Pregnancy Management in Women with Antiphospholidic Syndrome

Abstract

The antiphospholipid syndrome (APS or Hughes Syndrome) is a systemic autoimmune disease characterised by the presence of specific and persistent circulating antiphospholipid antibodies (APL) and the subsequent morbidities they cause, including pregnancy complications and thrombosis.

The three main antiphospholipid antibodies are: lupus anticoagulant (LA); anticardiolipin antibodies (aCL) IgG and IgM; and anti-â2-glycoprotein 1 IgG and IgM antibodies. Antiphospholipid syndrome is associated with pregnancy complications such as recurrent early fetal loss, fetal death, preeclampsia (PE), and fetal growth restriction (FGR).

Although autoimmune disorders may have serious implication during pregnancy important advancements in pregnancy outcome have been reported in women with APL. The challenge arises in case of women refractory to conventional treatment (heparine/aspirin combination), which occurs in about 20-30% of cases. The management of pregnant women with non-criteria APS manifestations and that of APL carriers during their first pregnancy is also discussed. This paper aims to discuss the risk stratification, clinical and pregnancy implications and current treatment strategies for pregnant women.

Keywords:autoimmune disease, antiphospholipid syndrome, antiphospholipid antibodies, recurrent miscarriages, thrombosis.

I . APS DEFINITIONS AND THEIR EVOLUTION

The antiphospholipid syndrome (APS or Hughes Syndrome) is a systemic autoimmune disease characterised by the presence of specific and persistent circulating antiphospholipid antibodies (APL) and the subsequent morbidities they cause, namely pregnancy complications and reccurent thrombosis.

The three main antiphospholipid antibodies are:

1. anticardiolipin antibodies (aCL) IgG and IgM by ELISA;

2. anti-β2-glycoprotein 1 IgG and IgM antibodies by ELISA;

3. lupus anticoagulant (LA) which is determined by a three-step complex procedure.

It is recommended to detect the antibodies by using ELISA (enzyme-linked immunosorbent assay), which is known to be the most common and easy to perform method in daily clinical practice.

In 1975, Nilsson et al. described for the first time a possible connection between miscarriages and a circulating anticoagulant which was supposed to inhibit the action of thromboplastin (1). Almost 10 years later, after a comprehensive decade of study, Graham Hughes and his team proved the association between antiphospholipid antibodies and clinical manifestations such as arterial and venous thrombosis, livedo reticularis (Figure 1), strokes and obstetrical morbidities, emphasizing the fact that this conditition is different from lupus and should be regarded as a separate syndrome (2).

The preliminary classification criteria for APS were formulated in Sapporo, Japan, in 1998 (3), and were based on clinical manifestations (thrombosis or pregnancy morbidities) and laboratory findings (positive tests results for lupus anticoagulant or/and anticardiolipin – on more than two occasions, SIX weeks apart). These criteria were revised and updated in 2006, in Sydney, leading to two main modifications: anti-â2-glycoprotein 1 IgG and IgM were added to the laboratory criteria, while the six week previously required period between the two positive tests for APL was extended to 12 weeks (Table 1) (4).

Some ideeas regarding the above criteria should however be mentioned. For instance, the authors recommend that the classification of APS should be avoided if the positive aPL test and the clinical manifestations are separated by a period of less than 12 weeks or more than five years.

When it comes to laboratory criteria, investigators are advised to classify APS patients into one of the following categories:

I. More than one laboratory criteria are present (any combination)

IIa. LA alone is present

IIb. aCL antibody present alone and

IIc. Anti-β2 glycoprotein 1 antibody present alone.

This clasiffication is useful not only in studies, but also in stratifying the risk, as the presence of LA for example has repeatedly been considered to be the best predictor for pregnancy loss and thrombosis (4).

II. CLINICAL SPECTRUM OF APS

Asymptomatic carriers of antiphospholipid antibodies are those indiviuals who do not present vascular and obstetric disease despite their persistent positive titres of aPLs. There are some authors considering that these patients are at risk for future thrombosis and adverse pregnancy outcomes, despite the poor predictive value of positive aPL results. However, more concrete recommandations regarding their management can still be improved (see Treatment of patients with APS) (14).

