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Rheumatology 2008 47(Supplement 3):iii23-iii27; doi:10.1093/rheumatology/ken181
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Management of the controversial aspects of the antiphospholipid syndrome pregnancies: a guide for clinicians and researchers

D. Erkan1, S. Patel1, M. Nuzzo2, M. Gerosa3, P. L. Meroni3, A. Tincani2 and M. D. Lockshin1

1Division of Rheumatology, Hospital for Special Surgery, Weill Medical College of Cornell University, NY, USA, 2Rheumatology and Clinical Immunology Unit, University of Brescia, Brescia and 3Department of Infant Medicine, University of Milan, IRCCS Istituto Auxologico Italiano, Milan, Italy.

Correspondence to: D. Erkan, The Barbara Volcker Center for Women and Rheumatic Disease, Hospital for Special Surgery, 535 E 70th Street, New York, NY 10021, USA. E-mail: erkand{at}hss.edu


   Abstract
Top
 Abstract
Background
 Methods
 Results and Discussion
 Conclusion
 Acknowledgements
 References
 
Background. Recommendations for the treatment of aPL-positive patients with pregnancy morbidity are based on a limited number of well-designed clinical trials. However, the management of pregnant aPL-positive women still displays several open questions.

Objective. To determine the practice patterns of experienced physicians in the management of the controversial aspects of aPL pregnancies.

Methods. A questionnaire reproducing debated conditions was initially sent to the Advisory Board members (ABMs) of the 12th Congress of aPL and the Fifth Conference on Sex Hormones, Pregnancy and Rheumatic Diseases (Florence, Italy, April 2007), and then the same questionnaire was posted at the Hospital for Special Surgery (www.hss.edu) website and all attendees (ATS) of the above meetings were invited to participate via e-mail. Answers have been collected and analysed in a descriptive fashion and responses of the two groups evaluated by Chi-square or Fisher's exact test.

Results. As a whole 75 responses from the ABMs and ATS were included in the analysis. In general, there was no significant difference between the opinions of two groups.

Conclusions. Management recommendations displayed reasonable consistence: (i) for the use of low-dose aspirin and low-molecular weight heparin during pregnancy and during ovarian stimulation for in vitro fertilization; (ii) against oestrogen-containing oral contraceptives; and (iii) for the use of anticoagulants in the post-partum period.

KEY WORDS: Antiphospholipid syndrome, Lupus anticoagulant, Pregnancy, In vitro fertilization, Aspirin, Heparin


   Background
Top
 Abstract
 Background
Methods
 Results and Discussion
 Conclusion
 Acknowledgements
 References
 
APS is diagnosed when thrombosis or pregnancy morbidity occurs in persistently aPL-positive individuals. Although the management of aPL-positive pregnant patients is controversial due to limited well-designed controlled trials, the current recommendation is: (i) low-dose aspirin (LDA) and prophylactic dose heparin for patients fulfilling the Updated Sapporo APS Classification Criteria based on pregnancy morbidity only; (ii) LDA and therapeutic dose heparin for patients fulfilling the Updated Sapporo APS Classification Criteria based on a vascular event; and (iii) no treatment for asymptomatic (no history of pregnancy and thrombosis) persistently aPL-positive patients (LDA may be considered although there are no data to support this strategy) [1].

Despite these recommendations, many open questions without evidence-based answers remain for the management of pregnant aPL-positive patients, especially when the initial treatment fails. Thus, the primary objective of this study was to determine the practice patterns of experienced physicians in the management of the controversial aspects of the aPL pregnancies. Detailed information about the management of APS pregnancies can be found elsewhere [1].


   Methods
Top
 Abstract
 Background
 Methods
Results and Discussion
 Conclusion
 Acknowledgements
 References
 
We surveyed the Advisory Board members (ABMs) and attendees (ATS) of the 12th Congress of aPL and the Fifth Conference on Sex Hormones, Pregnancy and Rheumatic Diseases, which were held in Florence, Italy (April 2007). In March 2007, during the first phase of the survey, a close-ended questionnaire with short patient scenarios was e-mailed to ABMs. In June 2007, during the second phase of the survey, the same questionnaire was posted at the Hospital for Special Surgery (www.hss.edu) website and all ATS of the above meetings were invited to participate via e-mail.

The questions were about responders’ medical background, experience with APS patients and pregnancies, and controversial issues in the management of APS pregnancies. Multiple-choice questions allowed respondents to choose medication combinations as needed.

Although responses were analysed in a descriptive fashion, we compared the responses of the ABMs to the responses of the ATS by Chi-square or Fisher's exact test. Also, a literature review was performed to determine the clinical relevance of our survey.


