Antiphospholipid syndrome: Obstetric implications and management in pregnancy

INTRODUCTION — Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by venous or arterial thrombosis and/or pregnancy loss in the presence of persistent expression of antiphospholipid antibodies (aPL). The main types of aPL of concern are: lupus anticoagulant (LA), anticardiolipin antibodies (aCL), and anti-beta-2-glycoprotein 1 antibodies (aB2GP1). Of note, aPL can also be found in healthy individuals.

Treatment of APS during pregnancy reduces the frequency of thrombosis and probably reduces the risk of an adverse pregnancy outcome.

This topic will discuss potential pregnancy outcomes in patients with APS and the management of APS in pregnant and postpartum patients. The medical management of patients with nonobstetric APS and the prenatal care of patients with systemic lupus erythematosus with or without aPL are reviewed separately:

●(See "Management of antiphospholipid syndrome".)

●(See "Pregnancy in women with systemic lupus erythematosus".)

ADVERSE PREGNANCY OUTCOMES DEFINING APS — APS is characterized by the presence of both clinical and laboratory findings. 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 1) [1]. The new classification system has higher specificity than the 2006 Sapporo classification system (99 versus 86 percent) but lower sensitivity (84 versus 99 percent). Changes in definitions of pregnancy morbidity included more explicit criteria for gestational age and placental insufficiency. The diagnosis of APS is discussed in detail separately. (See "Diagnosis of antiphospholipid syndrome".):

Obstetric criteria — "Obstetric APS" is a term sometimes used to describe patients with all of the following:

●Pregnancy morbidity (table 2)

●Positive antiphospholipid antibody (aPL) test (lupus anticoagulant test, or moderate-to-high titers of anticardiolipin or anti-β2-glycoprotein-I antibodies [IgG or IgM]) within three years of the pregnancy morbidity

●Findings not attributable to one of the other four APS domains (macrovascular, microvascular, cardiac valve, hematologic)  

There are several limitations to the criteria used to diagnose obstetric APS. The adverse pregnancy outcomes designated in the criteria are relatively common in all pregnancies. Furthermore, an association between these outcomes and aPL antibodies is not proven because studies have often measured different aPL antibodies, used different thresholds for positive results, often lacked confirmatory testing, and have been biased in selection of patients and controls [2].

New biomarkers, such as low C4 complement, are gaining credence as additional predictors of adverse outcome of patients with aPL antibodies, but require further study before clinical use can be recommended [3-5].

Factors associated with a higher risk of adverse obstetric outcome

●Lupus anticoagulant – In prospective studies, LA appears to be the major predictor of poor pregnancy outcomes in patients with APS [6,7]. In a prospective cohort study of 144 singleton pregnancies among patients with systemic lupus erythematous or primary APS with moderate to high titer aPL, 39 percent with LA had an adverse outcome [7]. Among patients who did not have LA, the frequency of adverse outcomes was 8 percent for immunoglobulin G (IgG) aCL, 0 percent for IgM aCL, 0 percent for IgG aB2GP1, and 13 percent for IgM aB2GP1. In a multicenter, international, aPL-positive cohort of 55 first pregnancies observed prospectively, 15 (27 percent) were complicated by early pregnancy loss [8]. Of the remaining 40 pregnancies, composite pregnancy morbidity was observed in nine (23 percent) pregnancies.

●Triple positivity – Triple positivity (positive tests for LA, aCL, and aB2GP1) also appears to be a poor prognostic factor [9-13]. In a multicenter retrospective cohort study of 750 singleton pregnancies with primary APS treated with low-dose aspirin and prophylactic low molecular weight heparin from the first trimester, only 30 percent of patients positive for all three aPLs had a live birth [9]. 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 not routinely performed in all patients. In this study, for example, only 10 percent of the patients with any aPL had LA, which is a low number for most clinics.

Pathogenesis of APS-related pregnancy morbidity — The pathogenesis of pregnancy morbidity in APS is incompletely understood but aPLs appear to affect a variety of cellular processes including blastocyst implantation in the endometrium; subsequent trophoblast proliferation, migration, and differentiation; complement activation and uterine vasculopathy; and, ultimately, antiangiogenic and prothrombotic activation, which impairs fetal growth [4,14]. The following table summarizes proposed pathogenic mechanisms in APS (table 3).