APS with vascular/thrombotic events is most common form of clinical manifestation. Moreover, thromboses are considered to be one of the hallmarks of this disease, affecting not only the venous system but also the arterial bed, and leading to clinical features such as venous thrombosis, pulmonary embolism as well as strokes or transient ischaemic attacks (15)

Pregnancy morbidities represent the other hallmark and frequent manifestation of APS with recurrent miscarriages as leading complications. APS can also be the source of placental insufficiency, pre-eclampsia or late fetal death, as we shall discuss later.

However, obstetrical and thromboembolic complications can sometimes be found in the same patients with APS, especially due to the fact that the pregnancy itself represents a hypercoagulable condition.

The most severe form of APS is the Catastrophic APS (CAPS), which is a life-threatening disease defined by the presence of widespread intravascular thrombosis leading to multiorgan ischemia, failure and death, unless a rapid and aggressive treatment is initiated. Moreover, statistics show that almost half of the patients who develop CAPS do not have a history of aPL positivity, which could lead to a more difficult road to establish the diagnosis (16, 17). The mortality rate in this rare but severe presentation of APS has recently declined from 53% to 33%, thanks to the use of combined treatment strategies containing anticoagulation, glucocorticoids, plasma exchange, cyclophosphamide, intravenous immunoglobulins and anti-platelet agents (18).

One of the non-criteria but important APS manifestations is livedo reticularis (Figure 1), which is present in almost a quarter of patients and can be correlated with high risk of thrombosis (15). This is the reason why this clinical finding should raise suspicion of antiphospholipid syndrome.

Other non-criteria clinical manifestations of APS were analyzed too by an International Task Force in order to evaluate the quality of evidence of medical literature of each of the following items: superficial vein thrombosis, thrombocytopenia, renal microangiopathy, heart valve disease, livedo reticularis, migraine, chorea, seizures and myelitis. The purpose was to analyze these manifestations and to support their inclusion as APS classification criteria. The results showed that thrombocytopenia, APS nephropathy, valve heart lesions, livedo reticularis, chorea, longitudinal myelitis and seronegative APS are recommended to be included in the next revised APS criteria (19).

Some non-criteria manifestations of obstetric antiphospholipid syndrome have also been observed.

Clinical manifestations include:

- two unexplained miscarriages (<10th week of gestation)

- three non-consecutive unexplained miscarriages (<10th week of gestation)

- placental abruption and late premature birth (.34th week of gestation)

Laboratory manifestations refer to:

- low titre IgG/IgM anticardiolipin antibodies (between the 95th and the 99th percentile)

- low titre of IgG/IgM anti-b2 Glycoprotein I antibodies (between the 95th and the 99th percentile)

- intermittent IgG/IgM anticardiolipin and/or IgG/IgM anti-b2 Glycoprotein I antibodies and/or lupus anticoagulants, detected 6-12 weeks apart (20).

III. TO SCREEN OR NOT TO SCREEN. WHO SHOULD BE SCREENED FOR APS

The latest guidelines regarding the investigation of APS date back to 2012 and are about to be revised soon. According to these, women who have experienced reccurent spontaneous abortions, as well as patients with an unprovoked proximal deep vein thrombosis (DVT) or pulmonary embolism (PE) after discontinuing anticoagulation of at least seven days should be tested for APS. This also applies to adults under 50 years who have had a ischemic stroke (21).

Other authors suggest that there are two main clinical scenarios that should raise suspicion for APS: patients, especially the young ones, with one or more unexplained venous or arterial thrombotic events and women with at least one specific pregnancy morbidity including fetal death after 10 weeks of gestation, premature birth due to severe pre-eclampsia or placental insuffiency or multiple embryonic losses under 10 weeks gestation (22).

Additional findings such as cognitive deficits, white matter lesions, valvular heart disease or livedo reticularis should increase the suspicion for APS. Moreover, the presence of a systemic autoimmune disease, especially systemic lupus erythematosus, should also considerably increase the clinical suspicion (23)

Several laboratory abnormalities also have a potential diagnostic significance in the presence of the above described scenarios (thromboembolic events and obstetrical morbidities):

- a history of a false positive serologic test for syphilis

- the prolongation of a blood coagulation test (activated partial thromboplastin time aPTT-a false prolongation in fact)

-unexplained mild thrombocytopenia.

However, an elaborate discussion with the patient should help us identify other risk factors for thromboembolism, especially in older adult patients which have a low risk for APS, and should not be tested for APS (22, 24).

