ANTIPHOSPHOLIPID SYNDROME (APS) and Pregnancy DR. Hanaa Al ani

Background Antiphospholipid syndrome (APS) is a disorder that manifests clinically as recurrent venous or arterial thrombosis and/or fetal loss.

Background Characteristic laboratory abnormalities in APS include persistently elevated levels of antibodies directed against membrane anionic phospholipids anticardiolipin [aCL] antibody, antiphosphatidylserine predominantly beta-2 glycoprotein I or evidence of a circulating anticoagulant.

Incidence It was first described in patients with SLE, but it is now recognized both that most patients with APS do not fulfill the diagnostic criteria for SLE and that those with primary APS do not usually progress to SLE. The prevalence of aPL in the general obstetric population is low (<2%).

Table 1 - Clinical criteria for the diagnosis of APS Thrombosis Venous Arterial Small vessel (e.g. thrombotic microangiopathy in kidney) Pregnancy morbidity ≥3 consecutive miscarriages (<10 weeks' gestation) ≥1 fetal death (>10 weeks' gestation with normal fetal morphology) ≥1 premature birth (<34 weeks' gestation with normal fetal morphology) due to pre-eclampsia or severe placental insufficiency .

Table 2 - Other recognized features of APS Thrombocytopenia Haemolytic anaemia Livedo reticularis Cerebral involvement Epilepsy, cerebral infarction, chorea and migraine, transverse myelopathy/myelitis mitral valve Heart valve disease Hypertension Pulmonary hypertension Leg ulcers About 30-40% of women with SLE have aPL. About 30% of those with aPL have thrombosis. Up to 30% of women with severe early-onset pre-eclampsia may have aPL

Antiphospholipid syndrome. Livedo reticularis

Antiphospholipid syndrome. Arterial thrombosis

Clinical features Although the clinical features of primary and SLE-associated APS are similar, and the antibody specificity is the same, the distinction is important, and patients with primary APS should not be labeled as having lupus.

Pathogenesis The pathogenesis of APS involve a co- factor, β2 glycoprotein In APS-associated fetal loss, there is typically massive infarction and thrombosis of the placental and decidual vessels, probably secondary to spiral arte vasculopathy. Platelet deposition and prostanoid imbalance may be implicate in a similar way to pre-eclampsia.

Pathogenesis Many of the adverse outcomes described are the end result of defective or abnormal placentation and these findings support placental failure, being the mechanism by which aPL are associated with late loss.

Pathogenesis aPL bind to human trophoblasts in vitro. Trophoblast cell membranes behave as targets for both β2GPI-dependent and β2GPI-independent aPL. aPL reduce hCG release and inhibit trophoblast invasiveness.

Diagnosis: Firm diagnosis of APS requires two or more positive readings for LA and/or aCL at least 6 weeks apart, plus at least one of the clinical criteria listed before.

Diagnosis: . Lupus anticoagulant is a misnomer coined because it prolongs coagulation times in vitro. It is detected by the prolongation of the activated partial thromboplastin time (aPTT) or the dilute Russell's viper venom time (dRVVT).

Diagnosis: Anticardiolipin antibodies are measured using commercially available enzyme-linked immunosorbent assay (ELISA) kits. Medium or high titres of IgG or IgM are required.

Effect of pregnancy on APS The risk of thrombosis is exacerbated by the hypercoagulable pregnant state. Pre-existing thrombocytopenia may worsen

Effect of APS on pregnancy The risks of miscarriage, second and third trimester fetal death, pre-eclampsia, IUGR and placental abruption are increased. Establishing causality for first trimester losses is difficult, since the risk of mis­carriage is high (10-15%) in the normal population. aPL are more common in women suffering three or more first-trimester miscarriages, than in those with one or two miscarriages.

Effect of APS on pregnancy Fetal death in APS is typically preceded by IUGR and oligohydramnios. The risk of fetal loss is directly related to antibody titre, particularly the IgG aCL, although many women with a history of recurrent loss have only IgM antibodies.

Management Pre-pregnancy Women with a history of thrombosis, recurrent miscarriage, intrauterine fetal death, or severe early-onset pre-eclampsia or.IUGR should be screened for the presence of LA. or aCL. A detailed history of the circumstances of the fetal loss is essential to exclude other causes of late miscarriage, such as cervical incompetence or idiopathic premature labour. The presence of aPL does not constitute a diagnosis of APS unless the clinical features are suggestive.

Management (Cont…) Antenatal Care of pregnant women with APS should be multidisciplinary and in centres with expertise of caring for these high-risk pregnancies. Aspirin inhibits thromboxane and may reduce the risk of vascular thrombosis. There are many non-randomized studies suggesting that low-dose aspirin is effective and it can prevent pregnancy loss in experimental APS mice. Aspirin is a logical treatment in those with aPLs but no clinical features of aps.

