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Objective: This study evaluates the endometrial receptivity of obstetric anticardiolipin syndrome (OAPS) patients using various ultrasound indicators and the efficacy of low-dose aspirin (LDA) treatment., Methods: This retrospective study recruited patients from Shanghai Ren Ji Hospital, China from January 2022 to December 2023. Doppler parameters of the endometrium and uterine artery blood flow were recorded to assess the endometrial receptivity of OAPS patients compared with normal pregnant women and an other immune diseases group. The receiver operating characteristic curve was used to predict the risk of OAPS patients. Doppler parameters of OAPS patients were conducted repeatedly after a 2-month period of treatment with LDA., Results: Compared with normal pregnant women, the OAPS group showed remarkably increased endometrial perfusion resistance (PI, RI, S/D) and uterine artery perfusion resistance (RI and S/D) (P < 0.001) and had good predictive values (area under the curve = 0.806, 0.976, 0.942, 0.902, and 0.901, respectively). The endometrial thickness of the OAPS group was much thinner than that of the normal group (P < 0.001). Uterine blood flow impedance PI showed no difference in both groups (P = 0.68). In comparison to other autoimmune diseases, the OAPS group also showed an increasing trend in the resistance of endometrium and uterine artery blood flow. After LDA treatment, there was an obvious improvement in the endometrial blood flow perfusion in the OAPS group (P < 0.01)., Conclusion: Compared with the normal group and other autoimmune diseases, the resistance of endometrial and uterine artery blood flow in the OAPS group was increased significantly. The Doppler index showed the predictive value of OAPS, and it was confirmed that LDA could enhance blood perfusion among OAPS women., (© 2024 International Federation of Gynecology and Obstetrics.)

Background: Autoimmune diseases as antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE) could cause many maternal complications. The most common maternal complications of autoimmune diseases are lupus flare, hypertension, nephritis, preeclampsia (PE), eclampsia, and poor pregnancy outcomes which including preterm delivery and pregnancy loss. Only the lupus anticoagulant in the greatest prospective multicenter study has been associated with adverse pregnancy outcomes of the APS., Purpose: This review aims to provide a comprehensive update for predictors in pregnant women with APS/SLE., Methods: These data have been collected from clinical and pathological studies, systematic reviews, and meta-analysis., Results: In recent years the SLE and APS demonstrated to have different and valuable clinical and biomarker predictors for the pregnancy outcome. Treatment of pregnant women with APS is low molecular weight heparin (LMWH) and aspirin; however, around 75% of this management is considered successful., Conclusion: This review summarizes recent research that focuses on biochemical and clinical predictors of adverse pregnancy outcomes (APOs) of pregnant women with SLE and APS. Furthermore, we have collected more evidence that confirms the safety and efficacy of hydroxychloroquine (HCQ) preventing APOs., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Antiphospholipid syndrome is associated with recurrent pregnancy loss. Low-molecular-weight heparin (LMWH) and/or aspirin (ASA) prophylaxis during pregnancy to prevent future loss is based on limited trial data with mixed results., Objectives: Given the clinical equipoise, we sought to understand how patients and physicians navigate the decision-making process for use of LMWH and/or ASA in pregnancy., Methods: We interviewed 10 patients and 10 thrombosis physicians in Ottawa, Canada from January 2017 to March 2018. Patients who had ≥1 late pregnancy loss or ≥2 early losses and persistently positive antiphospholipid antibodies based on the revised Sapporo/Sydney criteria were identified in the a Thrombosis Clinic. Patients were also identified by the TIPPS Study screening logs of excluded patients. Data collection and analysis occurred iteratively, in keeping with constructivist grounded theory methodology., Results: Our analysis generated three themes, present across both patient and physician interviews, which captured a patient-led decision-making experience: (1) managing high stakes, (2) accepting uncertainty, and (3) focusing on safety. 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 by "[leaving] it up to the patient.", Conclusion: Our findings should be considered when designing future research on studying the role for LMWH/ASA in this population, as it suggests that the perceived benefits of treatment go beyond improving pregnancy rates. Rather, patients described potential benefit from the process of taking action, even in the absence of a guaranteed good outcome., Competing Interests: L.S.: honoraria from LEO Pharma; Research funding from CSL Behring. M.A.R.: no conflicts of interest to report. S.M.B.: honoraria from LEO Pharma. C.G.: no conflicts of interests to report. A.K.: no conflicts of interest to report. T.S.T.: no conflicts of interest to report. S.M.B. holds the Eli Lilly Canada/May Cohen Chair in Women's Health. M.R. is the McGill Harry Webster Thorp Professor of Medicine., (Thieme. All rights reserved.)

Objectives: To compare and rank currently available pharmacological interventions for the prevention of recurrent miscarriage (RM) in women with antiphospholipid syndrome (APS)., Methods: A search was performed using PubMed, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, CNKI, ClinicalTrials.gov, and the UK National Research Register on December 15, 2019. Studies comparing any types of active interventions with placebo/inactive control or another active intervention for the prevention of RM in patients with APS were considered for inclusion. The primary outcomes were efficacy (measured by live birth rate) and acceptability (measured by all-cause discontinuation); secondary outcomes were birthweight, preterm birth, preeclampsia, and intrauterine growth retardation. The protocol of this study was registered with Open Science Framework (DOI: 10.17605/OSF.IO/B9T4E)., Results: In total, 54 randomized controlled trials (RCTs) comprising 4,957 participants were included. Low-molecular-weight heparin (LMWH) alone, aspirin plus LMWH or unfractionated heparin (UFH), aspirin plus LMWH plus intravenous immunoglobulin (IVIG), aspirin plus LMWH plus IVIG plus prednisone were found to be effective pharmacological interventions for increasing live birth rate (ORs ranging between 2.88 to 11.24). In terms of acceptability, no significant difference was found between treatments. In terms of adverse perinatal outcomes, aspirin alone was associated with a higher risk of preterm birth than aspirin plus LMWH (OR 3.92, 95% CI 1.16 to 16.44) and with lower birthweight than LMWH (SMD -808.76, 95% CI -1596.54 to -5.07)., Conclusions: Our findings support the use of low-dose aspirin plus heparin as the first-line treatment for prevention of RM in women with APS, and support the efficacy of hydroxychloroquine, IVIG, and prednisone when added to current treatment regimens. More large-scale, high-quality RCTs are needed to confirm these findings, and new pharmacological options should be further evaluated.

