treatment considerations and effectiveness are reviewed separately (see "Antiphospholipid syndrome: Management"). When these patients become pregnant, the risk of pregnancy-related thrombosis in the absence of anticoagulation is more than 10 percent [21]. This risk is likely lower in anticoagulated patients [22], but high-quality data on the frequency of thrombosis are not available.
Patients with OAPS alone appear to have a lower risk of pregnancy-related thrombosis. In a retrospective study of 87 patients with APS without prior thrombosis (ie, antiphospholipid antibodies [aPL] plus recurrent pregnancy loss), no antepartum thrombotic events occurred; 51 percent of the patients received prophylactic low molecular weight heparin (LMWH) plus aspirin during pregnancy, 31 percent received aspirin alone, and 18 percent received no prophylactic treatment [23]. Only four patients received postpartum prophylactic anticoagulation; the only patient with postpartum thrombosis was triple aPL positive and received 5000 international units/day LMWH (dalteparin). This patient had a cesarean birth and was diagnosed with a deep vein thrombosis approximately three weeks later.
Risk of APS-related pregnancy morbidity — Patients with thrombotic APS and/or OAPS are at risk for APS-related pregnancy morbidity (table 2). A retrospective cohort study provided comparative data. In this study, 49 patients who were eventually classified as OAPS and 22 patients eventually classified as thrombotic APS had the following frequencies of pregnancy morbidity compared with the general obstetric population: late fetal loss (61, 0, and 3.8 percent, respectively), fetal growth restriction (43, 14, and 15 percent, respectively), preeclampsia (35, 27, and 11 percent, respectively), preterm birth (61, 18, and 19 percent, respectively), stillbirth (14, 5, and 1 percent, respectively), abruption (6, 5, and 2 percent, respectively) [24]. In other studies, patients with thrombotic APS had higher rates of pregnancy morbidity than those with only OAPS [25,26].
Risk reduction — Nonpregnant patients with thrombotic APS are often already on anticoagulation (and possibly daily LDA). These patients are switched to therapeutic-dose LMWH when they become pregnant, with continuation or addition of LDA. Patients with OAPS alone are begun on LDA when they begin attempting to conceive, with the addition of prophylactic-dose LMWH when intrauterine pregnancy is confirmed. Administration of antithrombotic therapy is discussed in more detail below. (See 'Antithrombotic therapy' below.)
This approach is based on the following lines of evidence:
●In a 2020 meta-analysis of five trials including 1295 patients with OAPS, the combination of heparin plus LDA compared with LDA alone reduced pregnancy loss (16 versus 33 percent, relative risk [RR] 0.48, 95% CI 0.32-0.71) and increased live births (86 versus 68 percent; RR 1.27, 95% CI 1.09-1.49) [22]. Earlier meta-analyses and a network meta-analysis had similar findings [27-31].
There are some limitations to these analyses, including the aPL profile and inclusion criteria, the small sample size in each trial, and the low quality of the trials themselves. For example, information about patient dropout and some adverse outcomes was not always available, and patients/providers were not blinded to the treatment. (See "Pregnancy loss (miscarriage): Counseling and comparison of treatment options and discussion of related care", section on 'Role of low-dose aspirin to reduce risk of pregnancy loss'.)
●There is consistent evidence regarding the efficacy of LDA alone for reducing the frequency of preeclampsia and its sequelae in high-risk pregnant patients. This evidence is reviewed in detail separately (see "Preeclampsia: Prevention", section on 'Low-dose aspirin'). Combination therapy (heparin plus LDA) may further reduce this risk in patients with OAPS [22,31,32]. For example, in patients with systemic lupus erythematosus (SLE) and aPL, a meta-analysis found that heparin with or without LDA decreased the rate of preeclampsia compared with any comparator (RR 0.34, 95% CI 0.13-0.90; eight trials, 485 participants) [32].
There is no strong evidence that LMWH or LDA reduces other adverse pregnancy outcomes, such as preterm birth and fetal growth restriction, in APS [22]. In terms of the harms of therapy, heparin and LDA are associated with minor bleeding (bruises, epistaxis), but serious maternal or neonatal adverse bleeding events have not been reported [31].