RISK OF THROMBOSIS IN PREGNANT PATIENTS WITH APS — Thromboses are the hallmark of APS, and venous thromboses are more common than arterial thromboses in nonpregnant patients. The deep veins of the lower extremities are the most common sites of venous thrombosis, and the cerebral vasculature (stroke and transient ischemic attack) is the most common site for arterial thrombosis. (See "Clinical manifestations of antiphospholipid syndrome", section on 'Thrombotic events'.)

Pregnancy and the puerperium are normally associated with an increased risk for thrombosis, and this risk is particularly high in patients with APS [15]. In prospective studies, the risk of thromboembolic disease during pregnancy or postpartum was 5 to 12 percent among patients with known APS, compared with 0.025 to 0.10 percent in the general obstetric population [16,17]. However, criteria used to establish the diagnosis of APS in patients studied may affect assessment of the magnitude of risk. In a retrospective study of 87 patients with APS without prior thrombosis (ie, 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 [18]. Only four patients received postpartum prophylactic anticoagulation; the only patient who suffered a postpartum thrombosis was triple antibody positive and receiving 5000 international units/day LMWH (dalteparin). This patient had a cesarean birth and was diagnosed with a deep vein thrombosis approximately three weeks later.

Patients with thrombosis-associated APS have higher rates of pregnancy complications/fetal loss than those with only obstetric-associated APS [19,20].

MANAGEMENT OF APS DURING PREGNANCY

Selection of patients for antithrombotic therapy — Our approach to use of antithrombotic therapy for pregnant patients with APS varies depending on whether they have APS based on a prior thrombosis versus APS-associated pregnancy morbidity only. A suggested approach is summarized in the table and algorithm, as well as the clinical scenarios discussed below (table 4 and algorithm 1).

APS based on aPL and prior thrombosis, with/without APS-defining pregnancy morbidity — Nonpregnant patients with a diagnosis of APS based on laboratory criteria for aPL plus a history of arterial or venous thrombosis are at high risk of recurrent thrombosis and are generally treated with warfarin and possibly low-dose aspirin for an indefinite period that may be lifelong. Treatment considerations and effectiveness are reviewed separately. (See "Management of antiphospholipid syndrome", section on 'Secondary thrombosis prevention' and "Management of antiphospholipid syndrome", section on 'Long-term anticoagulation'.)

●Therapeutic anticoagulation – For treatment of these patients during pregnancy, we agree with the American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines suggesting use of low molecular weight heparin (LMWH) for anticoagulation [21]. Risk of thrombosis in untreated patients is more than 10 percent; in treated patients, the risk is unknown but likely less than 1 percent [22]. We prefer LMWH because of its potentially greater safety and efficacy and convenience compared with unfractionated heparin, but unfractionated heparin is an acceptable alternative.

We administer a therapeutic dose of LMWH (table 4), as suggested by the American College of Rheumatology (ACR) and by the European Alliance of Associations for Rheumatology (EULAR) [23,24]. Fixed dose LMWH is as effective as weight-adjusted intermediate dosing [25]. The ACCP also suggests using therapeutic rather than prophylactic LMWH dosing in this setting. Risk of hemorrhage is low [20]. Management of anticoagulation (eg, advantages and disadvantages of LMWH versus unfractionated heparin, switching from warfarin to LMWH, dosing, and monitoring) is discussed in detail separately. (See "Use of anticoagulants during pregnancy and postpartum".)

●Low-dose aspirin (LDA) – We administer low-dose aspirin (LDA), as APS is one of the risk criteria the United States Preventive Services Task Force and the American College of Obstetricians and Gynecologists consider sufficient for using this therapy to reduce the risk of preeclampsia. LDA may also reduce the risk of arterial thrombosis and pregnancy loss. We begin LDA before pregnancy, if possible, otherwise as soon as pregnancy is known.

In the United States, the lowest available aspirin doses are 81 and 325 mg tablets; thus, LDA generally is prescribed as one or two 81 mg tablets daily during pregnancy. LDA doses in other countries reflect local availability and range from 75 to 180 mg daily. (See "Preeclampsia: Prevention", section on 'Low-dose aspirin' and "Management of antiphospholipid syndrome", section on 'Secondary thrombosis prevention'.)

