Obstetrics and Gynecology

Antiphospholipid Syndrome

Antiphospholipid Syndrome (APS)

1. What every clinician should know

Clinical features and incidence

Antiphospholipid antibodies (aPL) are a heterogeneous group of autoantibodies recognizing epitopes expressed by negatively charged phospholipids, proteins or a phospholipid-protein complex. The true epitope in vivo is unknown.

aPL are associated with a variety of medical and obstetric problems. Medical problems include:

  • Arterial and venous thromboses. In contrast, most thrombophilias are associated with only venous thromboembolism.

  • Autoimmune thrombocytopenia. Typically, platelet counts are between 50,000 and 150,000/υL.

  • Several less common medical problems, including hemolytic anemia, livedo reticularis, chorea gravidarum, transverse myelitis, pyoderma-like leg ulcers and cardiac valve disease.

  • Catastrophic APS, a severe illness characterized by numerous microvascular thromboses in multiple organs, most commonly the kidneys, lungs and gastrointestinal tract. The most common presenting symptom is severe dyspnea and mortality rates are 50-65%. It often presents postpartum.

Obstetric problems associated with aPL include:

  • Complications characterized by placental insufficiency.

  • Pregnancy loss. Losses are typically fetal deaths occurring after 10 weeks gestation. They also are associated with recurrent early losses, albeit to a much weaker degree.

  • Preeclampsia.

  • Fetal growth impairment.

  • Abnormal fetal heart rate tracings and cesarean delivery.

  • Medically indicated preterm birth.

Clinical features of APS

Antiphospholipid syndrome (APS) is characterized by clinical features and confirmatory laboratory testing. Individuals with APS and no other autoimmune disease are considered to have primary APS, whereas individuals with APS and another autoimmune disease are considered to have secondary APS. The most common disorder is SLE.


  1. One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation with normal fetal morphology documented by ultrasound or by direct examination of the fetus; OR

  2. One or more premature births of a morphologically normal neonate at or before the 34th week of gestation because of eclampsia, severe preeclampsia or placental insufficiency; OR

  3. Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal abnormalities excluded.


  1. One or more clinical episodes of arterial, venous or small vessel thrombosis in any tissue organ; AND

  2. Thrombosis confirmed by objective, validated criteria (i.e. unequivocal findings of appropriate imaging studies or histopathology; AND

  3. For histopathologic confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall.

Laboratory criteria

  1. Lupus anticoagulant present in plasma on two or more occasions at least 12 weeks apart detected according to the guidelines of the International Society on Thrombosis and Hemostasis; OR

  2. Anticardiolipin antibody of IgG and/or IgM isotype in blood, present in medium or high titer, on at least two occasions at least 12 weeks apart, measured by standardized enzyme-linked imunosorbent assay; OR

  3. Anti-β 2-glycoprotein-I antibody (anti-β 2-GP-I) of IgG and/or IgM isotype in blood, present in medium or high titer, on at least two occasions at least 12 weeks apart, measured by standardized enzyme-linked immunosorbent assay.

APS may occur alone or in combination with other autoimmune disease such as systemic lupus erythematosus (SLE).

The true prevalence of APS is unknown. 1-5% of healthy individuals will have positive tests for aPL. However, most of these people will not have clinical criteria for APS. The condition is more common in women than men and can develop at any age.

Risk factors

The only major risk factor for APS is autoimmune disease, especially SLE.

Pathophysiology of APS

The pathophysiology of APS is uncertain.

The pathophysiology of thrombosis appears to be mediated at least in part by the autoantibodies themselves. Indeed, the administration of aPL results in a prolongation of the aPTT, a prothrombotic state and thrombosis in murine models. aPL activate endothelial cells, monocytes and platelets. In turn, numerous adhesion molecules and procoagulant factors are upregulated. Examples include tissue factor, thromboxane A 2, and glycoprotein 2b-3a. Also, aPL appear to interfere with the activity of several anticoagulant proteins such as protein S and Annexin 5.

The pathophysiology of obstetric complications also is uncertain. aPL given to mice causes pregnancy loss in murine models. Since APS is associated with thrombosis, it was logical to conclude that aPL lead to thrombosis in the placenta. In turn, this causes infarction, placental insufficiency and clinical problems associated with placental insufficiency, such as pregnancy loss. This hypothesis was supported by the observation of thromboses and infarction in the placentas of women with APS.

However, it has been become clear that placental findings in women with APS are non-specific and inconsistent. In addition, it appears that inflammation may be a more important pathway for obstetric complications than thrombosis in pregnancies complicated by APS. Complement activation appears to be an especially important mechanism of placental insufficiency in APS pregnancies.

