Acquired thrombophilias and pregnancy

Best Practice & Research Clinical Obstetrics & Gynaecology Vol. 17, No. 3, pp. 491 –507, 2003 doi:10.1053/S1521-6934(03)00013-0, www.elsevier.com/locate/jnlabr/ybeog

9 Acquired thrombophilias and pregnancy Manjiri Khare

MRCOG , MD

Subspeciality Trainee in Maternal– Fetal Medicine University Hospitals of Leicester, Women’s and Perinatal Services, Gwendolen Road, Leicester LE5 4PW, UK

Catherine Nelson-Piercy*

MD, FRCP

Consultant Obstetric Physician Guys and St Thomas’ Hospital NHS Trust, London, 10th floor, North Wing St Thomas’ Hospital, Lambeth Palace Road, London SE1 7EH, UK

Acquired thrombophilias are hypercoagulable states secondary to various aetiologies. In particular, during pregnancy the risks are exaggerated due to the underlying physiological changes. The commonest cause of acquired thrombophilia in pregnancy is antiphospholipid syndrome. Antiphospholipid syndrome (APS) is a complex multisystem disorder that has been associated with varied medical and obstetric complications. The pathogenesis of APS has been further elucidated in recent studies. The two most clinically significant antiphospholipid antibodies that are associated with recurrent pregnancy loss and thromboembolism are anticardiolipin antibodies (aCL) and lupus anticoagulant (LA). The laboratory diagnosis is based on the presence of moderate to high positive aCL and/or LA antibodies. It is crucial that APS is not inappropriately diagnosed as this has implications for counselling and management with thromboprophylaxis during pregnancy. Over the last decade there have been significant changes in the laboratory and clinical criteria for the diagnosis of APS. National and international collaborations have made efforts to standardize the laboratory methods. There have been very few randomized placebo-controlled trials of drug therapy and so not all drug treatment strategies have a strong evidence base. With current management strategies, using low-molecular-weight heparin and aspirin, a greater than 70% live birth rate may be achieved in affected pregnancies. A multidisciplinary approach in the management of these women is vital. Key words: antiphospholipid syndrome; anticardiolipin antibodies; lupus anticoagulant; recurrent miscarriage; thrombosis; low-molecular-weight heparin; aspirin.

Acquired thrombophilia may be defined as an acquired hypercoagulable state associated with an increased risk of thrombosis. Changes in the coagulation system during pregnancy produce a physiological hypercoagulable state. There are many other causes of acquired thrombophilia states in pregnancy, i.e. antiphospholipid syndrome (APS), ulcerative colitis, diabetes mellitus, pre-eclampsia, nephrotic syndrome and ovarian hyperstimulation. (see Table 1). However, the scope of this chapter is limited to the antiphospholipid syndrome and pregnancy. * Corresponding author. Tel.: þ44-207-928-9292; Fax: þ44-207-922-8135. E-mail address: [email protected] 1521-6934/03/$ - see front matter Q 2003 Elsevier Science Ltd. All rights reserved.

492 M. Khare and C. Nelson-Piercy

Table 1. Other acquired thrombophilia states in pregnancy. Antiphospholipid syndrome Autoimmune disease systemic lupus erythematosus ulcerative colitis Haematological problems e.g. myeloproliferative disorders such as polycythaemia rubra vera essential thrombocythaemia Endocrine conditions Diabetes mellitus Cushing’s syndrome Others Nephrotic syndrome Liver disease Heparin-induced thrombocytopenia Malignancy Combined oral contraceptives, especially those containing third-generation progestogens Modified from Girling J and de Swiet M (1997, Baillie`re’s Clinical Obstetrics and Gynaecology 11: 447 – 462).