   Results and Discussion
Top
 Abstract
 Background
 Methods
 Results and Discussion
Conclusion
 Acknowledgements
 References
 
We received 26/50 (52%) responses from the ABMs and 61/525 (12%) responses from the ATS. Twelve of 61 (20%) of the ATS who responded preferred not to fill out the questionnaire due to their limited experience with APS pregnancies; thus, 49 responses from the ATS were included in the analysis. Table 1 demonstrates the characteristics of the responders.


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  		TABLE 1. Characteristics of the responders

 
Physicians treating APS patients during pregnancy often face problems that do not have an answer in evidence-based medicine but that require decisions nonetheless. This survey was performed to identify the behaviour of physicians (ABMs) who have long experience with pregnant APS patients; in addition, we explored the opinions of ATS of the same conferences, to see if they would make the same decisions. Results show that ABMs and ATS do not significantly differ in most cases; this allows us to identify a general behaviour.

Recurrent pregnancy loss despite treatment
Next pregnancy of an APS patient with a late fetal loss on LDA and prophylactic dose low-molecular weight heparin (LMWH) (Fig. 1A): almost 80% of all responders increased LMWH dose to a therapeutic dose, 20% used intravenous immunoglobulin (IVIG) with or without other medications, and 30% chose to monitor factor Xa (FXa) levels during the next pregnancy. Next pregnancy of an APS patient (history of deep vein thrombosis) with a late fetal loss on LDA and therapeutic dose LMWH (Fig. 1B): the use of IVIG and FXa monitoring was 37 and 41%, respectively among all responders. The use of FXa monitoring in heparin-receiving pregnant patients: in general, 55% of the responders considered FXa monitoring as a useful tool (ABM: 46% and ATS: 64%, P = NS).


Figure 1
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  		FIG. 1. (A) What are your treatment recommendation(s) for a persistent lupus anticoagulant test-positive APS patient with a mid-pregnancy fetal loss (despite treatment with LDA and prophylactic dose LMWH) when she starts a new pregnancy? The patient has no history of arterial/venous events. The responses were not significantly different between ABMs and ATS except the choice of FXa monitoring during pregnancy (P = 0.03). (B) What are your treatment recommendation(s) for a persistently lupus anticoagulant test-positive APS patient with a mid-pregnancy fetal loss (despite treatment with low dose aspirin and therapeutic dose LMWH) when she starts a new pregnancy? The patient has a history of deep vein thrombosis 5 yrs ago. The responses were not significantly different between ABMs and ATS. CS: corticosteroids; PE: plasma exchange; IVIG: intravenous immunoglobulin; LMWH: low-molecular-weight heparin; PE: plasma exchange.

 
APS patients without previous thrombosis usually receive LDA and prophylactic doses of heparin during subsequent pregnancies, as therapeutic doses of heparin do not provide additional benefit [2]. However, from a practical point of view, when patients fail prophylactic heparin, almost 80% of responders would increase LMWH to a therapeutic dose (Fig. 1A), although such dosing is not proven to be effective by controlled studies. IVIG may be used for aPL-associated pregnancy losses that are refractory to LDA and heparin (prophylactic or therapeutic dose); 37% of the responders suggested the addition of IVIG with or without other medications (Fig. 1B) in APS patients who fail LDA and therapeutic dose LMWH; however, there are no controlled data supporting this approach [3].

The physiological changes that occur in pregnancy (increase in heparin-binding proteins, increased clearance of heparin, and larger volume of distribution of heparin due to pregnancy-associated increase in plasma volume) may result in a decrease in plasma half-life of heparin [2] resulting in pregnancy failure. According to our survey, about half of the physicians looking after pregnant patients with APS consider FXa plasma levels as a useful tool to assess the adequate dose of heparin therapy as suggested by Barbour et al. [2]. These results are in agreement with the available literature, although reports both support [4] and question the role of anti-FXa level monitoring for heparin [5].

Medium/high doses of corticosteroids do not offer advantages in comparison with the standard therapy and are known to be associated with important side-effects (pre-term delivery, pre-eclampsia). In our survey, only a small percentage of physicians suggested the use of low doses of corticosteroids as an additional treatment for pregnancy loss recurrences despite LDA and heparin therapy.

HELLP syndrome
Recommendation against pregnancy in a patient with a history of HELLP (haemolysis, elevated liver enzymes, low platelet) syndrome: 68% of responders advised that a future pregnancy is feasible (ABM: 73% and ATS 64%, P = NS). Recurrence rate of HELLP syndrome in APS patients: the majority estimated <50% chance of recurrence (ABM: 81% and ATS: 80%, P = NS).

