July-August 2014, Volume 11, Issue 4
Anti-Phospholipid Antibodies and Pregnancy
Published on: July 01, 2014
In 2016, this article was included in the Ask the Hematologist Compendium. At that time, the authors indicated that there had been no update regarding the content of this article since the original publication date in 2014.
What is your approach to a patient with laboratory evidence of anti-phospholipid antibodies who is pregnant or considering pregnancy?
Antiphospholipid antibody syndrome (APS) is a heterogeneous autoimmune disorder characterized by arterial and venous thromboembolic events and obstetric complications (especially recurrent fetal losses) in association with persistent laboratory evidence of anti-phospholipid antibodies (aPL). The aPL that characterizes the disease belongs to a heterogenous family of autoantibodies, including the lupus anticoagulant (LA), anti-cardiolipin (α-CL), and anti-β2 glycoprotein-1 (anti-β2 GP-1). APS and aPL can occur in isolation (i.e., primary) or in association with other disease processes (i.e., secondary) including connective tissue diseases, most commonly systemic lupus erythematosus (SLE).
Diagnostic Criteria for APS
The presence of aPL alone does not constitute APS. The international classification criteria for APS (the Sapporo criteria) were introduced in 1998 and revised in 2006.1 To make a definitive diagnosis of APS, the presence of at least one clinical feature (thrombosis or pregnancy morbidity) and one laboratory abnormality must be observed, and the laboratory abnormality must be present on two or more occasions at least 12 weeks apart. Laboratory parameters are as follows: IgG and/or IgM α-CL or anti-β2 GP-1 in moderate to high titre (i.e., a titre > 40 for IgG or for IgM or a titre > the 99th percentile), or documentation of the LA. Further details about the diagnostic criteria for APS can be found in the Journal of Thrombosis and Haemostasis.1
Maternal and Fetal Morbidity
The pathogenesis of aPL-related pregnancy morbidity is incompletely understood. For a pregnant woman, APS (and perhaps the presence of aPL) raises the possibility that she is at increased risk for thrombotic events and/or obstetric complications such as recurrent pregnancy losses, preeclampsia, eclampsia, intra-uterine growth restriction, and Hemolysis, Elevated Liver enzymes, Low Platelets (HELLP) syndrome. In a European referral center cohort of 1,000 patients with APS (many of whom had a connective tissue disease), 188 pregnancies were documented over 10 years; among patients in this group, early pregnancy loss (16.5%), intra-uterine growth restriction (26.3%), and prematurity (48.2%) were common.2 A systematic review found that lupus anticoagulant was associated with preeclampsia (OR 2.34), intra-uterine growth restriction (OR 4.65), and late (after 10 weeks of gestation) fetal loss (OR 4.73); however, numerous case-control studies were included in the analysis. When the analysis was restricted to cohort studies, late fetal loss was the only outcome associated with the aPL.3 Catastrophic APS (CAPS), a rare but devastating form of this syndrome, has been associated with pregnancy and the puerperium with 0.9 percent of the pregnancies from the aforementioned cohort being complicated by CAPS.2
Laboratory Diagnosis of aPL
The lab identification of aPL can be problematic because of variability in the sensitivity of assays and reagents, high false-negative and false-positive detection rates, lack of standardization of assays, and lack of adherence to established guidelines. To address these issues, guidelines for lab detection of aPL were published in 2009 by the Scientific Standardization Subcommittee (SSC) of the International Society of Thrombosis and Haemostasis (ISTH) and by the British Committee on Standards in Hematology. The Clinical Laboratory Standards Institute (CLSI) also has prepared guidelines for laboratory testing for LAC that is to be published soon. Before counseling a patient about risk or recommending therapy, we suggest that the hematologist ensure that aPL testing is not only confirmed on more than one occasion but also performed by a laboratory that follows approved aPL testing guidelines.
Management of a woman with APS should start with pre-pregnancy counseling that focuses on the involved risks. Discussion should include risks of maternal thrombosis and fetal loss (both early- and late-term) as well as the increased risk of placenta-mediated complications such as preeclampsia, HELLP syndrome, preterm delivery, and intra-uterine growth restriction. Involvement by a multidisciplinary management team that includes a maternal-fetal medicine specialist and a hematologist experienced in the management of thrombophilic conditions is recommended. APS patients on chronic anticoagulation should be informed about the potential teratogenic effects of warfarin, and oral anticoagulation should be switched to a therapeutic dose of low-molecular-weight heparin (LMWH) either before or very shortly after conception.