APS based on aPL and APS-defining pregnancy morbidity alone, no prior thrombosis — We offer pharmacologic treatment (as described below) to pregnant patients who have APS based on laboratory criteria for aPL and a history of pregnancy-related morbidity but have no history of venous or arterial thrombosis. Some experts consider close clinical surveillance for maternal thrombosis or pregnancy complications, with or without the addition of hydroxychloroquine, to be a reasonable alternative approach in this population [26]. (See 'Management of patients with poor pregnancy outcome despite antithrombotic therapy' below.)

Patients with early or late loss — For patients with APS based on laboratory criteria for aPL and embryonic or fetal death (table 2), we suggest [21,26-30]:

●Prophylactic-dose LMWH upon confirmation of intrauterine pregnancy (prophylactic-dose unfractionated heparin is a reasonable alternative) (table 4), plus

●LDA (one or two 81 mg tablets daily in the United States) before pregnancy if possible, otherwise as soon as pregnancy is known.

In a trial of patients with previous pregnancy losses not specifically related to APS, the impact of LDA (81 mg) on pregnancy loss and live birth was greater when aspirin was started prior to conception and continued throughout pregnancy and attenuated if the treatment was taken less than four of seven days per week [31]. Management of prophylactic heparin dosing is described separately. (See "Use of anticoagulants during pregnancy and postpartum" and "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'.)

In meta-analyses of randomized trials in patients with APS, compared with LDA alone, the combination of heparin and LDA significantly reduced pregnancy loss (relative risk [RR] 0.46, 95% CI 0.29-0.71) [27] or first-trimester pregnancy loss (odds ratio 0.39, 95% CI 0.24-0.65) [32] and increased live births (74.3 versus 55.8 percent, RR 1.30, 95% CI 1.04-1.63 [33]; 87 versus 67 percent, RR 1.27, 95%CI 1.09-1.49 [34]). A network meta-analysis comparing these therapies reached a similar conclusion [35]. However, there are several limitations to these analyses, including the small number of trials, 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. Both therapies (LDA alone or combination of heparin and LDA) were associated with relatively high live birth rates, ranging from 71 to 84 percent for combined therapy and 42 to 80 percent for LDA alone. Therefore, the improvement in outcome with combined therapy versus LDA alone appears to be modest at best.

Even among patients with live births, there is an increased risk of pregnancy complications, such as preterm birth, preeclampsia, and fetal growth restriction [16].

Patients with preeclampsia with severe features or placental insufficiency with severe features — For most patients with APS based on laboratory criteria for aPL and preeclampsia with severe features or placental insufficiency with severe features before 34 weeks of gestation (table 2), we suggest LDA therapy [21,26]. Although some clinicians prescribe LMWH as well as LDA, available evidence does not support this approach as a significant reduction in hypertensive disorders of pregnancy has not been demonstrated [36]. The effectiveness of LDA for reducing the frequency of preeclampsia and its sequelae are reviewed separately. (See "Preeclampsia: Prevention", section on 'Low-dose aspirin'.)

However, we do prescribe prophylactic-dose LMWH with LDA selectively in cases of LDA failure or when postdelivery placental examination in prior pregnancies showed extensive decidual inflammation and vasculopathy and/or thrombosis, although this approach has not been validated by a randomized trial. Postdelivery histopathologic placental examination is performed when the clinician believes that the information may aid understanding of obstetric, fetal, or neonatal issues; a partial list of indications is shown in the table (table 5). In a systematic review, the most common histopathologic features of the placenta in patients with APS were infarction, impaired spiral artery remodeling, decidual inflammation, increased syncytial knots, decreased vasculosyncytial membranes, and deposition of complement split product C4d [37].

Anticoagulation and aspirin regimens

●Anticoagulation – When selecting anticoagulation regimens for use during pregnancy, we prefer LMWH to unfractionated heparin and avoid oral anticoagulants (eg, warfarin, which is teratogenic) and factor Xa inhibitors (eg, fondaparinux). Direct oral anticoagulants, such as rivaroxaban, dabigatran etexilate, and apixaban, may be ineffective in APS [38,39] and should not be used because they cross the placenta and there is a lack of safety data. (See "Use of anticoagulants during pregnancy and postpartum", section on 'Choice of anticoagulant'.)

