Alana B. Levine1 and Michael D. Lockshin1
(1)
Division of Rheumatology, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021, USA
Alana B. Levine
Email: levinea@hss.edu
Historical Perspective
The earliest investigations of antiphospholipid syndrome (APS) took place in 1906 when Wasserman et al. described autoantibodies in the sera of patients with syphilis [1]. This led, in 1941, to a more sophisticated understanding of the association between the false-positive test for syphilis and a substance in beef heart extract (later described as cardiolipin) [2], and a description of the “biological false positive test for syphilis” in 1952 [3]. Reports of women with adverse pregnancy outcomes found to have “circulating anticoagulant” were first published in 1954 [4] and 1969 [5], and later further described in 1980 [6]. A comprehensive review of the seminal reports that have contributed to our understanding of obstetric APS is available [7].
Pathogenesis of Adverse Pregnancy Outcome
Animal studies have elucidated the pathogenic role antiphospholipid antibodies (aPL) play in pregnancy complications. When aPL from women with histories of fetal loss were introduced into pregnant mice, adverse pregnancy outcomes, including lower fecundity rate, increased resorption of embryos, lower number of embryos per pregnancy, and lower mean weights of embryos and placentae, were seen when compared to mice injected with control immunoglobulin [8–10].
Various pathways have been implicated in the pathogenesis of obstetric APS. Early theories focused on thrombosis in the uteroplacental circulation as the causative mechanism [11–13]. Antiphospholipid antibodies have been shown to reduce the levels of trophoblast-associated annexin A5, resulting in placental villus thrombosis [14, 15]. These antibodies were also shown to increase monocytic expression of tissue factor in mouse models [16].
Because not all affected placentas have signs of thrombosis or infarction, other models invoking inflammatory (as opposed to thrombotic) mechanisms have been considered. These include activation of complement [17–20], decreased levels of interleukin-3 (IL-3) [21], and a direct effect of aPL on the human placental trophoblast [22]. One proposed mechanism for the genesis of preeclampsia in aPL-positive patients invokes defective regulation of the complement system, allowing for excessive complement activation which leads to abnormal placental development, placental damage, generalized endothelial activation, and release of antiangiogenic factors toxic to glomerular endothelium and liver sinusoids [23].
Epidemiology
The lack of adequate standardized assays and variable interpretations of antibody titers have made estimating the prevalence of aPL a challenging task. Antiphospholipid antibodies are detectable in up to 5 % of asymptomatic individuals and, as with other autoantibodies, become increasingly common with increasing age [24]. Their prevalence in women with uncomplicated pregnancies ranges from 0.3 to 7 % [25–30].
Antiphospholipid antibodies are more commonly detected in patients with systemic autoimmune diseases, particularly systemic lupus erythematosus (SLE) [31], than in the general population. The frequency of aPL in SLE patients is approximately 30 % [31]. As many as 50 % of SLE patients with a lupus anticoagulant (LAC) will go on to develop APS [32]. Antiphospholipid antibodies may also be seen in association with a wide variety of infections, including viral hepatitis, Lyme disease, Chagas disease, and leprosy [33–39]. They are also associated with medications (such as antiepileptic drugs, amoxicillin, oral contraceptives, and propranolol) [40] and malignancies [41]. When seen in these contexts, aPL are typically transient and are infrequently associated with thrombosis.
Classification Criteria for APS
The classification criteria for APS were first outlined in Sapporo, Japan in 1999 and subsequently updated in 2006 [42, 43]. These criteria were developed for research purposes but are helpful both in making the diagnosis and in preventing the overdiagnosis of APS. According to these guidelines, a definite diagnosis of APS is made when at least one clinical criterion and one laboratory criterion are met (Table 6.1) [43].
Table 6.1
Revised Sapporo classification criteria for antiphospholipid syndrome (adapted from Miyakis et al. [43])
|
Clinical criteria |
|
1. Vascular thrombosisa |
|
One or more clinical episodesb of arterial, venous, or small vessel thrombosisc, in any tissue or organ |
|
2. Pregnancy morbidity |
|
(a) One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, or |
|
(b) One or more premature births of a morphologically normal neonate before the 34th week of gestation because of eclampsia, severe preeclampsia, or recognized features of placental insufficiencyd, or |
|
(c) Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded |
|
Laboratory criteria e |
|
1. Lupus anticoagulant present in plasma, on two or more occasions at least 12 weeks apart, detected according to the guidelines of the International Society on Thrombosis and Haemostasis |
|
2. Anticardiolipin antibody of immunoglobulin IgG and/or IgM isotype in serum or plasma, present in medium or high titer (>40 GPL or MPL, or >99th percentile), on two or more occasions at least 12 weeks apart, measured by a standardized enzyme-linked immunosorbent assay (ELISA) |
|
3. Anti-β2-glycoprotein-I antibody of IgG and/or IgM isotype in serum or plasma (>40 GPL or MPL, or > 99th percentile), on two or more occasions at least 12 weeks apart, measured by a standardized ELISA |
|
Definite APS is present if at least one of the clinical criteria and one of the laboratory criteria are met. Classification of APS should be avoided if fewer than 12 weeks or more than 5 years separate the positive antiphospholipid antibody test and the clinical manifestation. In studies of populations of patients who have more than one type of pregnancy morbidity, investigators are strongly encouraged to stratify groups of subjects according to (a), (b), or (c) above |
From Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome. J Thromb Haemost. 2006;4:295–306
aCoexisting inherited or acquired factors for thrombosis are not reasons for excluding patients from APS trials. However, two subgroups of APS patients should be recognized, according to: (a) the presence and (b) the absence of additional risk factors for thrombosis. Indicative (but not exhaustive) of such cases include: age (>55 in men, and >65 in women), and the presence of any of the established risk factors for cardiovascular disease (hypertension, diabetes mellitus, elevated LDL or low HDL cholesterol, cigarette smoking, family history of premature cardiovascular disease, body mass index ≥30 kg/m2), microalbuminuria, estimated GFR <60 mL/min), inherited thrombophilias, oral contraceptives, nephrotic syndrome, malignancy, immobilization, and surgery. Thus, patients who fulfil criteria should be stratified according to contributing causes of thrombosis
bA thrombotic episode in the past could be considered as a clinical criterion, provided that thrombosis is proved by appropriate diagnostic means and that no alternative diagnosis or cause of thrombosis is found
cSuperficial venous thrombosis is not included in the clinical criteria
dGenerally accepted features of placental insufficiency include an abnormal or non-reassuring fetal surveillance test (e.g., nonreactive non-stress test) suggestive of fetal hypoxemia, an abnormal Doppler flow velocimetry waveform analysis suggestive of fetal hypoxemia (e.g., absent end-diastolic flow in the umbilical artery), oligohydramnios (e.g., an amniotic fluid index ≤5 cm), or a postnatal birth weight less than the tenth percentile for the gestational age
eInvestigators are strongly advised to classify APS patients in studies into one of the following categories: I, more than one laboratory criteria present (any combination); IIa, LA present alone; IIb, aCL antibody present alone; IIc, anti-β2 glycoprotein-I antibody present alone
Clinical criteria include thrombotic and/or pregnancy events with the following definitions: (1) one or more episodes of arterial, venous, or small vessel thrombosis in any organ or tissue, with unequivocal evidence (by imaging or histologic) of thrombosis; (2) one or more unexplained deaths of a morphologically normal fetus at or beyond 10 weeks of gestation or one or more premature births of a morphologically normal neonate before 34 weeks of gestation due to eclampsia, severe preeclampsia, or placental insufficiency or three or more consecutive unexplained spontaneous pregnancy losses before 10 weeks of gestation without other explanation (chromosomal, anatomic, or hormonal abnormalities).
