Thrombophilia, Antiphospholipid Syndrome and Recurrent Loss

Antiphospholipid syndrome is the best-established treatable cause of recurrent pregnancy loss, defined by persistent antiphospholipid antibodies together with vascular thrombosis or characteristic pregnancy morbidity. This entry distinguishes that acquired syndrome, which has clear classification criteria and an evidence base for intervention, from inherited thrombophilias, whose causal link to recurrent loss is far weaker and contested.

Definition

Antiphospholipid syndrome is an acquired autoimmune disorder defined by persistent laboratory evidence of antiphospholipid antibodies plus clinical thrombosis or defined pregnancy morbidity, including recurrent early loss or later fetal death; inherited thrombophilias are heritable predispositions to thrombosis whose role in recurrent loss is comparatively weak.

Scope

The entry covers the classification criteria for antiphospholipid syndrome, the obstetric manifestations that connect it to recurrent loss, the proposed mechanisms at the maternal-fetal interface, and the more uncertain association between inherited thrombophilias and pregnancy loss. It is a reference orientation and does not provide testing thresholds, dosing, or individualized treatment advice.

Core questions

• How is antiphospholipid syndrome classified, and which obstetric events qualify?
• By what mechanisms might antiphospholipid antibodies cause pregnancy loss?
• How strong is the evidence that inherited thrombophilias cause recurrent loss?
• What does the trial evidence show about anticoagulant intervention?

Key concepts

• Antiphospholipid antibodies
• Lupus anticoagulant
• Obstetric antiphospholipid syndrome
• Sapporo and revised classification criteria
• Inherited thrombophilia
• Placental and decidual injury

Mechanisms

In antiphospholipid syndrome, persistent antibodies against phospholipid-binding proteins are associated with pregnancy loss through more than thrombosis alone: proposed mechanisms include impaired trophoblast function, complement activation, and a local inflammatory response at the maternal-fetal interface, alongside placental thrombotic injury. Diagnosis requires persistent antibody positivity confirmed on repeat testing together with defined clinical criteria. Inherited thrombophilias such as factor V Leiden could in principle promote placental thrombosis, but the epidemiological link to recurrent early loss is inconsistent.

Clinical relevance

Because antiphospholipid syndrome is a recognized and potentially modifiable contributor to recurrent loss, it occupies a central place in how the field is evaluated, whereas routine testing for inherited thrombophilia in recurrent loss is widely questioned. This entry describes classification, mechanisms, and the evidence landscape for reference and is not a basis for individual diagnosis, testing decisions, or treatment.

Epidemiology

Antiphospholipid antibodies are found in a minority of women with recurrent pregnancy loss and represent one of the more consistently identified causes; inherited thrombophilias are common in the general population, which complicates attributing recurrent early loss to them given the inconsistent association.

Evidence & guidelines

International consensus criteria define antiphospholipid syndrome for classification, and guidelines including ESHRE address testing in recurrent loss. A Cochrane systematic review evaluated aspirin and heparin for women with antiphospholipid antibodies, and randomized trials such as the ALIFE study found no benefit of anticoagulation for unexplained recurrent miscarriage without antiphospholipid syndrome, sharpening the distinction between the two situations.

History

The association between antiphospholipid antibodies and recurrent pregnancy loss and thrombosis was recognized in the late twentieth century and formalized through international consensus classification criteria. Subsequent randomized trials clarified that anticoagulant therapy is relevant to the antiphospholipid subgroup but not to unexplained recurrent loss, and the once-popular practice of broad thrombophilia testing was progressively challenged.

Debates

Should women with recurrent loss be tested for inherited thrombophilia?

Given the weak and inconsistent association and the lack of demonstrated treatment benefit, routine inherited-thrombophilia testing in recurrent loss is widely discouraged outside specific contexts.

Does anticoagulation help unexplained recurrent miscarriage?

Trial evidence indicates that aspirin and heparin do not improve outcomes in unexplained recurrent miscarriage without antiphospholipid syndrome, contrasting with their role in the antiphospholipid subgroup.

Key figures

• Graham Hughes
• Munther Khamashta
• Saskia Middeldorp
• D. Ware Branch

Seminal works

• miyakis-2006
• kaandorp-2010
• empson-2005

Frequently asked questions

What is obstetric antiphospholipid syndrome?

It is antiphospholipid syndrome diagnosed on the basis of pregnancy morbidity, such as recurrent early loss or later fetal death, together with persistent antiphospholipid antibodies, rather than on thrombosis.

Do inherited clotting disorders cause recurrent miscarriage?

The link is weak and inconsistent. Unlike antiphospholipid syndrome, inherited thrombophilias are not reliably shown to cause recurrent early loss, and routine testing for them is generally not recommended.