Objectives: A previous pilot study showed that pravastatin supplementation improved pregnancy outcomes in women with obstetric antiphospholipid syndrome (OAPS) that developed placental insufficiency despite standard of care treatment low molecular weight heparin plus low dose aspirin (LMWH + LDA). In this study we investigated the mechanism behind the beneficial effects of the triple therapy LMWH + LDA + pravastatin in improving uteroplacental vascular function and reducing pregnancy complications in OAPS. We hypothesized that nitric oxide (NO) is involved in the vasculoprotective effects of the triple therapy. A mouse model of OAPS that resembles the clinical scenario was used to test this hypothesis., Methods: Eleven women with OAPS that developed preeclampsia (PE) and/or intrauterine growth restriction (IUGR) associated with uteroplacental vascular dysfunction despite treatment with LMWH + LDA participated in this study after given informed written consent. Seven women were supplemented with pravastatin at the time abnormal uterine artery Dopplers were detected and 4 remained on LMWH + LDA treatment only. Wire myography was used to identify the mechanisms underpinning the protective effects of the triple therapy in the mouse model of OAPS., Results: The triple therapy increased serum NO levels, diminished uteroplacental vessels resistance improving placental function and prolonged pregnancies compared to conventional treatment LMWH + LDA, leading to live births in women with OAPS. Comparable to the observations in women, the triple therapy protected pregnancies in OAPS-mice, increasing placental perfusion and pregnancy outcomes. A synergistic vasculoprotective effect of the triple therapy on uterine arteries and aorta was demonstrated in OAPS-mice. LMWH + LDA showed a partial protection on endothelial function. Addition of pravastatin increase eNOS synthesis, expression and activity/signaling leading to a significant increment in nitric oxide (NO) generation, resulting in improved placental vascular function and total protection of pregnancies., Conclusion: LMWH + LDA + PRAV increased serum NO levels and significantly improved placental haemodynamics and maternal and neonatal outcomes in women and mice with OAPS. A role for eNOS/NO in mediating the placental vasculoprotective effects in OAPS-mice was demonstrated, strengthening the concept that impaired NO production is a crucial mediator in the pathogenesis of OAPS and a potential target for pharmacological interventions. The efficacy of pravastatin supplementation should be confirmed in a larger clinical trial., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Placenta-mediated pregnancy complications are clinically important conditions and include preeclampsia, placental abruption, intrauterine growth restriction, and late fetal loss. Pathophysiology is complex, and may be linked to prothrombotic disorders such as antiphospholipid syndrome, whose understanding is still evolving. In this narrative review, we will present the latest evidence to better understand hemostatic mechanisms of preeclampsia, as well as in women with placenta-mediated pregnancy complications and inherited thrombophilia or antiphospholipid antibodies. Using four clinical scenarios, the mixed results of preventive efforts through the use of antithrombotic drugs (aspirin, heparin) will be discussed. We will also review knowledge gaps and ongoing research., Competing Interests: L.S.: Honoraria from Leo Pharma; research funding from CSL Behring. M.B: no conflicts of interest. F.N.A.: Research funding (paid via an IIS to the host university) from Bayer, Leo Pharma, and Actelion., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: The current treatment to prevent pregnancy morbidity (PM) associated with antiphospholipid antibodies (aPL) is based on the use of low dose aspirin and low molecular weight heparin (henceforth defined as standard of care (SoC) treatment). Despite the SoC, up to 30% of women with aPL continue to have pregnancy complications. The global antiphospholipid syndrome (APS) score (GAPSS) is a tool to quantify the risk for the aPL-related clinical manifestations. In this study, we investigated the individual clinical response to SoC in women with aPL after stratifying them according to their GAPSS., Methods: One-hundred-fourty-three women (352 pregnancies) with aPL ever pregnant treated with SoC therapy were included. The patients GAPSS was then grouped according to the patients' GAPSS into low risk (< 6), medium risk (6-11), and high risk (≥12)., Results: The live birth rate was 70.5% (248 out of the 352 pregnancies), 45 patients (31%) experienced at least one event of PM, defined as early or late. Patients were stratified according to GAPSS values, in order to identify a low risk group (GAPSS <6, n = 72), a medium risk group (GAPSS 6-11, n = 66) and a high risk group (GAPSS ≥12, n = 5). When considering patients who ever experienced any PM while treated with SoC, all patients in the high risk group experienced PM, while patients in the medium group had a significant higher rate of PM when compared to the low risk group [29 (43.9%) patients V.s. 11 (15.3%), respectively; p < 0.001]. When analysing the number of pregnancies in the three groups, patients in the high risk group had significantly lower live birth rates, when compared to the other groups [11 (40.7%) live births vs. 100 (62.1%) and 137 (82.5%), respectively; p < 0.05]. Furthermore, patients with medium risk group also had significantly lower live birth rates, when compared to the lower risk group (p < 0.001)., Conclusions: GAPSS might be a valuable tool for to identify patients with a higher likelihood of response to SoC., Competing Interests: Declaration of Competing Interest None declared, (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: To compare clinical features, laboratory data and fetal-maternal outcomes between 1000 women with obstetric APS (OAPS) and 640 with aPL-related obstetric complications not fulfilling Sydney criteria (non-criteria OAPS, NC-OAPS)., Methods: This was a retrospective and prospective multicentre study from the European Registry on Obstetric Antiphospholipid Syndrome., Results: A total of 1650 women with 5251 episodes, 3601 of which were historical and 1650 latest episodes, were included. Altogether, 1000 cases (OAPS group) fulfilled the Sydney classification criteria and 650 (NC-OAPS group) did not. Ten NC-OAPS cases were excluded for presenting thrombosis during follow-up. All cases were classified as category I (triple positivity or double positivity for aPL) or category II (simple positivity). Overall, aPL laboratory categories showed significant differences: 29.20% in OAPS vs 17.96% in NC-OAPS (P < 0.0001) for category I, and 70.8% in OAPS vs 82% in NC-OAPS (P < 0.0001) for category II. Significant differences were observed when current obstetric complications were compared (P < 0.001). However, major differences between groups were not observed in treatment rates, livebirths and thrombotic complications. In the NC-OAPS group, 176/640 (27.5%) did not fulfil Sydney clinical criteria (subgroup A), 175/640 (27.34%) had a low titre and/or non-persistent aPL positivity but did meet the clinical criteria (subgroup B) and 289/640 (45.15%) had a high aPL titre but did not fulfil Sydney clinical criteria (subgroup C)., Conclusion: Significant clinical and laboratory differences were found between groups. Fetal-maternal outcomes were similar in both groups when treated. These results suggest that we could improve our clinical practice with better understanding of NC-OAPS patients., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose of Review: Antiphospholipid syndrome (APS), more common than once believed, is an autoimmune disease best known for its high risk of incident and recurrent thrombotic events. The approach to treatment potentially differs from treatment of thrombosis in the general population, and this article endeavors to review the latest updates on this topic., Recent Findings: The epidemiology of APS is being increasingly elucidated by large population-based studies, with APS perhaps affecting as many as 1 in 2000 individuals. Vitamin K antagonists, aspirin, and heparinoids continue to have obvious roles in the management of patients with APS. There has recently been intensive study of direct oral anticoagulants in APS, with the most recent randomized studies raising concerns about their inferiority to vitamin K antagonists, at least in some subgroups. Other approaches to treating APS beyond anticoagulants and antiaggregants are also receiving increased attention in mechanistic and preclinical studies with an eye toward future roles in patients with refractory and/or microvascular disease. Pediatric APS is identified as an area in desperate need of additional prospective research., Summary: Progress continues to be made in pursuit of improving the lives of individuals afflicted with APS. The most important future directions would seem to involve leveraging modern molecular technologies in order to improve subphenotyping of antiphospholipid antibody-positive individuals. This will help personalize risk profiles and ideally define the optimal approach to therapy based on future risk, rather than past morbid events.