Patients with SLE — Specific issues in patients with SLE are discussed separately (see "Pregnancy in women with systemic lupus erythematosus"). For most pregnant patients with SLE, we continue hydroxychloroquine (HCQ) to reduce the risk of SLE flares. If the patient is not already taking HCQ, it takes approximately three months for the drug to have an effect; thus, it should be started well before attempts at planned conception. The dosing, adverse effects, contraindications, and monitoring for side effects of HCQ, including the potential for checking drug levels, are discussed elsewhere. (See "Antimalarial drugs in the treatment of rheumatic disease".)
Patients with aPL (with or without APS) planning IVF — Ovarian stimulation during in vitro fertilization (IVF) doubles the venous thrombosis risk observed in the general population, although the absolute risk is low (0.1 to 0.3 percent) [33].
●Patients with APS – IVF can have potentially serious complications in patients with APS since ovulation induction regimens trigger an estrogen-induced hypercoagulable state. In patients with APS who are considering IVF, we discuss the significant risk of thrombosis, which is particularly high for those with prior venous thromboembolism as opposed to OAPS without this history [34]. However, information on absolute risk is imprecise given extremely limited data.
A series including four patients with APS and SLE and 10 patients with APS alone undergoing IVF reported three had a total of four thromboembolic events (one lumbo-ovarian thrombosis, two distal deep venous thromboses, one distal pulmonary embolism) associated with IVF [35]. In two of these patients, thrombosis was attributed to discontinuing anticoagulant treatment after the oocyte retrieval (LMWH, prophylactic for one, therapeutic for the other); thus, adherence to treatment may have prevented these complications. All complications occurred in cycles that included gonadotropin-releasing hormone (GnRH) agonists for ovulation induction. Using a GnRH antagonist protocol or natural cycles may minimize risk of thrombosis.
In a prospective multicenter European study of 111 ART cycles in 60 patients with a rheumatological disorder (only eight with APS), no patients developed thromboses [36]. Forty-five cycles were in patients with APS or with positive aPL, and 40 of these were treated with thromboprophylaxis.
•Risk reduction – If IVF is performed, we suggest switching patients with a history of thrombotic APS from their usual oral anticoagulant to therapeutic-dose LMWH, which should be held before and resumed after oocyte retrieval. If the patient conceives, they are continued on LMWH, as described above (see 'Risk reduction' above). If the patient does not conceive, they are maintained on LMWH through repeated IVF cycles or switched back to their usual anticoagulant if further cycles are not planned.
The American College of Rheumatology (ACR) strongly recommended prophylactic-dose anticoagulation therapy during assisted reproductive technologies (ARTs) for patients with OAPS and therapeutic anticoagulation for those with thrombotic APS [34].
●Patients with aPL but not APS – The presence of aPL alone does not appear to adversely affect pregnancy rates or outcomes in patients who are undergoing IVF, although data are limited [35,37-39]. A meta-analysis by the American Society for Reproductive Medicine (ASRM) Practice Committee concluded that assessment of aPL was not indicated among patients undergoing IVF, and treatment was not justified in this population based upon existing data [40,41]. However, this issue remains controversial because of the heterogeneity of these studies and the use of different aPL assay methodologies [42,43]. The American Society for Reproductive Immunology Antiphospholipid Antibody Committee strongly disagreed with the ASRM recommendation and called for studies to determine whether there are circumstances when evaluation and treatment of patients with aPL undergoing fertility therapy are important [42].
•Risk reduction – We suggest prophylactic anticoagulation during IVF for patients with aPL even if they do not have APS-related clinical symptoms, despite limited data, because both IVF and aPL increase the risk for thrombosis. While reported rates of thrombosis during IVF for aPL-positive patients are low, most of these patients have been treated with empiric thromboprophylaxis [44].
The ACR conditionally recommended prophylactic-dose anticoagulation therapy during ART for patients with rheumatic and musculoskeletal diseases plus positive aPL and no history of clinical manifestations of APS [34].
PREGNANCY MANAGEMENT
Antithrombotic therapy — Our approach is summarized in the table (table 3). This approach aligns with recommendations from the American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR) [34,45].
Thrombotic APS, with or without APS-defining pregnancy morbidity — Patients on warfarin before pregnancy are generally switched to therapeutic-dose low molecular weight heparin (LMWH) and low-dose aspirin (LDA) during pregnancy [33,46-48].