IV. RECOMMENDATIONS FOR WOMEN WITH APS, SLE AND APS (25)

In 2016, several EULAR (European League Against Rheumatism) recommendations for women with systemic lupus erythematosus and/ or antiphospholipid syndrome have been formulated using an evidence-based approach followed by expert consensus and regarding the following subjects: family planning, assisted reproduction, pregnancy and menopause. The experts were talking about several “unmet needs” in the management of reproductive and other women’s health issues that may impact on relationships and the decision to have children (26). The purpose of these recommendations was to help the phsysicians involved in the care of patients with APS and/or SLE, and to facilitate the communication between phsyician and patients

These recommendations reffer both to SLE and APS because the association of these conditions is relatively frequent: around 40% of patients with SLE have APS. Furthermore, it has been estimated that APS may develop in 50-70% of patients with SLE and positive aPL after 20 years of follow-up (27, 28).

When it comes to patients with primary APS, the situation is different, only few of them having the tendency to evolve, after a long period of time, into SLE. In 2015, Cervera et al. published the results of a multicentre prospective study of 1000 patients, regarding the morbidity and mortality in the APS during a 10-year period, and concluded that only eight patients diagnosed with primary APS developed anti-dsDNA antibodies during the 10 year-follow-up (29).

Preconception counselling and risk stratification

According to the author, family planning should be discussed from the first encounter between the patient and the rheumatologist/obstetrician. In women with APS as well as in those with SLE-associated APS, there are some risk factors that should be paid attention to (Table 2), as their presence will influence not only the monitoring plan before and during the pregnancy, but also the therapeutic attitude (25).

Contraceptive measures

Contraceptive measures should be taken into account by women with SLE and/or APS, especially in order to prevent unwanted pregnancies during high disease activity periods and during intake of teratogenic drugs. The presence of general risk factors such as hypertension, obesity, tobacco use or family history of hormonal-dependent cancers should also be attentively searched for, as well as disease-related risk factors (disease activity and thrombotic risk-the titres of aPLs).

Authors concluded that the intrauterine device (IUD) can be recommended to all patients, unless gynaecological contraindications exist. To be more specific, copper IUD cand be used by any patient, while levonorgestrel-containing IUD should be considered only if the benefits of the related hormone outweigh the risk of thrombosis (32). A recent systematic review concluded that the levonorgestrel IUD does not increase the risk of deep vein thrombosis and pulmonary thrombembolism (33).

When it comes to women with positive aPL and contraception with combined hormones such as oral pill, vaginal ring or transdermal patch, some precautions should be taken. Actually the use of these contraceptions methods should be discouraged not only in patients with definite APS, but also in women with positive aPL. Studies have shown that the use of the combined pill in young women with myocardial infarction or ischaemic stroke and positive lupus anticoagulant, increases the risk of arterial events in comparison to non-users (34).

Women with a low-risk aPL profile but fully anticoagulated can benefit from estrogens in order to treat gynaecological disorders that can not be managed otherwise. They cand also benefit from compounds containing progestin (pill, subcutaneous depot injectios), with the caution that their use should be weighed against the risk of thrombosis. The emergency progestin-based pill is not contraindicated in patients with SLE and/ore APS (35, 36) .

Fertility issues

Statistics show that there is no concrete evidence that APS or SLE decrease fertility (37, 38).

However, problems can occur in women who use immunosuppressive drugs such as alkylating agents (cyclophosphamide), which can cause menstrual irregularities and even lead to premature ovarian failure (39, 40). For this reason, experts decided that fertility preservation methods (GnRH analogues) should be considered for all menstruating women who are going to receive alkylating agents (41).

Assisted reproduction techniques (ARTs) – ovulation induction therapy and in vitro fertilisation in women with SLE and APS

Studies show that efficacy of these methods in terms of pregnancy rate is similar to that in the general population (up to 30%).These procedures are more likely to be successful if an appropriate antithrombotic treatment is prescribed for aPL positive women (42). Experts recommend the same treatment as during pregnancy, according to the individual risk profile (see Treatment of obstetrical APS). To be more specific, low-dose aspirin and/or low molecular weight heparin (LMWH) could be recommended. The authors also suggest that low-dose aspirin should be stopped three days before egg retrieval and resumed the the following day, while patients taking LMWH are advised to stop it at least 12 hours prior to the procedure and to resume it the same day (if there is no bleeding complication) (43).

