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 Table of Contents  
REVIEW ARTICLE
Year : 2016  |  Volume : 11  |  Issue : 6  |  Page : 117-121

Antiphospholipid syndrome in pregnancy


Department of Rheumatology, University College London, London, United Kingdom

Date of Web Publication22-Nov-2016

Correspondence Address:
Anisur Rahman
Centre for Rheumatology Research, Division of Medicine, University College London, Room 412, Rayne Institute, 5 University Street, London WC1E 6JF
United Kingdom
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-3698.194543

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  Abstract 

Antiphospholipid syndrome (APS) is an autoimmune condition, in which antiphospholipid antibodies (aPL) cause clinical features including thrombosis, fetal loss, and preterm delivery. Studies in large numbers of patients with APS show that they suffer both early and late fetal loss as well as complications of pregnancy such as preeclampsia. The fetal loss in patients with APS is not caused primarily by thrombosis, but by a number of biological effects of aPL that affect implantation of the embryo. These factors are not yet understood fully but include effects on trophoblast cell viability and migration, inflammation at the fetal-maternal interface, and activation of complement. The established management of pregnancy in patients with known obstetric APS is to give daily low-dose oral aspirin plus daily subcutaneous heparin. This gives a live birth rate of over 70%. The trials that led to this form of management being adopted were small but overall do support the use of the heparin/aspirin combination over aspirin alone. There is no definite evidence supporting the use of heparin plus aspirin in patients who are aPL-positive, but who have never suffered any problems in pregnancy. However, patients taking long-term warfarin for thrombotic APS should have this changed to heparin during pregnancy.

Keywords: Antibodies, antiphospholipid syndrome, heparin, pregnancy, trophoblast


How to cite this article:
Rahman A. Antiphospholipid syndrome in pregnancy. Indian J Rheumatol 2016;11, Suppl S2:117-21

How to cite this URL:
Rahman A. Antiphospholipid syndrome in pregnancy. Indian J Rheumatol [serial online] 2016 [cited 2017 Jul 23];11, Suppl S2:117-21. Available from: http://www.indianjrheumatol.com/text.asp?2016/11/6/117/194543


  What is the Antiphospholipid Syndrome? Top


The antiphospholipid syndrome (APS) is an autoimmune condition, in which antiphospholipid antibodies (aPL) interact with phospholipid-binding proteins in the body, of which the most important is beta-2-glycoprotein I (β2GPI). The aPL-β2GPI complexes then bind to the surface membranes of target cells (which are composed of phospholipids) and this leads to changes in the behavior of those cells. [1] This cellular dysfunction, in turn, leads to the clinical features of APS.

APS was initially described by Hughes in 1983 as a subset of patients with systemic lupus erythematosus (SLE). [2] These patients were characterized by vascular thromboses and/or pregnancy loss and their blood tested positive for aPL. Subsequently, it was discovered that APS can also occur in patients who do not have SLE (primary APS [PAPS]). Classification criteria for APS were developed and updated. The currently accepted criteria are summarized in [Table 1] and stipulate that the patient must have suffered either arterial thrombosis or venous thrombosis or pregnancy loss or a combination of these and must also have persistently positive serological tests for aPL. [3] The serological tests most commonly used are the anticardiolipin enzyme-linked immunosorbent assay (ELISA) and the lupus anticoagulant (LA) test. In some units, a third assay, the anti-β2GPI ELISA is also available. The name "LA" is a confusing one. It is not a test for lupus. Most patients who are LA-positive do not have SLE and most patients with SLE are not LA-positive. LA is a test for APS. LA-positivity is caused by aPL in blood which tends to inhibit clotting of blood in a test tube (this is why it is called the LA test) but has the opposite effect, causing increased clotting, in the human body.
Table 1: Summary of classification criteria for antiphospholipid syndrome (modified from Miyakis et al.[3])

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It is important to remember that Miyakis et al. criteria [3] are primarily designed for classification in research studies and not for diagnosis. Thus, it is not always necessary to wait for two positive aPL tests before making the diagnosis of APS. Although only thrombosis and pregnancy loss are included in the criteria, patients with APS can develop many other clinical features. For example, a retrospective study of 1000 European patients (Euro-Phospholipid study) with APS reported that arthritis, epilepsy, and livedo reticularis were all common clinical features and occur in PAPS as well as SLE-associated APS. [4]