●Dosing – We begin therapeutic-dose LMWH upon confirmation of intrauterine pregnancy (table 3). We begin LDA (one or two 81 mg tablets daily) when the patient begins to attempt to conceive, if possible, but otherwise, as soon as pregnancy is confirmed. Many experts suggest an LDA dose of 100 or 150 mg daily. In the United States, the available aspirin doses are 81 and 325 mg tablets; thus, LDA generally is prescribed as one or two 81 mg tablets daily during pregnancy. Doses >100 mg daily may be more effective in the prevention of preeclampsia [49]. LDA doses in other countries reflect local availability.
We prefer LMWH because of its potentially greater safety, efficacy, and convenience compared with unfractionated heparin, but unfractionated heparin is an acceptable alternative [31]. Fixed-dose LMWH is as effective as weight-adjusted intermediate dosing [50]. Risk of maternal hemorrhage is low [25]. Our approach is consistent with guidance from the ACR, EULAR, American College of Chest Physicians (ACCP), and others [34,45,51].
We avoid oral anticoagulants (eg, warfarin, which is teratogenic) in pregnant patients. We also avoid using direct oral anticoagulants (DOACs), such as rivaroxaban, dabigatran etexilate, and apixaban, because they cross the placenta and lack safety data (see "Anticoagulation during pregnancy and postpartum: Agent selection and dosing", section on 'Choice of anticoagulant'). However, if heparin is contraindicated because of heparin-induced thrombocytopenia (HIT), which occurs rarely in pregnancy, then danaparoid or fondaparinux are reasonable options [52]. (See "Anticoagulation during pregnancy and postpartum: Agent selection and dosing", section on 'HIT during or immediately preceding pregnancy'.)
Ideally, patients should be taking LDA when attempting to conceive. In a trial of patients with previous pregnancy losses not specifically related to APS, the impact of LDA on pregnancy loss and live birth was greater when LDA was started prior to conception and continued throughout pregnancy, and attenuated if the treatment was taken for less than four days per week [53]. (See "Preeclampsia: Prevention", section on 'Low-dose aspirin' and "Antiphospholipid syndrome: Management", section on 'Secondary thrombosis prevention'.)
Additional information regarding the management of anticoagulation (eg, advantages and disadvantages of LMWH versus unfractionated heparin, switching from warfarin to LMWH, dosing, and monitoring) is available separately. (See "Anticoagulation during pregnancy and postpartum: Agent selection and dosing".)
Obstetric APS: APS based on APS-defining pregnancy morbidity and no prior thrombosis — We suggest prophylactic-dose LMWH and LDA for pregnant patients who have OAPS based on a history of pregnancy-related morbidity (table 2) but no history of venous or arterial thrombosis) [51,54-59]. This aligns with OAPS treatment recommendations from ACR and EULAR [34,45]. (See 'Patients with poor pregnancy outcome despite antithrombotic therapy' below.)
In patients with antiphospholipid antibodies (aPL) without a history of prior thrombosis or obstetric morbidity meeting 2023 APS classification criteria, other factors may influence a clinical decision for prophylactic-dose LMWH and LDA in pregnancy. These include the presence of a high-risk aPL profile, especially in a first pregnancy, and/or in the setting of underlying systemic lupus erythematosus (SLE), older maternal age, infertility, or other risk factors for adverse pregnancy outcome. A decision for therapy in this setting should be based on joint discussion of the risks and benefits for the specific clinical situation as well as the patient's values and preferences.
●Dosing – We begin prophylactic-dose LMWH upon confirmation of intrauterine pregnancy (table 3). As described above, we begin LDA (one or two 81 mg tablets daily) when the patient begins attempting to conceive, if possible, but otherwise as soon as pregnancy is confirmed. (See 'Thrombotic APS, with or without APS-defining pregnancy morbidity' above.)
Prenatal care — There is no high-quality evidence on which to base recommendations for maternal and fetal monitoring in addition to routine prenatal care (see "Prenatal care: Initial assessment" and "Prenatal care: Second and third trimesters"). As in all pregnancies at increased risk of complications, the frequency and content of prenatal care in APS are tailored to allow timely intervention in the event of maternal or pregnancy complications, such as preeclampsia. The ACR Reproductive Health Guidelines [34] are concordant with and provide data to support the following recommendations:
●Assessment of baseline laboratory values for comparison in the event of new or ongoing clinical manifestations of thrombotic or obstetric APS or other complications later in pregnancy:
•aPL (lupus anticoagulant [LA], anticardiolipin antibodies [aCL; IgG and IgM], anti-beta2 glycoprotein I antibodies [anti-beta2GPI; IgG and IgM])
•Platelet count
•Serum creatinine concentration
•Urine protein-to-creatinine ratio
•Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
•Serum complement (C3 and C4d) levels
•Anti-Ro/SSA and anti-La/SSB antibodies in patients with APS who have an underlying connective tissue disease, including SLE, Sjögren's disease, or rheumatoid arthritis, to guide risk assessment for development of neonatal lupus and congenital heart block (see "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Autoantibodies' and "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Clinical manifestations')
●Ultrasound examination:
•Before 20 weeks of gestation (ideally in the first trimester) to establish the estimated date of delivery. (See "Prenatal assessment of gestational age, date of delivery, and fetal weight".)