Antiphospholipid syndrome (APS) is a rare condition clinically characterized by thrombotic events or pregnancy complications and confirmed by one or more repeatedly positive antiphospholipid antibodies on two or more occasions at least 12 weeks apart. Several factors are thought to have roles in the pathogenesis of adverse obstetric events related to APS, including platelet and endothelial cell activation, complement activation, and ultimate activation of the thrombotic pathway. Despite standard treatment with a heparin agent and low-dose aspirin, 30% of women with definite APS cannot achieve a successful pregnancy outcome. Additional treatment options are still controversial, and prospective trials with appropriate controls are needed to investigate the efficiency of alternative treatments. In this chapter, we discuss diagnostic, clinical, and therapeutic approaches in the treatment of APS syndrome in pregnancy., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest., (Copyright © 2019. Published by Elsevier Ltd.)

Antiphospholipid syndrome (APS) is one of the treatable causes for pregnant women with recurrent pregnancy loss (RPL). This review compares the efficacy of a few treatment interventions (low-dose aspirin (LDA), aspirin plus low molecular weight heparin (LMWH), or unfractionated heparin (UFH)) in preventing complications during pregnancy and miscarriages for women with RPL and APS, and the potential differences in therapeutic effects of UFH and LMWH when combined with aspirin. We searched randomized controlled trials (RCTs) in MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials and performed a systematic review and a Bayesian network meta-analysis (NMA). Finally, we found aspirin alone had a lower live birth rate compared to LMWH plus aspirin (OR = 0.37; 95% CrI, 0.17, 0.71), and UFH plus aspirin showed a higher live birth rate than aspirin alone (OR = 2.63; 95% CrI, 1.04, 5.39) in NMA, treating with UFH plus aspirin or LMWH plus aspirin did not have difference on live birth. Furthermore, LDA alone resulted in a lower birthweight compared to heparin plus aspirin, while higher birthweight was found when compared UFH plus aspirin to LMWH plus aspirin (MD = 895.40; 95% CrI, 817.40, 988.57) in NMA. Additionally, in women with RPL and APS and without a prior thrombosis, heparin plus aspirin improved birthweight but could not promote live birth rate compared to aspirin alone. In conclusion, heparin plus aspirin is recommended for women with RPL and APS. Notably UFH plus aspirin demonstrates the most significant therapeutic efficacy among these interventions in improving birthweight., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The current study evaluates the efficacy and safety of different treatment strategies for pregnant patients with antiphospholipid syndrome. One hundred twenty-seven consecutive pregnancies were assessed; 87 (68.5%) with a history of pregnancy morbidity alone were treated with prophylactic low molecular weight heparin (LMWH) + low-dose aspirin (LDA, 100 mg) (group I) and 40 (31.5%) with a history of thrombosis and/or severe pregnancy complications with therapeutic LMWH + LDA (group II). LMWH doses were increased throughout the pregnancies depending on the patients' weight gain, and treatment was switched to a more intensive one at the first sign of maternal/fetal complications. The study's primary outcome was live births. There were no significant differences in live birth rate between group I (95.4%) and group II (87.5%). Even fetal complication rate was similar in the two groups; group II nevertheless had a higher prevalence of maternal and neonatal complications ( p  = 0.0005 and p  = 0.01, respectively) and registered a significantly lower gestational age at delivery and birth weight ( p  = 0.0001 and p  = 0.0005, respectively). Two patients in group I switched to group II therapy, six patients in group II switched to a more intensive treatment strategy (weekly plasma exchange + fortnightly intravenous immunoglobulins in addition to therapeutic LMWH + LDA). The multivariate analysis uncovered that triple antiphospholipid antibodies positivity was an independent factor leading to a more intensive therapy. All eight switched patients achieved a live birth. Study results revealed that adjusted LMWH doses and switching therapy at first signs of severe pregnancy complications led to a high rate of live births in antiphospholipid syndrome patients., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

Objective: Antiphospholipid antibodies (aPL) are risk factors for thrombosis and adverse pregnancy outcomes (APO). The management of the so called "aPL carriers" (subjects with aPL positivity without the clinical criteria manifestations of APS) is still undefined. This study aims at retrospectively evaluating the outcomes and the factors associated with APO and maternal complications in 62 pregnant aPL carriers. Methods: Medical records of pregnant women regularly attending the Pregnancy Clinic of 3 Rheumatology centers from January 1994 to December 2015 were retrospectively evaluated. Patients with concomitant autoimmune diseases or other causes of pregnancy complications were excluded. Results: An aPL-related event was recorded in 8 out of 62 patients (12.9%) during pregnancy: 2 thrombosis and 6 APO. At univariate analysis, factors associated with pregnancy complications were acquired risk factors (p:0.008), non-criteria aPL manifestations (p:0.024), lupus-like manifestations (p:0.013), and triple positive aPL profile (p:0.001). At multivariate analysis, only the association with a triple aPL profile was confirmed (p:0.01, OR 21.3, CI 95% 1.84-247). Patients with triple aPL positivity had a higher rate of pregnancy complications, despite they were more frequently receiving combined treatment of low dose aspirin (LDA) and low molecular weight heparin (LMWH) at prophylactic dose. Conclusion: This study highlights the importance of risk stratification in pregnant aPL carriers, in terms of both immunologic and non-immunologic features. Combination treatment with LDA and LMWH did not prevent APO in some cases, especially in carriers of triple aPL positivity. Triple positive aPL carriers may deserve additional therapeutic strategies during pregnancy.