We begin anticoagulation upon confirmation of intrauterine pregnancy. The dose (prophylactic versus therapeutic) depends on the indication for anticoagulation (table 4), as described above. (See 'APS based on aPL and prior thrombosis, with/without APS-defining pregnancy morbidity' above and 'APS based on aPL and APS-defining pregnancy morbidity alone, no prior thrombosis' above.)

If heparin is contraindicated because of heparin-induced thrombocytopenia (HIT), which occurs rarely in pregnancy, then danaparoid or fondaparinux are reasonable options [40]. (See "Use of anticoagulants during pregnancy and postpartum", section on 'HIT during or immediately preceding pregnancy'.)

●LDA (one or two 81 mg tablets daily in the United States) before pregnancy, if possible, otherwise as soon as pregnancy is known. Although LDA is typically started at 12 to 16 weeks in patients at high risk of developing preeclampsia, we start it earlier in patients with APS since APS is also associated with an increased risk of pregnancy loss. (See "Preeclampsia: Prevention", section on 'Dose'.)

Antepartum maternal and fetal monitoring — There are no high-quality data on which to base recommendations for maternal and fetal monitoring. 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 are concordant with and provide data to support the following recommendations (in addition to routine prenatal care):

●Assessment of baseline aPL levels (lupus anticoagulant, anticardiolipin antibodies [IgG and IgM], anti-beta-2-glycoprotein 1 antibodies), platelet count, serum creatinine concentration, urine protein-to-creatinine ratio, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and complement (C3 and C4 levels) for comparison in the event of new or ongoing clinical manifestations of thrombotic or obstetrical APS or other complications later in pregnancy.

●Screening for both anti-Ro/SSA and anti-La/SSB antibodies. Some patients, particularly those with Sjögren's disease (SjD), have anti-Ro/SSA and anti-La/SSB antibodies specific for protein antigens: anti-Ro 52 and 60, anti-La 48, or a combination of these antibodies. The specific antibody is less important to outcome than the number of antibodies and titer: one antibody is associated with the lowest risk for congenital heart block, the risk is higher with two and highest with three, regardless of the maternal rheumatologic diagnosis [41]. A high titer of any of the antibodies is associated with a high risk for congenital heart block; a low titer confers less risk. Monitoring for, evaluation, and management of fetal heart block are reviewed separately. (See "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Fetal surveillance for heart block'.)

●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".)

We also perform 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 per week tests of fetal well-being (nonstress tests and/or biophysical profile scoring) beginning at 32 weeks of gestation because of the increased risk of antepartum fetal death. (See "Overview of antepartum fetal assessment".)

●Routine maternal APS monitoring/management. (See "Management of antiphospholipid syndrome".)

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: Timing, management of medications, and route — In the absence of standard medical or obstetric indications for early delivery (eg, preeclampsia, fetal growth restriction, oligohydramnios, nonreassuring fetal testing), we schedule delivery (induction or cesarean) at 39+0 weeks of gestation to control the timing of discontinuation of antithrombotic drugs.

●Anticoagulation – Patients receiving therapeutic LMWH may be switched to therapeutic doses of unfractionated heparin at 36 to 37 weeks to exploit the latter agent's shorter half-life and thus allow administration of neuraxial anesthesia and minimize delivery-related bleeding if spontaneous labor occurs in the late preterm or early term period. Anesthesia guidelines recommend at least a 24-hour interval between the last dose of therapeutic dose LMWH and placement of an epidural catheter (at least 12 hours for prophylactic dose). (See "Neuraxial anesthesia/analgesia techniques in the patient receiving anticoagulant or antiplatelet medication", section on 'Low molecular weight heparin (LMWH)'.)

Therapeutic unfractionated heparin therapy is then discontinued 24 hours before labor and delivery, also to allow administration of neuraxial anesthesia and minimize delivery-related bleeding. This approach generally ensures that patients with prior thromboses are not off anticoagulants for more than 48 hours.