THE ANTIPHOSPHOLIPID SYNDROME (APS) APS is defined by the association of vascular thrombosis and/or pregnancy morbidity with the presence of antiphospholipid (aPL) antibodies and/or lupus anticoagulant (LA). It is the most common cause of acquired thrombophilia in pregnancy. The APS is of clinical importance to obstetricians and gynaecologists because of its association with recurrent pregnancy loss, pre-eclampsia, intrauterine growth restriction and thrombosis. Thrombosis is now the leading cause of maternal mortality in the United Kingdom, accounting for 35 deaths in the last triennium.1 The condition also has important implications for the management of future pregnancies and long-term anticoagulation if there has been a thrombotic complication. APS predominantly affects young women.

ANTIPHOSPHOLIPID ANTIBODIES (aPL) These are a heterogeneous collection of autoantibodies united by their reactivity with negatively charged phospholipid components of cell membranes. Although it is an accepted term in respect of the clinical syndrome, it is a misnomer in that the autoantibodies of clinical relevance are directed against phospholipid-binding proteins, or conformation epitopes involving the binding proteins, and not against the phospholipid antigens per se.2 Thus, many antiphospholipid antibodies require b2glycoprotein-I (b2-GP-1), a phospholipid-binding plasma protein with weak anticoagulant activity, for binding to acidic phospholipids such as phosphatidylserine and cardiolipin.3 – 5

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The prevalence of aPL (LA and anticardiolipin antibodies, aCL) in the general obstetric population has been reported as approximately 2%6, which is comparable with those found in healthy young control subjects at a prevalence of 1 –5%.7 However, a range of prevalences have been reported in the literature owing to interlaboratory differences in cut-off levels used, variation in assay methods for detection of antibodies and population profiles.6,8 – 10 The prevalence in selected populations with fetal loss is higher. The precise relationships among b2-GP-1, phospholipid and autoantibody are disputed. One possibility is that cryptic epitopes are exposed on b2-GP-I when it binds to phospholipid. Alternatively, binding of the glycoprotein to phospholipid may concentrate the antigenic sites and promote bivalent antibody binding. Whichever mechanism is active, it also applies when b2-GP-1 interacts with other negatively charged surfaces, including the plastic of an enzyme-linked immunosorbent assay (ELISA) plate. This observation has allowed the development of new, possibly more specific, assays for antiphospholipid antibodies which use purified b2-GP-1. However, other proteins share this property of binding to phospholipid in a manner that promotes interaction with antiphospholipid antibodies. These include prothrombin, annexin V, protein C, protein S, thrombomodulin and high-molecular-weight kininogen. The in vitro phenomenon known as LA can be due to antibodies reactive to b2-GPI/phospholipid or prothrombin– phospholipid. The b2-GP-I-dependent antibodies also bind in traditional anti-cardiolipin assays as the glycoprotein is present in test serum and often in assay reagents.11 Anticardiolipin antibodies (aCL) These antibodies are measured using commercially available enzyme-linked immunosorbent assay (ELISA) kits. Solid-phase immunoassay is performed on cardiolipincoated plates, usually in the presence of bovine serum b2-GP-I. aCL detected by currently available methods is positive in more than 80 –90% of patients with APS.12 Persistent medium to high levels of aCL are more likely to be associated with clinical features of APS. The presence of the IgG isotype is more common than isolated IgM isotype in patients with APS.13 Interlaboratory variations in the interpretation and reporting of aCL have been recognized as a problem in the study and understanding of APS. There have been major national and international collaborations in order to standardize the anticardiolipin test. Lupus anticoagulants (LA) The name for these antiphospholipid antibodies is a misnomer. They were originally found in patients with systemic lupus erythematosus (SLE) but not all patients will have SLE. Secondly, the name suggests that these antibodies are associated with haemorrhage from the prolongation of coagulation time in in vitro studies. However in vivo they are associated with thromboses. The LA test is a measure of the ability of aPL autoantibodies to prolong phospholipid-dependent clotting reactions. Current criteria for the detection of LA antibodies12 require: 1. Prolongation of coagulation in at least one phospholipid-dependent coagulation assay using platelet-poor plasma (prolonged activated partial thromboplastin time (aPTT) or the dilute Russell’s viper venom time (dRVVT)). 2. Failure to correct the prolonged coagulation time by mixing the patient’s plasma with normal plasma.