For all women with APS, the American College of Chest Physicians (ACCP) evidence-based guidelines4 recommend commencing low-dose aspirin on confirmation of pregnancy, not only for its antithrombotic effects but also to reduce the risk of preeclampsia.5 In practice, it would be reasonable for a woman with obstetric APS to begin aspirin during the time that she and her partner are trying to conceive, because the risk of ASA is low and the impact of a delay between conception and ASA use is unknown.
Pregnancy with aPL or APS–Clinical Management Scenarios
Table. Overview of the Therapeutic Options Used in Antiphospholipid Syndrome Pregnancy
|Drug||Use||Evidence||Safety in pregnancy||Safety in breastfeeding|
75-100 mg daily from conception until ≥ 36 weeks gestation
|Reduction of fetal loss|
Prevention of eclampsia
|No randomized controlled trials of aspirin for preventing VTE|
Some evidence for aspirin use in improving pregnancy outcomes, specifically reduction in rates of preeclampsia6
|Will cross the placenta; human data inconsistent, but risk is likely low|
Some first-trimester analyses have shown small increased risk of gastroschisis
|Does enter breast milk, but at low doses; should be safe|
Discontinue as soon as pregnancy is confirmed
|Not recommended in pregnancy unless LMWH may be less effective (e.g., prosthetic heart valves)||Teratogenic between 6-12 weeks of gestation; switch to LMWH before 6 weeks of gestation||Teratogenic||Not excreted in breast milk|
|Unfractionated heparin (UFH)||May be used in event of massive pulmonary embolism|
If rapid reversal of anticoagulation is needed during peripartum period or operative procedures
|Most studies using UFH have been superseded by studies using LMWH.||Safe||Not excreted in breast milk|
|LMWH||Drug of choice for women on warfarin, women who have had VTE or arterial thrombosis during pregnancy, women with previous pregnancy complications, or women who require thromboprophylaxis||Evidence for its role in preventing first-trimester loss remains controversial7||Does not cross placenta||Does enter breast milk, but of little concern due to low bioavailability|
|Steroids (e.g., prednisone)||Little evidence for benefit in APS; used in immune thrombocytopenia associated with APS or SLE||Minimal evidence of therapeutic benefit|
Benefit outweighed by its adverse effects (e.g., preeclampsia, gestational diabetes, increased risk of preterm deliveries)
|Cleft palate reported with first-trimester use||Low concentrations in breast milk|
|Intravenous immunoglobulins||Used in a small number of women with APS as therapy for concomitant, immune-mediated thrombocytopenia||No additional benefit when added to conventional therapy with ASA and LMWH||Crosses placenta after 30 weeks of gestation||Excretion is unknown|
|Hydroxychloroquine (HCQ)||Used when women have coexisting SLE||Mild antithrombotic effects|
Decreased risk of congenital heart block in women on HCQ in case-controlled studies
|No reports of fetal toxicity||Considered safe despite excretions in breast milk|
|Plasmapheresis||Reserved for treatment of catastrophic APS||Limited to case reports||Rarely used in pregnancy||Unknown|
Adapted with permission from Soh MC and Nelson-Piercy C. Antiphospholipid syndrome in pregnancy. Expert Rev Obstet Gynecol. 2010;5:748,749.
1. Pregnant women with persistent evidence of aPL who do not fulfill the diagnostic criteria for APS
There are no robust data to guide management of pregnant women in this cohort. Dr. Anne Lynch et al. measured aPLs in early pregnancy in 451 low-risk nulliparous women and found that 24.4 percent had aPLs.8 The rate of fetal loss in this cohort was higher than those without aPLs (15.8 vs. 6.5%), but the rate of adverse maternal outcomes was similar in both groups. We usually recommend low-dose ASA because it is easy to take and there is a reasonably high quality of evidence that it reduces the risk of preeclampsia; however, the significant uncertainty about the benefit of any antepartum, antithrombotic therapy in women who do not meet criteria for APS means that decisions should be individualized. The role of post-partum thromboprophylaxis in this patient group is not established.