Laboratory criteria include persistently positive aPL on at least two occasions 12 weeks apart as demonstrated by at least one of the following: (1) anticardiolipin antibody (aCL) IgG and/or IgM in moderate or high titer (>40 units GPL or MPL or >99th percentile for the testing laboratory), (2) anti-β2-glycoprotein-I (aβ2GPI) antibody IgG and/or IgM in moderate or high titer (>40 units GPL or MPL or >99th percentile for the testing laboratory), and/or (3) LAC activity detected according to published guidelines [44, 45].
Clinical Manifestations of APS
The clinical manifestations of APS can be divided into pregnancy-related and vascular thrombotic events. Adverse obstetrical outcomes associated with APS include recurrent early pregnancy loss, fetal demise, intrauterine growth restriction (IUGR), pregnancy-related maternal thromboembolic disease, early and severe preeclampsia/eclampsia, hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome, and catastrophic antiphospholipid syndrome (CAPS). Vascular thrombotic events may be venous, arterial, or microvascular and can result in deep vein thrombosis (DVT), pulmonary embolism (PE), or stroke. A variety of associated non-criteria complications are also described, including livedo reticularis, thrombocytopenia, and valvular heart disease. Individual patients may have experienced one or more of these complications; therefore, each patient’s situation should be considered unique.
Obstetric Manifestations of APS
Definitions of Pregnancy Loss
The imprecise terminology used to define adverse pregnancy outcomes in APS has resulted in inconsistencies in the literature, with varied definitions amongst studies. Here we define pregnancy loss at different gestational ages as follows:
Abortion is spontaneous or elective delivery of a pregnancy before 20 weeks of gestation; spontaneous loss after 20 weeks gestation is defined as stillbirth. An abortion through the end of the fourth week of gestation is referred to as pre-embryonic loss while an abortion occurring between the fifth and ninth week is an embryonic loss. Fetal demise is defined as an intrauterine death after 10 weeks of gestation. Recurrent pregnancy loss (or recurrent abortion) is defined as three or more consecutive spontaneous abortions in the same patient.
Recurrent Early Pregnancy Loss
The association of aPL with recurrent pregnancy loss prior to 10 weeks of gestation is controversial. Due to the high rate and numerous possible causes of first trimester loss (including chromosomal anomalies, maternal endocrinopathies, or abnormalities of uterine anatomy), a causal relationship between aPL and recurrent early loss has been difficult to establish; as Macklon et al. noted, more than 30 % of clinically recognized pregnancies end before completion of the first trimester, with the majority of those losses caused by fetal chromosomal abnormalities [46].
Several studies support the link between aPL and early losses [47–50], while others have failed to define this association [51, 52]. A systematic review of 25 publications found significant associations between both aCL (OR 3.40; 95 % CI 1.33–8.68) and LAC (OR 2.7; 95 % CI 1.03–8.56) and recurrent loss before 10 weeks gestation [49]. A prospective study followed 20 aPL-positive women with a history of at least two first trimester losses (exact number of gestational weeks not defined) who declined treatment in their next pregnancy; 90 % of these women had miscarriages compared to 34 % of aPL-negative control patients with recurrent miscarriage of unknown etiology [50]. In another report, LAC was found to be strongly associated with loss before 10 weeks gestation, while aβ2GPI positivity was not clinically relevant [47]. Conversely, Roque et al. failed to find an association between maternal thrombophilias, including aCL, and embryonic loss in a cohort of 491 patients with a history of adverse obstetric outcomes [51].
Some literature actually suggests that maternal thrombophilias, including aPL, confer protection against early loss [51]. In the case of aPL, this may be related to the low oxygen environment of early pregnancy which prevents exposure of aPL to the uteroplacental circulation [53, 54].
Fetal Demise/Death
The association of aPL with recurrent fetal demise has been well described [48–50, 55, 56]. A 2006 meta-analysis investigating the relationship between aPL and recurrent fetal loss demonstrated a strong association with both LAC (OR 7.79, 95 % CI 2.30–26.45) and moderate to high titer aCL IgG (OR 4.68, 95 % CI 2.96–7.40), but no association with aβ2GPI [56]. Robertson et al. showed a significant association between aCL and late pregnancy loss (OR 3.30, 95 % CI 1.62–6.70) [49]. A retrospective analysis of aPL-positive women with a history of two or more pregnancy losses found that 50 % of those losses had been fetal deaths, compared to only 15 % of losses to aPL-negative women, suggesting that fetal death is more characteristic of aPL-related loss than early miscarriage [55].