•Serial sonograms approximately every four weeks beginning in the late second or early third trimester to evaluate fetal growth and amniotic fluid volume. (See "Fetal growth restriction: Screening and diagnosis" and "Assessment of amniotic fluid volume".)
●Weekly or twice weekly tests of fetal well-being (nonstress tests and/or biophysical profile scoring) beginning at approximately 32 weeks of gestation because of the increased risk for antepartum fetal death. (See "Fetal assessment: Overview of antepartum tests of fetal well-being".)
●Routine maternal APS monitoring/management. (See "Antiphospholipid syndrome: Management".)
If fetal growth restriction, oligohydramnios, and/or preeclampsia are diagnosed, management is the same as in pregnancies with these complications without APS. (See "Fetal growth restriction: Evaluation" and "Preeclampsia: Antepartum management and timing of delivery" and "Oligohydramnios: Etiology, diagnosis, and management in singleton gestations".)
Delivery issues
●Timing and route – In the absence of standard medical or obstetric indications for early delivery (eg, preeclampsia, fetal growth restriction, oligohydramnios, nonreassuring fetal testing [nonreactive nonstress test, low biophysical profile score]), we schedule delivery (induction or cesarean) at 39+0 weeks of gestation to control the timing of discontinuation of antithrombotic drugs. Scheduled delivery at 39+0 weeks has benefits in any pregnancy, as reviewed separately. (See "Induction of labor with oxytocin", section on 'Scheduled induction at 39 weeks'.)
●Management of anticoagulation – Normal coagulation is desirable intrapartum to allow safe administration of a neuraxial anesthetic and reduce the risk of excessive bleeding at delivery. Anticoagulation during labor is avoided except in the highest-risk settings (eg, recent pulmonary embolus). Predelivery management of anticoagulation, which may be initiated at 36 weeks or earlier in patients at risk for preterm birth, is discussed separately. (See "Anticoagulation during pregnancy and postpartum: Agent selection and dosing", section on 'Labor and delivery'.)
●Low-dose aspirin (LDA) – LDA can be stopped at any time after 36 weeks of gestation in patients with no history of thrombosis. Stopping LDA 7 to 10 days before delivery avoids the slight increase in mostly minor perioperative bleeding observed with continuing the drug [60]. However, in patients with a history of serious arterial thrombotic complications, such as stroke or myocardial infarction, we continue LDA through labor and delivery because the potential benefit of reducing the risk of these serious complications outweighs the small risk of excessive incisional bleeding.
●Placenta – We typically send the placenta for histologic examination in any pregnancy complicated by obstetric, fetal, or neonatal problems. Indications for obtaining this examination and interpretation of findings are reviewed separately. (See "The placental pathology report".)
POSTPARTUM CARE —
In the postpartum period, patients require adjustment of antithrombotic therapy as follows:
●Patients with thrombotic APS – These patients are at high risk of recurrent thrombosis and are generally treated with warfarin and possibly low-dose aspirin (LDA) when not pregnant. Their postpartum thrombotic risk has not been specifically studied, but such patients would likely be at particularly high risk postpartum, given that the postpartum state is a risk factor for thromboembolic events. Antithrombotic medications should be resumed postpartum. (See "Antiphospholipid syndrome: Management".)
Antithrombotic therapy generally can be resumed safely 4 to 6 hours after vaginal birth or 6 to 12 hours after cesarean birth unless there is significant bleeding, risk for significant bleeding, or traumatic neuraxial catheter placement [25]. In patients who had a neuraxial catheter placed, guidelines have been developed by anesthesiologists for the timing of administration of antithrombotic medications after catheter placement/removal to minimize the risk of spinal epidural hematoma. Choice of medication, timing of initiation, and dosing are described in detail separately. (See "Anticoagulation during pregnancy and postpartum: Agent selection and dosing", section on 'Postpartum and breastfeeding'.)
