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 during pregnancy are lupus anticoagulant (LA), anticardiolipin antibodies (aCL), and anti-beta-2-glycoprotein I antibodies. 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 women with APS and the management of APS in pregnant and postpartum women. The medical management of women with nonobstetric APS and the prenatal care of women 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 of the following clinical and laboratory findings (table 1) (see "Diagnosis of antiphospholipid syndrome"):

●Arterial or venous thrombosis and/or specific adverse pregnancy outcomes

●Laboratory evidence of relevant autoantibodies conventionally called aPL

Sapporo (or Sydney) criteria — Updated Sapporo criteria (also called Sydney criteria) for defining pregnancy morbidity in the diagnosis of APS for classification purposes are [1]:

●≥1 unexplained fetal deaths ≥10 weeks of gestation with normal fetal anatomy by prenatal ultrasound examination or direct postnatal examination.

●≥1 preterm deliveries of a morphologically normal infant before 34 weeks of gestation due to severe preeclampsia, eclampsia, or features consistent with placental insufficiency. Generally accepted features of placental insufficiency include any of the following:

•Abnormal or nonreassuring fetal surveillance tests (eg, lack of fetal heart rate accelerations [nonreactive nonstress test], low score on a biophysical profile)

•Abnormal Doppler waveform (eg, absent or reversed end-diastolic flow in the umbilical artery)

•Oligohydramnios (ie, low amniotic fluid volume)

•Birth weight <10^th percentile for the gestational age (fetal growth restriction/small for gestational age infant)

●≥3 unexplained, consecutive, spontaneous pregnancy losses <10 weeks of gestation, after exclusion of maternal anatomic and hormonal abnormalities and paternal and maternal chromosomal abnormalities.

Although placental abruption has been associated with placental insufficiency, APS is not associated with placental abruption, and placental abruption is not a defining morbidity for APS.

There are several limitations to these widely accepted criteria used to diagnose APS, including obstetric APS. The adverse pregnancy outcomes for obstetric APS are relatively common, and 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].

The criteria are now being revised; when published, they will offer guidelines to more rigorously interpret test results. New biomarkers, such as C4 complement, will not be included in the revision but are gaining credence as additional predictors of outcome of patients with aPL antibodies [3].

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 women with APS [4,5]. 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 of patients with LA had an adverse outcome [5]. 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 anti-beta-2-glycoprotein I, and 13 percent for IgM anti-beta-2-glycoprotein I.

●Triple positivity – Triple positivity (LA, aCL, and anti-beta-2-glycoprotein I antibody) also appears to be a poor prognostic factor [6-9]. 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 women positive for all three aPLs had a live birth [6]. In comparison, women 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 had LA, which is a low number for most clinics.

Pathogenesis of APS-related pregnancy morbidity — The following table summarizes proposed pathogenic mechanisms in APS (table 2) . The pathogenesis of pregnancy morbidity in APS is incompletely understood. Uteroplacental thrombosis and vascular insufficiency may be one mechanism for adverse pregnancy outcomes, but not all affected placentas display signs of thrombosis or infarction. aPL appears to have a direct effect on human placental trophoblast function [10], decreasing trophoblast viability, syncytialization, and capacity for invasion as measured by an in vitro assay [11]. APS-associated pregnancy complications may also reflect a general autoimmune mechanism [12], and aPL may affect the production of hormones and signaling molecules by cells in the trophoblast [12,13]. In a study of pathology from lupus pregnancies, several of which were complicated by APS-related thromboses, placental tissue revealed marked inflammatory and vascular changes that were essentially indistinguishable from placental tissue of preeclampsia pregnancies [14]. Another hypothesis to explain the association of aPL and pregnancy morbidity is that aPL (anti-beta-2-glycoprotein I) activates toll-like receptor 4 on trophoblast, resulting in inflammation at the maternal-fetal interface and alteration of trophoblast function [15].

RISK OF THROMBOSIS IN PREGNANT WOMEN WITH APS — Thromboses are the hallmark of APS, and venous thromboses are more common than arterial thromboses in the nonpregnancy setting. 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 pregnant women with APS. In prospective studies, the risk of thromboembolic disease during pregnancy or postpartum was 5 to 12 percent among women with known APS, compared with 0.025 to 0.10 percent in the general obstetric population [16,17]. However, the 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 women 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 anticoagulation; the only patient who suffered postpartum thrombosis was "triple antibody positive" and was receiving LMWH.