To better understand the relationship between aPL and late fetal demise, the National Institutes of Health (NIH)-sponsored Stillbirth Collaborative Research Network sought to determine the frequency of immunoassay aPL in this population. This large, multicenter, population-based study includes over 650 women with stillbirth from five ethnically and geographically diverse catchment areas in the USA who were enrolled between March 2006 and September 2008. Of the 190 women who were tested for LAC, 3.2 % had a positive result, while 4.8 % of the 458 women tested for aCL had a positive result [57]. Given the aPL prevalence of up to 5 % in the general population, and the lack of a control group in this study, the significance of this finding is unclear.
Intrauterine Growth Restriction
IUGR (also known as fetal growth restriction) describes a fetus that has not reached its growth potential because of genetic or environmental factors. Definitions vary among studies, some considering IUGR to have occurred if the fetus weighs less than the tenth percentile, while others use less than the fifth percentile. While the rate of IUGR in the general population is approximately 10 %, the frequency ranges from 3 to 30 % in APS patients [58–60]. An association of aCL with IUGR has been suggested. In a prospective study of 860 Japanese women, Yasuda et al. found a strong association between IUGR and aCL (OR 6.91, 95 % CI 2.70–17.68) [61]. Another study of mothers of fetuses with IUGR found that one third of those women had aCL; none had LAC [62].
Pregnancy-Related Maternal Thromboembolic Disease
Pregnancy and the puerperium are risk factors for thrombosis, independent of the presence of thrombophilia. Women with APS are at greater risk for pregnancy-related thrombosis than the general population with an incidence of 5–12 % [59, 60]. Women without LAC or with low levels of aCL are at lower risk for thrombosis [63].
Early and Severe Preeclampsia/Eclampsia
Severe preeclampsia at or before 34 weeks of gestation is one of the clinical criteria used to define APS. The incidence of preeclampsia in APS patients ranges from 18 to 48 %, and studies of patients with preeclampsia show significant levels of aPL in 11.7–17 % of subjects [48].
In a meta-analysis, do Prado et al. found an association between aCL and preeclampsia (pooled OR 2.86, 95 % CI 1.37–5.98); this association was strengthened by selecting for subjects with severe preeclampsia (pooled OR 11.15, 95 % CI 2.66–4.75) [64]. A systematic review demonstrated a similar relationship between both mild and severe preeclampsia and aCL, with an odds ratio of 2.73 (95 % CI 1.65–4.51) [49].
In a study of 860 pregnant women, severe preeclampsia (defined by published guidelines [65]) occurred more frequently in aCL-positive women (RR 22.2, 95 % CI 5.27–93.5). A more recent study of 56 women with severe preeclampsia (defined as diastolic blood pressure greater than 110 mmHg and proteinuria >3 g per 24-h collection period) found positive aPL in 19.6 % of subjects, with a higher rate in women with onset of preeclampsia before 34 weeks of gestation [66].
Despite its inclusion in the APS diagnostic criteria, some authors have suggested a weaker association between preeclampsia and APS, with particular skepticism about its association with mild or term preeclampsia [67–69].
HELLP Syndrome
A number of reports describe HELLP syndrome in pregnant APS patients [70–73]. Nausea, vomiting, and abdominal pain may be early signs of impending danger, and infarcts of the liver, spleen, kidneys, and other organs of tissues may occur. This syndrome can be considered on the severe end of the preeclampsia spectrum, is likely associated with CAPS, and may also occur following delivery [74].
Non-obstetric Manifestations of APS
Vascular Thrombosis
Vascular thrombotic events are defined as one or more clinical episodes of arterial, venous, or small vessel thrombosis, in any tissue or organ [43]. Venous thrombosis occurs more commonly than arterial thrombosis. DVT of the calf is most common, but other sites include veins of the upper extremities and vena cava; renal, hepatic, retinal veins; and cerebral sinus thrombosis. Arterial thrombosis of the cerebral, coronary, renal, and mesenteric arteries can result in stroke, myocardial infarction, and infarcts of the kidneys and gut, respectively. Microvascular thrombosis of the kidney, also known as thrombotic microangiopathy, may occur and causes a spectrum of disease including asymptomatic proteinuria, marked hypertension, end-stage renal disease, and renal failure.
Thrombosis must be confirmed by objective validated criteria, i.e., unequivocal findings of appropriate imaging studies or histopathology. For histopathologic confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall (which would suggest vasculitis). In making the diagnosis of APS, superficial venous thrombosis does not qualify as a thrombotic event.
Catastrophic Antiphospholipid Syndrome
CAPS is a rare event occurring in fewer than 1 % of APS patients [31]. This syndrome results in widespread thrombotic disease and multiorgan failure. Criteria include (1) evidence of involvement of three or more organs, systems, and/or tissues; (2) development of manifestations simultaneously or in less than a week; (3) confirmation by histopathology of small vessel occlusion in at least one organ or tissue; and (4) laboratory confirmation of the presence of aPL [75]. CAPS has a high mortality rate of approximately 50 %, even when patients are treated with anticoagulation and aggressive immunosuppression [76].
Non-criteria Manifestations
APS can cause a wide variety of clinical manifestations that are not included in the classification criteria [77]. These include thrombocytopenia, hemolytic anemia, livedo reticularis, cardiac valve disease and intracardiac thrombi, non-stroke central nervous system disease (cognitive dysfunction, hyperintense non-enhancing white matter lesions on brain MRI), and a renal lesion known as thrombotic microangiopathy. Rarely, these manifestations can occur in pregnancy.
Laboratory Considerations
Antiphospholipid antibodies are immunoglobulins directed against phospholipid-binding plasma proteins. LAC, anticardiolipin, and anti-β2-glycoprotein-I antibodies are known to play a role in thrombotic and pregnancy events. Formal definitions for these tests exist [44, 45].
Lupus Anticoagulant
Of note, the name “lupus anticoagulant” is misleading. While LAC is frequently seen (and was first identified) in lupus patients, many patients with LAC do not actually carry a diagnosis of lupus. In addition, LAC-positive patients are, in fact, more likely to develop thromboses in spite of the name “anticoagulant,” a term derived from its in vitro but not in vivo function.
