Antiphospholipid syndrome in pregnancy

Abstract

Antiphospholipid syndrome is a heterogenous disorder with many pregnancy-related complications. Despite the refinement of laboratory testing and classification criteria, controversy continues regarding the management of women with antiphospholipid antibodies (aPLs) in pregnancy. This is compounded by the lack of large randomized placebo-controlled trials in pregnancy. This article attempts to address some of the controversies and suggest management guidelines. The issues discussed include: pathogenesis and clinical relevance of aPLs, clinical implications of aPLs for the mother and fetus, management of the different clinical phenotypes of antiphospholipid syndrome and its overlap with systemic lupus erythematosus, treatment options in pregnancy and breast feeding. We review controversies regarding the appropriateness of anticoagulant use in women with recurrent pregnancy losses and aPLs, and issues surrounding heparin dosing regimens. We have also included suggestions for the directions of future studies.

Keywords::

• β2-glycoprotein I
• anticardiolipin antibodies
• anticoagulation
• antiphospholipid antibodies
• antiphospholipid syndrome
• lupus anticoagulant
• pregnancy
• recurrent fetal loss
• teratogenicity
• thrombosis

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Learning objectives

Upon completion of this activity, participants should be able to:

• • Examine the application of classification criteria for APS and the complications of APS during pregnancy

• • Evaluate management guidelines and the evidence in support of therapeutic options for varying clinical presentations of APS in pregnancy

Financial & competing interests disclosure

EDITOR

Elisa Manzotti,Editorial Director, Future Science Group, London, UK.

Disclosure:Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Charles P Vega, MD, Associate Professor; Residency Director, Department of Family Medicine, University of California, Irvine, CA, USA.

Disclosure:Charles P Vega, MD, has disclosed no relevant financial relationships.

AUTHORS AND CREDENTIALS

May Ching Soh,MBChB, FRACP, Guy’s and St Thomas’ Trust, Women’s Health Services, 10th Floor of St Thomas’ Hospital, Westminster Bridge Road, London, SE1 7EH, UK.

Disclosure:May Ching Soh, MBChB, FRACP, is supported by the Rose Hellaby Medical Scholarship Trust from New Zealand.

Catherine Nelson-Piercy,MA, FRCP, Guys and St. Thomas’ Trust and Imperial College Healthcare Trust; King’s College London; St. Thomas’ Hospital, London, UK.

Disclosure:Catherine Nelson-Piercy, MA, FRCP, has disclosed no relevant financial relationships.

A 32-year-old woman with a past history of two previous miscarriages and a diagnosis of ‘possible’ antiphospholipid syndrome (APS) has been referred to you for prepregnancy counseling. She is wondering whether low-molecular-weight heparin (LMWH) may be helpful.

Since antiphospholipid antibodies (aPLs) were first described more than two decades ago, this is a common clinical scenario that clinicians have faced. Controversy continues as to how APS is managed, particularly in pregnancy, where randomized controlled trials are uncommon and practices range widely from center to center [1]. Clinicians dealing with pregnant women are often expected to base their decisions on evidence extrapolated from studies of nonpregnant patients.

Antiphospholipid antibodies are prevalent in the general population. Cross-sectional studies of healthy blood donors have shown that lupus anticoagulant (LA) was present in 8% and anticardiolipin antibodies (aCLs) were present in almost 10% of the cohort [2]. However, persistence of these antibodies was less common (<2%) [3]. In a general obstetric population, the prevalence of LA is 0.3% and the prevalence of aCL is 2.2–9.1%, which is similar to that observed among patients who are not pregnant (5.6%) [4]. In patients with thrombosis, the prevalence of aPLs was much higher (4–21%) than in the general population [5,6]. However, what remains unclear is whether the presence of these antibodies is of any clinical significance in women without previous history of thrombosis or adverse obstetric outcomes.

What are aPLs?

Antiphospholipid antibodies are autoantibodies that target phospholipid-binding proteins, and may cause prolongation of phospholipid-dependent coagulation assays in vitro. In vivo aPLs conversely cause thrombotic rather than bleeding complications.

Lupus anticoagulant is a nonspecific inhibitor. Its detection occurs through functional clotting tests. LA causes a prolongation of in vitro clotting assays such as the activated partial thromboplastin time, the dilute Russell viper venom time, the kaolin clotting time and, infrequently, the prothrombin time. More than one antibody is associated with LA activity. For example, both aCLs and antibodies to β2-glycoprotein-I (β2GP-I) can have LA activity. aCLs are antibodies to cardiolipin and other phospholipids. They are detected through ELISA tests to screen IgG and IgM anticardiolipin antibodies. Their levels for aCL of IgG and IgM type are reported in units as GPL and MPL. Medium- to high-titre aCLs (>40 GPL or MPL, or >99th percentile) of IgG or IgM isoforms are of clinical significance. β2GP-I is the major target for aCLs and many LAs. It is the cofactor required for aPL–phospholipid interaction [7,8].

Antiphospholipid antibodies are acquired antibodies that can be generated after incidental exposure to medications (e.g., chlorpromazine, procainamide, quinidine, quinine, phenytoin and IFN-α) or after infection (e.g., HIV, HTLV-1, hepatitis A, B or C, cytomegalovirus, Epstein–Barr virus, varicella-zoster virus, TB, post-streptococcal rheumatic fever, infective endocarditis, syphilis, leptospirosis, Klebsiella, Pneumocystis jirovecii or malaria) through the mechanism of molecular mimicry [9]. Transient aPLs generated after exposure are usually the IgM aCL isoforms and do not have anti-β2GP-I activity – they are therefore less pathogenetic. aPLs can be associated with malignancies, especially solid tumors, Hodgkin’s and non-Hodgkin’s lymphoma, myelofibrosis and polycythemia vera [10]. Systemic lupus erythematosus (SLE), rheumatoid arthritis and autoimmune thrombocytopenia are among the rheumatic and autoimmune conditions associated with aPLs. Up to 30–50% of patients with SLE have aPLs [4]. Familial aPLs with autosomal dominant inheritance has also been described [11].

How do aPL cause injury?

The pathogenic mechanisms whereby aPLs lead to in vivo injury is poorly understood. Intraplacental thrombosis with maternal–fetal blood exchange impairment was traditionally suggested to be the main pathogenic event for obstetric complications. This was supported by the histologic findings of widespread placental infarcts originally described by De Wolf [12]. aPLs show placental trophism, resulting in placental infarcts from abnormalities of the decidual vessels, narrowing of spiral arteries, intimal thickening, acute atherosis and fibrinoid necrosis. Nevertheless, these findings are not specific to APS, and may occur without aPL-mediated thrombotic injury [13,14].

Annexin V, a natural anticoagulant plasma protein that binds to the phospholipid bilayers of cell membranes and protects phospholipids from interacting with coagulation enzymes, may be disrupted by aPLs (particularly anti-β2GP-I), causing increased cell surface generation of thrombin with resultant thrombosis [15]. The disruption of phospholipid bilayers extends to all cell membranes, including those of placental trophoblasts and platelets [16]. Endothelial microparticles from endothelial activation are raised in patients with APS, thereby intensifying the procoagulant and proinflammatory milieu [17].

In in vitro murine models of APS, aPLs bind directly to trophoblasts, resulting in direct cellular injury, inhibition of cellular division and apoptosis [18]. The aPLs also affect syncytial invasion, and therefore human chorionic gonadotrophin production is decreased [19].