Women 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 of pregnant women with APS varies depending on whether the patient has APS based on a prior thrombosis versus an APS-associated pregnancy morbidity. A suggested approach is summarized in the table and algorithm, as well as the clinical scenarios discussed below (table 3 and algorithm 1).

APS based on aPL and prior thrombosis, with/without APS-defining pregnancy morbidity — Nonpregnant women 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 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'.)

For treatment of women 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, as suggested by the American College of Rheumatology (ACR) Reproductive Health Guidelines and by the European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) [23,24]. The ACCP also suggests using therapeutic rather than prophylactic LMWH dosing in this setting. 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. Risk of hemorrhage is low [20]. Management of therapeutic dosing is described separately. (See "Use of anticoagulants during pregnancy and postpartum".)

We also administer low-dose aspirin (ASA; 50 to 100 mg daily) during pregnancy, 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. ASA may also reduce the risk of arterial thrombosis. (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 women who have APS based on laboratory criteria for aPL and 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 [25]. (See 'Management of patients with poor pregnancy outcome despite antithrombotic therapy' below.)

Early or late loss — For women with APS based on laboratory criteria for aPL and ≥1 fetal losses ≥10 weeks of gestation or ≥3 unexplained consecutive spontaneous pregnancy losses <10 weeks of gestation, we suggest combined therapy with low-dose ASA (50 to 100 mg per day), beginning when conception is attempted, and prophylactic-dose LMWH upon confirmation of intrauterine pregnancy; low-dose ASA and unfractionated heparin is a reasonable alternative [21,25-29]. In a trial of patients with previous miscarriage not specifically related to APS, the impact of low-dose ASA 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 [30]. Management of prophylactic heparin dosing is described separately. (See "Use of anticoagulants during pregnancy and postpartum" and "Pregnancy loss (miscarriage): 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 women with APS, compared with ASA alone, the combination of heparin and ASA significantly reduced pregnancy loss (relative risk [RR] 0.46, 95% CI 0.29-0.71) [26] or first-trimester pregnancy loss (odds ratio 0.39, 95% CI 0.24-0.65) [31] and increased live births (RR 1.30, 95% CI 1.04-1.63 [32], RR 1.27, 95%CI 1.09-1.49 [33]). A network meta-analysis comparing these therapies reached a similar conclusion [34]. 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 (ASA alone or combination of heparin and ASA) were associated with relatively high live birth rates, ranging from 71 to 84 percent for combined therapy and 42 to 80 percent for ASA alone. Therefore, the improvement in outcome with combined therapy versus ASA alone appears to be modest at best.

In women with a prior history of ≥2 fetal losses, a live-birth rate of 70 to 80 percent has been reported for patients treated with medication (eg, heparin, low-dose ASA, and/or prednisone) [17,35-40]. However, even among patients with live births, there is an increased risk of complications relating to the pregnancy (preterm birth, preeclampsia, growth restriction) [16].

Preterm delivery related to uteroplacental insufficiency — For women with APS based on aPL and ≥1 preterm deliveries of a morphologically normal infant before 34 weeks of gestation due to preeclampsia with severe features, eclampsia, or other findings consistent with placental insufficiency, we suggest low-dose ASA therapy (50 to 100 mg per day), beginning at the end of the first trimester and continuing through delivery [21,25]. Although some clinicians prescribe LMWH as well as ASA, available evidence does not support this approach [41]. The effectiveness of low-dose ASA 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 low-dose ASA selectively in cases of ASA 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. In a systematic review, the most common histopathologic features of the placenta in women with APS were infarction, impaired spiral artery remodeling, decidual inflammation, increased syncytial knots, decreased vasculosyncytial membranes, and deposition of complement split product C4d [42].

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 [43,44] 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'.)

The dose (prophylactic versus therapeutic) depends on the indication for anticoagulation, 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 [45]. (See "Use of anticoagulants during pregnancy and postpartum", section on 'HIT during or immediately preceding pregnancy'.)

●Low-dose ASA – The optimum low dose of ASA, which may be used either alone or in combination with anticoagulation depending on the clinical scenario, is unclear. Doses of 50 to 100 mg have been commonly used. Although some data suggest that the optimum dose to reduce the risk of preeclampsia may be 100 to 150 mg, 81 mg is a more practical dose as 100 to 150 mg doses are not readily available in the United States. Taking one and one-half 81 mg tablets is an option. (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):

●Baseline platelet count, serum creatinine concentration, urine protein-to-creatinine ratio, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) for comparison in the event of active APS or other complications later in pregnancy.