LAC is a heterogeneous population of immunoglobulins (IgG, IgM, and IgA) that interferes with one or more phospholipid-dependent tests of in vitro coagulation, including the activated partial thromboplastin time (aPTT), kaolin clotting time (KCT), dilute Russell viper venom time (DRVVT), and dilute prothrombin time (dPT). Two or more of these tests should be used to screen for LAC, followed by a mixing study to confirm the presence of an inhibitor in the patient’s plasma (as opposed to a factor deficiency). Finally, confirmatory testing is performed by increasing the concentration of the phospholipid in the screening test (or tests) that was abnormal.
The results of the LAC are unreliable in patients being treated with anticoagulants due to the risk of false-positive results [78–80], although some believe LAC activity can be accurately detected in patients taking warfarin if the international normalized ratio (INR) is less than 3.5 [43].
Anticardiolipin and Anti-β2-Glycoprotein-I Antibodies
Anticardiolipin antibodies (aCL) and anti-β2-glycoprotein-I (aβ2GPI) antibodies of the IgG, IgM, and IgA isotypes are detected using either the solid phase immunoassay or enzyme-linked immunosorbent assay (ELISA). The main antigenic target of these antibodies is β2-glycoprotein-I (β2GPI), a cationic plasma protein that binds phospholipid cell membranes. Antibodies should be present in moderate to high titer (≥40 units or >99 % for all isotypes) to be considered “positive” [43].
Other Antibodies
Other antiphospholipid antibodies, including those directed against prothrombin, annexin A5, phosphatidylserine, and phosphatidylinositol, have been described as playing a role in the pathogenesis of APS. However, these tests have not been standardized against clinical populations or by international criteria committees and their clinical and prognostic significance is not clearly understood [81].
Type of aPL and Risk
Certain subtypes of aPL seem to impose a greater risk of pregnancy complications than others. It was long believed that “triple positivity,” i.e. the simultaneous presence of LAC, aCL, and aβ2GPI in the same woman, conferred the worst prognosis [82, 83], and it has been suggested that aCL is the most sensitive assay to predict fetal distress or death [84]. More recent reports contend that LAC alone portends the greatest risk, independent of the presence of aCL or aβ2GPI [58].
The PROMISSE study (Predictors of PRegnancy Outcome: BioMarkers In Antiphospholipid Syndrome and Systemic Lupus Erythematosus) is a large, multicenter observational study on pregnancies of patients with APS, SLE, or both, compared to healthy controls. Pregnancy outcomes of 144 aPL-positive patients have been described [58]. Adverse outcomes, defined as fetal death at ≥12 weeks, neonatal death, preterm delivery before 34 weeks due to gestational hypertension, preeclampsia, or placental insufficiency, or fetal size <5th percentile, occurred in 28 women. Of LAC-positive women, 39 % had adverse pregnancy outcomes, compared with only 3 % of LAC-negative women. Of women with moderate to high titer IgG aCL, 43 % who were also LAC positive had adverse outcomes, whereas complications occurred in only 8 % of women without LAC. IgM aCL, IgG aβ2GPI, and IgM aβ2GPI did not independently predict adverse pregnancy outcome [58] (Table 6.2).
Table 6.2
Adverse pregnancy outcome in aPL-positive patients, according to demographic, clinical, and serologic characteristics at the first study visit (adapted from Lockshin et al. [58])
|
Characteristic |
All patients with aPL (n = 144)a |
Patients with aPL and adverse pregnancy outcome (n = 28 [19 %])b |
P |
|
Demographic |
|||
|
Race |
0.11 |
||
|
White |
117 |
26 (22) |
|
|
Nonwhite |
27 |
2 (7) |
|
|
Age |
0.05 |
||
|
<30 years |
48 |
14 (29) |
|
|
≥30 years |
96 |
14 (15) |
|
|
Clinical |
|||
|
SLE |
0.52 |
||
|
Absent |
87 |
15 (17) |
|
|
Present |
57 |
13 (23) |
|
|
Prior thrombosis |
0.00005 |
||
|
No |
119 |
15 (13) |
|
|
Yes |
25 |
13 (52) |
|
|
Serologic |
|||
|
LACc |
<0.0001 |
||
|
Negative |
76 |
2(3) |
|
|
Positive |
64 |
25 (39) |
|
|
IgG aCL |
0.01d |
||
|
<40 units/mL |
77 |
9 (12) |
<0.0001e |
|
With LAC |
26 |
9 (35) |
|
|
Without LAC |
50 |
0 (0) |
|
|
≥40 units/mL |
66 |
19 (29) |
0.002e |
|
With LAC |
37 |
16 (43) |
|
|
Without LAC |
26 |
2 (8) |
|
|
IgM aCL |
1.00d |
||
|
<40 units/mL |
120 |
24 (20) |
<0.0001e |
|
With LAC |
51 |
21 (41) |
|
|
Without LAC |
66 |
2 (3) |
|
|
≥40 units/mL |
23 |
4 (17) |
0.10e |
|
With LAC |
12 |
4 (33) |
|
|
Without LAC |
10 |
0 (0) |
|
|
IgG anti-β2GPI |
0.09d |
||
|
<40 units/mL |
106 |
16 (15) |
<0.0001e |
|
With LAC |
36 |
13 (36) |
|
|
Without LAC |
66 |
2 (3) |
|
|
≥40 units/mL |
37 |
11 (30) |
0.02e |
|
With LAC |
27 |
11 (41) |
|
|
Without LAC |
10 |
0 (0) |
|
|
IgM anti-β2GPI |
0.37d |
||
|
<40 units/mL |
121 |
21 (17) |
<0.0001e |
|
With LAC |
49 |
19 (39) |
|
|
Without LAC |
68 |
1 (1) |
|
|
≥40 units/mL |
22 |
6 (27) |
0.35e |
|
With LAC |
14 |
5 (36) |
|
|
Without LAC |
8 |
1 (13) |
|
aPL antiphospholipid antibody, SLE systemic lupus erythematosus, aCL anticardiolipin antibody, anti-β2 GPI anti-β2glycoprotein I
aValues are the number of patients. For some tests, data were not available on all patients
bValues are the number (%) of patients
cData missing for one patient
d<40 units/mL versus ≥40 units/mL
eWith lupus anticoagulant (LAC) versus without LAC
A 2006 meta-analysis supports the role of LAC as the strongest predictor of poor pregnancy outcome, showing LAC to be more strongly associated with recurrent fetal loss before the 24th week of gestation than other aPL (OR, 7.79; 95 % CI, 2.30–26.45); aCL IgG at moderate to high titer (OR 4.68, 95 % CI 2.96–7.40) conferred a lesser risk and there was no association with aβ2GPI [56]. Thus, the magnitude of the association between aPL and adverse pregnancy outcome varies according to type of aPL; LAC is the best predictor of adverse outcome, low titer aCL and aβ2GPI are seemingly unimportant, and the importance of high titer aCL and aβ2GPI in the absence of LAC remains controversial.