Complement activation as a result of specific antigenic reactivity of aPLs are crucial to their effects [13]. During trophoblast differentiation, phosphatidylserine, which is a target for aPLs, is externalized on the outer leaflets of the trophoblast. This results in activation of complement via both the classical and alternative pathways. The generation of its split products (in particular C3 and C5) leads to fetal loss and fetal growth restriction (FGR). This is why heparin, which inhibits complement in vitro, is able to prevent pregnancy loss even at doses that do not cause detectable interference with coagulation [13]. Anticoagulants without complement-inhibiting effects (e.g., hirudin and fondaparinux) are ineffective in preventing pregnancy loss in APS [20].

Since the discovery of aPLs, numerous papers hypothesizing various mechanisms by which aPLs cause thrombosis and pregnancy complications have been published. For a fuller discussion of these mechanisms the reader is directed towards the review article of Salmon et al.[13].

The presence of aPLs alone is not sufficient to induce APS, and it is proposed that a ‘second hit’ is required in the form of infection, traumatic injury to the vascular bed or nonimmunologic procoagulant factors [14,21].

What is the APS?

The presence of aPLs does not necessarily confer pathology or disease given its prevalence in the general population. Refinement of the diagnostic criteria in recent years has led to a greater understanding of this syndrome (Box 1) [22,23].

A woman may be further defined as having obstetric or thrombotic APS based on clinical presentation. APS may also be defined as primary – where it occurs in isolation – and secondary APS – where there is concurrent disease, most commonly SLE.

The association of aPLs & thrombosis, & recurrent fetal loss

In a retrospective review of a cohort of women without SLE, the prevalence of aPLs was 20% in women with recurrent fetal losses compared with only 5% in healthy women [24].

A meta-analysis has demonstrated that the association with thrombosis was much higher with LA (odds ratio [OR] for thrombosis: 11.0) compared with aCLs (OR: 1.6) [25]. These findings are mirrored in a meta-analysis, which demonstrated that LA is more strongly and consistently associated with recurrent fetal loss compared with any other aPL [26]. LA is associated with late recurrent fetal loss (OR: 7.79; 95% CI: 2.3–26.45). A contributing factor for this observation could be that ELISA testing for aCLs was not well standardized and concordance between laboratories remains poor [27].

The use of anti-β2GP-I is not thought to increase diagnostic yield and standardization of its testing between laboratories is poor [21]. However, persistently positive IgG anti-β2GP-I has been shown to be associated with increased risk of both venous and arterial thrombosis [28]. Its role in recurrent fetal loss has yet to be determined [26].

The causal relationship of aPLs and thrombosis is difficult to establish as they are present in normal, asymptomatic individuals [29]. The risk of thrombosis and poor obstetric outcomes in pregnant patients with aPLs is still poorly defined. Reasons for this include:

• • Poorly standardized assays for detection of these antibodies, particularly aCL [27];

• • Many studies (particularly the older studies) include patients with low positive aPL titres, especially low positive IgM aCLs or excluded women with LA [30–34];

• • Anticoagulant use has gradually changed over time with LMWH replacing unfractionated heparin (UH). Large studies directly comparing LMWH and UH are lacking in the obstetric setting. Thus, it is unclear if the use of one drug or another has influenced the obstetric outcomes [35,36]. Furthermore, in many centers the threshold for use of LMWH is very low, such that ascertaining pregnancy outcomes in untreated women who are positive for aPLs is difficult;

• • Patient cohorts in some studies are heterogenous. Not all the women included may have APS defined by our current Sapporo criteria. Others have concurrent disease processes such as active SLE, underlying renal impairment, hypertension, and so on, which contribute to thrombotic potential or poor obstetric outcomes [30,31,33,37];

• • Lifestyle factors such as smoking, BMI, recreational drug use, and so on are major factors in obstetric outcomes, but are rarely addressed in APS studies [38].

Hence, decisions regarding therapeutic intervention in these women are difficult. These controversies are discussed in the section on management of APS in pregnancy herein.

Complications related to APS in pregnancy

Maternal

Pregnancy and the puerperium are hypercoagulable states. Women who are pregnant have increased concentrations of most coagulation factors, increased activated protein C resistance and reduced protein S levels, raised concentrations of plasminogen activator inhibitors and hyperprolactinemia. This, in addition to a gravid uterus, causing sluggish blood flow in the pelvic and deep leg veins, coupled with prolonged bed rest, infections or dehydration (which could be exacerbated by blood loss during delivery), may all contribute to thrombosis [39].

Pregnant women with aPLs or APS are likely to have an increased risk of venous thromboembolism (VTE) [40]. In a study cohort of women with aPLs, 24% of thrombotic events occurred during pregnancy [41]. Similarly, VTE was more common in pregnant women with APS compared with the general population (5% risk of thrombosis in women with APS compared with 0.025–0.10% in the general population) [42]. The risk of VTE is increased throughout pregnancy, although studies indicate that the incidence is highest in the first trimester [43–45].

Postpartum risk remains elevated, with risk-per-day greatest in the weeks following delivery [46,47]. These factors need to be considered when deciding on duration of thromboprophylaxis for women with APS who are not on long-term anticoagulation [201].

Women with APS are predisposed to both arterial and venous thromboses. APS can cause thromboses in unusual vascular beds that are infrequently affected by other prothrombotic states [48]. The suboptimal vascular bed and poor placentation is likely to contribute to reduced uteroplacental supply with resultant FGR, development of preeclampsia or hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. Renal involvement may be related to secondary APS with immune complex deposition from SLE, resulting in glomerulonephritis. In primary APS, renal involvement is typically a result of occlusion of renal vessels ranging from thrombosis of the renal artery or vein, to the glomerular capillaries. The histological findings resemble those of other diseases associated with thrombotic microangiopathy.

The most common manifestation of arterial thromboses in APS is stroke or transient ischemic attacks. Stroke is rare in young adults. However, in a nationwide survey of approximately 1000 hospitals in the USA, the rate of stroke was 34.2 per 100,000 deliveries [49]. Thrombophilia (including APS) was a major risk factor for stroke in pregnancy and puerperium with a OR of 16.0 (95% CI: 9.4–27.2) [50].

The relationship between aPL and preeclampsia is still uncertain, with conflicting data from studies [38,51,52]. Some studies that have included women with SLE and prior thrombosis have estimated the median rate of gestational hypertension/preeclampsia at 32–50% [53]. Preeclampsia in women with APS generally occurs earlier (<34 weeks) and is more severe. A systematic review has concluded that there is a significant link between the presence of aCL and preeclampsia (OR: 2.73; 95% CI: 1.65–4.51), and to a lesser degree LA (OR: 1.45; 95% CI: 0.70–4.61) [54]. The presence of more than one type of aPL (both LA and aCLs) greatly increases the woman’s risk of pregnancy-induced hypertension and predisposes her to more severe preeclampsia [38]. Women with early-onset severe preeclampsia should be screened for APS [55].

Similarly, HELLP syndrome (which is a severe form of preeclampsia and has the same pathogenic mechanisms as APS [56]) is also reported to occur more frequently in women with APS, and may occasionally precede the diagnosis of APS [57]. Like preeclampsia, HELLP syndrome also occurs earlier in pregnancy – frequently in the second trimester – and may worsen for up to 3 weeks postpartum [58]. The exact prevalence is still unclear [14].

Fetal

The most common early complication is fetal loss, which is thought to result from poor development of the feto–placental circulation and impaired trophoblastic development.

