Obstetric Antiphospholipid Syndrome Research Articles

Characteristics of pregnancy complications and treatment in obstetric antiphospholipid syndrome in China.

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by obstetric complications and thrombotic events associated with antiphospholipid antibodies (aPL). We aimed to compare the clinical characteristics and treatment of primary APS (PAPS) and secondary APS (systemic lupus erythematosus-APS, SAPS) patients and investigate risk factors associated with obstetric complications in Shanghai, China. We retrospectively collected and analyzed the data of obstetric APS (OAPS) patients from 2000 to 2017 in the APS-Shanghai (APS-SH) database. One hundred eighty OAPS patients with a total of 450 pregnancies were included in this study. Two hundred twenty-one (49.11%) pregnancies resulted in miscarriage, and 161 (35.77%) pregnancies resulted in intrauterine death. In our cohort, when women were treated, 57 out of 66 pregnancies resulted in live births (86%). Of the 9 treated patients who failed to have live births, 3 had intrauterine deaths, 3 had fetal growth restriction, 2 had pneumorrhagia of the newborn, and 1 had a miscarriage. OAPS patients were divided into two groups: PAPS and SAPS. More SAPS patients than PAPS patients used glucocorticoids (GCs) and hydroxychloroquine (both p < 0.001). However, there was no significant difference in the GC dosage between SAPS and PAPS patients (p = 0.188). Lupus anticoagulant (LAC) and IgG aβ2GPI were risk factors for miscarriage (odds ratio (OR) = 2.398, 95% confidence interval (CI) = 1.276-4.505, p = 0.002; OR = 2.907, 95% CI = 1.558-5.405, p = 0.001, respectively) and intrauterine death (OR = 2.439, 95% CI = 1.299-4.580, p = 0.006; OR = 2.060, 95% CI = 1.089-3.897, p = 0.026, respectively). The live birth rate of OAPS patients in Shanghai was 86%. Even if OAPS patients were treated, pregnancy complications could occur, and these patients might need further second-line treatment. Key Points • This is the first study to report data on Chinese OAPS patients. The live birth rate was 86%. • Lupus anticoagulant and IgG aβ2GPI were risk factors for miscarriage and intrauterine death in our cohort. • Despite active treatment, 9 patients had obstetric complications. Therefore, further second-line treatment is still needed.

THE PREVALENCE OF ANTIPHOSPHOLIPID SYNDROME IN WOMEN AFTER PREECLAMPSIA

Objective:Preeclampsia (PE) is a multisystem progressive disorder that affects 2–8% of all pregnancies. Severe and early PE (<34 weeks) is one of the clinical criteria of the obstetric antiphospholipid syndrome (APS). The aim of this study was to assess the prevalence of APS in women after PE.Design

Obstetric outcomes in patients with primary thrombotic and obstetric antiphospholipid syndrome and its relation to the antiphospholipid antibody profile.

Introduction: Previous studies suggested different obstetric outcomes between patients with thrombotic or obstetric antiphospholipid syndrome, but the data are inconclusive. Aims: To investigate obstetric outcomes and their relation to the antiphospholipid antibody profile in primary thrombotic or obstetric antiphospholipid syndrome patients and compare those to a control population. Materials and methods: A retrospective single-centre study on a cohort of 30 pregnant women with primary antiphospholipid syndrome treated at Karolinska University Hospital Solna, Sweden between 2000 and 2016. The pregnancy outcomes were compared to the outcomes of all pregnancies in Stockholm County during the same period. Results: Preeclampsia (p < 0.001), low birth weight at delivery (p = 0.001), Apgar < 7 at 5 minutes (p < 0.001) and small infants (p < 0.001) were more common in antiphospholipid syndrome patients compared to controls. Obstetric antiphospholipid syndrome patients had a higher incidence of small infants (p = 0.023), lower birth weight (p = 0.013) and infants born with complications (p=0.004) compared to thrombotic antiphospholipid syndrome. Mothers with triple antibody positivity had a higher incidence of preeclampsia (p = 0.03), preterm delivery (p = 0.011), small infants (p=0.002) and infants born with complications (p = 0.012). Conclusions: Patients with primary antiphospholipid syndrome, especially those with obstetric antiphospholipid syndrome and triple antibody positivity, are at higher risk for adverse pregnancy outcomes, even under antithrombotic treatment. More frequent antenatal controls in high-risk patients can further improve outcomes.