2. Diagnosis and differential diagnosis

Establishing the diagnosis

Candidates for aPL testing

Diagnosis is made based on clinical and laboratory criteria for APS. It is controversial as to who should undergo testing for aPL. Most authorities would advise testing patients who meet clinical criteria for APS. These are outlined earlier in this chapter and include unexplained thrombosis, unexplained recurrent early pregnancy loss, unexplained fetal death and medically indicated preterm birth prior to 34 weeks gestation due to eclampsia, preeclampsia or placental insufficiency.

There are a few other more controversial indications for aPL testing. One is patients with a false positive serologic test for syphilis. These women are often identified since syphilis serology is routinely assessed during prenatal care. Another is patients with unexplained prolonged clotting assays.

Most authorities advise testing patients with unexplained transient ischemic attacks, amaurosis fugax, autoimmune thrombocytopenia, autoimmune hemolytic anemia, livedo reticularis and chorea gravidarum. Also, it is probably worthwhile to test women with SLE and other connective tissue diseases.

It is not worthwhile to test all patients with preeclampsia or small for gestational age fetus for aPL. These conditions are extremely common and the vast majority of patients will not have APS. aPL testing should be considered in patients with recurrent pregnancies complicated by severe placental insufficiency.

Testing for aPL

Numerous aPL have been described. However, the three that are best characterized and recommended for clinical use are lupus anticoagulant (LA), anticardiolipin antibodies (aCL) and anti-β 2-GP-I antibodies.

Testing for aPL is still plagued by intra-laboratory variation. Ideally, testing should be done in experienced reference laboratories with interest and expertise in aPL testing. Regular international workshops are held and international standards are available to optimize quality and consistency among laboratories.

LA is a funny name for an antibody and a misnomer to boot. Patients need not have lupus and they are prone to thrombosis as opposed to being anticoagulated. LA is detected in plasma using one of several phospholipid dependent clotting assays. Perhaps the most widely used is the activated partial thromboplastin time. Others include the dilute Russel viper venom time, Kaolin clotting time, and the plasma clotting time.

If the LA antibody is present, it will interfere with clotting, thus prolonging the clotting time in the assay. Of course there are other reasons for prolonged clotting tests, such as clotting factor deficiencies. Accordingly, the presence of LA is confirmed by using additional assays. Such confirmatory assays include adding normal plasma (with clotting factors) to the patients plasma. If a clotting factor is causing the prolongation in clotting, the assay will normalize.

If the patient has LA interfering with clotting, the assay will not normalize even after the addition of normal plasma. Fortunately, clinicians do not need to understand the assays for LA. They can simply order a "lupus anticoagulant screen" and obtain a "blue top" tube (citrated plasma) of blood. The laboratory will provide a binary answer - the patient either has or does not have LA.

Anticardiolipin antibodies (aCL) are assessed through a more conventional immunoassay. The assay uses purified cardiolipin as the antigen with β 2-GP-I as a cofactor. The assay is standardized using standard sera and results are reported in a semi-quantitative fashion. Medium-high titers of IgG or IgM antibodies are considered laboratory criteria for APS. The IgG isotype is more strongly associated with clinical features of APS than the IgM isotype. Low titers of either isotype can occur in normal individuals and are not associated with an increased risk for clinical problems linked to aPL. Positive results should be confirmed in two samples obtained 12 weeks apart.

Anti-β 2-GP-I antibodies are assessed through a conventional immunoassay. The assay uses purified β 2-GP-I as the antigen. The assay is standardized using standard sera and results are reported in a semi-quantitative fashion. As with aCL, medium-high titers of IgG or IgM isotype are considered laboratory criteria for APS. The IgG isotype is more strongly associated with APS than the IgM isotype. Low titers of either isotype can occur in normal individuals and are not associated an increased risk for clinical problems linked to APS. Positive results should be confirmed in two samples obtained 12 weeks apart.

Several other aPL have been described. Examples include the false positive serologic test for syphilis, antiphosphatidylserine antibodies, antiphosphatidylinositol antibodies and antiethanolamine antibodies. Although some of these may eventually prove to be clinically useful, they are not currently recommended for routine testing.

It is important to be wary of laboratories that perform aPL "panel" testing. Often numerous aPL are simultaneously tested in individual patients. Typically 10 or more antibodies with three isotypes (including IgA) are tested. Usually, abnormal results are defined as the upper 5% of a normal population. In such cases, the vast majority of normal individuals have at least one positive test for aPL. However, the clinical implications of the positive test are uncertain and likely meaningless.