Prevalence of aPLs is approximately 20% in women with recurrent fetal loss compared with 5% in healthy women [24]. Fetal loss in APS can be divided into early pregnancy loss and those over 10 weeks gestation. This is the result of poor development of the feto–placental circulation and impaired trophoblastic development. The association between aPLs and fetal loss is strongest for losses after more than 10 weeks of gestation [59]. A meta-analysis of 25 studies reported that LA has the strongest association with late fetal loss (OR: 7.79; 95% CI: 2.30–26.45) [26]. Another study (n = 451) demonstrated that a positive aCL measured at the first antenatal visit was associated with fetal loss [51].

As a result of poor placentation, there is FGR. In a large study (n = 1155) by Yamada et al., aPLs were associated with low birth weight and preterm delivery (<37 weeks). The presence of more than one type of aPL is associated with a greater risk [38]. A smaller study by Polzin et al. (n = 55) demonstrated that positive aCL was associated with FGR; however, LA was not detected in any of the women in this cohort [60].

Late pregnancy complications are likely to be a result of damage to the utero–placental vasculature. Intrauterine death and stillbirth have been reported to occur in women with APS as a result of placental abruption [61].

For a summary of maternal and fetal complications in pregnancy for women with APS, please refer to Box 2.

Catastrophic APS or Asherson’s syndrome

Asherson first described this in 1992 to highlight an accelerated form of APS leading to multiorgan failure. It is a rare (<1% of patients with APS are affected) but life-threatening variant of APS presenting with acute thromboses of multiple (usually small) vessels. The preliminary diagnostic criteria are listed in Box 3[62].

Precipitants for catastrophic APS include infections (35%; the most common being respiratory), surgery, trauma or other invasive procedures (13%), withdrawal of anticoagulation (8%), malignancy (8%), obstetric complications (6%), flares of SLE (5%) and idiopathic (35%) [63]. Of the initial cohort of Catastrophic APS Registry patients (n = 250), the mortality rate was 46%. The most common cause of death was cerebral involvement (stroke), followed by cardiac involvement and infection. Poor prognostic factors are older age (>36 years), SLE (with a positive antinuclear antibody), pulmonary and renal involvement [64].

In the obstetric setting, 15 cases have been described in a review by Gomez-Puerta et al.[65]. Severe, early-onset HELLP syndrome appeared to be a major feature in this cohort. Other microangiopathic disorders (e.g., thrombotic thrombocytopenic purpura) need to be excluded. Management includes prompt anticoagulation, steroids, plasma exchange and delivery of the baby – if there is superimposed HELLP syndrome. Mortality from the obstetric catastrophic APS cohort was extraordinarily high, with 46% (seven out of 15) of the mothers and 64% (seven out of 13) of the neonates succumbing to the disease process. Hence, there is a need for prompt recognition and definitive management of this rampant thrombotic process and its associated manifestations of the systemic inflammatory response syndrome, which are presumed to be due to excessive cytokine release from affected and necrotic tissues [64].

Management of APS in pregnancy

Prepregnancy counseling

Management of a woman with APS should start with prepregnancy counseling of the risks involved. Discussion should include the risks of fetal loss (both early and late), the increased risk of preeclampsia and HELLP syndrome, risk of thromboses (both arterial and venous), the need for anticoagulation, the risk of giving birth to a small-for-gestational-age baby or FGR, and the likelihood of a preterm delivery.

Ideally, a pregnant woman with APS should be managed in a specialist center with a multidisciplinary approach to her care. A rheumatologist or hematologist with a special interest in APS should be involved. Ongoing close surveillance (to be outlined later) is needed for optimal timing of delivery. Women who have had previous obstetric APS and who are concerned about recurrence in subsequent pregnancies can be reassured that the risk of recurrence with treatment and close surveillance is low. Women with purely obstetric APS appear to have better outcomes compared with women with thrombotic APS when on treatment. In a study by Bramham et al., despite treatment with aspirin and LMWH, women with thrombotic APS had a much higher incidence of preterm deliveries, small-for-gestational-age babies and preeclampsia. Thromboembolic events occurred in 4.9% despite anticoagulation (none occurred in the obstetric APS group) [66]. Women who have had catastrophic APS are usually advised not to get pregnant again, as there are no data available about the risk of recurrent disease. HELLP often coexists with catastrophic APS, and the risk of recurrent preeclampsia is 5–28% and that of HELLP syndrome is 2–24.5% in subsequent pregnancies [67–69].

Systemic lupus erythematosus and APS frequently coexist. Women with either diagnosis should be screened prepregnancy or at least in early pregnancy for the other [70,71]. Screening for SLE with clinically relevant questions, and laboratory testing with antinuclear antibody, anti-dsDNA antibodies and extractable nuclear antigens (ENAs). The presence of Ro and La antibodies is of particular importance in view of the risk of fetal heart block. Renal function should be checked and urine should be examined for the presence of casts. Baseline quantification of proteinuria by protein:creatinine ratio, liver function tests, urate and a platelet count for comparison in case of development of preeclampsia or HELLP should be carried out. If SLE is present, screening for lupus activity is essential. Women with active SLE should be advised to defer pregnancy until their disease has been quiescent for at least 6 months [72,73]. aPL levels should be quantified. As lifestyle factors impact on obstetric outcomes, a baseline BMI, smoking history and recreational drug-use history should be sought. A comprehensive clinical examination to quantify disease activity and disease damage from SLE should be performed and blood pressure measured.

Warfarin is teratogenic between 6 and 12 weeks of gestation. If the woman is taking warfarin, then she should be told to be vigilant for missed periods, perform regular pregnancy tests and to swap to LMWH within 2 weeks after a missed period. Some women, particularly those with recurrent pregnancy loss (RPL) and those not receiving warfarin, may be advised to start aspirin prepregnancy. For all women with aPLs, it is recommended that low-dose aspirin should be commenced on confirmation of pregnancy (in those that are not already receiving it), not merely for its antiplatelet benefits, but also to reduce the risk of preeclampsia [33,74,75].

Antenatal surveillance

For women with APS, it is generally suggested that they are seen at least every 4–6 weeks for preeclampsia screening, fetal growth monitoring after 20 weeks and maternal disease activity monitoring (particularly if there is concurrent SLE) [55,76,77]. Early dating scans and screening for any chromosomal abnormalities are recommended. Women should be screened for both thrombotic and bleeding problems, especially those receiving anticoagulants. Women should also be made aware of the symptoms of preeclampsia, and they should have their blood pressure measured and urine dipsticked for proteinuria at each visit.

Uterine artery waveforms are usually assessed between 20 and 22 weeks gestation. Women who have a notched waveform require closer surveillance with regular growth scans [55,78]. If there is evidence of FGR, then Doppler flow of the umbilical artery should be quantified (absent or reversal of end-diastolic flow is indicative of poor fetal outcomes), serial measurement of fetal growth carried out, and biophysical profile and weight measured. Amniotic fluid volume measurements will help determine optimal timing of delivery and need for antenatal glucocorticoids for fetal lung maturation. There should be a low threshold for requesting laboratory investigations to support a diagnosis of preeclampsia or HELLP syndrome in this group.

Measurement of anti-Factor Xa levels for women receiving LMWH for thromboprophylaxis to determine adequacy of anticoagulation is not required in this situation unless the woman has evidence of renal impairment (creatinine clearance <30 ml/min) [79,201].

Women with concurrent SLE will need other disease-specific measures if there is any evidence of a flare. In women with clinically quiescent disease for 6 months prior to conception, screening for disease activity should be carried out at each trimester. Flares of SLE can be clinically very difficult to distinguish from preeclampsia [70–72,77]. An increase of anti-dsDNA antibodies and a decrease of complement levels is suggestive of a flare of SLE [80]. Table 1 contains a summary of the recommendations [56,70,73,75,77,78,81–91].