Heparin (unfractionated or low molecular weight [LMWH]) and warfarin are acceptable to use during breastfeeding. For patients with systemic lupus erythematosus (SLE), a detailed discussion on the use of immunosuppressive drugs during lactation can be found separately. (See "Safety of rheumatic disease medication use during pregnancy and lactation".)
●Patients with OAPS and no history of prior thrombosis – There is no high-quality evidence to guide postpartum management of patients with OAPS and no history of prior thrombosis. Our usual approach is to administer prophylactic-dose LMWH or heparin and LDA for six weeks after giving birth, the period of highest venous thromboembolism risk, taking into account past medical and obstetric history, antepartum therapy, and route of delivery.
For patients who have an early pregnancy loss (ie, spontaneous or induced loss before 20 weeks of gestation), we do not administer antithrombotic therapy after expulsion of the products of conception. In contrast to patients who give birth preterm or at term, these patients are probably not at increased risk of developing venous or arterial thrombosis proximate to the loss.
The lifetime risk of thrombosis in patients with OAPS alone is increased, although the absolute risk is low. The Nimes Obstetricians and Hematologists Antiphospholipid Syndrome study followed patients with APS based on pregnancy morbidity alone (no history of venous or arterial thrombosis) for a median of 9.3 years [61]. Compared with patients with no thrombophilia, these patients were at increased lifetime risk of deep vein thrombosis (adjusted hazard ratio [aHR] 1.85, 95% CI 1.50-2.28, annualized rate 1.46 percent) and stroke (aHR 2.10, 95% CI 1.08-4.08, annualized rate 0.17 percent). A prospective study of 186 patients with OAPS followed for a mean of 5.4 years identified thrombotic events in 5.9 percent. Multivariate binary logistic regression analysis revealed that triple-positive antiphospholipid antibodies (aPL; odds ratio [OR] 11.7, 95% CI 2.1-64.2) and hypocomplementemia (OR 9.0, 95% CI 1.5-53.5) were independent risk factors for the first thrombosis, after adjustment for LDA and hydroxychloroquine (HCQ) [62].
Decision-making regarding long-term management of patients with OAPS and no history of prior thrombosis is complex and should be individualized, given the risk of bleeding from antithrombotic therapy. Patients at higher risk of thrombosis would benefit most. Multiple aPL positivity appears to increase the risk of first thrombosis [62,63]. Long-term LDA is more commonly recommended for patients with additional risk factors (eg, high-risk aPL profile or underlying SLE) who do not have a contraindication to therapy. Anticoagulant therapy is reserved for those with OAPS who develop subsequent thromboses. (See "Antiphospholipid syndrome: Management", section on 'Primary thrombosis prevention'.)
Other aspects of postpartum care are generally routine, as discussed in detail elsewhere. Breastfeeding carries short- and long-term health benefits to mothers and infants and should be supported when possible. (See "Overview of the postpartum period: Normal physiology and routine maternal care" and "Maternal and economic benefits of breastfeeding" and "Infant benefits of breastfeeding".)
SELECTED OTHER ISSUES
Patients with poor pregnancy outcome despite antithrombotic therapy — Patients with obstetric APS treated with standard combination low-dose aspirin (LDA) and low molecular weight heparin (LMWH) may require additional treatment measures as conventional treatment fails to prevent obstetric morbidity in 20 percent of cases [12]. For patients who have a history of APS-associated adverse pregnancy outcomes despite standard combination therapy, there is no second-line therapy with proven efficacy. Optimal management is debated; most often another medication is added to standard therapy of LMWH and LDA. Medications most often suggested include hydroxychloroquine (HCQ), intravenous immunoglobulin (IVIG), and low-dose prednisone. Due to ease of administration and low risk for side effects, HCQ is most commonly used as initial add-on therapy and is conditionally recommended for this purpose by the American College of Rheumatology (ACR) Reproductive Health Guideline [34]. Although pravastatin [64] or plasmapheresis [65] have been suggested, they are much less well supported and very rarely used.
Tissue necrosis factor (TNF) inhibitor therapy [66] has been suggested as adjunct therapy and a large-scale clinical trial is underway.