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3. Confirmation of the LA by correction or shortening of the prolonged coagulation time by addition of excess phospholipid or platelets that have been frozen and then thawed. 4. Use of specific factor assays to rule out other coagulopathies. The sensitivity for anti-b2-GP-1 has been reported to be between 40 and 90%.14,15 Despite better understanding of antiphospholipid antibodies and their reactivity, as the clinical utility of the newer assays has not been completely evaluated the laboratory diagnosis of APS still relies predominantly on coagulation-based assays for lupus anticoagulant and solid-phase assays (ELISAs) using cardiolipin. Both types of assay should be used in evaluating a patient for APS as they do not necessarily coexist, and should never be considered as synonymous. Approximately 25% are positive for aCL and negative for LA, while 10 –16% are positive for LA and negative for aCL.12 There are some clinical situations where testing for anti-b2-GP-1 may be used to confirm the diagnosis of APS16: for example, patients with venous or arterial thrombosis, pregnancy loss with low positive levels for IgG aCL, equivocal features of APS, patients with idiopathic thrombocytopenia, recurrent first-trimester pregnancy losses or patients in whom the clinical presentations may be attributable to factors other than APS. All positive results should be confirmed after 6 –8 weeks to eliminate transient antibodies of infection. Low or transient concentrations detected in infections and connective tissue diseases are not relevant to the diagnosis of antiphospholipid syndrome. IgG class antibodies are the most prevalent and demonstrate the greatest clinical correlation. The clinical significance of IgM antibodies is uncertain, and although IgA antibodies have been described, their clinical relevance is unproven.17 Tests for antibodies are best performed pre-conceptually or in early pregnancy, as maternal antibodies may be down-regulated in pregnancy.18 Widespread screening for APS in women with infertility, one or two pregnancy losses at less than 10 weeks of gestation or in those with later losses typical of cervical incompetence or preterm labour is inappropriate.19 APS should be diagnosed only when the clinical criteria (see Table 2) are met.

CRITERIA FOR CLASSIFICATION AND DIAGNOSIS An international consensus statement on preliminary criteria for the classification of APS states that a patient with APS must meet at least one of the two clinical criteria (vascular thrombosis or complications of pregnancy, as defined in Table 2) and at least one of two laboratory criteria.

PATHOGENESIS There have been several hypotheses proposed to explain cellular and molecular mechanisms by which aPL promote thrombosis: † activation of endothelial cells; † oxidant-mediated injury of the vascular endothelium;

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Table 2. International consensus statement on preliminary criteria for the classification of the antiphospholipid syndrome. Clinical criteria Thrombosis Pregnancy morbidity

Laboratory criteria Anticardiolipin antibodies

Lupus anticoagulant

Venous, arterial or small vessel $3 consecutive miscarriages (,10 weeks’ gestation) $1 unexplained fetal death (.10 weeks’ gestation with fetal heart documented/morphologically normal fetus) $1 premature births of morphologically normal neonates at or before the 34th week of gestation

Anticardiolipin IgG or IgM antibodies present in moderate or high levels in the blood on two or more occasions at least 6 weeks apart Lupus anticoagulant detected in the blood on two or more occasions at least 6 weeks apart, according to the guidelines of the International Society on Thrombosis and Haemostasis83

Modified from Levine JS et al (2002, New England Journal of Medicine 346: 752 –763) with permission.