HELLP syndrome occurs in <1% of normal pregnancies and 10–15% of pre-eclamptic patients [6, 7]. In aPL-negative patients, HELLP syndrome usually develops between 24 and 32 weeks, only 1% of the patients develop serious liver complications, and it usually resolves with delivery [6, 7]. However, in aPL-positive patients, the HELLP syndrome usually occurs during the second trimester of the pregnancy, almost one-third of the patients develop hepatic infarcts, and aggressive treatment is needed to reverse the syndrome as the majority of the patients develop thrombotic complications and rarely catastrophic APS [7].

Despite this life-threatening nature of HELLP syndrome in APS patients (microangiopathic form of APS), the majority of responders do not contraindicate a new pregnancy, even if they consider the rate of recurrence high compared with that recorded in the general population (2–6%) [8]. Although the recurrence rate of HELLP syndrome is unknown in aPL-positive patients, a possible interpretation of this unexpected result could be that most of the responders underestimate the severity of the problem due to not being involved in the direct management of patients suffering form HELLP syndrome.

LDA during pregnancy
Recommendation of LDA in pregnant, persistently aPL-positive patients (Fig. 2): the recommendation based on all the responses was 85, 92, 93 and 89% in asymptomatic aPL-positive patients, aPL-positive patients with one embryonic loss, aPL-positive patients with two embryonic losses and aPL-positive patients with non-criteria aPL features, respectively. Notably, the use of LDA for patients with one or two early (<10 weeks) miscarriages was significantly more common among the ATS.


Figure 2
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  		FIG. 2. Do you recommend the use of LDA in a persistently aPL-positive pregnant patient (lupus anticoagulant test positive and/or aCL IgG ≥80 U tested twice 12 weeks apart) and A: asymptomatic (no history of vascular or pregnancy events)? B: with only one early (<10 weeks) miscarriage? C: with two early (<10 weeks) miscarriages? D: asymptomatic but with headache, livedo or heart valve disease? The responses were not significantly different between ABMs and ATS except B (P = 0.02) and C (P = 0.05).

 
There are no clear guidelines for the management of pregnant aPL-positive patients who do not fulfill Sapporo criteria for definite APS. Since pregnancy and aPL can be additive risk factors for vascular thrombosis, LDA therapy can be justified as it has minimal maternal or fetal side-effects. However, there are no controlled studies demonstrating that LDA affects pregnancy outcomes in persistently aPL-positive patients without the diagnosis of APS.

Heparin during pregnancy
Recommendation of heparin in pregnant, persistently aPL-positive patients: the recommendation based on all the responses was 7, 27, 75 and 63% in asymptomatic aPL-positive patients, aPL-positive patients with one early miscarriage (embryonic loss), aPL-positive patients with two early miscarriages and aPL-positive patients with non-criteria aPL features, respectively. The responses were not significantly different between ABM and ATS.

Although the risk of pregnancy morbidity can be as high as 90% in untreated APS patients with a history of pregnancy morbidities, the risk is unknown in asymptomatic, persistently aPL-positive patients or in APS patient with a history of thrombosis. Despite the lack of evidence, when treatment is considered, aspirin is usually the first choice in persistently aPL-positive patients who do not have history of thrombosis or late fetal loss. Heparin is usually added to LDA for highly selected reasons such as older maternal age, assisted reproduction techniques or in pregnant women with significant aPL profile (positivity for lupus anticoagulant test and/or high titres of anti-cardiolipin/anti-β2-glycoprotein-I antibodies).

Our survey shows that patients with non-criteria APS features and particularly those suffering from two or less early miscarriages are treated as classical APS pregnancies. This behaviour can be attributed to relative safety of heparin therapy in pregnancy and also to the profound awareness of the pathogenic potential of aPL.

LDA or heparin during IVF
Recommendation of LDA in pregnant, persistently aPL-positive patients during in vitro fertilization (IVF): 69–83% said yes to LDA independent of the APS classification criteria. Recommendation of heparin in pregnant, persistently aPL-positive patients during IVF: the recommendation based on all the responses was 31, 84 and 73% in asymptomatic aPL-positive patients, APS patients with vascular events and APS patients with only pregnancy events, respectively. The responses were not significantly different between ABM and ATS.