Treatment options

Table 2 gives a summary of the various therapeutic options available and a brief summary of the evidence supporting each option [30–33,37,42,53,74,75,92–117].

Immunosuppressants such as azathioprine, mycophenolate mofetil, cyclophosphamide and rituximab are used to treat concurrent flares of SLE (in secondary APS) that may have precipitated acute thrombosis or treatment of catastrophic APS. Azathioprine has a well-established safety profile in pregnancy. In life-threatening flares (e.g., alveolar hemorrhage), cyclophosphamide can be used after the first trimester [118,119]. Rituximab is an anti-CD20 monoclonal antibody that suppresses B-cell formation, and is an emerging therapy for a variety of autoimmune diseases. Its safety profile in pregnancy is yet to be determined, but suppression of neonatal B-cell development is a concern [120]. Mycophenolate mofetil is a known teratogen in rabbits and rats. In humans, the evidence for teratogenesis has been limited to a handful of published cases where the fetuses exposed to mycophenolate mofetil were reported to suffer from moderate-to-severe microtia or anotia, with external auditory canal atresia along with other craniofacial malformations, and its use is therefore contraindicated in pregnancy [121].

Controversial issues in the management of a pregnant woman with APS

To give LMWH or not?

Antiphospholipid syndrome is a heterogeneous disorder with different clinical phenotypes and a variety of aPLs with different thrombogenic potentials. There are few good randomized controlled studies, particularly in pregnancy, to guide management decisions. Ultimately, these decisions should be individualized to each woman.

Much research has centered on the prevention of recurrent miscarriage in women with APS. There are only limited data available on the management of other phenotypes of APS. The two most recently published multicenter randomized controlled trials on RPL have excluded women with APS [122,123].

In the past steroids and unfractionated heparin (UH) were the first-line therapy [30,124]. With the introduction of LMWH with its longer half-life, predictable bioavailability, ease of daily or twice-daily subcutaneous dosing and favorable side-effect profile, the use of intravenous or subcutaneous UH has largely become obsolete. The more predictable dose response of LMWH has taken away the need for close monitoring of APTT or anti-Factor Xa levels [79]. LMWH is associated with a lower incidence of heparin-induced thrombocytopenia and heparin-induced osteoporosis compared with UH [125].

However, the use of LMWH (and its dose and duration) is controversial in the following groups:

• • Women with obstetric APS (recurrent early miscarriages) but no previous VTE;

• • Women who have had adverse obstetric outcomes (e.g., late pregnancy loss, early-onset preeclampsia or HELLP syndrome, previous FGR baby, or preterm delivery <34 weeks), but no VTE;

• • Women with high-positive aPLs but who do not fulfill the diagnostic criteria for APS;

• • Postpartum thromboprophylaxis in women with RPLs (obstetric APS).

Women with obstetric APS (recurrent early pregnancy losses) but no previous VTE

Initial enthusiasm for aspirin and heparin use came from early randomized studies on small cohorts of women (n = 50) by Kutteh et al. [34] and (n = 90) by Rai et al. [31] that did show improved pregnancy outcomes in women with aPLs and RPLs (live birth rate of 72–80% in those on aspirin plus heparin vs 42–44% live birth in those on aspirin alone). Rai et al. found that the addition of heparin improved pregnancy outcomes, particularly in those with early (<13 weeks gestation) pregnancy losses [31]. Of note, the women were carefully screened for other causes of recurrent fetal losses, including chromosomal or uterine anomalies, and other underlying conditions including SLE. Kutteh et al. specifically excluded women with positive LA [34]. In an earlier study Rai et al. had found that women with aPLs who were untreated had a 90% chance of RPL compared with women who had recurrent miscarriages from idiopathic causes (only 34%) [59].

However, this initial enthusiasm for aspirin and heparin use was challenged by subsequent studies that showed less promising results. Pattison et al. studied the effect of low-dose aspirin 75 mg daily for the treatment of early miscarriages in aPL-positive women (n = 50) and showed that aspirin was of no additional benefit over the best supportive care. Of interest, most of the women in this cohort had aCLs and only nine out of 50 had LA (another six had both LA and aCLs) [32].

In another randomized controlled trial of aspirin versus aspirin plus LMWH for the treatment of RPL in APS (n = 98), Farquharson et al. demonstrated that the addition of LMWH did not provide additional benefit [33].

This finding was supported by another recent randomized open-label trial by Laskin et al., where women (n = 88) with RPL and primary APS or inherited thrombophilias were randomized to receive aspirin or aspirin plus LMWH. Again, there was no difference in the incidences of live births between these two groups [100]. However, these two studies did not distinguish between early pregnancy losses versus late pregnancy losses, and maternal complications such as preeclampsia, HELLP syndrome, and so on.

Postpartum anticoagulation is felt to be important in this group [126]. The RCOG Green-Top Guidelines recommend the use of postpartum thromboprophylaxis for 7 days in this group, even though the absolute risk of VTE in women with APS but without previous VTE is small [201].

Table 3 demonstrates the heterogenous nature of the studies using various therapeutic interventions in women with aPLs and a history of RPL [30–36,100,127–129]. Some studies included patients who did not fulfill laboratory criteria for APS with either low-positive aCLs or excluded women with LA [31,33,127,128]. Of note, the more recent studies with larger cohorts (Farquaharson et al. [33] and Laskin et al. [100]) demonstrated live birth rates of more than 70% with low-dose aspirin alone.

Women who have had adverse obstetric outcomes (late pregnancy loss, early-onset preeclampsia or HELLP syndrome, previous FGR baby, preterm delivery <34 weeks) but no VTE

Stone et al. carried out a study on women with obstetric versus thrombotic primary APS (n = 33). Some of these groups studied included those with late pregnancy complications or those who had complications in the first trimester despite taking low-dose aspirin. These women were treated with both low-dose aspirin and LMWH (dalteparin 5000 IU daily, with the dose doubling at 16–20 weeks gestation). The live birth rate using their protocol was 91% – one of the highest reported in the published literature [97]. Rey et al. have recently demonstrated that in women without APS or heritable thrombophilia, dalteparin (5000 IU per day) was effective in decreasing the recurrence of placental-mediated complications (e.g., severe preeclampsia, FGR or abruption) [130].

Most centers with expertise in the management of APS in pregnancy recommend prophylactic doses of LMWH for women with adverse obstetric outcomes other than recurrent early losses.

Women with thrombotic APS & on long-term anticoagulation with warfarin

Most women with recurrent thromboses are maintained on long-term anticoagulation:

• • These women should be swapped immediately to LMWH on confirmation of an intrauterine pregnancy (preferably <6 weeks gestation);

• • Intensity of anticoagulation with LMWH in this group is also controversial. If the woman is prone to recurrent VTE outside pregnancy, then therapeutic-dose LMWH (e.g., enoxaparin 1 mg/kg every 12 h or dalteparin 100 IU/kg every 12 h) is suggested;

• • If the woman has no history of recurrent VTE during or outside pregnancy, then many centers use high-dose prophylactic (50–75% therapeutic) LMWH;

• • If the woman is on therapeutic doses of LMWH, delivery should be planned. LMWH should be discontinued 24 h prior to planned delivery (and regional anesthesia). Some centers suggest changing the woman to lower prophylactic doses of LMWH for the day prior to planned delivery;

• • Postpartum, the LMWH can be started more than 4 h after spinal or epidural anesthesia. If the cannula for spinal or epidural anesthesia is removed, LMWH should be withheld for 12 h afterwards;

• • Warfarin can be commenced postpartum with ongoing LMWH cover until international normalized ratio (INR) is within therapeutic range. Reintroduction of warfarin is often delayed until day 5–7 postpartum to reduce the bleeding risk when LMWH and warfarin are used concurrently.