Pregnancy monitoring

Women with SLE and/or APS should be followed up like those who present a high risk for hypertensive disorders and/or placental insuffiency. The purpose of the monitoring is to identify an eventually placental insuffiency with fetal growth restriction and to decide the best timing for delivery in order to reduce the risk of perinatal morbidity and mortality (44, 45). These patients should not only perform routine ultrasonograhic screening (first trimester: 11-14 weeks of gestation, second trimester (with Doppler, preferably at 20-24 weeks of gestation) but also supplementary fetal monitoring in the third trimester at monthly intervals (middle cerebral, umbilical and uterine arteries Doplper sonography to identify signs of intrauterine growth restriction, non-stress test and biophysical profile) (46, 47).

Specific attention is given to patients with positive anti-Ro/SSA or anti-La/SSB antibodies, as their presence is associated with fetal congenital heart block (CHB). The risk for CHB in women with no previous CHB is low (0,7-2%) but increases to almost 16% reccurence rate in women with a previously affected child. For this reason, fetal echocardiograms has been proposed by some to be performed weekly from 16 weeks of gestation onward (48, 49). Specific treatment in pregnancy Although the use of hydroxycloroquine (HCQ) in women with SLE is highly recommended not only preconceptionally but also throughout pregnancy (50), there is insufficient data to prescribe it to patients with APS, despite it’s beneficial role that has already been suggested (51). Furthermore, HCQ is known to reduce the risk of congenital heart block in women with positive anti-RO/SSA antibodies, especially in women who already have a child with this condition (52). For women with obstetrical APS many recommendations are formulated, regarding for instance low-dose aspirin (LDA), which should preferably be given before conception or no later than gestational week 16 (53). Furthermore, the double-therapy with LDA and low molecular weight heparin has proved to be more efficient in decreasing the risk of adverse pregnancy outcomes than the mono-therapy. As it will be later discussed (see treatment), this recommendation applies to women with positive aPL but with no definite classification of APS too, as long as they are considered at moderate to high risk of maternal and fetal complications. (see Table 2) (54, 55). In patients with refractory obstetric APS, history of thrombosis (especially cerebrovascular events) or triple aPL positivity, several therapies such as intravenous immunoglobulin, plasmapheresis or prednisolone 10 mg/day in the third trimester can be considered (56).

Menopause and hormone replacement therapy

The guidelines suggest the use of hormone replacement therapy (HRT) should be attentively weighted against thrombotic and cardiovascular risks when it comes to women with APS. These therapies should only be prescribed for the shortest possible period and if the menopause symptoms are severe enough (57).

HPV vaccination

Venous thromboembolic events (VTEs) associated with the quadrivalent HPV vaccine have been reported, but 90% of the patients had a known risk factor for VTE (58). According to the EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases, HPV vaccination should be reserved to young women with stable or inactive SLE and/or APS, with particular attention for those with high-risk aPL profile (59).

V. TREATMENT AND MANAGEMENT OF WOMEN WITH APS

1. Treatment of aPL carriers during the first pregnancy

A common challenge that the clinicians have to face is to decide if and what prophylactic therapy to use during the patient’s first pregnancy. Unfortunatelly, this decision is based only on personal experience and expert opinion because there are insufficient studies evaluating the influence of various treatments in this patients. Moreover, there is a systematic review regarding the effect of low-dose aspirin (LDA) on preventing obstetric complications in aPL carriers but the authors discovered that there is no evidence showing that aspirin was superior to placebo in preventing unfavourable obstetrical outcomes (20, 60). On the other hand, a meta-analysis by Arnaud et al. concluded that LDA prevents arterial but not venous events in asymptomatic aPL carriers (61). The treatment with LDA is also recommended by the 13th Congress of Antiphospholipid Antibodies Task Force when it comes to carriers with a highrisk aPL profile (see Table 2) (62). Furthermore, these patients should be carefully screened for other cardiovascular conditions, as in these situations as well as during surgery or hospitalisation, with LMWH may be considered (63).

A special recommendation is reserved to women with SLE and positive aPL, but with no previous thrombotic events or pregnancy morbidity and it refers to the association between hydroxychloroquine and LDA. The individual risk assessment depending on aPL profile is very important in these situations, during pregnancy some cases may require LMWH in prophylactic dose (30).