Cohort studies demonstrated that aPL positivity does not predict a successful conception [9]; a meta-analysis of seven studies found no relationship with infertility and aPL [10]. A double-blind randomized controlled study demonstrated no benefit of heparin and LDA (compared with placebo) for aPL-positive patients undergoing IVF [11]. However, the major limitation of these studies is the lack of correction for karyotypic aberrations [9].

Given that IVF is associated with increased oestrogen production and, rarely, with ovarian hyperstimulation syndrome (OHSS), anticoagulation can be considered for thrombosis prevention in aPL-positive patients [9]. There are no guidelines about the optimal prevention strategy. Our survey shows that the majority of responders are keen to use anticoagulation during IVF in patients with a formal diagnosis of either thrombotic or obstetric APS, while in asymptomatic aPL-positive carriers LDA seems to be the treatment of choice.

Oestrogen or oral contraceptives in APS
Recommendation against oestrogen/oral contraceptive use for APS patients as long as they are anticoagulated: overall 73% of all the responders recommended against oral contraceptive use (ABM: 73% and ATS: 74%, P = NS). Recommendation against oestrogen/oral contraceptive use for asymptomatic, persistently aPL-positive patients if they are on LDA: overall 91% of all the responders recommended against oral contraceptive use (ABM: 96% and ATS: 86%, P = NS).

Oestrogen-containing contraceptives increase the risk of thrombosis in general population and, given multiple case reports of APS patients developing thrombosis on contraception, oral contraceptives are generally contraindicated in aPL-positive patients. Approximately 25% of the ABMs and the ATS allowed oestrogen-containing pills in fully anticoagulated patients, but the percentage decreased for patients that are on LDA only. Progesterone-only contraceptives do not increase the thrombosis risk [12] and thus they can be considered in aPL-positive patients. However, there are no controlled data supporting this approach.

Post-partum thrombosis prophylaxis
Duration of postpartum thrombosis prophylaxis: the most commonly recommended postpartum thrombosis prophylaxis periods among all responders were 4–6 weeks (36%) and 6–8 weeks (27%) (ABM: 19% recommended 2–4 weeks, 58% 4–6 weeks, 19% 6–8 weeks and 4% 8–12 weeks) (ATS: 14% recommended 1–2 weeks, 14% 2–4 weeks, 24% 4–6 weeks, 30% 6–8 weeks and 18% 8–12 weeks).

Despite the lack of controlled studies regarding duration of anticoagulation, it is well accepted that persistently aPL-positive patients require post-partum anticoagulation given that post-partum period is a risk for thrombosis; the duration recommendations range from 3–5 days [13] to 6–8 weeks [1] to 12 weeks [14]. In a recent Canadian survey, physicians most frequently selected long-term post-partum anticoagulation (defined as up to 8 weeks) independently of the medication chosen [15]. Our survey confirms the usual choice of long-term post-partum anticoagulation that is generally prolonged for an average of 6 weeks.


   Conclusion
Top
 Abstract
 Background
 Methods
 Results and Discussion
 Conclusion
Acknowledgements
 References
 
Although evidence-based and experts’ guidelines are available for the general management of pregnancy loss and complications in APS women, several common practical aspects have not been addressed in a systemic manner. Our survey was planned in order to offer suggestions for these problems, to provide practical information that may help the everyday management of these patients, and to identify opportunities for further research questions.

Despite the fact that these opinions are not evidence-based, there is not a significant difference between ABMs’ and ATS’ suggestions. As a whole, the management recommendations for aPL-positive patients have a reasonable consistency for: (i) the use of LDA and LMWH during pregnancy and during ovarian stimulation for IVF; (ii) oestrogen-containing oral contraceptives are usually avoided; and (iii) there is agreement in the use of anticoagulation in post-partum period.

Formula


   Acknowledgements
Top
 Abstract
 Background
 Methods
 Results and Discussion
 Conclusion
 Acknowledgements
References
 