Despite the well-established need for ongoing anticoagulation in this cohort of women, the dosing of heparin or LMWH remains controversial. In women with previous thrombotic events, there is debate about whether high-prophylactic or therapeutic dosing should be used. Stone et al. attempted to address this issue in their study (n = 33), where different dosing regimens were used in different APS phenotypes (e.g., obstetric APS – low-dose aspirin plus 5000 IU daily of dalteparin; APS plus venous thrombotic event – low-dose aspirin plus initial 5000 IU dalteparin dose that was escalated to twice-daily dosing from 16 weeks; APS plus previous arterial or microvascular event – low-dose aspirin plus twice-daily LMWH, and if symptoms were present, to full therapeutic doses of dalteparin). They found that the strong predictors of thrombotic events in pregnancy include the presence of LA (positive-predictive value: 30%; 95% CI: 12–54%) and past thrombotic events (positive predictive value: 33%; 95% CI: 9.9–65%). Using these guidelines, the authors found a live birth rate of 91%. The authors concluded that modified treatment plans to suit the individual’s needs and past history was crucial to a successful pregnancy outcome [97]. Various authorities in this field have developed a variety of heparin and LMWH dosing guidelines [53,131]. Two studies (not confined to women with APS) have attempted to develop guidelines on the intensity of anticoagulation based on risk stratification of VTE in pregnancy. Both of these studies reported a low incidence of VTE (antepartum VTE: 0.35%; postpartum VTE: 0.7%; another study had total incidence VTE: 0.6%) and bleeding complications (0.35–3%) [132,133].

In women with previous arterial thromboses, recurrent thrombosis despite therapeutic doses of anticoagulation or cerebral thrombotic events, judicious use of warfarin may be appropriate (between the 16th and 34th week of gestation) [93,131,134].

Women with thrombotic APS (with a previous history of VTE), but not anticoagulated prepregnancy

A subset of women with prior thromboses may have discontinued their anticoagulation. However, on confirmation of pregnancy, they should be commenced on aspirin and high-dose prophylactic LMWH (e.g., enoxaprin 40 mg subcutaneously every 12 h or dalteparin 5000 IU every 12 h) on confirmation of intrauterine pregnancy:

• • During labor, women receiving prophylactic doses of LMWH, and requesting regional anesthesia should be discussed with a senior anesthetist. A 12-h interval is required between a prophylactic dose of LMWH and administration of regional anesthesia or analgesia;

• • Postpartum, the woman will need at least 6 weeks of thromboprophylaxis. The need for ongoing anticoagulation should also be reviewed.

Women with incidental findings of high-positive aPL without fulfilling the diagnosis of APS

There are no trials specifically looking at this cohort of women. However, Lynch et al. prospectively measured aPLs in early pregnancy in 451 low-risk nulliparous women. They found that 24.4% had aPLs, and that rate of fetal loss in this group was much higher than those without aPLs (15.8 vs 6.5%), but the rate of adverse maternal outcomes was similar in both groups [51]. Hence, it is not known if treatment of an asymptomatic cohort will actually improve their obstetric outcomes.

Surveillance antenatally but postpartum thromboprophylaxis for 1 week is suggested unless additional risk factors are present (e.g., prolonged immobility, operative delivery, BMI >40 kg/m², infection, and so on) [201].

Women with RPL & aPL

Many clinics seeing women with miscarriages may screen women prematurely (after only two early pregnancy losses) for the presence of aPLs. Given that 8–10% of the normal population have aPLs, its presence in a woman with recurrent (but <three) pregnancy losses does not necessarily establish the diagnosis of APS. Early pregnancy losses are not uncommon, and there are many causes of early pregnancy losses such as blighted embryos, chromosomal abnormalities, idiopathic symptoms, and so on. Hence, strict criteria for establishing the diagnosis of APS should be maintained.

However, it is not uncommon to find women with less than three consecutive early pregnancy losses with aPLs detected on premature screening for APS, treated with low-dose aspirin and LMWH. It is likely that the rationale for this is extrapolation from the results of earlier studies that suggested benefit from the use of aspirin and heparin in treating women with obstetric APS, in particular recurrent miscarriages [31,34],

There is no evidence to support the use of aspirin and heparin in women with aPLs who do not fulfill the diagnostic criteria for APS, and indeed, as discussed earlier, evidence is mounting against a beneficial role for LMWH in addition to aspirin in women with recurrent early pregnancy loss and APS. Routine screening for aPLs in early miscarriage clinics should be discouraged.

Women undergoing IVF therapy with aPLs

Women undergoing IVF are a particularly vulnerable group. The hyperstimulation of the ovaries with resultant ascites and sluggish lower limb blood flow coupled with prolonged bed rest and dehydration from hyperemesis (more common in multiple pregnancy) are all factors that would predispose any woman to thrombosis. Both APS and SLE may present for the first time in women undergoing ovulation-induction therapy [135].

The 5th International Conference on Sex Hormones, Pregnancy and the Rheumatic Disease (2007, Florence, Italy) has recommended that anticoagulation with heparin is mandatory in any woman with APS undergoing IVF [136]. They also recommended that aspirin be used in all women with aPLs.

There is very little evidence for the use of LMWH in aPL-positive women without APS who are undergoing IVF. A randomized, placebo-controlled trial of heparin and aspirin use in women undergoing IVF conducted by Stern et al. did not show improved pregnancy or even implantation rates in aPL-positive women with previous IVF implantation failure [137]. These findings were similar to a previous nonrandomized study by Kutteh et al., which failed to demonstrate any statistically significant differences in pregnancy and implantation rates in the heparin-treated group [127]. The use of repeated courses of heparin with each cycle of IVF could predispose the woman to developing osteopenia, although the risk is very low with LMWH [138].

For women with concurrent SLE, there is a 25–27% risk of flares with induction of ovulation, especially when gonadotrophin and/or gonadotrophin receptor antagonists are used [135,138].

Table 4 contains a summary of clinical scenarios and suggested management guidelines, including evidence to support the recommendations [31–34,53,93,96,122,123,127,130–133,137,201].

Expert commentary

Despite the controversies regarding the management of women with APS in pregnancy, obstetric outcomes are good when these women are managed in specialist centers according to multidisciplinary guidelines [93,139]. Care should commence at prepregnancy and continue until at least 6 weeks postpartum.

There are ongoing debates with regards to intensity of anticoagulation with LMWH in women with thrombotic APS. Only one study has attempted to address this issue with a framework to guide therapeutic decisions regarding the dosing of LMWH [93]. However, several expert guidelines have been formulated, although ultimately the intensity of anticoagulation will need to be guided by the patient’s thrombotic symptoms, which may recur in pregnancy (refer to Table 4 for suggested LMWH doses) [53,93,131].

With regard to the management of obstetric APS with previous preeclampsia, FGR or late fetal deaths, most centers use aspirin and prophylactic LMWH [93]. This is based on the rationale that late pregnancy losses are more likely to be related to placental thrombosis, and therefore the use of LMWH may be of benefit.