Management (Cont…) Antenatal . Most centres now advocate treatment with low-doses aspirin for all women with APS, prior to conception, in the belief that the placental damage occurs early in gestation, and that aspirin may prevent failure of placentation.

Antenatal (Cont…) Women with APS and previous thromboembolism are at extremely high risk of further thromboembolism in pregnancy and the puerperium and should receive antenatal thromboprophylaxis with a high prophylactic dose of low molecular-weight heparin (LMWH) (e.g. Enoxaparin 40 mg b.d.) . Many of these women are on life-long anticoagulation therapy with warfarin. The change from warfarin to heparin should be achieved prior to 6 weeks' gestation to avoid warfarin embryopathy. A few women with cerebral arterial thrombosis due to APS on long-term warfarin may experience transient ischemic symptoms when LMWH is substituted for warfarin. If these do not improve on higher (full anticoagulant) doses of LMWH, the reintroduction of warfarin is justified to prevent mater­nal stroke.

Antenatal (Cont…) Opinion is divided about the best therapy for those with recurrent pregnancy loss, but without a history of thromboembolism. Treatment with high-dose steroids (in the absence of active lupus) to suppress LA and aCL, in combination with aspirin, is no longer recommended because of the maternal side effects from such prolonged high doses of steroids. This strategy has been abandoned in favour of anticoagulant treatment with aspirin and/or s.c. LMWH. Such regimens give equivalent fetal outcome with fewer maternal side effects than combinations of aspirin and steroids.

Table 3 - Therapeutic management of APS pregnancies Clinical History Anticoagulant therapy No thrombosis, no miscarriage, no adverse pregnancy outcome Aspirin 75 mg o.d. from pre-conception Previous thrombosis On maintenance warfarin: transfer to aspirin and LMWH (enoxaparin 40 mg b.d.) as soon as pregnancy confirmed Not on warfarin: aspirin 75 mg o.d. from pre­conception and commence LMWH (enoxaparin 40 mg o.d.) once pregnancy confirmed. Increase LMWH to bd at 16-20 weeks No prior

Table 4 - Therapeutic management of APS pregnancies Clinical History Anticoagulant therapy Recurrent miscarriage <10 weeks No prior anticoagulant therapy: Aspirin 75 mg o.d. from pre-conception Prior miscarriage with aspirin alone: Aspirin 75 mg o.d. from pre-conception and LMWH (enoxaparin 40 mg o.d.) once pregnancy confirmed. Consider discontinuation of LWWH at 20 weeks' gestation if uterine artery waveform is normal Late fetal loss, neonatal death or adverse outcome due to pre-eclampsia, IUGR or abruption Aspirin 75 mg o.d. from pre-conception and LMWH (enoxaparin 40 mg o.d.) once pregnancy confirmed

Antenatal (Cont…) Any additional benefit of heparin must be balanced against the risk of heparin-induced osteoporosis (0.04% with LMWHs), and the cost and inconvenience of daily injections. In women with recurrent miscarriage, but without a history of thrombosis, there is evidence to support the use of no therapy, aspirin alone, and aspirin and LMWH. A pragmatic approach is to offer aspirin alone, particularly if the history is of less than three miscarriages and then if miscarriage occurs despite aspirin therapy to offer LMWH in addition.

Antenatal (Cont…) Antithrombotic strategies vary in different centres around the world. LMWH is given in prophylactic doses (enoxaparin [Clexane®] 40 mg o.d.; dal-teparin [Fragmin®] 5000 units o.d.) when given for fetal indications, but in women with previous thrombosis higher doses (e.g. enoxaparin [Clexane®] 40 mg b.d.; dalteparin [Fragmin®] 5000 units b.d.), are indicated.

Antenatal (Cont…) Immunosuppression with azathioprine, i.v. immunoglobulin (IVIg) and plasmapheresis have all been tried. The numbers treated do not allow firm conclusions regarding efficacy, although there is some evidence available for IVIg. IVIg is extremely expensive, precluding its use outside a research setting in most centres.

Antenatal (Cont…) Close fetal monitoring is essential. Uterine artery Doppler waveform analysis at 20-24 weeks' gestation helps predict the higher-risk pregnancies. Monthly growth scans are performed from 28 weeks if the uterine artery Doppler wave form at 24 weeks shows pre-diastolic 'notching'. High-risk women require closer surveillance with regular blood pressure checks and urinalysis to detect early-onset pre-eclampsia. Such intensive monitoring allows for timely delivery, which may improve fetal outcome.

Postpartum Women on long-term warfarin treatment may recommence this postpartum (starting days 2-3) and LMWH is discontinued when the international normalised ratio (INR) is >2.0. Women with previous thrombosis should receive postpartum heparin or warfarin for 6 weeks. Women without previous thrombosis should receive postpartum heparin for at least 5 days to 6 weeks, depending on the presence of other risk factors.

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