Purpose The purpose of this study was to evaluate the safety of antithrombotic treatments prescribed during pregnancy in patients with antiphospholipid syndrome (APS). Methods This international, multicenter study included two cohorts of patients: a retrospective French cohort and a prospective US cohort (PROMISSE study). Inclusion criteria were (1) APS (Sydney criteria), (2) live pregnancy at 12 weeks of gestation (WG) with (3) follow-up data until six weeks post-partum. According to APS standard of care, patients were treated with aspirin and/or low-molecular weight heparin (LMWH) at prophylactic (pure obstetric APS) or therapeutic doses (history of thrombosis). Major bleeding was defined as abnormal blood loss during the pregnancy and/or post-partum period requiring intervention for hemostasis or transfusion, or during the peripartum period greater than 500 mL and/or requiring surgery or transfusion. Other bleeding events were classified as minor. Results Two hundred and sixty-four pregnancies (87 prospectively collected) in 204 patients were included (46% with history of thrombosis, 23% with associated systemic lupus). During pregnancy, treatment included LMWH ( n = 253; 96%) or low-dose aspirin ( n = 223; 84%), and 215 (81%) patients received both therapies. The live birth rate was 89% and 82% in the retrospective and prospective cohorts, respectively. Adverse pregnancy outcomes occurred in 28% of the retrospective cohort and in 40% of the prospective cohort. No maternal death was observed in either cohort. A combined total of 45 hemorrhagic events (25%) occurred in the retrospective cohort, but major bleeding was reported in only six pregnancies (3%). Neither heparin nor aspirin alone nor combined therapy increased the risk of hemorrhage. We also did not observe an increased rate of bleeding in the case of a short interval between last LMWH (less than 24 hours) or aspirin (less than five days) doses and delivery. Only emergency Caesarean section was significantly associated with an increased risk of bleeding (odds ratio (OR) 5.03 (1.41-17.96); p=.016). In the prospective cohort, only one minor bleeding event was reported (vaginal bleeding). Conclusion Our findings support the safety of antithrombotic therapy with aspirin and/or LMWH during pregnancy in high-risk women with APS, and highlight the need for better treatments to improve pregnancy outcomes in APS. PROMISSE Study ClinicalTrials.gov identifier: NCT00198068.

Purpose of Review: This review focuses on new pathogenesis and clinical-therapeutic aspects of obstetric anti-phospholipid syndrome (ob-APS) in the last 5 years., Recent Findings: The pathogenesis of ob-APS is multifactorial, including placental infarctions, infiltration of inflammatory cells that cause acute and chronic inflammation, leading to uncontrolled inflammation and poor pregnancy outcomes. A preconception counseling and a patient-tailored treatment are fundamental to improve maternal and fetal outcomes. Thanks to conventional treatment, based on low-dose aspirin and heparin, 70% of women with ob-APS can have successful pregnancies. Women with positive anti-phospholipid antibodies (aPL) without clinical manifestations ("aPL carriers") or with obstetric manifestation not fulfilling ob-APS criteria need to be further investigated in order to assess their best management. Great interest has been given to drugs that could interact in the pathophysiological mechanisms, such as hydroxychloroquine, statins, and eculizumab. These drugs could be considered for patients refractory to conventional therapy.

Problem: Women with antiphospholipid antibodies (aPL) are at risk for pregnancy complications despite treatment with low molecular weight heparin (LMWH) or aspirin (ASA). aPL recognizing beta 2 glycoprotein I can target the uterine endothelium, however, little is known about its response to aPL. This study characterized the effect of aPL on human endometrial endothelial cells (HEECs), and the influence of LMWH and ASA., Method of Study: HEECs were exposed to aPL or control IgG, with or without low-dose LMWH and ASA, alone or in combination. Chemokine and angiogenic factor secretion were measured by ELISA. A tube formation assay was used to measure angiogenesis., Results: aPL increased HEEC secretion of pro-angiogenic VEGF and PlGF; increased anti-angiogenic sFlt-1; inhibited basal secretion of the chemokines MCP-1, G-CSF, and GRO-α; and impaired angiogenesis. LMWH and ASA, alone and in combination, exacerbated the aPL-induced changes in the HEEC angiogenic factor and chemokine profile. There was no reversal of the aPL inhibition of HEEC angiogenesis by either single or combination therapy., Conclusion: By aPL inhibiting HEEC chemokine secretion and promoting sFlt-1 release, the uterine endothelium may contribute to impaired placentation and vascular transformation. LMWH and ASA may further contribute to endothelium dysfunction in women with obstetric APS., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: To describe the consecutive pregnancy outcome and treatment in refractory obstetrical antiphospholipid syndrome (APS)., Methods: Retrospective multicenter open-labelled study from December 2015 to June 2016. We analyzed the outcome of pregnancies in patients with obstetrical APS (Sydney criteria) and previous adverse obstetrical event despite low-dose aspirin and low-molecular weight heparin LMWH (LMWH) conventional treatment who experienced at least one subsequent pregnancy., Results: Forty nine patients with median age 27years (23-32) were included from 8 European centers. Obstetrical APS was present in 71%, while 26% had obstetrical and thrombotic APS. Lupus anticoagulant was present in 76% and triple antiphospholipid antibody (APL) positivity in 45% of patients. Pregnancy loss was noted in 71% with a median age of gestation of 11 (8-21) weeks. The presence of APS non-criteria features (35% vs 17% in pregnancies without adverse obstetrical event; p=0.09), previous intrauterine death (65% vs 38%; p=0.06), of LA (90% vs 65%; p=0.05) were more frequent in pregnancies with adverse pregnancy outcome, whereas isolated recurrent miscarriage profile was more frequent in pregnancies without any adverse pregnancy outcome (15% vs 41%; p=0.04). In univariate analysis considering all pregnancies (index and subsequent ones), an history of previous intrauterine death was associated with pregnancy loss (odds-ratio 2.51 (95% CI 1.274.96); p=0.008), whereas previous history of prematurity related to APS (odds-ratio 0.13 95%CI 0.04 0.41, P=0.006), steroids use during the pregnancy (odds-ratio 0.30 95% CI 0.11-0.82, p=0.019) and anticardiolipids isolated profile (odds-ratio 0.51 95% CI 0.26-1.03, p=0.0588) were associated with favorable outcome. In multivariate analysis, only previous history of prematurity, steroids use and anticardiolipids isolated profiles were associated with live-birth pregnancy., Conclusion: The main features of refractory obstetrical APS were the high rates of LA and triple APL positivity. Steroids could be effective in this APS profile, but prospective studies are necessary., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The use of low-dose aspirin in pregnancy should remain a highly targeted indication since its long-term safety has not been established and should be restricted to women at high risk of vascular complications. Indications for which the benefit of aspirin has been shown are women with a history of preeclampsia responsible for a premature birth before 34 weeks, those having at least two history of preeclampsia, those with an antiphospholipid syndrome and those with lupus associated with positive antiphospholipid antibodies or renal failure. In all other cases, the level of evidence of the benefit of aspirin is insufficient to recommend its routine prescription., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Objective: To relate anticoagulant use to pregnancy complications in women with systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (APS)., Methods: All ongoing pregnancies, 184, in two Dutch tertiary centers between 2000 and 2015., Results: LMWH and aspirin was prescribed in 15/109 SLE women without antiphospholipid antibodies (aPL), 5/14 with aPL, 11/13 with APS, 45/48 with primary APS. Main complications in the four treatment groups (no anticoagulant treatment, aspirin, LMWH, aspirin and LMWH) included hypertensive disorders of pregnancy (9.4%, 23.3%, 50%, 18.4%, respectively, p = 0.12) and preterm birth (16.7%, 34.3%, 75%, 36.8%, respectively, p < 0.001)., Conclusion: Maternal and perinatal complications occurred frequently, despite LMWH and aspirin use.