For women with recurrent early pregnancy losses, the use of LMWH remains controversial, although more recently published studies suggest that LMWH offers no advantage over the use of aspirin alone [33,96]. If LMWH is used in recurrent miscarriage, then we advise that it is stopped after 12 weeks or at 20 weeks if the uterine artery Doppler scan is normal. The use of LMWH has become commonplace in the management of women undergoing IVF and in women with recurrent miscarriage but without aPLs or APS, even though this is based on extrapolation from older studies of women with APS and RPLs. For women with RPLs, there are now two large randomized controlled trials demonstrating that the addition of aspirin or aspirin plus LMWH is no better than placebo in treating women with recurrent unexplained pregnancy losses [122,123].

In the setting of IVF, there is very little evidence to support the use of LMWH to improve pregnancy outcomes and increase the chances of successful implantation [127,137]. However, there is an ongoing need to provide thromboprophylaxis in this group, particularly if they are admitted into hospital with complications owing to IVF therapy, such as ovarian hyperstimulation syndrome.

Five-year view

There is increasing evidence that the outcome of pregnancy in APS is influenced by the underlying phenotype. Women with obstetric APS have better pregnancy outcomes than women with thrombotic APS. More intense anticoagulation is needed in the latter group. Hence, better subclassification of APS is likely to shape different management recommendations.

The importance of understanding and adhering to the classification criteria for APS cannot be overemphasized. This will hopefully ensure that women with aPLs and early pregnancy losses are not mislabeled as suffering from APS and then treated inappropriately.

Over the next 5 years, clearer guidelines will lead to more appropriate screening of women with late fetal losses, early-onset preeclampsia and FGR, and ensure that those with APS are diagnosed and given the opportunity for treatment in their next pregnancy.

Our suggestions for future studies include:

• • Cohort selection is of prime importance – women with primary APS would make a better-defined cohort. Large, multicenter collaborative studies may be necessary to obtain a sufficiently large patient population;

• • Obstetric APS may need to be further defined – differentiating women with recurrent early pregnancy losses less than 10 weeks from women who have had late pregnancy losses, preterm delivery less than 34 weeks, severe early-onset preeclampsia or HELLP syndrome, and so on;

• • Lifestyle factors will need to be rigorously addressed – in particular smoking, BMI, alcohol and recreational drug use;

• • Standardization of anticoagulation regimens used so that various studies can be compared head-to-head;

• • Optimal duration of postpartum thromboprophylaxis in women with obstetric APS.

In the case of the aforementioned woman with two miscarriages enquiring about the possible benefit of LMWH, the first step would be to determine if she has any other features of APS, and then whether she has obstetric or thrombotic APS. If she has had no other pregnancy complications and no prior thrombosis, then she does not meet the criteria for APS and therefore a screen for aPLs is not appropriate. She should be advised that the use of LMWH is also inappropriate. She could be offered low-dose aspirin after an explanation of the contradictory results of different studies.

Table 1. Summary of recommended tests for women with antiphospholipid syndrome prior to and during pregnancy.

Indications	Recommended tests	Ref.
For SLE disease activity	ANAs, anti-dsDNA, ENAs (especially Ro and La antibodies), complement levels SLEDAI or any other scoring system the hospital uses for determining SLE activity (usually performed by a rheumatologist)	[70,73,77,81,82]
For those with current/previous nephritis	Urine should be dipsticked for proteinuria at each visit Urine PCR and a 24-h quantification for proteinuria should be performed at baseline Check full blood count, liver and renal function at baseline	[83,84]
Early dating scan and scans for congenital abnormalities and markers of chromosomal abnormalities	Accurate dating scans essential to determine dates from an early stage as risk of FGR Check for fetal malformations, especially if the woman is on multiple medications that are potentially teratogenic such as warfarin, mycophonolate mofetil, and so on	[85–87]
For pregnancy-induced hypertension or preeclampsia	At each antenatal visit, women should be screened for symptoms of preeclampsia, have their BP checked and urine dipsticked for proteinuria Clinicians should have a low threshold for initiating investigations for presumed preeclampsia/HELLP syndrome Flares of SLE may be difficult to distinguish from preeclampsia, but low complement and elevated anti-dsDNA suggest SLE flare	[56,83,88]
For FGR	Uterine artery waveforms at 20–22 weeks gestation. Those with notched waveforms will require closer surveillance for FGR Doppler flow of the umbilical artery (for those with FGR): absent or reversal of end-diastolic flow is indicative of poor fetal outcomes Serial measurement of fetal growth, weight and amniotic fluid measurements Fetal biophysical profile	[75,78,89–91]

ANA: Antinuclear antibody; BP: Blood pressure; ENA: Extractable nuclear antigen; FGR: Fetal growth restriction; HELLP: Hemolysis, elevated liver enzymes and low platelets; SLE: Systemic lupus erythematosus; SLEDAI: SLE disease activity index.

Table 2. Brief overview of the drugs and other therapies used in antiphospholipid syndrome pregnancy.

Drug	Use	Evidence	Safety in pregnancy	Safety in breastfeeding
Aspirin 75–100 mg daily from conception until ∼36 weeks gestation	Antiplatelet effect Reduction of fetal loss Prevention of preeclampsia	No controlled trials of aspirin for the prevention of VTE. However, there is evidence for aspirin use in improving pregnancy outcomes, particularly in the prevention of preeclampsia [32,33,74,75,92]	Will cross the placenta, but low doses have not been shown to cause fetal harm	Very low doses excreted in breast milk, and at low doses should be safe
Warfarin to be discontinued as soon as pregnancy is confirmed	Its use is not recommended in pregnancy unless risk of thrombosis is exceptionally high, such as in recurrent cerebral thrombotic events [53,93] Can be used postpartum as thromboprophylaxis	Teratogenic between 6 and 12 weeks of gestation Recommended that this is changed to LMWH at confirmation of intrauterine pregnancy	Teratogenic In general, fetal effects are dose dependent, and doses >5 mg daily are associated with increased risk [94] However, the genetic makeup of the mother and fetus can affect dose response, hence warfarin is best avoided if possible [95]	Does not enter breast milk
UH	Similar to that of LMWH May be used when therapeutic doses of anticoagulation are required in massive pulmonary embolism, or rapid reversal of anticoagulation may be needed peripartum or during operative procedures	Most of the studies using UH have since been superseded by studies using LMWH (as discussed in the next row)	Safe in pregnancy as it does not cross the placenta	Does not enter breast milk
LMWH can be started at confirmation of pregnancy	The drug of choice for women established on warfarin, or women who have had thrombosis during pregnancy or previous arterial thrombosis, women with previous late pregnancy complications, women who are immobile in hospital, and women who require thromboprophylaxis	Evidence for its role in preventing first-trimester fetal loss is controversial [31,93,96]	Does not cross the placenta	Has a high molecular weight, thereby reducing risk of excretion in breast milk. If consumed, will be broken down in the infant’s GI tract
Glucocorticoids (e.g., prednisone)	Little evidence for therapeutic benefit in APS However, it is used in immune thrombocytopenia associated with APS or coexistent active SLE	Little evidence of therapeutic benefit in obstetric APS [30,37,42,92,97,98] Any benefit is outweighed by its adverse effects (e.g., development of gestational diabetes, preeclampsia, increased risk of infections and preterm deliveries)	Low serum concentrations in the fetus Adverse events have been reported when massive doses used. Cleft palate has been reported in first-trimester use	Found in low concentrations in breast milk with no adverse events reported
HCQ	Most often used when woman has concurrent SLE It has a mild anti-thrombotic effect [99,100] Used in women with Ro and La antibodies	Cessation of HCQ may trigger flares of SLE in women [101,102] Anti-thrombotic effects are mild and do not replace conventional anticoagulation in women who need it [103–105] Case-controlled studies show reduced incidence of congenital heart block in women on HCQ [106]	No reports of fetal toxicity Benefits of disease control (particularly for SLE) outweigh any potential risks [107]	Considered safe despite excretion in breast milk [108]
Intravenous immunoglobulins	Used in a small number of women with APS as salvage therapy for refractory disease Also used to treat idiopathic thrombocytopenic purpura related to APS	No evidence of additional benefit when added to conventional therapy with aspirin and heparin [109,110] When added to conventional therapy (aspirin and heparin) in women with FGR after late second trimester, there is a temporary improvement of uteroplacental Doppler waveforms [111]	Will cross the placenta after 30 weeks of gestation	Excretion in breast milk is unknown
Plasmapheresis	Usually reserved for the treatment of catastrophic APS Able to rapidly remove clotting factors, cytokines and other pathogenic products	Evidence is limited to case reports [112,113]	Rarely used in pregnancy, small literature base limited to case reports [114–117]	Probably safe