† interference or modulation of the function of phospholipid-binding proteins involved in the regulation of coagulation. The currently favoured model is that: b2-GP-I is the target antigen for aCL.20 b2-GP-I is an endogenous coagulation inhibitor, and its binding by aCL may underlie APS-associated thrombosis. Early pregnancy failure may result from impaired development of the trophoblast and failure to establish an effective fetoplacental circulation. The factors governing trophoblast invasion and early placental development are multiple and complex. Although thrombosis in the uteroplacental vasculature has been implicated in the pathogenesis of miscarriage, placental infarction is not a universal finding and nonthrombotic mechanisms may be involved—such as failure of implantation or autoantibody binding to the trophoblast. Some factors have been well characterized as being specific to APS. A recent report from an in vitro study suggests that aPL recognition of anionic phospholipids and adhered b2-GP-1 on trophoblast cell structures might represent a potential pathogenic mechanism for defective placentation in women with APS.21 Chamley et al proposed that there may be abnormal trophoblast invasion of the maternal spiral arteries because of inhibition of endovascular trophoblast cell proliferation by aCL/b2GP complexes.22 Maternal endothelial cell activation (ECA) may contribute to defective placentation. Anti-endothelial antibodies causing ECA have been found in 67% of APS patients. In another study, women with APS pregnancy had high serum titres of the cell adhesion molecules ICAM and VCAM.23

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SLE

SLE

PAPS

ANA 98-100%

+

aCL + LA 99-100%

dsDNA 70%

APS

Anti-β2-GPI 70%

Figure 1. Relationship between systemic lupus erythematosus and antiphospholipid syndrome. SLE, systemic lupus erythematosus; ANA, antinuclear antibodies; dsDNA, anti-double-stranded DNA antibodies; PAPS, primary antiphospholipid syndrome; aCL, anticardiolipin antibodies; LA, lupus anticoagulant; anti-b2-GPI, antib2-glycoprotein I antibodies.

CLINICAL FEATURES Although APS was first described in patients with systemic lupus erythematosus (SLE), it is now recognized that most patients with APS do not fulfil the diagnostic criteria for SLE and also that those with primary APS do not usually progress to SLE. It is important to distinguish between primary APS and SLE-associated APS, even though the clinical features and antibody specificity are similar. Patients with primary APS should not be labelled as having lupus (Figure 1). There is a wide spectrum of clinical features of the antiphospholipid syndrome and virtually any organ can be involved (see Table 3). Thrombosis Several studies confirm a link between APS and venous or arterial thrombosis.24,25 Venous thrombosis, especially deep venous thrombosis of the legs, is the most common manifestation. It can also occur in unusual sites such as the inferior vena cava,

Table 3. Other recognized features of APS. Thrombocytopenia Haemolytic anaemia Livedo reticularis (the characteristic skin lesion for APS) Cerebral involvement (epilepsy, cerebral infarction, chorea, migraine, transverse myelopathy/myelitis) Heart valve disease (particularly mitral valve) Hypertension Pulmonary hypertension Leg ulcers

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axillary, ocular, renal and hepatic veins. Arterial thromboses are less common than venous thromboses and most frequently manifest with features consistent with ischaemia or infarction. Arterial thrombosis may affect the intracranial, retinal, coronary, mesenteric or peripheral arteries. The ratio of venous-to-arterial thrombosis in APS is 2:1, and in both cases thrombosis tends to be recurrent. If the initial thrombosis is venous, 76% of recurrences are also venous and if the initial thrombosis is arterial, 93% of recurrences are arterial.26 aPL are the only identifiable factor in 4– 28% of cases of stroke in otherwise healthy patients under the age of 50 years.27 Thrombotic microangiopathy in the kidney may cause proteinuria and renal impairment. Renal artery stenosis has also been described.28 Effect of pregnancy on APS The risk of thrombosis is exacerbated by the hypercoagulable pregnant state. In one report, more than half of the thrombotic episodes in patients with APS occurred in relation to pregnancy or the use of the combined oral contraceptive pill.29 Some studies show that a significant proportion of patients still have thrombotic episodes despite thromboprophylaxis.30,31 Pre-existing thrombocytopenia may worsen. This may be further compounded by medication because aspirin and heparin administered during pregnancy may cause thrombocytopenia. Effect of APS on pregnancy Early pregnancy failure Women with antiphospholipid antibodies have an unusually high proportion of pregnancy losses within the fetal period (10 or more weeks of gestation).32,33 In contrast, in unselected women with sporadic or recurrent miscarriage, pregnancy losses occur more commonly in the pre-embryonic period (less than 6 weeks of gestation) or the embryonic period (6 – 9 weeks of gestation).34 The association between APS and recurrent miscarriage is well known.35 – 37 Late pregnancy complications These include maternal risks (thrombosis, pre-eclampsia, abruption) and fetal risks (intrauterine growth restriction, prematurity). Recurrent pregnancy loss, typically in the second trimester, is one of the most consistent features of APS. The risk of fetal loss is directly related to the antibody titre, particularly the IgG aCL Previous poor obstetric history remains the most important predictor of future risk. Placental abnormalities in pregnancies with poor outcome are commonly described. The most frequently described lesions are placental infarction and fetal artery thrombosis along with other non-specific features of hypoxia.38 In a recent report39 there seems to be an association between primary APS and massive perivillous fibrous deposition and maternal surface of placental floor infarction. Although this finding is not common it may be used to predict the likelihood of complications in high-risk cases. There have been no reports of placental-bed biopsies in primary APS.23 Two case reports have implicated decidual vasculopathy in APS/SLE pregnancies.40,41