Obstetrical APS is defined by thrombosis and/or obstetrical morbidity associated with persistent antiphospholipid antibodies. The aspirin and low molecular weighted heparin combination dramatically improved obstetrical outcome in APS patients. Several factors could be associated with obstetrical prognosis, as previous history of thrombosis, associated SLE, the presence of lupus anticoagulant and triple positivity of antiphospholipid antibodies. Obstetrical APS with isolated recurrent miscarriages is mostly associated with isolated anticardiolipids antibodies and have better obstetrical outcome. The pregnancy loss despite aspirin and heparin combination define the refractory obstetrical APS, and the prevalence could be estimated to 20-39%. Several other treatments have been used in small and open labeled studies, as steroids, intravenous immunoglobulins, plasma exchanges and hydroxychloroquine to improve the obstetrical outcome. Some other drugs as eculizumab and statins could also have physiopathological rational, but studies are necessary to define the place of these various drugs., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

We present a case of a 37-year-old Chinese woman (gravida 4 para 0) with a history of immune thrombocytopenia and type IIb antiphospholipid syndrome. She was started on 100 mg of aspirin, 20 mg of prednisolone and 20 mg of subcutaneous low-molecular-weight heparin daily for her fourth pregnancy. She opted for non-invasive prenatal testing for aneuploidy screening but had failed results three times consecutively from insufficient fetal cfDNA initially or high variance in cfDNA counts on redraws. She declined invasive karyotyping. Her pregnancy was complicated by severe pre-eclampsia and fetal growth restriction at 19+6 weeks of gestation and was terminated. Subsequent fetal karyotyping revealed a normal karyotype of 46XY with no apparent abnormalities., Competing Interests: Conflicts of Interest: None declared., (2016 BMJ Publishing Group Ltd.)

Antiphospholipid syndrome (APS) is an acquired autoimmune condition characterized by thrombotic events, pregnancy morbidity, and laboratory evidence of antiphospholipid antibodies (aPL). Management of these patients includes the prevention of a first thrombotic episode in at-risk patients (primary prevention) and preventing recurrent thrombotic complications in patients with a history of thrombosis (secondary prevention). Assessment of thrombotic risk in these patients, balanced against estimated bleeding risks associated with antithrombotic therapy could assist clinicians in determining whether antithrombotic therapy is warranted. Thrombotic risk can be assessed by evaluating a patient's aPL profile and additional thrombotic risk factors. Although antithrombotic options for secondary prevention of venous thromboembolism (VTE) have been evaluated in clinical trials, studies in primary prevention of asymptomatic aPL-positive patients are needed. Primary prevention with aspirin may be considered in asymptomatic patients who have a high-risk aPL profile, particularly if additional risk factors are present. Secondary prevention with long-term anticoagulation is recommended based on estimated risks of VTE recurrence, although routine evaluation of thrombotic risk can assist in determining whether ongoing anticoagulation is warranted. Studies that stratify thrombotic risk in aPL-positive patients, and patients with APS evaluating antithrombotic and non-antithrombotic therapies will be useful in optimizing the management of these patients., (© 2016 by The American Society of Hematology. All rights reserved.)