APS: Antiphospholipid syndrome; FGR: Fetal growth restriction; HCQ: Hydroxychloroquine; LMWH: Low-molecular-weight heparin; SLE: Systemic lupus erythematosus; UH: Unfractionated heparin; VTE: Venous thromboembolism.

Table 3. Summary of various therapeutic interventions involving women with recurrent early pregnancy losses and antiphospholipid antibodies.

Study (year)	Intervention	Additional comments	Women (n)	ASA (n received ASA only)	UH (n)	LMWH (n)	Other (n)	LB (%)		Conclusions or comments	Ref.
								ASA alone	ASA + UH/LMWH
Cowchock et al. (1992)	ASA + UH vs ASA + prednisone 40 mg/day		20	Yes ^†All received ASA	Yes (12)		Yes Prednisone (8)	ASA + prednisone 75	75	Those on prednisone had higher rates of complications	[30]
Kutteh (1996)	ASA vs ASA + UH	Those with LA were excluded	50	Yes (25)	Yes (25)			44	80		[34]
Rai et al. (1997)	ASA vs ASA + UH	aCL-positive if IgG >5 GPL or IgM >3 MPL or LA-positive based on RVVT	90	Yes (45)	Yes (45)			42	71		[31]
Pattison et al. (2000)	ASA vs placebo	Only placebo-controlled trial. aCL-positive if IgG ≥5 GPL, IgM ≥5 MPL	40	Yes (20)				80	Placebo LB rate was 85	Addition of ASA is the same as best supportive care	[32]
Farquharson et al. (2002)	ASA vs ASA + LMWH	aCL positive IgG >9 GPL, IgM >5 MPL	98	Yes (47)		Yes (51)		72	78	High LB achieved with ASA alone	[33]
Franklin et al. (2002)	ASA vs ASA + UH	Complex definition of positive aPL^†. Both groups (group 1 and 2) received ASA + UH and group 3 received only ASA	79	Yes (26)	Yes (53)	–		46	ASA + UH – Group 1: 76; Group 2: 64	Study concluded that other aPLs may be associated with pregnancy loss	[129]
Stephenson et al. (2004)	ASA + LMWH vs ASA + UH	All medications were started preconceptually	26	Yes ^†All received ASA	Yes (13)	Yes (13)			ASA + LMWH 69 ASA + UH 31	Pilot study comparing UH with LMWH	[35]
Noble et al. (2005)	ASA + LMWH vs ASA + UH		50	Yes ^†All received ASA	Yes (25)	Yes (25)			ASA + LMWH 84 ASA + UH 80	No statistically different LB rates between both arms	[36]
Goel et al. (2006)	ASA vs ASA + UH	Only women with APS and high-positive IgG aCL were included in this study	72	Yes (39)	Yes (33)			61.5	84.8	Birthweight with UH was 3.21 ± 0.33 kg vs only 2.77 ± 0.14 kg	[128]
Laskin et al. (2009)	ASA vs ASA + LMWH	Study included women with RPL and either one of the following: aPL, an inherited thrombophilia or ANA. aPL was present in 47.7% of women in each group	88	Yes (43)		Yes (45)		79.1	77.8	Addition of LMWH to ASA may not confer additional benefit	[100]

^†Positive aPL defined as either positive to aCL, phosphatidyl serine ± or LA (group 1), or positive to phosphatidyl inositol, phosphatidyl glycerol ± phosphatidyl ethanolamine (Group 2).

aCL: Anticardiolipin antibody; ANA: Antinuclear antibody; aPL: Antiphosphloipid antibody; APS: Antiphospholipid syndrome; ASA: Aspirin; LB: Live birth; LMWH: Low-molecular-weight heparin; RPL: Recurrent pregnancy loss; UH: Unfractionated heparin.

Table 4. Summary of potential clinical scenarios, and suggested management guidelines and supporting evidence.

Clinical scenario	Therapeutic options in pregnancy (and the evidence)		Need for postpartum thromboprophylaxis/anticoagulation
	Aspirin	Heparin or LMWH
Women with aPL but no clinical features of APS	Yes^†	No ^†Only antenatal surveillance is required	Yes – for 1 week only of thromboprophylaxis, unless additional risk factors present [201]
Women with recurrent early pregnancy losses but no VTE (obstetric APS)	Yes [31,33,34]^†	No [33,32,96] More recent publications appear to indicate that LMWH was of little benefit when added to aspirin. Hence, LMWH should not be routinely started in this group. If it is used it should be stopped at 12 weeks or at 20 weeks if the uterine artery Doppler scan is normal Evidence to support the use of LMWH is based on older studies [31,34]	Yes – 1 week only of thromboprophylaxis, unless additional risk factors present [126,201]
Women with adverse obstetric outcomes (late pregnancy losses, early-onset preeclampsia, HELLP syndrome, previous FGR, preterm delivery <34 weeks) but no VTE (obstetric APS)	Yes	Yes [93,130] Prophylactic doses of LMWH suggested based on expert opinion and nonrandomized studies. LMWH appears to reduce the recurrence of placental-mediated complications. Specific randomized control trial data are not available	Yes – 1 week only of thromboprophylaxis, unless additional risk factors present
Women with thrombotic APS and on long-term anticoagulation with warfarin	Yes	Yes Swap from warfarin to LMWH immediately on confirmation of intrauterine pregnancy Intensity of anticoagulation debated, with some groups advocating the use of high-dose prophylactic regimen and others suggesting full therapeutic doses of LMWH [93,53,131]. Two studies have attempted to risk stratify VTE risks in pregnancy and set up guidelines for intensity of anticoagulation treatment. Studies were not specific to women with APS alone [132,133]	Yes. They can be swapped back to warfarin after delivery
Women with thrombotic APS who are experiencing recurrent thrombosis in pregnancy, despite high-dose prophylactic LMWH	Yes	Yes Swap to therapeutic doses of LMWH on confirmation of intrauterine pregnancy If high-risk women such as those with arterial thrombosis, cerebral thrombotic events, and so on, warfarin could be cautiously restarted after the first trimester [93]	Yes. Warfarin to be restarted
Women with thrombotic APS but not anticoagulated prepregnancy	Yes	Yes High-dose prophylactic LMWH suggested [201]	Need for anticoagulation should be reviewed postpartum and long-term anticoagulation should be considered
Women with aPLs and RPL (<three), but who do not fulfill the criteria for APS	No	No Evidence for the use of aspirin and heparin in this group is extrapolated from studies on women with APS and RPL [31,34], although two very recently published randomized controlled trials have not demonstrated any benefit over placebo [122,123]	Yes – 1 week only of thromboprophylaxis, unless additional risk factors present (see guideline on obstetric APS) [201]
Women with aPL undergoing IVF	Yes [136]	No [137] However, if the woman is admitted with complications of IVF (e.g., ovarian hyperstimulation syndrome, and so on) and is bed bound, then prophylactic doses of LMWH should be given	Yes Only 1 week of thromboprophylaxis, unless additional risk factors present [201]

^†There is no evidence to support the use of aspirin for VTE prevention in pregnant women. Its use in improving obstetric outcomes in women with APS is controversial. However, there is good evidence to support its use in the prevention of preeclampsia [74]. For this reason, the Royal College of Obstetricians and Gynaecologists recommends that all women with APS be started on aspirin [201].

aPL: Antiphospholipid antibody; APS: Antiphospholipid syndrome; FGR: Fetal growth restriction; HELLP: Hemolysis, elevated liver enzymes and low platelets; LMWH: Low-molecular-weight heparin; RPL: Recurrent pregnancy loss; VTE: Venous thromboembolism.