  What is the Effect of Antiphospholipid Syndrome on Pregnancy? Top


Without treatment, APS is a major risk factor for recurrent miscarriage. [5] As shown in [Table 1], the classification criteria for APS are very specific about the number and type of miscarriages that must be reported to have a confirmed diagnosis of APS. [3] Since first-trimester miscarriages are common even in healthy women, the criteria specify that there must be at least three successive first-trimester pregnancy losses or at least one fetal loss from later in pregnancy. Furthermore, there must be no other cause for the miscarriage (e.g., chromosomal abnormality). Premature births before the 34 th week of gestation can also be included in the definition of pregnancy morbidity included in these criteria.

The burden of pregnancy morbidity in patients with APS is underlined by the findings of the Euro-Phospholipid study. [4] Of 1580 pregnancies in 590 women, 560 pregnancies ended in early fetal loss (before 10 weeks), 267 in late fetal loss, and 80 in premature births. Preeclampsia occurred in 9.5% of pregnant women, eclampsia in 4.4%, and placental abruption in 2%. [4] In a subsequent prospective study following the same patients between the years 1999 and 2004, 77 women (9.4% of female patients) had one or more pregnancies. Of these pregnancies, 17.1% ended in early fetal loss and 35% in premature birth. [6]

The mechanism by which aPL causes pregnancy morbidity in patients with APS is not understood fully. Although it was initially thought to be due mainly to intraplacental thrombosis, this does not appear to be the case. Sebire et al. carried out a histological study of the products of conception comparing miscarriages from patients with and without APS and found no difference in the frequency of placental thrombosis between the groups. [7]

It seems more likely that the problem lies in an effect of aPL on implantation of the embryo in the uterus. This effect is probably multifactorial and involves inflammation at the fetal-maternal interface, inhibition of migration of trophoblast cells, and impaired expression of endometrial differentiation markers. [5] Studies in vitro have shown effects of aPL on both trophoblast [8],[9],[10] and endometrial [5] cells. Trophoblast expresses β2GPI and exogenous β2GPI can bind to the surface of trophoblast cells. [9] Thus, aPL can bind to β2GPI on trophoblast and exert pathogenic effects. For example, Mulla et al. showed that murine anti-β2GPI antibodies and polyclonal human IgG from patients with APS affect viability and cytokine production of human trophoblast cells. [9] The monoclonal antibodies inhibited the ability of the trophoblast cells to migrate through a membrane. [8] These authors suggested that the mechanism of action is the production of uric acid and activation of the inflammasome leading to inflammation at the fetal-maternal interface. [11] Poulton et al. showed that polyclonal IgG from patients with obstetric APS, but not IgG from patients with thrombotic APS, inhibited migration of human trophoblast cells. [10]

In a series of experiments in a murine model of APS pregnancy, Girardi et al. showed that infusing a large amount of IgG from patients with APS to mice early in pregnancy caused a significant decrease in the number of viable fetuses. [12] This effect, however, was reduced in complement-deficient mice [13] or in the presence of complement inhibitors. [14] Furthermore, whereas heparin (the most commonly utilized treatment for APS pregnancy) could also reverse these effects of the APS-IgG on fetal loss, an alternative anticoagulant called hirudin could not. [12] Heparin, but not hirudin, blocks the activation of complement. Thus, this group suggested that complement activation in the placenta plays a major role in APS pregnancy morbidity and this would fit with other work showing that endometrial biopsies from patients with APS had reduced expression of complement regulatory proteins. [5] However, complement modulating agents are not being used routinely in the management of APS pregnancy.