●Screening for both anti-Ro/SSA and anti-La/SSB antibodies. If one lupus-related autoantibody is present, another may be as well, and the presence of either of these antibodies has implications for the fetus/neonate in terms of neonatal lupus and heart block. 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 management" and "Preeclampsia: Management and prognosis" and "Oligohydramnios: Etiology, diagnosis, and management".)

Timing, management of medications, and route of delivery — In the absence of standard medical or obstetric indications for early delivery, we schedule delivery (induction or cesarean) at 39 weeks of gestation to control the timing of discontinuation of antithrombotic drugs.

●Anticoagulation – Patients receiving therapeutic LMWH are generally 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. Management of peripartum LMWH is described in detail separately. (See "Use of anticoagulants during pregnancy and postpartum", section on 'Labor and delivery'.)

●Low-dose ASA – Low-dose ASA can be stopped any time after 36 weeks of gestation in women with no history of thrombosis. Stopping ASA 7 to 10 days before delivery avoids the slight increase in mostly minor perioperative bleeding observed with continuation of the drug [46]. However, in women with a past history of serious arterial thrombotic complications, such as stroke or myocardial infarction, we continue ASA through labor and delivery because the potential benefit of reducing the risk of these serious complications outweighs the small risk of incisional bleeding.

Postpartum care — Women 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 delivery or 6 to 12 hours after cesarean delivery, unless there is significant bleeding or risk for significant bleeding. Heparin and warfarin are not contraindicated in breastfeeding mothers. Risk of hemorrhage is low [20]. (See "Management of antiphospholipid syndrome".)

There are no high-quality data to guide postpartum management of women with APS based on obstetric morbidity and no history of prior thrombosis or women 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 3).

In women 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 women with APS based on obstetric history and no history of thrombosis for a median of 9.3 years [47]. Compared with women with no thrombophilia, these women 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 women would likely be at particularly high risk postpartum, given that the postpartum state is a risk factor for thromboembolic events. In women 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 [48]. (See "Deep vein thrombosis in pregnancy: Epidemiology, pathogenesis, and diagnosis" and "Deep vein thrombosis and pulmonary embolism in pregnancy: Prevention".)

The ACCP Evidence-Based Clinical Practice Guidelines concluded that women 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/low molecular weight heparin (LMWH) may require additional treatment measures as conventional treatment fails to prevent obstetric morbidity in 20 percent of cases [7]. For women who have adverse pregnancy outcomes despite antithrombotic therapy, there is no second line therapy with proven efficacy.

The antimalarial drug hydroxychloroquine appears to depress aPL levels [49]. This effect might be beneficial in women 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) [9,50-53]. However, it takes approximately three months for hydroxychloroquine to have an effect; thus, it should be started prior to pregnancy. Case series have not described teratogenicity with use of hydroxychloroquine in pregnant women 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 [54]. Miscarriage rates have been similar in treated and untreated women. (See "Antimalarial drugs in the treatment of rheumatic disease" and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Hydroxychloroquine'.)

A network meta-analysis of randomized trials found a reduction in recurrent pregnancy loss in patients receiving aspirin plus LMWH plus intravenous immunoglobulin (IVIG) and in patients receiving aspirin plus LMWH plus IVIG plus prednisone [34]. 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.

SELECTED OTHER ISSUES

Pregnancy outcomes of women with aPL without APS — It is unclear whether women 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 [55-57]. The risk of first-time thrombosis in pregnant women with aPL and no personal history of thrombosis is also uncertain [21,58]. 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 [59-63].

Most patients without APS who are aPL positive in the first trimester (defined as aCL or anti-beta-2-glycoprotein I ≥40 units or LA-positive) remain in the high-positive range throughout pregnancy [64]. 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 women without APS, the association is weak. The reported prevalence of aCL in women with uncomplicated pregnancies ranges from 0 to 11 percent, with a median value of approximately 2 percent [55,56,65-71]. 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 abortion 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.

●Failure to perform repeat confirmatory aPL testing (repeat aPL testing should be performed >12 weeks after the first positive aPL test).

●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 women who have some type of adverse pregnancy outcome but do not meet Sapporo criteria. There is a paucity of information to guide management of pregnant women with the incidental finding of persistent aPL without meeting any of the clinical criteria for APS. Over 50 percent of such women will have a successful pregnancy without drug treatment [67,72,73].

Therapeutic options in pregnancy include no therapy, low-dose aspirin (ASA; 50 to 150 mg per day) alone, or low-dose ASA and prophylactic-dose heparin [28]. Given the uncertainty about pregnancy morbidity in these women, 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 low-dose ASA alone during pregnancy for these patients [27].