Increased incidence of cancer in the follow-up of obstetric antiphospholipid syndrome within the NOH-APS cohort.

Malignancies can be associated with positive antiphospholipid antibodies but the incidence of cancer among women with the purely obstetric form of antiphospholipid syndrome (APS) is currently unknown. Our aim was to investigate the comparative incidence of cancers in women with a history of obstetric APS within a referral university hospital-based cohort (NOH-APS cohort). We performed a 17-year observational study of 1,592 non-thrombotic women with three consecutive spontaneous abortions before the 10th week of gestation or one fetal death at or beyond the 10th week of gestation. We compared the incidence of cancer diagnosis during follow-up among the cohort of women positive for antiphospholipid antibodies (n=517), the cohort of women carrying the F5 rs6025 or F2 rs1799963 polymorphism (n=279) and a cohort of women with negative thrombophilia screening results (n=796). The annualized rate of cancer was 0.300% (0.20%-0.44%) for women with obstetric APS and their cancer risk was substantially higher than that of women with negative thrombophilia screening [adjusted hazard ratio (aHR) 2.483; 95% confidence interval (CI) 1.27-4.85]. The computed standardized incidence ratio for women with obstetric APS was 2.89; 95% CI: 1.89-4.23. Among antiphospholipid antibodies, lupus anticoagulant was associated with incident cancers (aHR 2.608; 95% CI: 1.091-6.236). Our cohort study shows that the risk of cancer is substantially higher in women with a history of obstetric APS than in the general population, and in women with a similar initial clinical history but negative for antiphospholipid antibodies.

Danaparoid is effective and safe for patients with obstetric antiphospholipid syndrome

Objectives: The objective is to evaluate whether danaparoid is effective in improving the live birth rate in patients with obstetric antiphospholipid syndrome (oAPS).Methods: This prospective study included 91 pregnancies of 60 patients with oAPS diagnosed according to criteria of the International Congress on APS. Live birth rates, adverse pregnancies and perinatal outcomes were compared among patients treated with danaparoid and low dose aspirin (danaparoid group, LDA), unfractionated heparin (UFH) and LDA (UFH group) and LDA and/or prednisolone (LDA group).Results: After excluding 11 miscarriages with abnormal embryonic chromosomes, one chemical pregnancy and one ectopic pregnancy, live birth rates were 87.5% (14/16) for the danaparoid group, 90.0% (36/40) for the UFH group and 63.6% (14/22) for the LDA group, respectively. The live birth rates of patients treated with danaparoid and UFH were similar and tended to be higher than that of patients treated with LDA, respectively (OR 4.0, 95% confidence interval 0.72–22.22 and 5.15, 1.33–20.00). No patient given danaparoid and one patient with UFH developed heparin-induced thrombocytopenia which resulted in a stillbirth. Another patient with UFH suffered a lumbar compression fracture.Conclusion: Danaparoid is effective for improving the live birth rate and is safe for patients with oAPS.

P036: Hydroxychloroquine: improving pregnancy outcomes in refractory obstetric antiphospholipid syndrome (OAPS)

P036: Hydroxychloroquine: improving pregnancy outcomes in refractory obstetric antiphospholipid syndrome (OAPS)

O002: Increased incidence of cancer in the follow-up of obstetric antiphospholipid syndrome: the NOHA-K observational study

O002: Increased incidence of cancer in the follow-up of obstetric antiphospholipid syndrome: the NOHA-K observational study

Антифосфолипидные антитела как диагностические маркеры акушерского антифосфолипидного cиндрома

Антифосфолипидные антитела как диагностические маркеры акушерского антифосфолипидного cиндрома

Treatment of refractory poor aPL-related obstetric outcomes with TNF-alpha blockers: Maternal-fetal outcomes in a series of 18 cases