2. Women with adverse obstetric outcomes plus aPL, but no history of thrombosis
In three meta-analyses of randomized trials in women with APS, the combination of ASA with prophylactic heparin significantly reduced pregnancy loss (RR 0.46)7 or first-trimester loss (OR 0.39)9 and increased live births (RR 2.3).10 These analyses, however, have several limitations, including a small number of trials from which to gather data, small sample size within trials, and low quality of trial design. Compared with women who have had recurrent pregnancy losses, but whose thrombophilia testing is negative, women with a history of obstetric APS are at increased risk for both arterial and venous thrombotic events.11 In the NOH-APS observational study among women with prior fetal loss, those treated with LMWH and low-dose aspirin had lower pregnancy loss but higher preeclampsia rates than other women. Therefore, the evidence that combined (LMWH + ASA) therapy improves outcomes is, at best, of modest quality. Nonetheless, we suggest combination LMWH + ASA for pregnant women with APS and adverse obstetric outcomes, not only because there is some evidence that this will decrease the likelihood of pregnancy complications, but also because LMWH + ASA should also reduce the risk of thrombosis during pregnancy. However, because the quality of evidence to support combination therapy over LMWH or ASA alone is not compelling, we suggest that the hematologist consider not only patient preferences, but also the recommendation of a maternal-fetal medicine specialist before choosing ASA + LMWH over LMWH or ASA alone. The optimal doses for LMWH and ASA have not been defined, but we suggest 75 to 100 mg of ASA per day plus prophylactic-dose LMWH (Table). For women with obstetric APS and no history of thrombosis, thromboprophylaxis during the postpartum period should be considered, but the net benefit is not well established.
3. Pregnant women with thrombotic APS
If a woman has APS and is anticoagulated for prior thrombosis, we suggest switching to therapeutic-dose LMWH before six weeks gestation. Full-intensity anticoagulation is important during the pregnancy and the postpartum period since these women have a significant, ongoing risk of thrombosis that is likely magnified by pregnancy. If a woman is on therapeutic-dose LMWH, delivery should be planned, and LMWH should be discontinued at least 24 hours prior to the procedure. Because there is no high-quality evidence to define the optimal anticoagulant management of patients who desire regional anesthesia, communication with maternal-fetal medicine and anesthesiology is especially important. For a woman with prior thrombosis who has discontinued anticoagulation, we suggest LMWH be started upon confirmation of pregnancy; whether to use prophylactic/intermediate or therapeutic-dose LMWH would depend on the perceived risks of thrombosis and bleeding. An elevated risk of thrombosis persists for up to 12 weeks following delivery.12 The absolute risk for thrombosis beyond six weeks, however, is small. Thus, thromboprophylaxis beyond the six-week mark of the postpartum period should be reserved for those patients with an especially high baseline risk.
Management of pregnant women with APS is challenging. Despite the imperfect data that are currently available, pregnancy outcomes in women with APS who are managed in centers that use a multidisciplinary approach, which includes input from clinicians experienced in thrombophilia management and fetal-maternal medicine, is often favorable. Future studies that expand our understanding of this complex disease, that clearly define obstetric and thrombotic risks, and that identify optimal antithrombotic regimens are needed.
Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4:295-306.
Cervera R, Serrano R, Pons-Estel GJ, et al. Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis. 2014. Epub ahead of print.
Abou-Nassar K, Carrier M, Ramsay T, et al. The association between antiphospholipid antibodies and placenta mediated complications: A systematic review and meta-analysis. Thromb Res. 2011;128:77-85.
Bates SM, Greer IA, Middeldorp S, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e691S-736S.
Farquharson RG, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment. Obstet Gynecol. 2002;100:408-413.
Empson M, Lassere M, Craig JC, et al. Recurrent pregnancy loss with antiphospholipid antibody: a systematic review of therapeutic trials. Obstet Gynecol. 2002;99:135-144.
Laskin CA, Spitzer KA, Clark CA, et al. Low molecular weight heparin and aspirin for recurrent pregnancy loss: results from the randomized, controlled HepASA Trial. J Rheumatol. 2009;36:279-287.
Lynch A, Marlar R, Murphy J, et al. Antiphospholipid antibodies in predicting adverse pregnancy outcome. A prospective study. Ann Intern Med. 1994;120:470-475.
Ziakas PD, Pavlou M, Voulgarelis M. Heparin treatment in antiphospholipid syndrome with recurrent pregnancy loss: a systematic review and meta-analysis. Obstet Gynecol. 2010;115:1256-1262.
Mak A, Cheung MW, Cheak AA, et al. 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;49:281-288.
Gris J, Bouvier S, Molinari N, et al. Comparative incidence of a first thrombotic event in purely obstetric antiphospholipid syndrome with pregnancy loss: The NOH-APS observational study. Blood. 2012;119:2624-2632.
Kamel H, Navi BB, Sriram N, et al. Risk of a thrombotic event after the 6-week postpartum period. N Engl J Med. 2014;370:1307-1315.
Conflict of Interests
Dr. Suryanarayan and Dr. Garcia indicated no relevant conflicts of interest.
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