The rationale for using low-dose ASA is that, in addition to its antiplatelet effects, low-dose ASA enhances leukocyte-derived interleukin-3 production, which stimulates normal trophoblast growth and hormone expression [74]. However, it should be noted that a 2015 systematic review of trials of primary prophylaxis to prevent obstetric complications in asymptomatic women with aCL did not find a benefit from ASA therapy but included only 154 pregnancies [75].

If prophylactic-dose low molecular weight heparin (LMWH) is given to selected women, it should begin in the first trimester after confirmation of intrauterine pregnancy.

Management of women with aPL or APS planning in vitro fertilization

●IVF in women with aPL – Experience with IVF in women with aPL is extremely limited [76]. We do not prescribe prophylactic antithrombotic therapy during IVF for women 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 [77-80]. A meta-analysis by the American Society for Reproductive Medicine (ASRM) Practice Committee concluded that assessment of aPL was not indicated among women undergoing IVF, and treatment was not justified in this population based upon existing data [61,81]. However, this issue remains controversial because of the heterogeneity of these studies and the different aPL assay methodologies used [60,82]. 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 women with aPL undergoing fertility therapy are important [82].

●IVF in women with APS – IVF is potentially dangerous in women with APS since ovulation induction regimens trigger an estrogen-induced hypercoagulable state. In women with APS who are considering IVF, the authors extensively counsel and caution these women about the significant risk of thrombosis, which is particularly high for women with a prior venous thromboembolism and APS [83]. However, information on the absolute risk is imprecise given extremely limited data. The best example of these data is a series including 4 women with APS plus systemic lupus erythematosus and 10 women with APS alone undergoing IVF in which 3 patients had a total of four thromboembolic events (one lumbo-ovarian thrombosis, two distal deep venous thromboses, one distal pulmonary embolism) associated with IVF [80]. 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 performed, women 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, the patient 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 [84]. 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 [85].

Neonatal APS is rare. Studies reporting the neonatal outcome of maternal APS have not described any cases of neonatal APS among 277 neonates [85-90]; 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 [91]. However, a literature review found 16 case reports of thrombosis in infants born to women with aPL, and 12 of these infants met criteria for neonatal APS (for the other four infants, aPL was detected only in the mother) [92]. Causality related to aPL has not been established. Some authors attribute morbidity to local vascular injury, others to the antibody itself [91,93-96].

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

●Pregnancy morbidity in antiphospholipid syndrome (APS) is defined by (see 'Adverse pregnancy outcomes defining APS' above):

•≥1 unexplained fetal deaths ≥10 weeks of gestation with normal morphology by prenatal ultrasound examination or direct postnatal examination.

•≥1 preterm deliveries of a morphologically normal infant before 34 weeks of gestation due to severe preeclampsia, eclampsia, or features consistent with placental insufficiency.

•≥3 unexplained, consecutive, spontaneous pregnancy losses <10 weeks of gestation, after exclusion of maternal anatomic and hormonal abnormalities and paternal and maternal chromosomal abnormalities.

●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, and have direct effects on the human placental trophoblast. (See 'Adverse pregnancy outcomes defining APS' above.)

●It is unclear whether asymptomatic healthy women 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 women with aPL without APS' above.)

●Nonpregnant women 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 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 women 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 low-dose aspirin (ASA) to reduce the risk of preeclampsia, whether or not they have a history of APS-defining pregnancy morbidity. (See 'APS based on aPL and prior thrombosis, with/without APS-defining pregnancy morbidity' above.)

●For women with laboratory criteria for aPL and ≥1 fetal losses ≥10 weeks of gestation or ≥3 unexplained consecutive, spontaneous pregnancy losses <10 weeks of gestation but no history of venous or arterial thrombosis, we suggest combined therapy with low-dose ASA (50 to 100 mg per day) and prophylactic-dose LMWH rather than low-dose ASA alone (Grade 2B). (See 'Early or late loss' above.)

●For women with laboratory criteria for aPL and ≥1 preterm deliveries of a morphologically normal infant before 34 weeks of gestation due to severe preeclampsia, eclampsia, or other findings consistent with placental insufficiency but no history of venous or arterial thrombosis, we suggest low-dose ASA therapy rather than no therapy or heparin (Grade 2C). We prescribe prophylactic-dose LMWH with low-dose ASA in cases of ASA 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. (See 'Preterm delivery related to uteroplacental insufficiency' above.)

●For pregnant women with the incidental finding of persistent aPL without meeting any of the clinical criteria for APS, we suggest low-dose ASA alone rather than no therapy (Grade 2C). (See 'Management' above.)

●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 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.