BackgroundNo absolute data on the treatment of antiphospholipid antibodies (aPL) related to refractory obstetric complications exist to date. TNF-α play a major role in this disorder. ObjectiveTo assess the effectiveness of TNF-α blockers in 18 aPL-positive women with recurrent infertility after therapy with low-molecular-weight heparin (LMWH) plus aspirin (LDA) plus hydroxychloroquine (HCQ). MethodsProspective case-series of 12 women fulfilling Sydney criteria for obstetric antiphospholipid syndrome (OAPS) and 6 with incomplete forms (OMAPS). All women tested positive for aPL at least twice. Non-criteria aPL were tested in 15/18. Complement, TNF-α and IL-10 were also evaluated. Women were closely monitored for fetal well-being and possible malformations throughout gestation and the postpartum period. ResultsSixteen patients were started on adalimumab and 2 on certolizumab. Twelve women completed gestation: 9 at term and 3 pre-term. Differences in laboratory categories and outcomes were observed when OAPS and OMAPS were compared. First trimester miscarriage or implantation failure recurred in 6 cases, all of the OAPS group. Malformations were not seen in the newborns. ConclusionsOverall, good obstetric results were obtained in 70% of previous LMWH-LDA+HCQ refractory cases. TNF-α blockers were well tolerated without adverse effects. The combination of LMWH plus LDA plus TNF-α blockers appears to be a promising treatment for refractory obstetric complaints related to aPL; nevertheless, outcome differences between OAPS and OMAPS do exist.

Obstetric APS and thrombosis; modelling future risks.

Obstetric APS and thrombosis; modelling future risks.

ASSOCIATED CONDITIONS AND SPECIFIC PREDICTS OF OBSTETRIC ANTIFOSPHOLIPID SYNDROME

The antiphospholipid syndrome (APS), or Hughes's disease, an autoimmune systemic disease, is the most common thrombophilias acquired in the young adult. In obstetrics, it is characterized clinically and may be associated with other diseases. The objective of this study was to identify the specific laboratory predictors of high risk for fetal loss, as well as the main associated symptomatologies. This study was performed through data analysis of 1557 pregnant patients diagnosed with classic antiphospholipid syndrome. The condition most associated with patients with obstetric SAF in the present study was the presence of previous abortion, followed by early delivery, thrombosis, fetal death, recurrent abortion and pre-eclampsia. The laboratory predictors associated with obstetric antiphospholipid syndrome were lupus anticoagulant and anticardiolipin IgG / IgM. It is necessary to carry out a study to complement the profile of the patients of this syndrome in pregnancy, because the development of antiphospholipid antibodies appear to be frequent in critically ill patients, but more studies are necessary to clarify their pathogenic role and its implications in clinical practice.

Management of pregnant women with antiphospholipid antibodies

ABSTRACTIntroduction: Important advancements in pregnancy outcome have been reported in women with antiphospholipid antibodies (aPL), despite the fact that the treatment of aPL related pregnancy morbidity is not guided by consistent findings from well-designed trials.Areas covered: The current study draws a picture of the studies in the literature by performing a Medline search of relevant English language articles and reports our experience in managing different subsets of obstetric antiphospholipid syndrome (APS), defined on the basis of their clinical and laboratory characteristics. The management of pregnant women with non-criteria APS manifestations and that of aPL carriers during their first pregnancy is also examined.Expert commentary: A heparin/aspirin combination constitutes conventional treatment for APS affected pregnant women. As this strategy fails in approximately 20–30% of cases, uncovering other options for women refractory to conventional treatment or at high risk of pregnancy complications has become an urgent undertaking. Some attempts have been made to prescribe additional treatments in the effort to improve live birth rates and/or reduce pregnancy complications, which often occur even in patients treated conventionally. The evidence from some studies and an individual risk/benefit assessment should instead guide treatment decisions for pregnant patients with non-criteria APS manifestations and aPL carriers.

Mechanisms of Endothelial Dysfunction in Antiphospholipid Syndrome: Association With Clinical Manifestations.