Aim: To analyze current practices in Bulgaria regarding antithrombotic medication (AM) during pregnancy, and to compare them with the ones recommended in literature., Materials and Methods: In 84 pregnant women who were low dose aspirin (LDA) or/and low molecular weight heparin (LMWH) or unfractionated heparin (UH), data about AM were collected and analyzed. A descriptive analysis was performed of the indications for AM, its type, the applied doses and therapeutic regimens., Results: 39/84 pregnant women (46.4%) had indications for AM. In 18/84 cases (21.4%) the type of AM was precisely selected according to the indications. Of them 12 were on LDA alone (8--history of early preeclampsia/IUGR, 2--diabetes, 1--autoimmune disease, 1--chronic hypertension), 4--on LMWH/UF alone (2--venous thromboembolism, 2--essential thrombocytemia) and 2 received both LMH and LDA (1--antiphospholipid syndrome, 1--phlebothrombosis and stillbirth). Another 21/84 cases (25%) had indications for AM but its type was not appropriately selected. This subgroup included cases with high risk inherited thrombophylia (IT), history of placental mediated disease (PMD) in previous pregnancies and/or accompanying medical disorders. These patients had indications for either LDA or LMA administration, but were on combined medication. In 45/84 cases (53.6%) with uneventful past obstetric history or early pregnancy losses (before 10 w.g.) but no PMD there were no indications for AM. Among them, 17/84 (20.2%) had low risk IT in 18/84 (21.4%) IT was ruled out and 10/84 (12%) were not tested for IT at all. In total, 64/84 patients (76.2%) were on LDA--alone (25/84 - 29.8%), or in combination with LMWH (39/84 - 46.4%). Treatment with LDA was indicated in 45/64 (70.3%) cases--12/25 (48%) of the ones who were on LDA alone and 23/39 (59%) of those on LDA and LMW In 19/64 cases (29.7%) LDA administration was not indicated. 59/84 (70.2%) of the patients were on LMW/UH- alone (20/84 - 23.8%) orin combination with LDA (39/84 - 46.4%). This therapy was indicated in only 6/59 cases (10.2%), treated with LMWH/UH - 4/20 (20%) of the ones on LMWH/UH alone and 2/39 (5.2%) of the ones on LDA plus LMWH. In 53/59 cases (89.8%) the administration of LMWH was not indicated. LDA was started preconceptionally, in the Ist or in the lind trimester in 12/64 (18.7%), 32/64 (50%) and 6/64 (9.4%) of the cases respectively. LMWN/UH was started preconceptionally, in the Ist orin the lind trimester in 5/59 (8.6%), 33/59 (56.9%) and 5/59 (8.6%) of the cases respectively. The information when AM was started was not reliable in 14/64 (21.9%) cases on LDA and in 16/59 (27.1%) - on LMWH. In 12/84 cases (14.3%) LDA and LMWH were administered every other day. This referred to 5/64 (7.8%) cases on LDA and to 7/58 (12.1%) - on LMWH. LDA and LMWH were administered in PAI 4G/4G polymorphism despite the fact that in'these cases fibrinolysis but not coagulation was affected., Conclusions: AM was administered according to strict indications and with appropriately selected preparations in only 21.4% of the studied cases. In another 25% there were indications for AM, but its type was not precisely selected. 53.6% of the patients had no indications for AM. LDA administration (alone or in combination with LMWH) was indicated in 70.9% of the cases; the same referred to only 10.2% of the ones who were on LMWH. Application/administration of AM every other day was inappropriate given the pharmacokinetics of the preparations. AM was also applied in IT with decreased fibrinolysis but not increased coagulability.

Purpose of Review: To review the recent diagnostic criteria, clinical implications, and therapeutic protocols for antiphospholipid antibody syndrome (APS)., Recent Findings: Much has been learned in the recent years concerning the diagnosis of and clinical implications associated with the APS. A number of studies demonstrate some pathophysiologic mechanisms that suggest the impact of antiphospholipid antibodies (APAs) on successful growth and development of the placenta, and ultimately the embryo. These findings are discussed in context with establishing the Bradford Hill criteria for causation between APAs and recurrent pregnancy loss. The recent clinical recommendations from the American Society for Reproductive Medicine and the American College of Obstetrics and Gynecology are included. Practical guidelines for clinicians faced with treating women with antiphospholipid syndrome are presented., Summary: The diagnosis of APS is defined and the clinical treatment protocol recommendations are discussed.

We performed a meta-analysis to determine whether aspirin has a significant protective effect on risk of first thrombosis among patients with antiphospholipid antibodies (aPL+). Observational and interventional studies identified from the Medline, Embase and Cochrane databases were selected if they assessed the incidence of first thrombosis in aPL+ patients treated with aspirin versus those without. Pooled effect estimates were obtained using a random-effects model. Of 1211 citation retrieved, 11 primary studies (10 observational and 1 interventional) met inclusion criteria, including a total of 1208 patients and 139 thrombotic events. The pooled odds ratio (OR) for the risk of first thrombosis in patients treated with aspirin (n=601) was 0.50 (95%CI: 0.27 to 0.93) compared to those without aspirin (n=607), with significant heterogeneity across studies (I(2)=46%, p=0.05). Subgroup analysis showed a protective effect of aspirin against arterial (OR: 0.48 [95%CI: 0.28-0.82]) but not venous (OR: 0.58 [95% CI: 0.32-1.06]) thrombosis, as well as in retrospective (OR: 0.23 [0.13-0.42]) but not prospective studies (OR: 0.91 [0.52-1.59]). Subgroup analysis according to underlying disease revealed a significant protective effect of aspirin for asymptomatic aPL+ individuals (OR: 0.50 [0.25-0.99]), for systemic lupus erythematosus (SLE) (OR: 0.55 [0.31-0.98]) and obstetrical antiphospholipid syndrome (APS) (OR: 0.25 [0.10-0.62]). This meta-analysis shows that the risk of first thrombotic event is significantly decreased by low dose aspirin among asymptomatic aPL individuals, patients with SLE or obstetrical APS. Importantly, no significant risk reduction was observed when considering only prospective studies or those with the best methodological quality., (© 2013.)

Objective: The effect of low-dose aspirin (LDA) on pregnancy outcome in antiphospholipid (aPL)-positive women not fulfilling the criteria for antiphospholipid antibody syndrome (APS) was evaluated retrospectively., Methods: We evaluated 139 pregnancies of 114 aPL-positive women not fulfilling the Sydney classification criteria for definite APS (104 treated with LDA, 35 untreated). Inclusion criteria consisted of (1) any titer of aPL and no previous pregnancy or no pregnancy losses (defined as aPL carriers); (2) any titer of aPL and 1 or 2 pregnancy losses before the 10th gestational week. No women had previous thrombosis. The rate of pregnancy loss, gestational age at delivery, and birth weight percentile were compared in the treated and untreated patients. Associations between clinical and laboratory characteristics and pregnancy outcomes were investigated., Results: The rate of pregnancy loss was low in both treated and untreated groups (7.7% vs 2.9%, respectively). There were no statistically significant differences in the rate of pregnancy loss, gestational age at birth, or birth weight percentile in the treated and untreated groups. There were significant associations between gestational age at birth ≤ 34th week and positivity for lupus anticoagulant (p = 0.025) and anti-ß2-glycoprotein I IgG antibodies at titers > 99th (p = 0.016)., Conclusion: LDA treatment does not appear to improve pregnancy outcome in low-risk women not fulfilling the criteria for APS. Because antibody profile seems to influence pregnancy outcome, further studies of patients stratified according to their antibody profile are warranted.