However, many obstetricians extend low- or intermediate-dose LMWH therapy to 38 to 39 weeks or beyond in patients they believe to be at very low risk of giving birth while receiving LMWH. Management of peripartum LMWH is described in detail separately. (See "Use of anticoagulants during pregnancy and postpartum", section on 'Labor and delivery'.)

●Low-dose aspirin (LDA) – LDA can be stopped 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 continuation of the drug [42]. However, in patients with a past 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.

We have a low threshold for sending 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 — Patients with APS by laboratory criteria for aPL and a prior history of arterial or venous thrombosis are at high risk of recurrence and are generally on an indefinite period of anticoagulation with warfarin, which should be resumed postpartum. Anticoagulation can generally be resumed 4 to 6 hours after vaginal birth or 6 to 12 hours after cesarean delivery unless there is significant bleeding or risk for significant bleeding. Heparin and warfarin are not contraindicated during breastfeeding. Risk of hemorrhage is low [20]. (See "Management of antiphospholipid syndrome".)

There are no high-quality data to guide postpartum management of patients with APS based on obstetric morbidity and no history of prior thrombosis or patients with aPL alone. Our approach is described in the table and takes into account past medical and obstetric history, antepartum therapy, and route of delivery (table 4).

In patients with APS based only on obstetric morbidity (no venous or arterial thrombotic events) who have an early pregnancy loss (ie, spontaneous or induced loss before 20 weeks of gestation), we would not administer anticoagulation after expulsion of the products of conception.

The Nimes Obstetricians and Hematologists Antiphospholipid Syndrome study followed patients with APS based on obstetric history and no history of thrombosis for a median of 9.3 years [43]. 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), although the absolute risk was low. Postpartum risk was not specifically studied, but these patients would likely be at particularly high risk postpartum, given that the postpartum state is a risk factor for thromboembolic events. In patients with aPL-related pregnancy morbidity, younger age at diagnosis of obstetric APS, concomitant cardiovascular risk factors, superficial vein thrombosis, heart valve disease, and multiple aPL positivity appear to increase the risk of first thrombosis [44]. (See "Deep vein thrombosis in pregnancy: Epidemiology, pathogenesis, and diagnosis" and "Venous thromboembolism in pregnancy: Prevention".)

The ACCP Evidence-Based Clinical Practice Guidelines concluded that patients with aPL and no personal or family history of thrombosis are probably not at increased risk of developing pregnancy-related venous thrombosis, but suggested postpartum anticoagulation for those with a family history of thrombosis [21].

MANAGEMENT OF PATIENTS WITH POOR PREGNANCY OUTCOME DESPITE ANTITHROMBOTIC THERAPY — Patients with obstetric APS treated with low-dose aspirin (LDA)/low molecular weight heparin (LMWH) may require additional treatment measures as conventional treatment fails to prevent obstetric morbidity in 20 percent of cases [10]. For patients who have adverse pregnancy outcomes despite antithrombotic therapy, there is no second line therapy with proven efficacy.

●Role of hydroxychloroquine – The antimalarial drug hydroxychloroquine appears to depress aCL levels (both IgG and IgM isotypes) [45]. This effect might be beneficial in patients with APS-related recurrent pregnancy loss. No high-quality data are available, but retrospective human and experimental animal data suggest that hydroxychloroquine prophylaxis may have some benefits in patients with APS or systemic lupus erythematosus (SLE) (eg, reduced risk for preeclampsia, preterm birth) [12,46-49]. However, it takes approximately three months for hydroxychloroquine to have an effect; thus, it should be started well before attempts at planned conception. If used, we would not remeasure aCL levels to assess whether hydroxychloroquine is having an effect; the change in aCL level is very slow to occur and quantitatively small. Case series have not described teratogenicity with use of hydroxychloroquine in pregnant patients with SLE but have been underpowered to identify small statistically significant differences. A large cohort study reported a small increase in malformations, with no specific pattern [50]. Miscarriage rates have been similar in treated and untreated patients. (See "Antimalarial drugs in the treatment of rheumatic disease" and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Hydroxychloroquine'.)

●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 aspirin plus LMWH plus IVIG and in patients receiving aspirin plus LMWH plus IVIG plus prednisone [35]. The combination of LMWH and hydroxychloroquine 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 hydroxychloroquine to aspirin and LMWH in patients refractory to treatment with aspirin and LMWH alone. When used, low-dose prednisone (1 to 30 mg/day) 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) [51].