The endothelium is a monolayer of cells that covers the inner surface of blood vessels and its integrity is essential for the maintenance of vascular health. Endothelial dysfunction is a key pathological component of antiphospholipid syndrome (APS). Its systemic complications include thrombotic endocarditis, valvular dysfunction, cerebrovascular occlusions, proliferative nephritis, deep vein thrombosis, and pulmonary embolism. In women, APS is also associated with pregnancy complications (obstetric APS). The conventional treatment regimens for APS are ineffective when the clinical symptoms are severe. Therefore, a better understanding of alterations in the endothelium caused by antiphospholipid antibodies (aPL) may lead to more effective therapies in patients with elevated aPL titers and severe clinical symptoms. Currently, while in vivo analyses of endothelial dysfunction in patients with APS have been reported, most research has been performed using in vitro models with endothelial cells exposed to either patient serum/plasma, monoclonal aPL, or IgGs isolated from patients with APS. These studies have described a reduction in endothelial cell nitric oxide synthesis, the induction of inflammatory and procoagulant phenotypes, an increase in endothelial proliferation, and impairments in vascular remodeling and angiogenesis. Despite these lines of evidence, further research is required to better understand the pathophysiology of endothelial dysfunction in patients with APS. In this review, we have compared the current understanding about the mechanisms of endothelial dysfunction induced by patient-derived aPL under the two main clinical manifestations of APS: thrombosis and gestational complications, either alone or in combination. We also discuss gaps in our current knowledge regarding aPL-induced endothelial dysfunction.

“Part of the Ritual”: a Qualitative Study of Patient and Physician Perspectives on the Use of Anticoagulation for Improving Pregnancy Outcomes in Obstetrical Antiphospholipid Syndrome

INTRODUCTIONAntiphospholipid syndrome is an acquired thrombophilia associated with recurrent pregnancy loss. Treatment with low-molecular-weight heparin (LMWH) and/or aspirin (ASA) during pregnancy to prevent future loss is based on limited trial data with mixed results. Given the clinical equipoise, we sought to understand how patients and physicians navigate the decision-making process for use of antepartum LMWH and/or ASA. This research is needed to inform the feasibility of future research that seeks to resolve the question of treatment efficacy in this patient population. METHODSFollowing constructivist grounded theory (CGT) methodology, we interviewed 10 patients and 10 thrombosis physicians in Ottawa, Canada from January 2017 to March 2018. Patients were drawn from women included in the TIPPS (Thrombophilia in Pregnancy Prophylaxis Study) screening logs and from consecutive women attending a specialty Thrombosis Clinic who met the revised Sapporo/Sydney laboratory criteria and had at least 1 prior late loss or 2 early losses (<10 weeks gestation). Data collection and analysis occurred iteratively, in keeping with CGT methodology. RESULTSOur analysis generated three predominant themes, present across both patient and physician interviews, which captured a patient-led decision-making experience: (1) Accepting Uncertainty, (2) Focusing on Safety and (3) Managing High Stakes. Many patients accepted the uncertainty of their situation; they felt hopeful but were also reluctant to expect a better pregnancy outcome. This was echoed in the physician interviews, which emphasized the uncertainty of LMWH/ASA in improving outcomes when counselling patients on their options. Both groups focused on the low-risk nature and safety of these medications. Patients focused on safety to the fetus, with little concern for maternal risk. Finally, patients and physicians acknowledged the high emotional burden and what was at stake: avoiding further pregnancy loss. Patients responded to their situation by taking action (i.e. using LMWH injections became a “ritual”) whereas physicians reacted by removing themselves from the final decision and “[leaving] it up to the patient”. CONCLUSIONIn this setting of clinical equipoise and in the absence of serious safety concerns, decision-making around antepartum LMWH/ASA was largely directed by informed patient choice. These findings should be considered when designing future research on the role for LMWH/ASA in this population, as it suggests that the perceived benefits of treatment go beyond improving pregnancy rates. Rather, patients seem to derive psychological benefit from the process of taking action, even in the absence of a guaranteed good outcome. DisclosuresSkeith:Leo Pharma: Honoraria; CSL Behring: Research Funding. Rodger:Biomerieux: Research Funding.

Engaging Patients in Clinical Trial Planning: Exploring the Concept of a Minimal Clinically Important Difference Among Patients with Obstetrical Antiphospholipid Syndrome