Differential diagnosis

Obstetric complications

APS is relatively uncommon. In contrast, obstetric complications are common. Accordingly, the vast majority of women experiencing obstetric complications do not have APS. Thus, obstetric complications per se should not necessarily prompt an evaluation for APS.

The etiology of most obstetric complications is uncertain. However, many cases of sporadic pregnancy loss and some cases of recurrent pregnancy loss will have a clear etiology. Thus, it is important to evaluate patients with sporadic and recurrent pregnancy loss for all potential etiologies before attributing their losses to APS. For example, an evaluation of patients with recurrent pregnancy loss would exclude causes such as uterine malformations and balanced parental translocations, as well as aneuploidy of the conceptus.

Patients with fetal death ideally should have a perinatal autopsy with placental examination, karyotype and a test to exclude fetal-maternal hemorrhage. Women with severe preeclampsia, especially of early onset, should have renal disease, chronic hypertension and diabetes excluded.


Approximately 2% of patients with unexplained arterial or venous thrombosis will have APS. Thromboses occur in about 30-55% of patients with APS. When thromboses occur, 65-70% are venous thromboses and up to 50% are pulmonary embolisms. They are more likely to occur in unusual locations than thromboses not associated with APS. Arterial thromboses are most likely to be cerebrovascular accidents (CVA). Approximately 4-5% of CVAs in younger patients will be associated with aPL. Coronary occlusions and arterial thromboses in unusual locations (e.g. retinal artery) also are more common than in individuals without APS.

There are numerous other conditions associated with thrombosis. The most common are heritable thrombophilias and malignancy.

Catastrophic APS

Catastrophic APS can be difficult to diagnose. The differential diagnosis includes disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, SLE and nephritis. Diagnosis is made by testing for aPL. Most patients have dyspnea. In addition, over half have central nervous system involvement, characterized by confusion, drowsiness, stupor, seizures and infarction of intracranial vessels. Abdominal pain due to occlusion of mesenteric vessels also is common.

3. Management


The goals of antepartum therapy are to reduce the risk of thrombosis and obstetric complications.

Obstetric management

Antepartum obstetric management is not evidence based. Nonetheless, antenatal fetal testing is advised by virtually all authorities, given the substantial risks for obstetric complications. Typically, sonograms are performed every 4-6 weeks gestation to assess interval growth. Non-stress testing is initiated at 32 weeks gestation. Testing may be initiated earlier with modalities such as biophysical profile and/or Doppler velocimetry in severe cases. There should be close surveillance for the development of preeclampsia. Also, there should be a low threshold for the administration of corticosteroids to enhance fetal pulmonary maturity, given the high rate of preterm birth.

Iatrogenic preterm birth is not routinely advised for all women with APS. Instead, medically indicated early delivery should be reserved for the usual obstetric indications. However, these are more common in women with APS.

Cesarean delivery is not required in women with APS. Cesarean should be reserved for the usual obstetric indications.

Medical therapy

In patients with prior thromboembolism and APS, full dose anticoagulant therapy is required for life, including during pregnancy. Once the patient becomes pregnant, she should discontinue wafarin therapy due to untoward fetal effects. Ideally, low molecular weight heparin (LMWH) should be initiated at full anticoagulant doses (for example, enoxaparin 1 mg/kg twice daily). Another option is unfractionated heparin administered every 8-12 hours to keep a mid-interval aPTT 1.5 X control. (The aPTT is unreliable in patients with LA; anti-Xa levels can be used to monitor therapy in such cases.)

Warfarin should be discontinued as soon as there is a "late" menses and a positive pregnancy test. It is critical to stop the warfarin prior to 6 weeks gestation. Alternatively, patients may choose to stop warfarin and switch to LMWH prior to conception. It is uncertain as to whether low dose aspirin (81 mg/day in the U.S.) should be added to this regimen in an attempt to improve obstetric outcomes.

In patients with obstetric APS (no prior thromboembolism), thromboprophylactic dose anticoagulant therapy is recommended. This is intended to improve obstetric outcomes. Several but not all trials have shown efficacy. Nonetheless, it is generally accepted and considered to be effective in meta-analyses. The optimal dosing regimen is uncertain and some authorities advise using slightly higher or full anticoagulant doses.