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Table 4. Pregnancy complications in different populations of women with antiphospholipid syndrome. Study population Branch et al 199284 Lima et al 199630 Granger and Farquharson 199785 Backos et al 199986

82 pregnancies in 54 patients, predominantly systemic 60 pregnancies in 47 patients, predominantly systemic 53 pregnancies, predominantly recurrent miscarriage 150 pregnancies, predominantly recurrent miscarriage

Pre-eclampsia (%) IUGR (%) Prematurity (%) 51 (severe 21%) 18

31

37 , 32/40, 92 , 37/40 43

3

11

8

11

15

24

31

IUGR. Intrauterine growth restriction. Modified from Langford K and Nelson-Piercy C (1999, Contemporary Reviews in Obstetrics and Gynecology 11: 93–98).

The outcome and complications of pregnancies complicated by APS in different centres are influenced by the presence of systemic manifestations of the disease. This heterogeneity is important when critically appraising the literature from different groups and also when advising patients (see Table 4). Relationship between congenital and acquired thrombophilia There is no evidence of an increased incidence of acquired thrombophilia in women with congenital thrombophilia, and therefore the possibility of a ‘second hit’ predisposition to thrombosis seems unlikely.42

MANAGEMENT OPTIONS General considerations Before conception It is essential that women with APS who are considering embarking on a pregnancy are aware of the risks involved so that they can make informed decisions about conception whenever possible. At the pre-conception counselling visit: 1. Women should be informed of the potential maternal and obstetric complications, including the possible risks of thrombosis or stroke as well as the risks of pregnancy loss, preterm delivery and possible neonatal physical or mental handicap, preeclampsia (PET), IUGR and placental abruption. 2. The presence of significant levels of aPL/LA should be confirmed. 3. Assess for evidence of anaemia, thrombocytopenia, underlying renal disease, or associated SLE and extractable nuclear antigens, particularly anti-Ro and anti-La antibodies. 4. Women should be made aware of the need to start low-dose aspirin (75 mg) with a positive pregnancy test. Many units (including our own) start patients on aspirin before conception although there is no evidence to support an increased benefit over aspirin started early in pregnancy.