SELECTED OTHER ISSUES

Pregnancy outcomes of patients with aPL without APS — It is unclear whether patients with aPL who do not meet criteria for APS are at increased risk of pregnancy morbidity. The body of evidence suggests little or no increase in risk in this group [52-54]. The risk of first-time thrombosis in pregnant patients with aPL and no personal history of thrombosis is also uncertain [21,55]. Furthermore, there is no strong evidence for an association between aPL and primary infertility, in vitro fertilization (IVF) failure, or mild or near-term/term preeclampsia [56-60].

Most patients without APS who are aPL positive in the first trimester (defined as aCL or aB2GP1 ≥40 units or LA-positive) remain in the high-positive range throughout pregnancy [61]. Modest decreases in aPL have been observed during the course of 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.

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 [52,53,62-68]. 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, systemic lupus erythematosus [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 "Diagnosis of antiphospholipid syndrome", section on 'When to suspect the diagnosis'.)

Management — Although not indicated, screening for aPL is sometimes performed in patients who have some type of adverse pregnancy outcome but do not meet ACR/EULAR criteria. There is a paucity of information to guide management of pregnant patients with the incidental finding of persistent aPL without meeting any of the clinical criteria for APS. Over 50 percent of such patients will have a successful pregnancy without drug treatment [64,69,70].

Since a sizable percentage of such patients have an adverse pregnancy outcome, the pregnancy should be closely monitored for signs of placental insufficiency. Therapeutic options in pregnancy include no therapy, low-dose aspirin (LDA, one or two 81 mg tablets daily in the United States) alone, or LDA plus prophylactic-dose heparin [29]. 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 10^th International Congress on aPL, which favored prescribing LDA alone during pregnancy for these patients [28].

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 [71]. However, it should be noted that a 2015 systematic review of trials of primary prophylaxis to prevent obstetric complications in asymptomatic patients with aCL did not find a benefit from LDA therapy but included only 154 pregnancies [72].

If prophylactic-dose low molecular weight heparin (LMWH) is given to selected patients, it should begin in the first trimester after confirmation of intrauterine pregnancy. Hydroxychloroquine is another option. (See 'Management of patients with poor pregnancy outcome despite antithrombotic therapy' above.)

Management of patients with aPL or APS planning in vitro fertilization

●IVF in patients with aPL – Experience with IVF in patients with aPL alone is extremely limited [73]. We suggest not prescribing prophylactic antithrombotic therapy during IVF for patients with aPL who have no clinical criteria for APS. The presence of aPL alone does not appear to adversely affect pregnancy rates or outcome in patients who are undergoing IVF [74-77]. 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 [58,78]. However, this issue remains controversial because of the heterogeneity of these studies and the different aPL assay methodologies used [57,79]. As an example, 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 [79]. The American College of Rheumatology conditionally recommended prophylactic dose anticoagulation therapy during assisted reproductive technologies for patients with rheumatic and musculoskeletal diseases plus positive aPL and no history of clinical manifestations of APS [80].

●IVF in patients with APS – IVF is potentially dangerous in patients with APS since ovulation induction regimens trigger an estrogen-induced hypercoagulable state. In patients with APS who are considering IVF, the authors extensively counsel and caution them about the significant risk of thrombosis, which is particularly high for those with a prior venous thromboembolism as opposed to APS based on pregnancy morbidity alone [80]. However, information on the absolute risk is imprecise given extremely limited data. The best example of these data is a series including four patients with APS plus systemic lupus erythematosus and 10 patients with APS alone undergoing IVF in which three had a total of four thromboembolic events (one lumbo-ovarian thrombosis, two distal deep venous thromboses, one distal pulmonary embolism) associated with IVF [77]. 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.

If IVF is performed, patients with a history of thrombosis-associated APS should be switched from their usual oral anticoagulant to therapeutic dose unfractionated heparin, which should be maintained after oocyte retrieval. If the patient conceives, the patient should be switched to LMWH, as described above (see 'APS based on aPL and prior thrombosis, with/without APS-defining pregnancy morbidity' above). If the patient does not conceive, they should be maintained on unfractionated heparin through repeated IVF cycles or switched back to the usual anticoagulant if further cycles are not planned.