  Which Pregnant Women should be Tested for Antiphospholipid Antibodies? Top


It is important to note that positive tests for aPL may occur in approximately 5% of the population [15] and that these "nonpathogenic" aPL do not carry increased risk of thrombosis or pregnancy morbidity. The binding properties of pathogenic and nonpathogenic antibodies differ. Notably, whereas nonpathogenic antibodies bind phospholipids in the absence of serum cofactors, pathogenic antibodies require cofactors of which the most important is β2GPI. [16]

Thus, there is no indication for routine testing of all pregnant women for APS and a recent review stated that evidence does not support routine testing of aPL in patients with infertility. [17]

Testing for aPL can be recommended in patients whose clinical history suggests that APS is a likely diagnosis, for example, those with two or more early miscarriages [18] or in patients with unexplained late miscarriage. In addition, aPL tests are routinely carried out in patients with SLE due to the high prevalence of aPL-positivity in those patients (about 25%). [15]


  How should Pregnant Women with Antiphospholipid Syndrome be Managed? Top


Prednisolone is not recommended. An early trial in twenty patients by Cowchock et al. [19] compared treatment with low-dose heparin and treatment with oral corticosteroids (40 mg prednisone daily). Both treatment groups received low-dose aspirin. Live birth rate was 75% in each group, but the patients treated with prednisone had significantly higher rates of maternal morbidity and preterm birth.

The standard management of pregnant women with obstetric APS is with daily low-dose aspirin plus daily subcutaneous heparin [Table 2]. This was originally based on the results of two randomized controlled trials (RCTs) published in the 1990s, which showed that the live birth rate was significantly higher in APS patients treated with the heparin/aspirin combination than in those treated with aspirin. [20],[21] It should be noted, however, that these were small studies with fewer than 100 patients included in each case and both used unfractionated heparin (UFH). Subsequent studies using low molecular weight heparin (LMWH) did not show a significant difference between the heparin plus aspirin and aspirin alone groups. [22],[23] These studies were also small, and it is important to note that the outcomes in heparin plus aspirin groups were not worse than in the two earlier studies. [20],[21] The lack of statistical significance between groups was because the response in the aspirin alone groups was better in the later trials. [22],[23] A meta-analysis of the literature on this subject in 2010 identified only five suitable RCTs, [24] which were overall of poor quality and included a total of 334 patients (171 on heparin plus aspirin and 163 on aspirin alone). Combining all the trials, the live birth rate was 74.27% (127/171) in patients on heparin plus aspirin compared to 55.83% (91/163) in patients on aspirin alone giving an odds ratio of 1.3 (95% confidence interval: 1.040-1.629) in favor of the combination. [24] There were no significant differences between the groups in secondary outcome measures such as preeclampsia and birth-weight. This review noted the lack of a trial comparing UFH and LMWH, which was important given that LMWH is increasingly the preferred choice in many clinical scenarios within and outside the field of APS.
Table 2: Summary of management in patients testing positive for antiphospholipid antibodies

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Subsequently, in 2011, an Egyptian group published a study of sixty women with a history of three or more consecutive spontaneous abortions and persistently positive serological tests for aPL who were randomized to UFH 5000 units twice daily plus low-dose aspirin or LMWH (enoxaparin 40 mg) daily plus low-dose aspirin. [25] There was no significant difference between the live birth rates in the two groups (80% for LMWH vs. 66.7% for UFH, P = 0.243).

A later review in 2014 included ten RCTs including all those studied by Mak et al. [24] The later review [17] did not restrict the analysis to trials that compared heparin plus low-dose aspirin to aspirin alone (for example, they included studies comparing heparin to corticosteroids or intravenous immunoglobulin). They found that live birth rate in patients treated with aspirin alone (seven studies had an aspirin alone arm with a median number of subjects 25) ranged from 42% to 80%. In comparison, live birth rate in patients treated with aspirin plus heparin (eight studies had a heparin plus aspirin arm with a median number of subjects 29.5) ranged from 71% to 85%. Overall, the authors concluded that the evidence did justify the use of heparin plus low-dose aspirin in patients with recurrent early miscarriage and positive aPL though they also stressed the need for larger well-designed studies. [17]


  How should Pregnancy be Managed in Antiphospholipid Antibodies-positive Women who do not have a History of Pregnancy Morbidity? Top


This situation might arise in patients who have suffered vascular thrombosis due to APS and are taking warfarin. Warfarin should be stopped and converted to LMWH, to be continued throughout the pregnancy [Table 2]. This is to prevent thrombosis rather than pregnancy loss, and thus there is no definite indication to add aspirin. Warfarin cannot be used in pregnancy because it is teratogenic.