Box 1. Revised classification criteria (Sapporo criteria) for the antiphospholipid syndrome.

Vascular thrombosis

One or more clinical episodes of arterial, venous or small-vessel thrombosis. Thrombosis must be objectively confirmed. For histopathologic confirmation, thrombosis must be present without inflammation of the vessel wall

Pregnancy morbidity

• • One or more unexplained deaths of a morphologically normal fetus ≥10 weeks of gestation

• • One or more premature deliveries of a morphologically normal fetus <34 weeks gestation owing to:

  – Severe preeclampsia or eclampsia defined according to standard definitions

  – Recognized features of placental insufficiency

• • ≥Three unexplained consecutive abortions <10 weeks gestation, with maternal and paternal factors (anatomic, hormonal or chromosomal abnormalities) excluded

Laboratory criteria

The presence of aPLs on two or more occasions at least 12 weeks apart and no more than 5 years prior to clinical manifestations, as demonstrated by ≥one of the following:

• • Presence of lupus anticoagulant in plasma

• • Medium- to high-titre anticardiolipin antibodies (>40 GPL or MPL, or >99th percentile) of IgG or IgM isoforms

• • Anti-β2GP-I of IgG or IgM present in plasma

Box 2. Complications of the antiphospholipid syndrome in pregnancy.

Maternal

• • Thrombosis – venous, arterial or capillary

• • Early-onset preeclampsia/eclampsia

• • HELLP syndrome

Fetal

• • Recurrent fetal loss

• • Small-for-gestational-age fetus or FGR

• • Preterm delivery

• • Intrauterine fetal death/stillbirth

Box 3. Preliminary diagnostic criteria for catastrophic antiphospholipid syndrome.

1. Evidence of involvement of ≥three organs or systems, and/or tissues^†

2. Clinical manifestations develop simultaneously or <1 week

3. Histopathological confirmation of small-vessel occlusion in at least one organ or tissue (significant thromboses needs to be present, although vasculitis may coexist)

4. Laboratory confirmation of the presence of aPLs:

Definite catastrophic APS – all four criteria present

Probable catastrophic APS – any of the following combinations:

a. All four criteria present, but only in two organs, systems and/or tissues

b. All four criteria present, but absence of laboratory confirmation of aPLs on repeat testing (owing to the early death of the patient)

c. Criteria 1, 2 and 4

d. Criteria 1, 3 and 4, and the development of a third event between 1 week and 1 month after the initial presentation, despite anticoagulation

Key issues

• • Antiphospholipid syndrome (APS) is a heterogenous disorder, with different antiphospholipid antibodies (aPLs) carrying different thrombogenic potential. A positive lupus anticoagulant is associated with a much higher risk of thrombosis and fetal loss compared with anticardiolipin antibodies. A combination of aPLs appears to have the worst outcomes.

• • In the absence of clinical thrombosis, the significance of aPL positivity is unclear. The risk per day of venous thromboembolism is highest postpartum. Even women with pure obstetric APS who have not received antenatal prophylaxis should receive postpartum thromboprophylaxis.

• • Women with thrombotic APS have worse pregnancy outcomes than women with obstetric APS alone.

• • Women who have concurrent systemic lupus erythematosus require close monitoring of disease activity. Hydroxychloroquine should not be discontinued during pregnancy.

• • Aspirin is safe and widely used in pregnancy for women with aPLs, even though evidence supporting its use in women with APS is controversial. However, it is effective in the prevention of preeclampsia.

• • Data to support the use of LMWH and aspirin for recurrent pregnancy loss in women with aPLs are lacking, despite early studies showing its benefit and widespread use.

• • The decision to use LMWH in pregnancy should be individualized with lifestyle factors and current clinical conditions factored in.

• • Prompt recognition and treatment of catastrophic APS with the use of steroids in combination with anticoagulation is critical.

• • Prepregnancy counseling is essential for all women with APS planning pregnancy. Once pregnant, they will require regular antenatal surveillance with a multidisciplinary team approach.

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Antiphospholipid syndrome in pregnancy

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1. A 28-year-old woman presents with a history of 2 first-trimester miscarriages and no live births. She is considering trying to become pregnant but is concerned about her risk for another miscarriage. Otherwise, her medical history is negative. You consider whether this woman has antiphospholipid syndrome (APS). Which of the following is part of the Sapporo criteria for the diagnosis of APS?

• □ A History of arterial thrombosis

• □ B At least 2 unexplained abortions at less than 10 weeks’ gestation

• □ C At least 2 previous pregnancies with significant intrauterine growth retardation

• □ D The presence of anticardiolipin antibodies on any blood sample

2. The patient has another miscarriage, this time in the second trimester, and is diagnosed with obstetric APS after laboratory testing. She still desires another pregnancy. Which of the following statements about the general care of women with APS considering pregnancy is most accurate?

• □ A Thrombotic APS has a better prognosis compared with purely obstetric APS

• □ B Treatment does not significantly improve the risk for recurrence of obstetric APS

• □ C Uterine artery waveforms should be assessed at 20-22 weeks’ gestation

• □ DWomen receiving low-molecular-weight heparin (LMWH) should be routinely assessed for antifactor Xa levels

3. The patient is now pregnant again. What should you consider in recommending treatment with aspirin for this woman with obstetric APS without a history of thrombosis?

• □ A She should not receive aspirin because it will not improve fetal outcomes

• □ B She should not receive even low-dose aspirin because of a high risk for fetal malformations

• □ C She should receive aspirin to prevent venous thromboembolism

• □ D She should receive aspirin to prevent preeclampsia and other negative pregnancy outcomes

4. What should you consider in prescribing this patient anticoagulation therapy?

• □ A LMWH will not help any outcome and should be avoided

• □ B LMWH should be avoided because of a higher risk of bleeding

• □ C The use of LMWH should be limited to the postpartum period

• □ D She should receive LMWH during the pregnancy as well as for 1 week postpartum

Notes

Anti-β2GP-I: β2 glycoprotein-I antibody; aPL: Antiphospholipid antibody.

Data taken from [22,23].

FGR: Fetal growth restriction; HELLP: Hemolysis, elevated liver enzymes and low platelets.

^†Clinical evidence of vessel occlusion needs to be confirmed; for example, renal involvement is defined by >50% rise in serum creatinine, severe hypertension (>180/100 mmHg) and/or proteinuria (>0.5 g/day).

aPL: Antiphosphlipid antibody; APS: Antiphospholipid syndrome.

Data taken from [62].