Treatment Options
The mainstays of therapy in obstetric APS are low-dose aspirin (LDA) and heparin; intravenous immunoglobulin (IVIG) and plasma exchange have been used with success in refractory cases. Comparing treatment trials in the literature is challenging due to variations in study design, patient selection, thresholds for positive aPL titers, and treatment regimens.
Aspirin
LDA is recommended for subsequent pregnancies in APS patients with a history of recurrent pregnancy loss [85]. In addition to its antiplatelet effects, aspirin modulates the balance of prostacyclin, thromboxane, and IL-3 production which is critical to embryo implantation and placental development [86].
Aspirin is nearly universally used in the treatment of APS pregnancy. In an observational study, the rate of adverse pregnancy outcome was lower among patients who were regularly receiving aspirin at the time of the first study visit [58]. However, a randomized, placebo-controlled trial of LDA versus placebo in APS patients with recurrent miscarriage failed to show a benefit in the LDA-treated group [88]. This result is difficult to interpret as live birth rates in the placebo group exceeded those in published studies.
Heparin
Heparin is thought to prevent adverse pregnancy outcomes in APS patients via anti-thrombotic effects, direct aPL binding, inhibition of complement activation, and ability to block tissue factor-mediated placental bed immunopathology [88]. While most studies find pregnancy outcomes following heparin and aspirin combination therapy to be superior to aspirin alone in preventing recurrent pregnancy loss in aPL-positive patients [63, 89–93], others have found no benefit of combination therapy over aspirin alone [94, 95]. In fact, one observational study found a higher rate of adverse pregnancy outcomes among those patients receiving heparin [58].
Studies of unfractionated heparin (UFH) versus low-molecular-weight heparin (LMWH) suggest that both formulations are safe and effective for preventing recurrent pregnancy loss [96, 97]. LMWH offers practical advantages, including once-daily dosing and lower risks of hemorrhage, drug-induced thrombocytopenia, and osteoporosis.
Table 6.3 provides a summary of major treatment trials of LDA and heparin.
Table 6.3
Prospective APS pregnancy treatment trials and pregnancy outcomes (adapted from Ernest et al. [7])
|
Reference |
Study design |
Size |
Clinical criteria |
Laboratory criteria |
Major exclusions |
Treatment 1 |
Treatment 2 |
Results (live birthrate) |
|
Kutteh [63] |
Randomized |
50 |
≥3 unexplained consecutive pregnancy losses |
aCL IgG ≥ 27 GPL or aPS IgM ≥23 MPL, positive twice, ≥6 week apart |
LAC positive, SLE, anticoagulation for another reason |
LDA preconception and UFH 5000U sc twice daily with positive pregnancy test |
LDA preconception |
LDA/UFH 20/25 (80 %) vs LDA alone 11/25 (44 %) |
|
Rai et al. [92] |
Randomized |
90 |
≥3 unexplained consecutive pregnancy losses |
LAC positive or aCL IgG ≥ 5 GPL or aCL IgM ≥3 MPL, positive twice, ≥8 week apart |
SLE, prior thrombosis |
LDA with positive pregnancy test and UFH 5000U twice daily with positive fetal heartbeat |
LDA with positive pregnancy test |
LDA/UFH 32/45 (71 %) vs LDA 19/45 (42 %) |
|
Pattison et al. [87] |
Randomized, double blind |
50 |
≥3 pregnancy losses |
LAC positive or aCL IgG ≥ 5 or aCL IgM ≥5 MPL, positive twice |
SLE, prior thrombosis, concomitant medications in pregnancy |
LDA |
Placebo |
LDA 16/20 (80 %) vs placebo 17/20 (85 %) |
|
Farquharson et al. [94] |
Randomized |
98 |
≥3 unexplained consecutive pregnancy losses ≤10 weeks or ≥2 consecutive fetal demise >10 weeks |
LAC or aCL IgG >9 GPL or ACL IgM >5 MPL, positive twice, ≥6 week apart |
SLE requiring medications or with nephritis, prior thrombosis, concomitant medications in pregnancy, other thrombophilia |
LDA and dalteparin 5000 U daily |
LDA |
LDA/dalteparin 40/51 (78 %) vs LDA 34/47 (72 %) |
|
Stephenson et al. [97] |
Randomized |
28 |
≥3 unexplained consecutive pregnancy losses <10 weeks or ≥1 fetal demise |
LAC positive or aCL IgG or IgM ≥4.6 MoM, positive twice, ≥6 week apart |
Inherited thrombophilia, prior heparin use |
LDA preconception and dalteparin 2500–7500 U starting in luteal phase or 1sttrimester |
LDA preconception and UFH 5000–10,000 U twice daily starting in lueteal phase or 1sttrimester |
LDA/dalteparin 9/13 (69 %) vs LDA/UFH 4/13 (31 %) |
|
Noble et al. [96] |
Multicenter pilot |
50 |
≥3 unexplained consecutive pregnancy losses <20 weeks |
LAC positive or aCL IgG >20 GPL or aCL IgM >20 MPL or aPS ≥3.0 MoM, positive twice, ≥6 week apart |
No major exclusions |
Center 1: LDA preconception and enoxaparin 40 mg with positive pregnancy test |
Center 2: LDA preconception and UFH 5000–6000 U twice daily with positive pregnancy test |
LDA/enoxaparin 21/25 (84 %) vs LDA/UFH 20/25 (80 %) |
|
Laskin et al. [95] |
Randomized |
88 |
≥2 unexplained consecutive pregnancy losses <32 weeks |
LAC positive or aCL IgG >15 GPL or aCL IgM >25 MPL or ANA >1:80 or inherited thrombophilia |
SLE, prior thrombosis, peptic ulcer disease, low bone density |
LDA preconception |
LDA preconception and dalteparin 5000 U daily with positive pregnancy test |
LDA/dalteparin 35/45 (78 %) vs LDA 34/43 (79 %) |
aCL anticardiolipin, ANA antinuclear antibody, aPL antiphosopholipid, GPL G phospholipid, Ig immunoglobulin, LAC lupus anticoagulant, LDA low-dose aspirin, MoM multiples of the mean, MPL M phospholipid, SLE systemic lupus erythematosus, U units, UFH unfractionated heparin
Hydroxychloroquine
Hydroxychloroquine (HCQ), having both anti-inflammatory and anti-thrombotic effects, may be an adjunctive therapy in the prevention of adverse pregnancy outcomes in aPL-positive women. This drug was used for prevention of DVT and PE after hip surgery [98] and was shown to reduce the incidence of thrombotic events in SLE patients [99–102].