However, higher doses of anticoagulant therapy have not been shown to be superior to thromboprophylactic doses. Typical dosing is 7,500 units twice daily of unfractionated heparin or 30-40 mg twice daily of enoxaparin. Doses are slightly higher than in non-pregnant individuals to account for the hypercoagulability of pregnancy. Although of uncertain efficacy, low dose aspirin is also administered.

The rationale for using heparins to prevent thrombosis in patients with APS is straightforward. It is uncertain how heparins and/or aspirin improves obstetric outcomes in pregnancies with APS. Low dose aspirin is thought to increase the prostacyclin to thromboxane ratio in the placenta, improving blood flow and decreasing thrombosis. Heparins also may decrease placental thrombosis. However, they also have been shown to have important anti-inflammatory and anti-complement activity which may be even more important. Heparins also act as an indirect growth factor for trophoblast, thus enhancing placental function.

In the past, high dose steroids also were used to treat patients with APS in an attempt to improve obstetric outcomes. Although efficacy was never proven in randomized trials, pregnancy outcomes were improved compared to historical controls with the use of prednisone. However, heparins are preferred as first line therapy due to untoward maternal and obstetric effects of steroids. Steroids can be used in patients who need them for other indications such as SLE. Great care must be taken if steroids and heparin are used together, since both drugs can lead to osteopenia.

Several other medications have been used to treat APS. Intravenous immune globulin (IVIG) has been reported to improve obstetric outcomes in patients who failed heparins. However, there was no difference in outcome in patients treated with low dose aspirin, heparin and IVIG compared to low dose aspirin and heparin alone in a small randomized trial. Given the considerable expense of IVIG, it is not recommended as first line therapy for APS.

Other drugs have been proposed as treatments for APS, including hydroxychloroquine, anticytokine therapy such as agents interfering with tumor necrosis alpha, and anti-complement therapy. Such medications should be considered investigational at present.


The major concern with intrapartum management is the avoidance of both thrombosis and bleeding. As stated earlier, cesarean should be reserved for the usual obstetric indications. Induction of labor or scheduled cesarean delivery is usually arranged between 39-40 weeks gestation. Patients taking thromboprophylactic doses of heparin or a LMWH such as enoxaparin can simply hold their dose for 12 hours prior to the need for neuraxial anesthesia or analgesia. They should use pneumatic compression devices during labor/cesarean and thromboprophylaxis should be restarted 6-12 hours after delivery/cesarean.

If women spontaneously labor, they should hold their dose of heparin/LMWH upon initiating labor or rupture of membranes. Such patients may or may not be able to safely receive neuraxial anesthesia depending on the timing of their last dose of anticoagulant. Protamine sulfate can be used to reverse the anticoagulant effects of heparins in cases of bleeding or urgent need for cesarean.

Patients taking full-dose anticoagulant doses of heparin or LMWH heparin should hold their dose for 24 hours prior to the need for neuraxial anesthesia or analgesia. They should use pneumatic compression devices during labor/cesarean and anticoagulation should be restarted 6-12 hours after delivery/cesarean.


The major concern with postpartum management is the avoidance of thrombosis. Patients with prior thrombosis should be treated with full anticoagulant doses of heparin or LMWH starting 6-12 hours after delivery. In addition, warfarin (typically at a dose of 5 mg per day) is initiated the day after delivery. Heparin or LMWH can be stopped when the INR is 2.0-3.0 for two consecutive days.

Patients with no prior thrombosis should be treated with thromboprophylactic doses of heparin (5,000 units twice daily) or LMWH (e.g. enoxaparin 40 mg daily) for 6 weeks after delivery to reduce the risk of thrombosis.

4. Complications


The major complication is thromboembolism. It is difficult to ascertain a precise prospective risk for thromboembolism during pregnancy in untreated women with APS because virtually all women with a diagnosis are treated. Retrospective studies estimate the risk to be 5% during pregnancy and the postpartum period. This risk can reduced to less than 1% with appropriate anticoagulant therapy.


Heparin has several potential maternal side effects, including bleeding, heparin induced thrombocytopenia, heparin induced osteopenia, local skin irritation and allergy, and interference with neuraxial anesthesia.

Bleeding is especially problematic in association with cesarean delivery. The most common complication is wound hematoma in patients who are fully anticoagulated. Meticulous attention to hemostasis and the use of a subcutaneous layer to close potential dead space may be helpful.

5. Prognosis and outcome


The major maternal risk is thrombosis as outlined above. All individuals with APS and a prior thrombosis should receive lifelong anticoagulation. Adding low dose aspirin to warfarin is not recommended.