INTRODUCTIONWomen with antiphospholipid syndrome are at increased risk of pregnancy loss. A large randomized controlled trial is still needed to confirm or refute the efficacy of low-molecular-weight heparin (LMWH) and aspirin (ASA) prophylaxis during pregnancy in women with antiphospholipid syndrome (APS) and past pregnancy loss. The minimal clinically important difference (MCID) is a statistical concept that quantifies the smallest amount of benefit from a treatment that a patient would identify as important, and is used to adequately power clinical trials. When planning a clinical trial, the MCID is most often determined by specialists in the field. How patients make sense of MCID as a concept, and how patients' perceptions of MCID compare to physician responses is unknown. In a challenging and high stakes situation, understanding different patients' perspectives must be considered when planning a large clinical trial. METHODSConsecutive patients were approached from a specialty Thrombosis clinic and from the TIPPS (Thrombophilia in Pregnancy Prophylaxis Study) screening logs between January 2017 and March 2018 in Ottawa, Canada to complete a survey and interview. Patients were eligible if they met the revised Sapporo/Sydney laboratory criteria for antiphospholipid syndrome and had at least 1 late pregnancy loss or 2 early losses (<10 weeks gestation). A similar survey was distributed to 350 specialists identified through 5 professional organizations between May-Sept 2016. Both patient and physician groups had access to an introductory video. The mean MCID between the patient group and physician group was compared using an independent t-test, with p<0.05 being significant. Patient interview data were collected and analysed iteratively, in keeping with constructivist grounded theory methodology. RESULTSThere were 22 (33%) patients who completed surveys and 10 patients who completed semi-structured interviews. Among the physician group, 72 (20.6%) responded to the survey, including obstetricians (34.7%), hematologists (26.4%), general internists (18%), maternal fetal medicine specialists (6.9%) and other specialties (12.6%). Assuming a live birth rate of 60% in the ASA alone arm, the mean MCID answered by physicians was 11.6% (range 5-25%, SD 5.2), compared to the mean MCID answered by patients was 10.0% (range 5-20%, SD 6.4) (p=0.28). The mean number needed to treat (NNT) answered by both physicians and patients was 16. In the majority of cases from both groups, the related concepts of MCID and NNT did not match statistically (i.e. an MCID of 15% is a NNT of 7).An overarching theme from the patient survey comments and interviews was that statistics were somewhat irrelevant. The majority of women thought that “any increase in a chance of live birth” was worth it. However, there was variation in patient responses where some women would only accept a certain success rate of LMWH to justify its use because of drug cost or side effects. Some women acknowledged that they would not use LMWH themselves, but still advocated for other patients to have the option of LMWH use for a chance of a live birth. CONCLUSIONThe mean MCID and NNT were similar between patient and physician groups. The low mean MCID and NNT values likely reflect the importance of the outcome studied (avoiding pregnancy loss) and the perceived safety of the proposed interventions of LMWH and/or ASA, which is supported by qualitative data from patient interviews. While the MCID and NNT responses were similar among physicians and patients, the understanding of statistics was somewhat limited in both groups. By better understanding patients' rationale and beliefs about LMWH use, we can better engage them in clinical trial planning and patient care and ensure that we are performing research that is relevant to patients. DisclosuresSkeith:Leo Pharma: Honoraria; CSL Behring: Research Funding. Rodger:Biomerieux: Research Funding.

HIBISCUS: Hydroxychloroquine for the secondary prevention of thrombotic and obstetrical events in primary antiphospholipid syndrome.

The relapse rate in antiphospholipid syndrome (APS) remains high, i.e. around 20%-21% at 5 years in thrombotic APS and 20-28% in obstetrical APS [2, 3]. Hydroxychloroquine (HCQ) appears as an additional therapy, as it possesses immunomodulatory and anti-thrombotic various effects [4-16]. Our group recently obtained the orphan designation of HCQ in antiphospholipid syndrome by the European Medicine Agency. Furthermore, the leaders of the project made the proposal of an international project, HIBISCUS, about the use of Hydroxychloroquine in secondary prevention of obstetrical and thrombotic events in primary APS. This study has been launched in several countries and at now, 53 centers from 16 countries participate to this international trial. This trial consists in two parts: a retrospective and a prospective study. The French part of the trial in thrombosis has been granted by the French Minister of Health in December 2015 (the academic trial independent of the pharmaceutical industry PHRC N PAPIRUS) and is coordinated by one of the members of the leading consortium of HIBISCUS.