The decision is more difficult in a pregnant patient who has been found to have aPL but has neither a thrombotic nor an obstetric history of clinical features of APS. This might happen in a patient with SLE whose aPL was measured as part of routine screening. There is no definite evidence to support the use of heparin plus aspirin or even aspirin alone in such a pregnancy. However, in a large recent study (PROMISSE) in 385 women with low activity SLE, Buyon et al. showed that LA-positivity was one of the strongest predictors of adverse pregnancy outcomes. [26]


  Conclusion Top


Since APS was first described as a separate condition, pregnancy loss and pregnancy complications have been among the major clinical features. It is important to recognize, however, that many women who test positive for aPL are not at increased risk of pregnancy loss and so aPL tests should not be done routinely in all pregnant women. Routine testing of that kind would lead to many false-positive results and cause unnecessary concern and possibly unnecessary treatment in those expectant mothers. Thus, aPL tests are primarily justified in patients who have either thrombotic or obstetric history suggestive of APS or in patients with SLE.

The mechanism by which aPL causes pregnancy morbidity is not fully understood and is multifactorial. It is not due simply to placental thrombosis. Further research may lead to the development of new treatments for APS pregnancy such as complement modulators.

The established treatment for pregnant women with a history of obstetric APS is daily low-dose aspirin plus daily subcutaneous heparin. Although the trial evidence is limited, perhaps the most important point is that this combination treatment gives a live birth rate of 70% or above. This fact is not disputed (though whether aspirin alone would give the same result is disputed), and thus it remains prudent to offer the combination regimen to all pregnant women with obstetric APS unless there is a strong reason to the contrary (e.g., high risk of bleeding).

Acknowledgment

Anisur Rahman is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Giannakopoulos B, Passam F, Rahgozar S, Krilis SA. Current concepts on the pathogenesis of the antiphospholipid syndrome. Blood 2007;109:422-30.  Back to cited text no. 1
    
2.
Hughes GR. Thrombosis, abortion, cerebral disease, and the lupus anticoagulant. Br Med J (Clin Res Ed) 1983;287:1088-9.  Back to cited text no. 2
    
3.
Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295-306.  Back to cited text no. 3
    
4.
Cervera R, Piette JC, Font J, Khamashta MA, Shoenfeld Y, Camps MT, et al. Antiphospholipid syndrome: Clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002;46:1019-27.  Back to cited text no. 4
    
5.
Francis J, Rai R, Sebire NJ, El-Gaddal S, Fernandes MS, Jindal P, et al. Impaired expression of endometrial differentiation markers and complement regulatory proteins in patients with recurrent pregnancy loss associated with antiphospholipid syndrome. Mol Hum Reprod 2006;12:435-42.  Back to cited text no. 5
    
6.
Cervera R, Khamashta MA, Shoenfeld Y, Camps MT, Jacobsen S, Kiss E, et al. Morbidity and mortality in the antiphospholipid syndrome during a 5-year period: A multicentre prospective study of 1000 patients. Ann Rheum Dis 2009;68:1428-32.  Back to cited text no. 6
    
7.
Sebire NJ, Fox H, Backos M, Rai R, Paterson C, Regan L. Defective endovascular trophoblast invasion in primary antiphospholipid antibody syndrome-associated early pregnancy failure. Hum Reprod 2002;17:1067-71.  Back to cited text no. 7
    
8.
Mulla MJ, Myrtolli K, Brosens JJ, Chamley LW, Kwak-Kim JY, Paidas MJ, et al. Antiphospholipid antibodies limit trophoblast migration by reducing IL-6 production and STAT3 activity. Am J Reprod Immunol 2010;63:339-48.  Back to cited text no. 8
    
9.
Mulla MJ, Brosens JJ, Chamley LW, Giles I, Pericleous C, Rahman A, et al. Antiphospholipid antibodies induce a pro-inflammatory response in first trimester trophoblast via the TLR4/MyD88 pathway. Am J Reprod Immunol 2009;62:96-111.  Back to cited text no. 9
    
10.
Poulton K, Ripoll VM, Pericleous C, Meroni PL, Gerosa M, Ioannou Y, et al. Purified IgG from patients with obstetric but not IgG from non-obstetric antiphospholipid syndrome inhibit trophoblast invasion. Am J Reprod Immunol 2015;73:390-401.  Back to cited text no. 10
    