It is uncertain as to the optimal treatment of women with obstetric APS and no prior thrombosis when they are not pregnant. There is no question that they are at increased risk for thromboembolism but the absolute risk is low. It seems as though women with conditions such as SLE, fetal death, and/or high titer antibodies are at higher risk than those with recurrent early pregnancy loss but clear data are lacking.

Currently, authorities do not recommend full anticoagulant therapy in women with APS when they are not pregnant. Some authorities recommend that patients with obstetric APS take low dose aspirin for life. It makes sense to modify risk factors such as obesity and smoking and to avoid high risk situations such as estrogen containing oral contraceptives

Adverse obstetric outcomes

There is a dramatic increase in the risk for adverse obstetric outcomes in untreated pregnancies with APS. Obstetric outcomes are greatly improved with medical treatment. However, even with treatment, adverse outcomes are common.

Preterm birth. The risk of preterm birth in pregnancies complicated by APS is 12-35%. The rate of spontaneous preterm birth is not increased. Preterm birth is increased due to iatrogenic delivery related to preeclampsia, fetal growth restriction, and abnormal fetal testing.

Placental insufficiency. There is an increased rate of placental insufficiency, abnormal fetal testing and need for cesarean delivery. Specific percentages vary greatly among studies. It is noteworthy that fetal assessment may be abnormal as early as the mid-second trimester in severe cases.

Fetal Growth Restriction (FGR): Approximately one-fourth of patients with thrombosis and/or prior fetal death will have FGR despite treatment. As with preeclampsia, the risk for FGR is much lower in patients with recurrent early pregnancy loss as their only aPL associated disorder.

Preeclampsia. There is an increased risk for preeclampsia in patients with APS. The rate is as a high as 35% even after treatment with heparin and aspirin in patients with either thrombosis or prior fetal death. It is lower in patients whose only feature of the syndrome is recurrent early pregnancy loss.

Pregnancy loss. The rate of pregnancy loss in untreated patients with both LA and high titer IgG aCL is as high as 90%! However, the risk is lowered to 15% with treatment - a rate very similar to the baseline rate of clinically recognized pregnancy loss.

Autoimmune disorders

Patients with APS are at increased risk of thrombosis and developing autoimmune disease when they are not pregnant. Women with primary APS are at increased risk for the subsequent development or presentation of SLE and other autoimmune diseases. The risk is highest in women with LA and high titer IgG aCL. There are no interventions shown to reduce this risk.

Bleeding complications

Patients with APS and prior thrombosis are at increased risk for bleeding complications. Women on life long anticoagulation with warfarin should be followed in a clinic that carefully monitors anticoagulant levels. Obstetrician gynecologists should be alert to an increased incidence of menorrhaghia and hemorrhagic ovarian cysts in these women.


APS has important implications for contraception. Women with APS should not take estrogen containing oral contraceptives if they are not fully anticoagulated. It is controversial as to whether patients with prior thrombosis on warfarin can safely take estrogen containing oral contraceptives. One could argue that the risk of pregnancy outweighs the risk of estrogen in these women. However, since effective alternative forms of contraception are available, many recommend that women with APS, even if anticoagulated, should avoid estrogen containing oral contraceptives.

Most other forms of contraception are safe in women with APS. Progesterone does not increase the risk of thrombosis and need not be avoided. Some women taking warfarin have increased menstrual bleeding wih Paraguard IUDs. Mirena IUDs may be preferable in these women.

6. What is the evidence for specific management and treatment recommendations

Miyakis, S, Lockshin, MD, Atsumi, T. "International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS)". J Thromb haemost. vol. 4. 2006. pp. 295.

(Classic paper outlining consensus criteria for APS.)

"ACOG Practice Bulletin No. 118: Antiphospholipid syndrome". Obstet Gynecol. vol. 117. 2011. pp. 192-9.

(General, practical review of APS for obstetrician gynecologists.)

Rai, R, Cohen, H, Dave, M, Regan, L. "Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies)". BMJ. vol. 314. 1997. pp. 253-7.

(Classic paper demonstrating efficacy of heparin.)

Farquharson, RG, Quenby, S, Greaves, M. "Antiphospholipid syndrome in pregnancy: A randomized, controlled trial of treatment". Obstet Gynecol. vol. 100. 2002. pp. 408-13.

(Well designed trial showing no benefit to heparin.)

Branch, DW, Silver, RM, Porter, TF. "Obstetric antiphospholipid syndrome: current uncertainties should guide our way". Lupus. vol. 19. 2010. pp. 446-52.

(Review of current controversies in obstetric APS.)
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