The authors would like to thank the following physicians for participating in the survey: A. Alaa Fadhil Alwan, Ales Ambrozic, Paul Ames, Mary-Carmen Amigo, Laura Andreoli, Jon Arnason, Francesca Bellisai, Andrea Bendrups, Eduardo Borba, Maria Bortolati, Ware Branch, Katarina Bremme, Antonio Brucato, Howard Carp, Ricard Cervera, Laura Contino, Maura Costa, Claudia Costo, Saabrina Cozzolino, Dorota Darmochwal-Kolarz, Sara De Carolis, Philippe de Moerloose, Ronald Derksen, Carlos Dias, Andrea Doria, Alina Laura Dumitrascu, Gerard Espinosa, Rebecca Fischer-Betz, Claudio Galarza, Inge-Margrethe Gilboe, Sonia Hammami, Kathryn Hassell, Gili Kenet, Munther Khamashta, Robert Lahita, Carl Laskin, Roger Levy, Andrea Lojacono, Aldo Maina, Maria Jose Mattioli, Gale McCarty, Gentry McIntyre, Federico Mecacci, Mayer Mitter, Jadranka Morovic-Vergles, Marta Mosca, Jack Murray, Srdan Novak, Cecilia Pappalardo, Jose Maria Pego-Reigosa, Vittorio Pengo, Michelle Petri, T. Flint Porter, Jacob Rand, J. Rauch, Robert Roubey, Amelia Rufatti, Guillermo Ruiz-Irastorza, Silvia Sanchez-Ramon, Debra Shepherd, Yehuda Shoenfeld, Mary Stephenson, Mayumi Sugiura-Ogasawara, Maria Tektonidou, Maria Bertero Tiziana, Aaron Tomer, Andrea L. Tranquilli, G. Valesini, Serena Wu and Masahide Yamazaki.

Disclosure statement: The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Background
 Methods
 Results and Discussion
 Conclusion
 Acknowledgements
 References
 

  1. Derksen RH, Khamashta MA, Branch DW. Management of the obstetric antiphospholipid syndrome. Arthritis Rheum (2004) 50:1028–39.[CrossRef][Web of Science][Medline]
  2. Barbour LA, Smith JM, Marlar RA. Heparin levels to guide thromboembolism prophylaxis during pregnancy. Am J Obstet Gynecol (1995) 173:1869–73.[CrossRef][Web of Science][Medline]
  3. Branch DW, Peaceman AM, Druzin M, et al. A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy. The Pregnancy Loss Study Group. Am J Obstet Gynecol (2000) 182:122–7.[CrossRef][Web of Science][Medline]
  4. Pappalardo C, Sarto A, Martinez M, et al. Third trimester fetal death associated to antiphospholipid syndrome and/or inherited thrombophilia: results of subsequent pregnancies with adjusted dose enoxaparin treatment plus aspirin (abstract). Clin Exp Rheumatol (2007) 25:26.
  5. Chandramouli NB, Rodgers GM. Management of thrombosis in women with antiphospholipid syndrome. Clin Obstet Gynecol (2001) 44:36–47.[CrossRef][Web of Science][Medline]
  6. Geary M. The HELLP syndrome. Br J Obstet Gynaecol (1997) 104:887–91.[Web of Science][Medline]
  7. Tsirigotis P, Mantzios G, Pappa V, et al. Antiphospholipid syndrome: a predisposing factor for early onset HELLP syndrome. Rheumatol Int (2007) 28:171–4.[CrossRef][Web of Science][Medline]
  8. Back Y, Sibai B. HELLP syndrome. UpToDate 2007. 15.
  9. Carp HJA. Infertility and antiphospholipid antibodies: update (abstract). Clin Exp Rheumatol (2007) 25:3.[Medline]
  10. Hornstein MD. Antiphospholipid antibodies in patients undergoing in vitro fertilization: the data do not support testing. Fertil Steril (2000) 74:635–6.[CrossRef][Web of Science][Medline]
  11. Stern C, Chamley L, Norris H, Hale L, Baker HW. A randomized, double-blind, placebo-controlled trial of heparin and aspirin for women with in vitro fertilization implantation failure and antiphospholipid or nuclear antibodies. Fertil Steril (2003) 80:376–83.[CrossRef][Web of Science][Medline]
  12. Sammaritano LR. Therapy insight: guidelines for selection of contraception in women with rheumatic diseases. Nat Clin Pract Rheumatol (2007) 3:273–81.[CrossRef][Web of Science][Medline]
  13. Royal College of Obstetricians and Gynaecologists. Thromboprophylaxis during pregnancy, labour and after vaginal delivery. Guideline. Royal College of Obstetricians and Gynaecologists (2007) 1–13.
  14. Erkan D. The relation between antiphospholipid syndrome-related pregnancy morbidity and non-gravid vascular thrombosis: review of the literature and management strategies. Curr Rheumatol Reports (2002) 4:379–86.[CrossRef]
  15. Spitzer KA, Murphy K, Crowther M, et al. Postpartum management of women at increased risk of thrombosis - results of a Canadian pilot survey. J Rheumatol (2006) 33:2108–9.[Free Full Text]
Submitted 18 March 2008; Accepted 2 April 2008


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Introduction: new trends in pregnancy and rheumatic diseases
Rheumatology, June 1, 2008; 47(suppl_3): iii1 - iii1.
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