Mechanistic studies have suggested that HCQ reverses the effects of aPL on syncytiotrophoblasts by reducing immunoglobulin binding and restoring annexin A5 expression [15]. HCQ is used routinely in pregnant SLE patients and is considered safe in both pregnancy and lactation [103].
Intravenous Immunoglobulin
IVIG has been used in APS patients with recurrent fetal loss who are refractory to more traditional treatments. An early report using IVIG for this indication described a patient with a history of nine abortions who, after receiving two courses of IVIG during her next pregnancy, delivered a healthy child at 34 weeks’ gestation.
Two randomized controlled trials have compared heparin and aspirin therapy to IVIG alone; patients treated with IVIG had fewer live births and a greater number of first trimester abortions [104, 105]. Another trial comparing combination heparin, aspirin, and IVIG with heparin and aspirin alone failed to show a significant difference in outcomes between the two groups, although it should be noted that all pregnancies resulted in live birth [106]. Reports of IVIG dosing range from 400 to 1000 mg/kg daily for one to five consecutive days each month; some studies began treatment after a positive pregnancy test, while others began at 13 weeks of gestation [106–108]. While IVIG is not indicated as a primary treatment strategy for prevention of recurrent fetal loss in obstetric APS, it may serve as an adjunctive therapy for refractory cases.
Plasma Exchange
Plasma exchange has been described in case reports and case series of obstetric APS patients who failed treatment with heparin and aspirin combination therapy. Plasma exchange reduces aPL titers following treatment [109, 110]. Regimens ranged from one to four times weekly and success rates were generally high [109–113]. Additional studies of plasma exchange for the treatment of refractory APS pregnancies are warranted.
Glucocorticoids
There is no evidence to support the use of glucocorticoids in the preventative treatment strategies for obstetric APS. These drugs increase the risk of pregnancy complications, including premature rupture of membranes, preterm delivery, IUGR, infection, preeclampsia, and gestational diabetes, as well as maternal osteopenia and avascular necrosis. Treatment with steroids is, therefore, not warranted in pregnant APS patients in the absence of other indications [114–118].
Manifestation-Specific Recommendations
Treatment for Patients with Recurrent Pregnancy Loss
Studies of recurrent pregnancy loss have generally not distinguished between embryonic loss and fetal demise, instead combining patients into one heterogeneous group. Recommendations include LDA and prophylactic doses of heparin.
Several randomized controlled trials have compared treatment with heparin and LDA to LDA alone; while two of these studies demonstrated better outcomes in patients receiving heparin, the third showed no additional benefit from this treatment. In 1996, Kutteh described a single-center trial of 50 persistently aPL-positive women, each with at least three consecutive spontaneous pregnancy losses, and found significantly improved outcomes in the UFH with LDA group as compared to the LDA alone group; live birth rates were 80 and 44 %, respectively [63]. Rai et al. published a trial of 90 aPL-positive recurrent pregnancy loss patients randomized to similar treatment arms; results were comparable, with live birth rates of 71 % in the heparin plus LDA group and 42 % in those treated with LDA alone [92]. Finally, Farquharson et al. randomized 98 persistently aPL-positive women to receive LMWH and LDA or LDA alone; this study failed to show a difference in outcomes between the two groups, although it should be noted that success rates in both groups were high (72–78 % live birth rate, respectively) [94].
The effect of heparin plus aspirin therapy on pregnancy outcome was further examined in a systematic review and meta-analyses by Ziakas et al. These authors pooled data from five randomized controlled trials and found an overall benefit to heparin therapy in decreasing the risk of first trimester losses (OR 0.39, 95 % CI 0.24–0.65, number needed to treat 6) [93]. On further analysis, the effect of UFH was significant, while the effect of LMWH was not. Regarding fetal demise, no formulation of heparin therapy combined with aspirin provided benefit [93].
Treatment of Patients with a History of Thrombosis
Recommendations dictate continued therapeutic anticoagulation throughout pregnancy and during the postpartum period for APS patients with a history of thrombosis [119, 120]. Patients treated with long-term warfarin should be transitioned to therapeutic doses of LMWH upon confirmation of a positive pregnancy test, if not before, as warfarin interferes with organogenesis between weeks 6 and 12 of gestation [121].
While many groups continue LMWH throughout pregnancy, others use warfarin during mid- to late-pregnancy, transitioning from LMWH to warfarin at 14 weeks of gestation, then back to heparin at 36 weeks or 2 weeks prior to a scheduled delivery. The INR must be monitored closely, usually maintaining a range of 2–3 [122].
Treatment of Patients with a History of Early, Severe Preeclampsia
Rigorous treatment trials for the prevention of preeclampsia in APS patients have not been performed. Treatment with aspirin and heparin should be considered in women with a history of this complication [123]. The treatment for preeclampsia, once it occurs, is delivery.