More information on the role of certain therapies is provided below:
●Role of hydroxychloroquine – The antimalarial drug HCQ appears to depress anticardiolipin antibody (aCL) levels (both immunoglobulin G [IgG] and immunoglobulin M [IgM] isotypes) [67] and may improve APS-related pregnancy outcomes. While no high-quality data are available, retrospective human and experimental animal data suggest that HCQ prophylaxis may have some benefits in patients with APS or systemic lupus erythematosus (SLE; eg, reduced risk for pregnancy morbidity including preeclampsia and preterm birth; higher chance of live birth) [14,67-71].
A 2023 systematic review on the addition of HCQ to empiric treatment for patients with primary APS and pregnancy morbidity included 12 studies: three demonstrated improved live birth rate and four demonstrated a reduction in pregnancy loss rate suggesting benefit [72]. Randomized trials are in progress (HYPATIA trial) [73].
As discussed above, it takes approximately three months for HCQ to have an effect; thus, it should be started well before attempts at planned conception (see 'Patients with SLE' above).
The use of HCQ during pregnancy and lactation and information on its mechanism, adverse effects, and monitoring is discussed in more detail separately. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Hydroxychloroquine' and "Antimalarial drugs in the treatment of rheumatic disease".)
●Role of intravenous immunoglobulin (IVIG) and/or prednisone – A network meta-analysis of randomized trials found a reduction in recurrent pregnancy loss in patients receiving LDA plus LMWH plus IVIG and in patients receiving LDA plus LMWH plus IVIG plus prednisone [30]. The combination of LMWH and HCQ also appeared to have favorable effects, but data were very limited. Further study is needed, but the analysis supported the addition of IVIG, prednisone, or HCQ to LDA and LMWH in patients refractory to treatment with LDA and LMWH alone. When used, low-dose prednisone is preferable to high-dose as it appears to be as effective and reduces the risk of maternal and fetal morbidities (preeclampsia, gestational diabetes, preterm prelabor rupture of membranes/preterm birth) [74]. More information on the use of IVIG and glucocorticoids in pregnancy is provided elsewhere. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Intravenous immune globulin' and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Glucocorticoids'.)
aPL-positive patients without APS — Most patients without clinical criteria for APS who are antiphospholipid antibody (aPL) positive in the first trimester (defined as aCL or anti-beta2 glycoprotein I antibodies [anti-beta2GPI] ≥40 units or LA-positive) remain in the positive range throughout pregnancy [75]. Modest decreases in aPL have been observed during pregnancy but have not been associated with changes in pregnancy outcomes. Conversion from negative to positive antibody tests occurs infrequently and is not associated with adverse pregnancy outcomes. Therefore, repeat measurement of aPL during pregnancy is unnecessary.
●Risks during pregnancy – Although associations between aPL and pregnancy morbidity have been reported in patients without APS, the association is weak. The reported prevalence of aCL in patients with uncomplicated pregnancies ranges from 0 to 11 percent, with a median value of approximately 2 percent [76-84]. Since aPL can be found in normal asymptomatic individuals, a causal relationship between these antibodies and a clinical event in any individual is difficult to prove, particularly when the adverse obstetric outcome is relatively common (eg, spontaneous pregnancy loss before 10 weeks). Additional explanations for the poor predictive value of positive aPL results include the following:
•Reliance upon nonstandardized assays for aPL and failure to use internationally recognized standards.
•Failure to control for the severity of coexisting disorders known to cause adverse obstetric outcomes (eg, SLE, kidney disease, chronic hypertension).
•Failure to perform repeat confirmatory aPL testing (repeat aPL testing should be performed >12 weeks after the first positive aPL test and >12 weeks postpartum).
•Inclusion of patients with low-positive aPL levels among patients considered positive.
•Broad criteria/definitions for case selection in series involving pregnancy loss.
•Variable thrombogenic potential of a given patient's aPL.
Indications for aPL testing are reviewed separately. (See "Antiphospholipid syndrome: Diagnosis", section on 'When to suspect the diagnosis'.)
●Management — Screening for aPL is sometimes performed in patients who have some type of adverse pregnancy outcome, or who have an underlying rheumatology disorder such as SLE, but who do not meet ACR/European Alliance of Associations for Rheumatology (EULAR) classification criteria for APS. There is a paucity of information to guide management of pregnant patients with the incidental finding of persistent aPL without meeting classification criteria for APS, and anywhere from 50 to 97 percent of such patients will have a successful pregnancy without drug treatment [80,85,86].