11.
Mulla MJ, Salmon JE, Chamley LW, Brosens JJ, Boeras CM, Kavathas PB, et al. A role for uric acid and the Nalp3 inflammasome in antiphospholipid antibody-induced IL-1ß production by human first trimester trophoblast. PLoS One 2013;8:e65237.  Back to cited text no. 11
    
12.
Girardi G, Redecha P, Salmon JE. Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation. Nat Med 2004;10:1222-6.  Back to cited text no. 12
    
13.
Berman J, Girardi G, Salmon JE. TNF-alpha is a critical effector and a target for therapy in antiphospholipid antibody-induced pregnancy loss. J Immunol 2005;174:485-90.  Back to cited text no. 13
    
14.
Holers VM, Girardi G, Mo L, Guthridge JM, Molina H, Pierangeli SS, et al. Complement C3 activation is required for antiphospholipid antibody-induced fetal loss. J Exp Med 2002;195:211-20.  Back to cited text no. 14
    
15.
Petri M. Epidemiology of antiphospholipid syndrome. In: Khamashta M, editor. Hughes Syndrome. 2 nd ed. London: Springer-Verlag; 2006. p. 22-8.  Back to cited text no. 15
    
16.
McNeil HP, Simpson RJ, Chesterman CN, Krilis SA. Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: Beta 2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci U S A 1990;87:4120-4.  Back to cited text no. 16
    
17.
de Jesus GR, Agmon-Levin N, Andrade CA, Andreoli L, Chighizola CB, Porter TF, et al. 14 th International Congress on antiphospholipid antibodies task force report on obstetric antiphospholipid syndrome. Autoimmun Rev 2014;13:795-813.  Back to cited text no. 17
    
18.
Rai RS, Regan L, Clifford K, Pickering W, Dave M, Mackie I, et al. Antiphospholipid antibodies and beta 2-glycoprotein-I in 500 women with recurrent miscarriage: Results of a comprehensive screening approach. Hum Reprod 1995;10:2001-5.  Back to cited text no. 18
    
19.
Cowchock FS, Reece EA, Balaban D, Branch DW, Plouffe L. Repeated fetal losses associated with antiphospholipid antibodies: A collaborative randomized trial comparing prednisone with low-dose heparin treatment. Am J Obstet Gynecol 1992;166:1318-23.  Back to cited text no. 19
    
20.
Kutteh WH. Antiphospholipid antibody-associated recurrent pregnancy loss: Treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. Am J Obstet Gynecol 1996;174:1584-9.  Back to cited text no. 20
    
21.
Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 1997;314:253-7.  Back to cited text no. 21
    
22.
Farquharson RG, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: A randomized, controlled trial of treatment. Obstet Gynecol 2002;100:408-13.  Back to cited text no. 22
    
23.
Laskin CA, Spitzer KA, Clark CA, Crowther MR, Ginsberg JS, Hawker GA, et al. Low molecular weight heparin and aspirin for recurrent pregnancy loss: Results from the randomized, controlled HepASA trial. J Rheumatol 2009;36:279-87.  Back to cited text no. 23
    
24.
Mak A, Cheung MW, Cheak AA, Ho RC. Combination of heparin and aspirin is superior to aspirin alone in enhancing live births in patients with recurrent pregnancy loss and positive anti-phospholipid antibodies: A meta-analysis of randomized controlled trials and meta-regression. Rheumatology (Oxford) 2010;49:281-8.  Back to cited text no. 24
    
25.
Fouda UM, Sayed AM, Abdou AM, Ramadan DI, Fouda IM, Zaki MM. Enoxaparin versus unfractionated heparin in the management of recurrent abortion secondary to antiphospholipid syndrome. Int J Gynaecol Obstet 2011;112:211-5.  Back to cited text no. 25
    
26.
Buyon JP, Kim MY, Guerra MM, Laskin CA, Petri M, Lockshin MD, et al. Predictors of pregnancy outcomes in patients with lupus: A cohort study. Ann Intern Med 2015;163:153-63.  Back to cited text no. 26
    



 
 
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