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5. Women with APS who have had previous episodes of thrombosis and are taking long-term warfarin will need to be changed to low-molecular-weight heparin (LMWH). Warfarin is teratogenic between the sixth and twelfth weeks of pregnancy; thus, women should be warned that although they can safely remain on warfarin until conception, it is desirable to change to LMWH within 2 weeks of their missed period. 6. Rubella status should be checked and pre-conceptual folic acid commenced. Antenatal period † Women with APS should be managed in a high-risk clinic setting in centres with expertise in the management of this condition. † An early dating scan should be carried out in the first trimester. † Uterine artery waveforms can be assessed at 20 and 24 weeks of gestation. Those pregnancies with evidence of early diastolic notch are monitored closely with growth scans every 2 –3 weeks because of the high risk of PET and IUGR. There is some evidence from one study in our unit that vitamin C and E in pregnancies with bilateral notches or previous pre-eclampsia, or those with APS, may reduce the risk of pre-eclampsia.43 When there is no uterine artery notch, we recommend assessment of growth and amniotic fluid volume every 4 weeks. Doppler flow studies of the umbilical artery may be used as in other high-risk pregnancies at risk of uteroplacental insufficiency to allow timely intervention for fetal reasons. A meta-analysis by Chien et al44 concluded that the use of uterine artery flow velocity waveform ^ diastolic notch has limited diagnostic prediction for PET, IUGR and perinatal death in both the low and high-risk populations. However, a more recent study by Lees et al showed that individualized risk of severe adverse pregnancy outcome can be determined by uterine artery Doppler screening at 23 weeks; at a mean Pulsatility index (PI) of 1.45, the 95th centile for their population, the likelihood ratio for severe adverse pregnancy outcome was 5.45 Another multicentre study used one-stage transvaginal colour doppler sonography for assessment of uterine arteries at 23 weeks of gestation. Sensitivity of uterine artery Doppler at predicting delivery earlier than 32 weeks with pre-eclampsia and fetal growth restriction was 93%.46 † High-risk women require close surveillance with regular blood pressure checks and urine analysis to detect early-onset pre-eclampsia. Drug therapy for improving pregnancy outcome The chance of a successful pregnancy outcome with treatment appears to depend in part upon the number of pregnancy losses or fetal deaths suffered in the past.29,47 In those women who have suffered a pregnancy loss in their last pregnancy the chance of a successful pregnancy without treatment is 20 –25%, whereas with treatment a 75 –80% live birth rate can be expected.30,48

Corticosteroids 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 i.e. gestational diabetes, hypertension and sepsis from such prolonged high

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doses of steroids.49,50 This strategy has been replaced by the use of aspirin and/or subcutaneous heparin or LMWH. These regimens give equivalent fetal outcome with fewer maternal side-effects than combinations of aspirin and steroids.51 As a result, the use of steroids in women with APS has been limited to maternal thrombocytopenia or coexistent SLE. Patients on long-term steroids should have regular blood glucose monitoring. Aspirin 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 mice.52 Its use as a single agent in APS pregnancy has been subjected to randomized clinical trial only in asymptomatic aPLpositive women or those with fewer than three early losses in whom it did not benefit pregnancy outcome, which was normal.53,54 In the randomized controlled study by Cowchock and Reece53, women with lowrisk APS pregnancies, i.e. no previous thrombosis or miscarriages, were randomized to taking aspirin versus no aspirin; the study showed that there was no benefit of treatment in this group of patients. In the randomized placebo controlled trial carried out by Pattison and his colleagues, aspirin was compared with placebo in women with three or more previous fetal losses and APS. Women with SLE/history of thromboses were excluded. This study reports that low-dose aspirin has no additional benefit over supportive care alone and there were no significant differences between the groups in the rate of fetal loss, maternal complications, or in early neonatal outcome. A potential drawback of this study is that there were many patients included who had very low levels of aCL, which may have been associated with a low risk of pregnancy loss.55 Aspirin can be continued until delivery, and low-dose aspirin does not affect the use of regional anaesthesia during labour.56 Heparin Women with APS and a previous history of thromboembolism require heparin for thromboprophylaxis in pregnancy. Two groups have shown improved fetal outcome using heparin alone.57,58 In women with recurrent pregnancy loss but without a history of thromboembolism there is no consensus regarding optimal management.59 The potential benefits of heparin should be balanced against the risk of heparin-induced osteoporosis.60,61 The problem of osteoporosis is compounded by concomitant use of steroid medications and, indeed, by pregnancy itself.62 – 64 Heparin is also associated with an uncommon idiosyncratic thrombocytopenia. This phenomenon is independent of the route of administration or dose and may have its onset from several days to several weeks after starting heparin. The frequency is difficult to determine, but probably occurs in less than 5% of patients treated with heparin. LMWH is commonly used in APS patients because of the convenience of once-daily administration, the improved antithrombotic (aXa)-to-anticoagulant (aIIa) ratio, the decreased risk of heparin-induced thrombocytopenia, and the decreased risk of heparin-induced osteoporosis. Data from observational studies and systematic review support the use of LMWH as a safe alternative to unfractionated heparin in pregnancy.65 – 67 Although factor Xa levels may be used to monitor LMWH use,