Since some percentage of these aPL-positive patients will have an adverse pregnancy outcome, the pregnancy should be closely monitored for signs of placental insufficiency. The risk of adverse pregnancy outcome likely depends on whether a clinical diagnosis of OAPS may be made, even if the patient does not meet strict classification criteria. Even in the absence of a clinical diagnosis of OAPS, a risk/benefit discussion may be undertaken depending on the clinical scenario (eg, underlying SLE, infertility, older maternal age) and/or the aPL profile. Rarely, prophylactic LDA and LMWH therapy is given to aPL-positive patients without a history of OAPS who are deemed to be at particularly high risk after discussion of risks and benefits with the patient.
Therapeutic options include no therapy, LDA alone (one or two 81 mg tablets daily in the United States), or LDA plus prophylactic-dose heparin in rare circumstances [56]. Given the uncertainty about pregnancy morbidity in these patients, treatment decisions should be made on an individual basis. We agree with the majority of the Advisory Board of the 10th International Congress on aPL, which favored prescribing LDA alone during pregnancy for these patients [55]. LDA is recommended to reduce the risk of preeclampsia in all patients at moderate to high risk of the disease, which included all patients with SLE. (See "Preeclampsia: Prevention", section on 'Low-dose aspirin' and "Pregnancy in women with systemic lupus erythematosus".)
The rationale for using LDA is that, in addition to its antiplatelet effects, LDA enhances leukocyte-derived interleukin-3 production, which stimulates normal trophoblast growth and hormone expression [87]. Although a systematic review of trials of primary prophylaxis to prevent obstetric complications in asymptomatic patients with aCL did not find a benefit from LDA therapy, it included only 154 pregnancies [88].
If prophylactic-dose LMWH is given to selected patients, it should begin in the first trimester after confirmation of intrauterine pregnancy. HCQ is another option. (See 'Patients with poor pregnancy outcome despite antithrombotic therapy' above.)
Neonatal APS — Neonatal APS is defined by the same criteria as APS in other populations: presence of at least one type of aPL in serum and the occurrence of at least one clinical feature, such as venous or arterial thromboses or thrombocytopenia [89]. A confounding factor, however, is that aPL in the neonate almost always results from placental transfer of maternal IgG antibody (IgM does not cross the placenta) and thus may not have the same significance as endogenously produced antibody. Passively acquired aPL completely disappears by 6 to 12 months of age [90].
Neonatal APS is extremely rare. Studies reporting the outcome of maternal APS on neonates have not described any cases of neonatal APS among 277 neonates [90-95]; a registry that collects outcome data on pregnancies complicated by APS also has not recorded any cases of neonatal APS during follow-up of 134 children [96]. However, a literature review found 16 case reports of clinically evident thrombosis in infants born to patients with aPL, and 12 of these infants met criteria for neonatal APS (for the other four infants, aPL was detected only in the mother) [97]. Causality related to aPL has not been established. Some authors attribute morbidity to local vascular injury, others to the antibody itself [96,98-101].
The clinical presentation of thrombosis in neonates varies. Neonatal thrombosis is often associated with thrombocytopenia, thus, the diagnosis of thrombosis should be considered in neonates with thrombocytopenia who lack an alternative explanation for the low platelet count. (See "Neonatal thrombosis: Clinical features and diagnosis".)
Catastrophic APS — Catastrophic APS (CAPS) is a life-threatening variant of APS characterized by rapid onset of symptoms, high titers of aPL, and widespread coagulopathy with thrombosis of large and especially small vessels resulting in multiorgan failure. Approximately 1 percent of patients with APS develop the severe clinical picture of CAPS and have a high frequency of fetal death when it develops early in pregnancy, before ex utero survival would be likely with delivery [102]. In the last half of pregnancy, the possibility of CAPS should be considered in aPL-positive patients with preeclampsia with severe features or HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count). (See "Preeclampsia: Clinical features and diagnosis" and "HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets)".)
Maternal treatment is the same as in nonpregnant patients, including use of rituximab (an anti-B cell therapy) or eculizumab (an anti-complement therapy) [102]. There is limited information on use of these drugs in pregnancy. They have not been associated with an increased risk of congenital anomalies but can immunocompromise the infant if exposed in utero in the weeks prior to birth. (See "Catastrophic antiphospholipid syndrome (CAPS)" and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Rituximab'.)