The prevention of thrombosis in the antiphospholipid syndrome (APS) remains controversial. The purpose of this review is to provide updated recommendations. There is evidence that patients at risk of thrombosis are those with "a pattern of high risk antiphospholipid antibodies (aPL)" (presence of a lupus anticoagulant [LA], association of several aPL, or persistent aCL at a medium or high level), or those with associated systemic lupus erythematosus (SLE). The prescription of aspirin in primary prevention is recommended in SLE patients with positive LA or persistent aCL at a significant level. Secondary prevention is based on a very prolonged anticoagulation. An INR around 2.5 seems to be sufficient in patients with venous APS. In case of arterial events, the attitude is debated. We propose to maintain a target INR between 3 and 3.5. The possible occurrence of relapse despite anticoagulation in the therapeutic target may lead to the addition of aspirin. The development of new anti-thrombotic agents might change the management of APS in the coming years., (Copyright © 2012 Société nationale Française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Study Objective: To compare the live birth rate of women presented with recurrent miscarriages in the first trimester due to antiphospholipid antibody syndrome (APS), randomized to either low molecular weight heparin (Bemiparin) or low dose aspirin (LDA) and to determine the maternal and fetal adverse effects in both treatment groups., Patients and Methods: A clinical comparative study was conducted in Maternity teaching Hospital, Erbil city, north of Iraq, Kurdistan region from 15th of September 2007 to the 1st of August 2010 on 141 women presented with 2 or more consecutive miscarriages due to APS, the women randomized to receive either prophylactic dose of Bemiparin with the diagnosis of pregnancy or LDA started preconceptioally and until 36 weeks gestation. The primary outcome was live birth rate in both treatment groups, the secondary outcomes were maternal and fetal complications in both trial groups., Result: There was no statistically significant difference between the two groups regarding demographic characters (age groups, parity, gestational age and history of previous abortion), and mode of delivery of the viable newborns. There was a statistically significant difference between the two treatment groups regarding live birth rate. The proportions of women who gave birth to a live infant were 72.13% in the LDA group and 86.25% in the Hibor group, the mean difference between the live birth rate in both group was 0.141 (95% Confidence interval of the difference, 0.08, 0.274). The average birth weight for women received LDA was significantly lower than women who received Bemiparin., Conclusion: The use of the new second generation LMWH (Bemiparin) in comparison to LDA during pregnancy for prevention of recurrent miscarriage in women with APS is a safe, reliable method with a high live birth rate and no maternal and fetal complications.

Introduction: The primary antiphospholipid syndrome (PAS) is an independent risk factor for cerebral infarction. AIM. To evaluate the risk of recurrence, to compare different treatments and determine the risk factors associated with recurrence and hemorrhagic complications in patients with cerebral infarction and PAS., Patients and Methods: Prospectively collected data from 92 patients under 45 years (71% female, mean age 33.8 ± 8.9 years) with confirmed diagnoses of cerebral infarction and PAS, treated with anticoagulants (n = 54) or aspirin (n = 38) were retrospectively analyzed. Clinical follow-up was obtained by neurological examination every 6 to 12 months. Outcome measures were: recurrence of CI, symptomatic intracerebral hemorrhage, and minor bleeding., Results: During a median follow-up of 54 months (range: 12-240 months), there were 8 (9%) recurrent cerebral infarctions, with no difference between treatment with aspirin (n = 0) or anticoagulants (n = 8). The annual rate of recurrence was 0,014 person-years of follow-up. The history of previous thrombosis and spontaneous abortions were more frequent in patients with recurrence. Aspirin-treated patients more frequently came from rural areas. Four anticoagulated patients developed bleeding complications, two minor bleeding and two subdural hematomas. 76% of the cases evolved with good outcome (modified Rankin scale: 0-2)., Conclusion: With the limitations of a nonrandomized study, our data suggest that the risk of recurrent arterial cerebral infarction in young patients with cerebral infarction secondary to PAS is low, probably non-uniform and independent of the type of antithrombotic.

Objective: Low molecular weight (LMW) heparin, with or without aspirin (acetylsalicylic acid [ASA]), is used to prevent complications in antiphospholipid syndrome in pregnancy. Our objective was to elucidate the actions of low-dose LMW heparin and ASA on basal and antiphospholipid antibody-induced modulation of trophoblast function., Methods: The human first-trimester trophoblast cell line (HTR-8) was treated with or without antiphospholipid antibody in the presence of no medication, low-dose LMW heparin, low-dose ASA, or combination therapy. Interleukin (IL)-6, IL-8, IL-1β, growth-regulated oncogene-α, vascular endothelial growth factor (VEGF), placental growth factor, soluble FMS-like tyrosine kinase-1, and soluble endoglin were measured in the supernatant. Cell migration was performed using a two-chamber assay., Results: Low molecular weight heparin improved basal trophoblast migration and induced potent increases in growth-regulated oncogene-α and soluble FMS-like tyrosine kinase-1. Aspirin did not affect basal function. Combined therapy promoted migration but did not reverse the LMW heparin-induced soluble FMS-like tyrosine kinase-1 effect. Antiphospholipid antibody increased IL-8, IL-1β, growth-regulated oncogene-alpha, VEGF, placental growth factor, and soluble endoglin secretion, while decreasing cell migration and IL-6 and soluble FMS-like tyrosine kinase-1 secretion. The antiphospholipid antibody-induced cytokine changes were best reversed with LMW heparin, with partial reversal of IL-8 and IL-1β upregulation. The antiphospholipid antibody-induced angiogenic changes were worsened by LMW heparin, with increased soluble FMS-like tyrosine kinase-1 secretion. The therapies did not reverse antiphospholipid antibody-induced decrease in migration., Conclusion: In the absence of antiphospholipid antibodies, LMW heparin induces potentially detrimental proinflammatory and antiangiogenic profile in the trophoblast. In the presence of antiphospholipid antibodies, single-agent LMW heparin may be the optimal therapy to counter trophoblast inflammation, but also induces an antiangiogenic response. These findings may explain the inability of current therapies to consistently prevent adverse outcomes.