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experience has shown that doses are virtually never altered as a result68; thus, it is no longer our advice to measure aXa levels routinely in pregnancy. Aspirin and heparin Aspirin and heparin may improve pregnancy outcome by a direct effect on platelet aggregation/activation or may modify endothelial cell function. It may be possible that, by treating women who have suffered early pregnancy loss in the first trimester with aspirin and heparin, we may increase late pregnancy complications. It may be that aspirin and heparin do not eradicate the underlying pathology but merely reduce the severity or alter disease expression.39 Aspirin and heparin versus aspirin alone have been compared in three recent trials in women with recurrent miscarriages (see Table 5). The findings from the first two trials show a significant reduction in pregnancy loss rate by 54% in pregnancies treated with aspirin and heparin. The last trial, however, did not show significant differences in outcome of pregnancies. It is not possible to exclude the possible increased risks of prematurity and IUGR in the first two trials due to lack of power. It is possible that the drug treatment is prolonging pregnancies which may have been lost in early stages. Our current therapeautic management plan is summarised in Table 6. Warfarin Warfarin is a form of coumarin with vitamin K antagonist activity. Its use in pregnancy is associated with a high incidence of fetal loss, congenital malformations (‘fetal warfarin syndrome’), and physical disability.69 Warfarin is avoided in the first trimester as it crosses the placenta and is potentially teratogenic. Its use in the second and third trimester should be justified on clinical grounds as there are reported central nervous system abnormalities, including dorsal midline dysplasia (agenesis of corpus callosum and Dandy Walker malformations) or ventral midline dysplasia (optic atrophy)70, mental retardation, delayed development, seizures and microcephaly.71 It may be necessary to start warfarin when there has been a thrombotic event in the index pregnancy despite adequate heparin thromboprophylaxis or in women with previous cerebrovascular thromboses and ongoing cerebral events as there is a high risk of recurrence.72

Table 5. Use of heparin/aspirin versus aspirin in women with recurrent miscarriages and their pregnancy outcomes. Rai et al 199787

Kutteh et al 199688

Farquharson et al 200189

Randomized trial; three or more consecutive miscarriages with aPL and no history of thromboembolism (All women were given aspirin pre-conception.) Randomized following first positive pregnancy test

Heparin/aspirin versus aspirin

Livebirths 71 versus 42%

Heparin/aspirin versus aspirin

Livebirths 80 versus 44%

LMWH/low-dose aspirin versus low-dose aspirin

Live birth 78 versus 72%

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Table 6. 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 or nil

Previous thrombosis On maintenance warfarin Not on warfarin

Recurrent miscarriage , 10 weeks No prior anticoagulant therapy Prior miscarriage with aspirin alone

Late fetal loss, neonatal death or adverse pregnancy outcome due to pre-eclampsia, IUGR or abruption

Tranfer to aspirin and LMWH as soon as pregnancy confirmed (e.g. Fragmin 5000 SC b.d.) Aspirin 75 mg o.d. from pre-conception and commence LMWH once pregnancy confirmed Aspirin 75 mg o.d. from pre-conception Aspirin 75 mg o.d. from pre-conception and LMWH (e.g. Fragmin 5000 SC o.d. or Clexane 40 mg o.d.) once pregnancy confirmed; consider discontinuation of LMWH at 20 weeks’ gestation if uterine artery waveform is normal Aspirin 75 mg o.d. from pre-conception and LMWH e.g. Fragmin 5000 u o.d. once pregnancy confirmed

b.d. ¼ twice daily; o.d. ¼ once daily; SC - subcutaneously. Reproduced from Nelson-Piercy C (2002, Handbook of Obstetric Medicine, 2nd edn; Martin Dunitz) with permission of Martin-Dunitz.