Treatment of Patients with Asymptomatic aPL
Little data exists to direct the treatment of aPL-positive patients who have not had thrombotic or pregnancy-related events. Greater than 50 % of such women will go on to have uncomplicated pregnancies without additional treatment [26]. Treatment possibilities include close monitoring and observation alone, LDA alone or LDA with heparin prophylaxis; HCQ could also be considered.
Treatment recommendations are summarized in Table 6.4.
Table 6.4
Treatment recommendations for aPL/APS pregnancy based on clinical scenarios
|
APS patients with prior thrombosis |
LDA and LMWH, therapeutic dose (e.g., enoxaparin 1 mg/kg subcutaneously, twice daily) |
|
APS patients with ≥3 consecutive embroyonic losses, fetal demise, or early, severe preeclampsia |
LDA and LMWH, prophylactic dose (e.g., 0.5–1 mg/kg once daily) |
|
aPL-positive patients without prior thrombosis or adverse pregnancy event (asymptomatic aPL-positive patients) |
LDA or Close monitoring and observation |
|
APS patients with recurrent pregnancy loss despite the use of LDA and LMWH |
Consider adding IVIG, plasma exchange, and/or hydroxychloroquine |
aPL antiphosphilipid antibody-positive, APS antiphospholipid syndrome, IVIG intravenous immunoglobulin, LDA low-dose aspirin, LMWH low-molecular-weight heparin
General Care and Monitoring of APS Pregnancy
Pregnancy in APS patients is considered high risk and should be managed by a team of maternal fetal medicine specialists and a rheumatologist or hematologist with experience in APS pregnancy. Women with APS who receive proper antenatal care have a 75 % chance of live birth, as opposed to a 15 % chance if untreated [122].
Evaluating for the Presence of aPL
Recommendations for screening vary amongst medical societies. The American College of Obstetricians and Gynecologists (ACOG) recommends testing in: (1) women with a history of unexplained arterial or venous thromboembolism, or a new arterial or venous thrombotic event during pregnancy and (2) women with a history of one fetal loss or three or more recurrent embryonic or fetal losses [120]. The American College of Chest Physicians Evidence-Based Clinical Practice Guidelines recommends evaluating for aPL in women with a history of recurrent early pregnancy loss defined as at least three miscarriages before 10 weeks of gestation [119].
Expert groups agree that the presence of aPL should be confirmed on two separate occasions at least 12 weeks apart. Of note, due to insufficient evidence that screening and treating women with a history of early, severe preeclampsia and early onset placental insufficiency leads to improved outcomes, the societies do not support testing for aPL in this population. Testing without indication should be avoided due to the potential for uninterpretable results and ensuing treatment dilemmas.
Women with a history of SLE, persistently elevated aPTT, and/or a biological false-positive syphilis test should also be considered for aPL screening in the setting of pregnancy planning.
Preconception Counseling
Care begins with a preconception counseling visit in which an individualized plan of care is set forth for each patient. Patients should be informed of the risks of APS pregnancy, including fetal loss, IUGR, prematurity, maternal thrombosis, hypertension, and preeclampsia. Particular attention should be given to patients with significant pulmonary hypertension or recent thrombotic events, including stroke, as the risk of maternal complications and death are significant in these groups; alternative methods of expanding a family, such as surrogacy or adoption, may be considered in these situations.
Baseline renal function, liver function, complete blood counts, and quantity of urine protein should be measured. Previously measured aPL profiles should be reviewed and repeated prior to pregnancy; there is no need to repeat profiles throughout pregnancy as a subsequent negative result does not reduce the risk of complications.
Efforts should be taken to minimize or eliminate modifiable thrombotic risk factors, such as smoking, thereby affording the best possible outcome for both mother and fetus. Prenatal vitamins should be prescribed prior to conception if possible and, due to the risk of osteoporosis associated with heparin therapy, those patients who will be treated with heparin throughout pregnancy should begin calcium supplementation and have vitamin D levels repleted. Patients not yet taking LDA may initiate treatment at this point, although no strong data exists to support this. Physicians should ask to be notified immediately upon confirmation of a positive pregnancy test.
Pregnancy Monitoring and General Care
Upon confirmation of an intrauterine pregnancy by ultrasound, patients with a history of recurrent pregnancy loss should initiate LMWH and LDA, if not already begun. Due to its theoretical role in aiding implantation, an argument may be made for initiating LMWH prior to conception; however, this may result in prolonged, unnecessary exposure to the drug while trying to conceive with possible side effects including osteoporosis and increased bleeding risk. Therefore, we suggest delaying administration until intrauterine pregnancy is confirmed.
Initially, patients should be seen monthly to monitor for maternal and fetal well-being. Blood pressure and urinary protein should be measured at each visit.
Patients should be educated about the signs and symptoms of venous thromboembolism and preeclampsia, including headache, blurred vision, abdominal pain, and elevated blood pressure, and should be advised to seek medical attention immediately if these symptoms occur. They should also be taught to assess for fetal movement as decreases in fetal movement may signify fetal distress [124]. The use of home blood pressure monitoring should be considered on a case-by-case basis.
Most experts recommend serial ultrasonographic assessment with or without umbilical artery Doppler velocimetry measurement to assess fetal growth and amniotic fluid volume beginning as early as 18 weeks of gestation. Abnormalities in end-diastolic umbilical artery Doppler flow in the second trimester of patients with APS and/or SLE have been associated with fetal and neonatal death [125]. Adverse pregnancy outcomes were also seen in association with notched uterine arteries in the second trimester; normal examinations are reassuring [125]. Such monitoring may indicate that early delivery is necessary and allow physicians to act promptly when fetal well-being is at risk.
Should pregnancy loss occur, obtaining the abortus to rule out loss due to chromosomal abnormality may be useful.
Labor and Delivery
Scheduled delivery is preferred to spontaneous delivery in patients being treated with anticoagulation. Heparin should be held 12 h before invasive procedures, such as epidural anesthesia and cesarean delivery, and may be restarted 12 h after completion of the procedure. Anticoagulation should be resumed as soon as possible following delivery.
Due to a slightly increased risk of perioperative bleeding, aspirin may be held 7–10 days prior to delivery; however, some authors recommend continuing aspirin therapy in those patients with a history of arterial thrombotic events, including myocardial infarction and stroke.