2. Management of pregnant women with non-criteria APS manifestations

Many retrospective and prospective studies demonstrate that the non-criteria clinical and laboratory manifestations of obstetric APS (see above: clinical spectrum of APS) have a very important role in clincal practice (64-67). Furthermore, we should pay attention to the fact that the international consensus criteria for APS classification were not intended to be used for diagnostic purposes but to improve standardization in studies and clinical trials (20).

However, studies including women with noncriteria clinical manifestations described no statistically significant differences in pregnancy outcomes during heparin + LDA treatment between women with obstetric APS, as defined by the International consensus criteria, and women with clinical non-criteria (67).

In 2006, Rai et al. suggested that persistently weak aCL titres (<99th percentile) in untreated women with reccurent miscarriage lead to fetal loss in more than 90% of the cases (68). The results of further prospective and retrospective studies concluded that low-titer aCL and/or antibeta2GPI antibodies are clinically significant in women with pure obstetric APS, while an international registry reported the same pregnancy outcomes in women with complete and incomplete laboratory APS classification criteria treated with conventional heparin+LD therapy during pregnancy (20, 67).

3. Management of pregnant women with APS and previous pregnancy morbidities

The most frequently recommended treatment in such patients contains LDA and heparin and leads to a live birth rate of up to 70-80% of cases (69).Their association has proved to be more efficient than the monotherapy with LDA, in two randomized clinical trials (70, 71) 140 women with a history of recurrent miscarriages and persistent aPL positivity were randomised to treatment with LDA alone or LDA in combination with heparin, resulting in a higher rate of live births for women receiving the double-therapy. Other studies (72-74) were focused on the therapy with unfractionated heparin versus therapy with LMWH and concluded that the last one is a better option, since it has a more predictable pharmacokinetics and is associated with less heparin-induced osteopenia, thrombocytopenia and bleeding.

However, there are some differences regarding the LMWH dosage (Table 3). Some authours suggest that in women with previous miscarriage and positive aPL, LDA+ LMWH in prophylactic dose should be prescribed, whereas LDA and LMWH in intermediate or full therapeutic dose should be reserved to those with history of late fetal loss/pre-eclampsia or FGR and positive aPL (30).

4. APS women with previous thrombosis +/- pregnancy morbidity

The most frequently prescribed treatment in women with APS and previous thrombosis+/- pregnancy morbidity is LDA+ therapeutic dose of heparin. However, many authors consider that the double-therapy is not effective enough in preventing fetal or maternal complications in this type of patients. Some studies even concluded that thrombotic events have been noted in up to 26% of treated patients (76) , which suggests the fact that patients with thrombotic APS have a more agrresive disease form. This is the reason why scientists are convinced that APS patients with a history of thrombosis should also receive additional treatments in association with conventional therapy in order to reduce pregnancy morbidities and to raise the live birth rates. Additional treatments that were analyzed include intravenous immunoglobulin infusions, plasma exchange and low-dose steroids (77).

5. APS treatment in women with high risk or refractory to conventional therapy

The idea of stratifying the risk in APS patients was introduced by the consensus statement of the classification criteria for definite APS and it is based on laboratory and clinical features (4). As we have alredy discussed above (see Classification criteria for APS), multiple aPL positivity is associated with a more severe course of the disease. Furthermore, several studies have proved that some specific aPL profiles are connected to a higher risk of poor pregnancy outcomes or to patients being refractory to conventional therapy (Table 4) (20).

The ideal management of women who are at high risk or refractory to treatment is still an important challenge. In addition to conventional therapy including LMWH in therapeutic dose and LDA, some other drugs can be used: intravenous immunoglobulines, low-dose steroids, plasma exchange and hydroxychloroquine. Many studies have proved the positive effects of the association between IVIG and the conventional therapy (78-80). However, the use of IVIG infusion remains limited, not only because of insufficient reported data regarding dosing or timing of administration, but also due to its high costs.

Steroids represent a therapeutic possibility because inflammatory changes and complement system activation are known to cause disorders in trophoblast invasion and placentation (81). There are studies showing that low doses of steroids (10 mg/day) combined with the conventional therapy from the moment a pregnancy test resulted positive and until the 14th week of gestation, lead to encouraging results in refractory APS women with previous pregnancy morbidity. These positive effects have not been observed in women suffering from previous thromboembolism or in those with triple aPL positivity (82).