Warfarin must be used cautiously, with close monitoring of mother and fetus. It should be discontinued 2 weeks prior to planned delivery to allow for clearance from the maternal – fetal circulation and heparin/LMWH should be substituted. Rapid reversal of warfarin with vitamin K should be avoided. Immunoglobulins A recent multicentre prospective randomized controlled pilot study of women with APS, all of whom were given heparin and low-dose aspirin, found no difference in obstetric or maternal outcomes between those who received intravenous immunoglobulin (IVIG) versus placebo (5% albumin solution).73 Because IVIG is expensive and its use has not been proved as a first-line therapy, it would seem prudent to limit its use to salvage therapy in women who are on aspirin plus heparin and still develop pregnancy complications. A 2 g/kg course of intravenous immunoglobulin administered in divided doses over 2 –5 days in the late second or

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early third trimester, where fetal IUGR developed despite aspirin and heparin, has been shown temporarily to improve uteroplacental Doppler waveforms.74 This may allow prolongation of intrauterine life and subsequent improvement in neonatal outcome, but more research is needed in this area. Alternative and recent approaches in management Other modalities that have been tried are azathioprine, plasma exchange75 and interleukin therapy.76 The number of patients in these studies and the variable course of the disease make it difficult to draw any conclusions of clinical value at present. Alternatives to oral anticoagulation are being investigated. Hydroxychloroquine has been shown to reduce the incidence of thrombosis in lupus patients with aPL77 and the use of antioxidants is being investigated.78 Intrapartum management † There should be a previously agreed written care plan in the notes for intrapartum and postpartum management. † The placenta should be sent for histology if there is pre-eclampsia/IUGR/previous stillbirth or miscarriage/s. Postpartum management Medications. Women on long-term warfarin treatment may recommence this postpartum (starting day 2 –3) and LMWH is discontinued when the international normalized ratio (INR) is . 2.0. Women with previous thrombosis should receive postpartum LMWH or warfarin for 6 weeks. Women without previous thrombosis should receive postpartum LMWH for 5 days. Breastfeeding. Although aspirin and LMWH are marked to be avoided during breastfeeding, we have had no adverse events in our unit with these drugs in breastfed infants, despite many years of use. There is no significant excretion of warfarin into breast milk79,80 and therefore we advocate that those mothers who wish to breast feed should do so. Counselling. These women should be made aware of the possible risks of developing non-obstetric disorders associated with aPL.81 In a 5-year follow-up study, about half of the women with APS developed a major medical complication.82

SUMMARY Acquired thrombophilia in pregnancy is a complex disorder with various aetiologies. Antiphospholipid syndrome is the commonest cause and requires a multidisciplinary approach involving obstetricans, physicians, haematologists and rheumatologists. Recurrent pregnancy loss, pre-eclampsia, intrauterine growth restriction, intrauterine fetal death and thrombosis are common clinical features of APS. Appropriate diagnosis with the laboratory and clinical criteria, drug treatment and surveillance during

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pregnancy can improve maternal and fetal outcome. Antenatal treatment with aspirin and LMWH is currently the mainstay of treatment.

Practice points † diagnosis of APS should be based on the presence of at least one of the two clinical criteria (vascular thrombosis or complications of pregnancy) and the presence of aCL and/or LA † recurrent pregnancy loss, pre-eclampsia, intrauterine growth restriction, intrauterine fetal death and thrombosis are common clinical features of APS † previous obstetric outcome is the best predictor for future pregnancy outcomes † a multidisciplinary team approach is essential for management † low-dose aspirin with or without LMWH remains the mainstay of treatment

Research agenda † studies of pathogenetic mechanisms should be carried out to improve current understanding so that treatment models can be planned † studies should be carried out on the role of placental pathology in APS and placental bed biopsies in APS pregnancies † techniques for detecting aCL and LA should be validated † better laboratory techniques should be developed to identify those women at risk of thrombosis † multicentre prospective randomized placebo controlled trials should be conducted on the prevention of fetal loss in women with APS

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