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Antiphospholipid syndrome" and "Society guideline links: Anticoagulation in pregnancy".)
SUMMARY AND RECOMMENDATIONS
●Diagnosis – Obstetric antiphospholipid syndrome (OAPS) should be suspected in patients with a history of specific pregnancy morbidities, which may be defined by domain 4 of the table (table 2). We diagnose OAPS in the presence of both characteristic pregnancy morbidity and persistent positive antiphospholipid antibodies (aPL) within three years of the pregnancy morbidity. Laboratory testing must be positive on two separate occasions at least 12 weeks apart to confirm persistence. (See 'Classification' above and 'When to suspect obstetric APS' above and 'Obstetric criteria' above.)
●Pregnancy management
•Thrombotic APS with or without APS-defining pregnancy morbidity – Patients with thrombotic APS (aPL and prior venous and/or arterial thrombosis) are at high risk of recurrent thrombosis. These patients are generally treated with an anticoagulant indefinitely, usually warfarin (a direct oral anticoagulant [DOAC] is used in select cases). During pregnancy, they are managed with therapeutic-dose low molecular weight heparin (LMWH), and then warfarin is resumed postpartum. The evidence supporting long-term anticoagulation for secondary prevention of thrombosis in patients with APS is discussed separately. (See "Antiphospholipid syndrome: Management", section on 'Long-term anticoagulation'.)
Low-dose aspirin (LDA; ie, one or two 81 mg tablets daily in the United States) is administered routinely to high-risk pregnant patients as it reduces the risk of developing preeclampsia (see "Preeclampsia: Prevention", section on 'Low-dose aspirin'). In patients with thrombotic APS on LMWH, the addition of LDA also reduces the risk of pregnancy loss and increases the chances of live birth. To reduce the risk of very early pregnancy loss, LDA is started before pregnancy if possible, otherwise as soon as pregnancy is known. (See 'Thrombotic APS, with or without APS-defining pregnancy morbidity' above.)
•OAPS – For patients with OAPS without a past history of thrombosis, we suggest combined therapy with LDA and prophylactic-dose LMWH rather than LDA alone (Grade 2C). We begin LDA before pregnancy if possible, otherwise as soon as pregnancy is known. We begin LMWH upon confirmation of intrauterine pregnancy. (See 'Risk of APS-related pregnancy morbidity' above and 'Obstetric APS: APS based on APS-defining pregnancy morbidity and no prior thrombosis' above.)
•Persistent aPL without APS – For pregnant patients with the incidental finding of persistent aPL without clinical features consistent with APS, we suggest LDA rather than no therapy (Grade 2C). We begin LDA before pregnancy if possible, otherwise as soon as pregnancy is known. Rarely, patients with a high-risk clinical scenario and/or high-risk aPL profile are treated with LDA and LMWH despite not having a diagnosis of APS, and after clinician/patient discussion regarding limitations of data suggesting benefit and risks of combination therapy. (See 'aPL-positive patients without APS' above.)
●Prenatal care – In addition to routine prenatal care, we obtain baseline laboratory tests (eg, platelet count, aPL, creatinine, liver transaminases, urine protein-to-creatinine ratio, complement levels), serial ultrasound examinations in the late second and the third trimesters to evaluate fetal growth, and nonstress tests/biophysical profile scoring beginning at 32 weeks. If fetal growth restriction, oligohydramnios, and/or preeclampsia are diagnosed, management is the same as in pregnancies with these complications without APS. (See 'Prenatal care' above.)
●Timing and route of delivery – In the absence of standard medical or obstetric indications for early delivery (eg, preeclampsia, fetal growth restriction, oligohydramnios, nonreassuring fetal testing [nonreactive nonstress test, low biophysical profile score]), we schedule delivery (induction or cesarean) at 39+0 weeks of gestation to control the timing of discontinuation of antithrombotic drugs. Scheduled delivery at 39+0 weeks has benefits in any pregnancy, as reviewed separately. (See 'Delivery issues' above and "Induction of labor with oxytocin", section on 'Scheduled induction at 39 weeks'.)
●Postpartum management – Our approach to postpartum venous thromboembolism prophylaxis depends on past medical and obstetric history and route of delivery, as shown in the table (table 3). (See 'Postpartum care' above.)
ACKNOWLEDGMENT —
The editorial staff at UpToDate acknowledge Peter Schur, MD, who contributed to an earlier version of this topic review.
