ANTIPHOSPHOLIPID SYNDROME (APS) and Pregnancy

DR. HAMED ELLAKWA

MD OB/Gyne MENOUFIYA UNIVERSITY EGYPT drhamedellakwa@yahoo.com

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 (ie, anticardiolipin [aCL] antibody, antiphosphatidylserine) or their associated plasma proteins, predominantly beta-2 glycoprotein I (apolipoprotein H); 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)

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 .

Pregnancy morbidity

Table 2 - Other recognized features of APS

Thrombocytopenia Haemolytic anaemia Livedo reticularis Cerebral involvement

Heart valve disease Hypertension Pulmonary hypertension Leg ulcers

Epilepsy, cerebral infarction, chorea and migraine, transverse myelopathy/myelitis Particularly mitral valve

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, 2 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 o abnormal placentation and these findings support placental failure, being the mechanism by which aPL are associated with late loss. But aPL-associate thrombosis within the placenta cannot explain all the recognized pregnancy complications in APS.

Pathogenesis
aPL bind to human trophoblasts in vitro. Trophoblast cell membranes behave as targets for both 2GPI-dependent and 2GPI-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). This prolongation fails to correct with the addition of platelet poor plasma, but corrects with excess phospholipid.

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 (1015%) in the normal population. aPL are more common in women suffering three or more firsttrimester 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.

Effect of APS on pregnancy

Quantifying the risk is difficult and the presence of aPL does not preclude successful pregnancy. Previous obstetric history is the best predictor of pregnancy outcome in women with APS.

Effect of APS on pregnancy

Reported outcomes vary depending on whether the study population is made up of those with predominantly recurrent miscarriage (in whom complications are less likely - 10% risk of preeclampsia/prematurity) or those with SLE, thrombosis or previous late intrauterine death (in whom the risk of premature delivery before 37 weeks' gestation is 30-40% and the risk of IUGR exceeds 30%). Pre-eclampsia is common and often severe, and of early onset in the latter group.

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 nonrandomized 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

Randomized, controlled trials of aspirin as a single agent in APS pregnancy do not support any benefit over placebo, however such studies have been undertaken in low-risk women. 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.) (see Chapter 3). Many of these women are on life-long anticoagulation therapy y 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 No thrombosis, no miscarriage, no adverse pregnancy outcome Previous thrombosis Anticoagulant therapy Aspirin 75 mg o.d. from pre-conception

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 1.6-20 weeks No prior

Table 4 - Therapeutic management of APS pregnancies

Clinical History Recurrent weeks miscarriage <10 Anticoagulant therapy 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 Aspirin 75 mg o.d. from pre-conception and LMWH (enoxaparin 40 mg o.d.) once pregnancy confirmed

Late fetal loss, neonatal death or adverse outcome due to preeclampsia, IUGR or abruption

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.; dalteparin [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.

Patient Education
1- Stress the importance of early recognition of a possible clinical event.
2- Educate the patient about anticoagulation

therapy.
3- Discuss the importance of planned pregnancies

so that long-term warfarin can be switched to aspirin and heparin before pregnancy is attempted.

Medicolegal Pitfalls
1- Failure to recognize antiphospholipid syndrome (APS) when suggested by history or clinical examination findings, especially thrombosis in a relatively young individual.
2- Failure to warn female patients about potential

complications with pregnancy.

3- Failure to discourage continuation of oral

contraceptives or other estrogen preparations..

References
1-Shehata et al (2001) antiphospholipid syndrome ,Rheumatic Disease Clinics of North America ,27:643. 1-Luesley and Baker (2004), Obstetrics and Gynecology an evidence based text for MRCOG. 2-Nelson-Piercy (2006) ,Handbook of Obstetric Medicine . 3-Langford and . Nelson-Piercy (1999) .Rev Obstet.Gyneccol:93 4-Belilos and Carsons (2010):www.emedicine.medscape.com.

The End