Plasma exchange and other aphaeresis procedures (extracorporeal blood purification, immunoadsorption procedures) have been described only in case reports and case series and resulted in lower levels of aPL. Their efficacy is difficult to assess, as they have always been administered in addition to other treatments including steroids and/or IVIG. However, in each of the cases their use has been associated to a live birth ranging between 71,4% and 100% of cases (83-85). The efficacy of HCQ has been proved (86, 87) in several studies which reported fewer pregnancy losses in the treated group (88, 89). Furthermore, its reputation for being a safe drug makes it a commonly prescribed drug in refractory patients. Other advantages of HCQ are: easy oral administration, availability in most centers and its low cost (86). These are some of the available second-line therapies in APS treatment. However, at the moment there are no concrete guidelines for the treatment of refractory APS and not even for conventional therapy. Further efforts need to be done by the experts in order to elaborate clear evidence-based recommentations for women with obstetrical APS.

6. Treatment perspectives in APS

As already discussed above, the current available treatments have improved pregnany outcomes to a live birth of over 70% which means that 30% of women continue to have pregnancy complications. This is the reason why further treatments need to be developed in the treatment of obstetrical APS (90). Pravastatin (20 mg), for example, has been studied on small groups of women that were already receving the conventional double-therapy. The results showed great improvement regarding signs of pre-eclampsia such as proteinuria or elevated blood presure, whereas the signs of placental insuffiency remained stable, without further deterioration, compared to the control group (91). The involvement of complement activation has already been associated with aPL-related pregnany morbidities. As a result, some authors mention eculizumab as a potential target for APS therapy. Although several case reports have described the successful use of eculizumab in severe cases of APS such as CAPS or APS and thrombotic microangiopathy, its potential role still needs to be investigated (92, 93).

Many authors have focused on the immunemodulator hydroxycloroquine, supposing that its association with the conventional treatment will improve aPL-related adverse pregnancy outcomes. Unfortunately, current data to suggest a role of HCQ in these patients is inadequate. In 2017, a very important randomized control study has been initiated (HYPATIA study), aiming to provide an evidence-base for the decision to use HCQ in women with APS (94).

7. Treatment in the post-partum period

Some authours consider that the same treatment as during pregnancy should be continued during 6-12 weeks post-partum, but concrete recommendations regarding the treatment after the postpartum period are still awaited (30). There are many prospective and retrospective studies showing that women with obstetric APS are at higher risk not only for venous thromboembolism and ischaemic cerebrovascular disease, but also for future pregnancy complications (95, 96). Hovever, their aPL profile should be carefully analyzed postpregnancy, and in the case of persistent triple positivity or positive LA, a form of anticoagulation should pe considered (30).

VI. DISCUSSIONS

The antiphospholipidic syndrome is considered to be one of the main acquired prothrombotic conditions and the most frequent acquired risk factor for a treatable cause of recurrent pregnancy loss (97).

The outcome of pregnancies in women with APS has a lot to do not only with simultaneous risk factors but also with the presence of an adequate treatment. To be more specific, more than 70% of pregnant women with APS will deliver a viable live infant with proper management (98). For this reason and not ony it is paramount to identify women who are at risk of having this disease. Several clinical scenarios and features have been discussed above (see To screen or not to screen) with the purpose of raising suspicion in such situations.

However, the biggest challenge for the physician is the moment when a certain treatment must be prescribed. At this moment, specialists sometimes have to wisely choose beetween non treating a pregnant woman with APS and prescribing off-label therapies. However, pregnancy outcomes in women with aPL have greatly improved over the last twenty years, due to the use of LDA and LMWH. Clear recommendations based on randomized control trials still have to be elaborated, as well as the results of the currently on-going studies regarding prospective treatments such as HCQ, IVIG and apheresis techniques.

Conflicts of interest: none declared.

Financial support: none declared.

FIGURE 1.

Livedo reticularis

TABLE 1.

Revized classification criteria for APS. (Adapted from the revised classification criteria for antiphospholipidic syndrome) (4)

TABLE 2.

Risk factors in women with APS +/- SLE based on (25)

TABLE 3.

Doses of heparins in pregnancy (75)

TABLE 4.

Doses of heparins in pregnancy (75)