8. Abstract Title: “Part of the Ritual”: A qualitative study of patient and physician perspectives on the use of anticoagulation for improving pregnancy outcomes in obstetrical antiphospholipid syndrome

Introduction: Antiphospholipid syndrome is an acquired thrombophilia associated with recurrent pregnancy loss. Treatment with low-molecular-weight heparin (LMWH) and/or aspirin (ASA) during pregnancy to prevent future loss is based on limited trial data with mixed results. Given the clinical equipoise, we sought to understand how patients and physicians navigate the decision-making process for use of antepartum LMWH and/or ASA. This research is needed to inform the feasibility of future research that seeks to resolve the question of treatment efficacy in this patient population.

7. Abstract Title: Engaging patients in clinical trial planning: Exploring the concept of a minimal clinically important difference among patients with obstetrical antiphospholipid syndrome

7. Abstract Title: Engaging patients in clinical trial planning: Exploring the concept of a minimal clinically important difference among patients with obstetrical antiphospholipid syndrome

Study of clinical utility of antibodies to phosphatidylserine/prothrombin complex in Asian-Indian patients with suspected APS.

Antiphospholipid syndrome (APS) is the most common acquired pro-thrombotic disorder, also associated with obstetric complications. Phosphatidylserine/Prothrombin complex antibody (aPSPT) though associated with various APS manifestations, is not included in the revised Sapporo Criteria. To study the prevalence of aPSPT in Asian-Indian patients with suspected APS and compare its performance with the criteria anti-phospholipid antibodies (APLs). Electronic charts of 372 individuals whose sera was tested for aPSPT in suspected APS between June 2014 and May 2016 were retrieved and analyzed. aPSPT was assayed by ELISA. aPSPT tested individuals were categorized into cases-seropositive and seronegative APS (SNAPS) and controls. aPSPT was positive in 24/58 (41.3%) cases and 17/314 (5.4%) controls (p < 0.001). aPSPT positivity was seen in 44.5%, 38.7%, and 58.4% in primary, secondary and SNAPS patients respectively. aPSPT had the best performance among all APLs, in obstetric APS with 31% sensitivity, 97.7% specificity, and an odds ratio of 18.8. It showed 41.4% sensitivity, 94.6% specificity for the classification/diagnosis of primary APS and 38.7% sensitivity, 91.5% specificity for secondary APS. Addition of aPSPT to current APS criteria to SNAPS patients led to reclassification of additional 12.1% patients as APS overall and 42.8% in obstetric APS category. In Asian-Indian patients with suspected APS, aPSPT outperformed all classical APLs in diagnosis/classification of obstetric APS and both isotypes of beta 2-glycoprotein-I antibodies in diagnosis/classification of APS. aPSPT could reclassify additional 12.1 and 42.8% patients as APS overall and obstetric APS respectively, over and above the cases satisfying revised Sapporo criteria.

Antiphospholipid syndrome – an update

Antiphospholipid syndrome (APS) is an autoantibody-mediated acquired thrombophilia. It is characterized by the presence of antiphospholipid antibodies (APL) that are directed against phospholipid-binding plasma proteins, such as beta-2-glycoprotein I (b2GPI). Its main manifestations are recurrent vascular thromboses (so-called "thrombotic APS") and pregnancy complications ("obstetric APS"). According to the current consensus criteria, a persistently positive functional lupus anticoagulant (LA) assay and/or the presence of anti-b2GPI and/or anti-cardiolipin antibodies, together with clinical symptoms, is mandatory for the diagnosis of APS. Other clinical features, such as thrombocytopenia, Coombs-positive haemolytic anaemia, heart valve disease, renal microangiopathy and neurologic disorders are also common in APL-positive patients. APS can be associated with other autoimmune disorders, such as systemic lupus erythematosus. In rare cases, catastrophic APS (CAPS) occurs, with the development of excessive thrombosis at multiple sites, usually affecting small vessels and leading to multi-organ dysfunction and organ failure. Treatment usually comprises antithrombotic therapy using antiplatelet and anticoagulant agents. However, there is no consensus concerning the intensity or duration of therapy. Despite apparently adequate anticoagulation, the risk of recurrent thrombosis remains high. For patients with CAPS, a combined therapeutic approach that includes anticoagulation, glucocorticoids, plasma exchange and/or intravenous immunoglobulin seems to be the best treatment option. Keywords: Antiphospholipid syndrome, lupus anticoagulants, anti-cardiolipin, anti-beta-2-glycoprotein I, vascular thrombosis, pregnancy complication.