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 [81]. 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 [82].

Neonatal APS is rare. Studies reporting the outcome of maternal APS on neonates have not described any cases of neonatal APS among 277 neonates [82-87]; 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 [88]. 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) [89]. Causality related to aPL has not been established. Some authors attribute morbidity to local vascular injury, others to the antibody itself [88,90-93].

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 aPLs, 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 [94].

Maternal treatment is the same as in nonpregnant patients, including use of rituximab (monoclonal IgG antibody) or eculizumab (complement C5 Inhibitor, monoclonal IgG antibody) [94]. 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)".)

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

●Criteria for APS-related pregnancy morbidity – Pregnancy morbidity in antiphospholipid syndrome (APS) is described in the table (table 2) (see 'Obstetric criteria' above):

The pathogenesis of pregnancy morbidity in APS is incompletely understood. Antiphospholipid antibodies (aPL) are thought to affect platelet and endothelial cell activation, promote coagulation, activate complement (via classical, lectin, or an alternative pathway), and have direct effects on the human placental trophoblast. (See 'Adverse pregnancy outcomes defining APS' above.)

●Patients with aPL alone – It is unclear whether asymptomatic healthy patients with aPL who do not meet criteria for APS are at increased risk of pregnancy morbidity. The body of evidence suggests little or no increase in risk in this group. (See 'Pregnancy outcomes of patients with aPL without APS' above.)

●Pregnancy management

•APS based on laboratory criteria for aPL and a history of arterial or venous thrombosis – Nonpregnant patients with a definite diagnosis of APS, based on laboratory criteria for aPL and a history of arterial or venous thrombosis, 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 (algorithm 1). We agree with American College of Chest Physicians Evidence-Based Clinical Practice Guidelines for use of low molecular weight heparin (LMWH) for anticoagulation of these patients during pregnancy, with resumption of warfarin postpartum. We suggest a therapeutic dose of LMWH throughout pregnancy rather than prophylactic-dose LMWH (Grade 2C).

We also prescribe LDA (one or two 81 mg tablets daily in the United States) to reduce the risk of preeclampsia, whether or not the patient has a history of APS-defining pregnancy morbidity. LDA is started before pregnancy if possible, otherwise as soon as pregnancy is known. (See 'APS based on aPL and prior thrombosis, with/without APS-defining pregnancy morbidity' above.)

•APS based on pregnancy morbidity alone

-For patients obstetric APS based on laboratory criteria for aPL and prefetal or fetal loss (table 2), we suggest combined therapy with LDA (one or two 81 mg tablets daily in the United States) and prophylactic-dose LMWH rather than LDA alone (Grade 2B). We begin LMWH upon confirmation of intrauterine pregnancy and we begin LDA before pregnancy if possible, otherwise as soon as pregnancy is known. (See 'Patients with early or late loss' above.)

-For patients with obstetric APS based on laboratory criteria for aPL and preeclampsia with severe features or placental insufficiency with severe features before 34 weeks (table 2), we suggest LDA therapy rather than no therapy or heparin (Grade 2C). We prescribe prophylactic-dose LMWH with LDA in cases of LDA failure or when placental examination shows extensive decidual inflammation and vasculopathy and/or thrombosis, although this approach has not been validated by a randomized trial. When used, we begin LMWH upon confirmation of intrauterine pregnancy and we begin LDA before pregnancy if possible, otherwise as soon as pregnancy is known. (See 'Patients with preeclampsia with severe features or placental insufficiency with severe features' above.)

•Persistent aPL but not meeting criteria for APS – For pregnant patients with the incidental finding of persistent aPL without meeting any of the clinical criteria for APS, we suggest LDA (one or two 81 mg tablets daily in the United States) alone rather than no therapy (Grade 2C). We begin LDA before pregnancy if possible, otherwise as soon as pregnancy is known. (See 'Management' above.)

●Postpartum management – Our approach to postpartum venous thromboembolism prophylaxis depends on past medical and obstetric history, antepartum therapy, and route of delivery, and is illustrated in the table (table 4). (See 'Postpartum care' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Peter Schur, MD, who contributed to an earlier version of this topic review.