Postpartum Considerations
There are no well-defined guidelines for the postpartum care of obstetric APS patients. Areas of interest include postpartum thromboprophylaxis, lactation, and contraception.
Postpartum Thromboprophylaxis
Optimal postpartum management of obstetric APS patients has not been defined. This is an area of great controversy and importance given the increased risk of thrombotic events in the postpartum period. Conservative measures in the prevention of thrombosis include early ambulation following vaginal delivery and the use of pneumatic compression stockings following cesarean delivery.
APS patients with a history of thrombosis should resume therapeutic anticoagulation as soon as possible following delivery; these individuals should be advised to maintain lifelong anticoagulation, usually with warfarin [119]. Postpartum thromboprophylaxis was discussed in great detail by the Obstetric APS Task Force of the 13th International Congress on Antiphospholipid Antibodies in 2010 [126]. Experts recommended using a prophylactic regimen based on the treatment used throughout pregnancy. For those women treated with LDA alone, most experts agreed that LDA should be continued for a minimum of 6–8 weeks postpartum, although others would continue LDA for life. For those women treated with UFH or LMWH during pregnancy, recommendations for the duration and choice of prophylactic treatment varied; while one expert recommended no thromboprophylaxis, other suggestions included warfarin, short-term heparin use (less than 1 week), and 6–8 weeks of heparin [126]. The American College of Chest Physicians Evidence-Based Clinical Practice Guidelines recommends 6 weeks of prophylactic- or intermediate-dose LMWH or warfarin with a target INR of two to three for women with a history of prior VTE [127]. Data to support guidelines for postpartum thromboprophylaxis is lacking.
Breastfeeding
Aspirin, heparin, and warfarin are safe for use in lactating women [128]. HCQ, a treatment commonly continued throughout pregnancy in lupus patients, is also safe to use while breastfeeding [128]. Calcium and vitamin D supplementation, as well as prenatal vitamins, should be continued during lactation, particularly in women receiving heparin thromboprophylaxis. (Refer to Chap. 14 for more information.)
Contraception
Progesterone-containing contraceptive options, as well as barrier methods and intrauterine devices, are available to aPL-positive women. Estrogen-containing therapies are contraindicated in these patients [129]. (Refer to Chap. 11for more information.)
Neonatal APS
Thrombotic events in babies born to aPL-positive mothers have been rarely described. Immunoglobulins of the IgG isotype can cross from mother to fetus through the placenta and typically clear from the infant by 6–12 months of age [130]. It is uncertain if this passively acquired antibody has the same pathologic significance as endogenously produced antibody.
Neonatal thrombosis in the presence of maternal aPL is exceedingly rare. Several studies of neonatal outcomes of babies born to aPL-positive mothers have failed to identify any cases of neonatal APS [130–134]. However, a 2007 review summarized 16 cases of perinatal thrombosis occurring in the presence of aPL [135]. Seven infants were born to mothers with APS while eight were born to mothers without APS but with aPL who were otherwise asymptomatic. Twelve of the 16 infants met criteria for thrombotic APS, while four infants did not themselves have aPL (which was present in the mother). Nearly all of these infants had additional risk factors for vascular thrombosis, including vascular catheters, infections, and asphyxia, so causality related to aPL could not be established.
APS and Infertility
The role of aPL in infertility is controversial. Proposed mechanisms for this association include the interference of aPL with implantation, placentation, and early embryonic development. At present, there is no evidence to support routine screening for aPL in patients with primary infertility [136]. Hatasaka et al. found no difference in the prevalence of aPL in women with unexplained infertility compared to fertile controls [137]. There is also no clear association between aPL positivity and implantation failure, clinical pregnancy, or live birth rates in women undergoing in vitro fertilization (IVF) and embryo transfer [52, 136, 138–142].
Ovulation induction, in which estrogen levels are artificially elevated, has been postulated to be particularly dangerous in aPL-positive patients who are already at increased risk for thrombosis. The literature on this topic is scarce. However, one retrospective cohort study of ten APS patients who underwent 47 cycles of ovulation induction did not develop thrombosis during treatment; all patients were treated with prophylactic LDA with or without heparin [143]. Another retrospective study of eight women with SLE and/or APS undergoing 69 cycles resulted in two cases of thrombophlebitis only [144]. The lack of evidence for increased thrombotic risk may be related to the relatively short duration of elevated estrogens and/or the nature of estrogens involved [145].
IVF in aPL-positive patients likely poses a greater risk of thrombosis than does ovulation induction; the risk of thromboembolism is increased tenfold with IVF compared to ovulation induction alone [124]. Ovarian hyperstimulation syndrome, a feared complication of ovarian stimulation presenting with bilateral ovarian enlargement, abdominal pain, ascites, and electrolyte imbalance, may be another risk factor for thrombosis. In a systematic review of thromboembolic complications related to assistive reproductive technologies, 79 % of thrombotic events were associated with ovarian hyperstimulation syndrome [146]. Ovulation induction and IVF in patients with APS are discussed in further detail in Chap. 12.
Long-term Risk of Thrombosis
Patients with obstetric APS may be at increased risk for lifetime thrombotic events. Gris et al. followed 1,592 obstetric APS patients over 9 years and found a significantly increased risk of DVT (adjusted HR 1.85, 95 % CI 1.50–2.28; annualized rate 1.46 %) and stroke (adjusted HR 2.10, 95 % CI 1.08–4.08; annualized rate 0.17 %) compared to women without known thrombophilia [147]. Another study following 215 obstetric APS patients also found a significantly higher 12-year cumulative thrombotic incidence rate compared to a control group [148].
Summary and Recommendations
Obstetric APS causes significant maternal and fetal morbidity, including recurrent early miscarriage, fetal demise, IUGR, early, severe preeclampsia, and maternal thromboembolic disease. LAC is the strongest predictor of poor obstetric outcomes. Specialists with experience with APS pregnancy are essential to maternal and fetal outcomes. Treatment trials are limited, but live birth rates exceed 70 % with heparin and aspirin treatment. Though great advances have been made in recent decades, ongoing research is needed to guide treatment recommendations.
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