Purpose: The objective of the present study was to evaluate fetal biometry, Doppler values, and perinatal outcomes in pregnant women with antiphospholipid syndrome treated with acetylsalicylic acid and heparin., Study Design: Twenty-five pregnant women with antiphospholipid syndrome using 100 mg/day acetylsalicylic acid and 5,000 IU heparin every 12 h were evaluated in this prospective observational study. Ultrasonography was performed between 24 and 38 weeks of gestational age to assess estimated fetal weight, placental thickness, amniotic fluid index, fetal biophysical profile and Doppler evaluation of maternal uterine arteries, and fetal middle cerebral and umbilical arteries. Data regarding Apgar score, gender, delivery mode, and birth weight and length were recorded after birth., Results: The observed values for ultrasonographic assessment and perinatal outcomes were not very different from the expected values for normal pregnancies. The birth weight was 2863.3 ± 737.7 g (mean ± SD) and length was 46.8 ± 4.2 cm. Only one newborn (4%) had the 1-min Apgar score <7 and all had the 5-min Apgar score >7., Conclusion: Gestational and perinatal evaluation of pregnant women with antiphospholipid syndrome using both acetylsalicylic acid and heparin was reassuring.

The objective of this study was to assess pregnancy outcome in women with a history of refractory antiphospholipid antibody-associated pregnancy loss(es) who were treated with early low-dose prednisolone in addition to aspirin and heparin. Eighteen women with antiphospholipid antibodies who had refractory pregnancy loss(es) were given prednisolone (10 mg) from the time of their positive pregnancy test to 14 weeks' gestation. Before low-dose prednisolone was given as treatment, 4 (4%) of 97 pregnancies had resulted in live births. Among 23 pregnancies supplemented with prednisolone, 9 women had 14 live births (61%), including 8 uncomplicated pregnancies. The remainder were complicated by preterm delivery, preeclampsia, and/or small-for-gestational-age infants. There were 8 first-trimester miscarriages and 1 ectopic pregnancy. There were no fetal deaths after 10 weeks' gestation and no evidence of maternal morbidity. The addition of first-trimester low-dose prednisolone to conventional treatment is worthy of further assessment in the management of refractory antiphospholipid antibody-related pregnancy loss(es), although complications remain elevated.

Purpose of Review: Presence of antiphospholipid antibodies (aPL) is associated with unsuccessful pregnancy outcome. Based on an early concept of aPL-induced thrombophilia and placental thrombosis, antithrombotic interventions have been used to reduce incidence of miscarriage in antiphospholipid antibody syndrome (APS). The aim of this review is to summarize current knowledge on pathogenesis of miscarriage in APS and the impact of different antithrombotic therapy strategies., Recent Findings: Pathogenetic concepts on miscarriage in APS comprise aPL-mediated cell activation, disturbance of coagulation along with increased complement activation. There is increasing evidence that heparin exerts its effect by inhibiting complement activation rather than by its anticoagulation capacity. In this regard, the outcome of pregnancies in APS has considerably improved by the invention of therapies using combinations of aspirin, unfractionated heparin (UFH) and/or low molecular weight heparin (LMWH). However, there is no clear evidence as to which treatment regimen should be preferred. Some studies indicate superiority of aspirin plus heparin over aspirin-only. Whether heparin-only treatment would confer equal effects and whether UFH and LMWH were of comparable efficacy currently is unknown., Summary: Treatment with aspirin and heparin decreases the risk of miscarriages in APS. Well designed trials as well as better patients-at-risk profiling are warranted that identify which treatment strategy should be favored and whether detailed characterization of aPL specificities could help in individualizing therapy.

Objectives: Current guidelines for the treatment of patients with obstetric antiphospholipid syndrome (APS) recommend low dose aspirin (LDA) and prophylactic doses of low molecular weight heparin (LMWH). Most clinicians use a fixed dosage of LMWH in pregnant APS women despite the fact that there are no clinical trials establishing that fixed doses are more efficacious than adjusted ones in preventing pregnancy complications. The efficacy and safety of adjusted single daily doses of LMWH (nadroparin) combined with LDA have thus been evaluated in 33 consecutive pregnancies in women with diagnosed obstetric APS., Methods: LMWH doses were augmented as the pregnancies progressed and maternal/foetal weight increased. 70-80-90 U/Kg doses ranging between 3800 and 6650 U were administered daily during the first, second and third trimesters, respectively. LDA (100 mg/day) was also prescribed., Results: Pregnancy outcome was successful in 97% of the patients studied, who delivered, between the 29th and 41st weeks of gestation (mean 37.4 ±2.1 SD), 32 infants with a mean birth weight of 3084 g ± 514 SD. One woman (3%) experienced a spontaneous abortion at the 8th week of gestation., Conclusions: The high live birth rate, the satisfactory mean gestational age and weight at birth and the absence of major pregnancy/neonatal-associated complications indicate that adjusted, once daily doses of LMWH together with LDA could be an efficacious treatment option for pregnant APS patients with no history of thrombosis.

Background: Antiphospholipid antibody syndrome (APAS) is regarded as the most frequently acquired risk factor for thrombophilia. The obstetric manifestations of APAS include early or late pregnancy losses and complications like preeclampsia and fetal growth restriction. Its timely diagnosis and treatment can improve maternal and neonatal outcome., Aims: To study the pregnancy outcome of patients with APAS treated with heparin and aspirin., Settings and Design: This was a retrospective study of pregnancy outcome in 42 consecutive women with APAS, treated with heparin and aspirin., Materials and Methods: The case records of 42 diagnosed cases of APAS with pregnancy, over a 3-year period, were studied. The pregnancy outcome in this group was compared before and after treatment with heparin and low-dose aspirin in terms of abortions, intrauterine deaths and live birth rate. The outcome of the present pregnancy in terms of fetal and maternal complications was analyzed., Results: The mean age and average parity of women with APAS were 30.1±4.1 years and 3.2±1.2, respectively. Among the treated patients of APAS, 13 (30.9%) had preeclampsia and 9 (21.4%) had intrauterine growth restriction (IUGR). There were 2 (4.7%) intrauterine deaths, 4 (9.5%) missed abortions and 3 (7.1%) abruptio placentae. Women with APAS had a live birth rate of 4.6% before treatment and 85.7% in the index pregnancy after treatment., Conclusion: Treatment of pregnant women with APAS results in marked improvement in the live birth rate (4.6-85.7%). However, complications like preeclampsia and IUGR occur even after treatment, requiring strict monitoring and timely delivery.

This retrospective review of hospital records analysed pregnancy outcome with 2 different treatments for women with recurrent miscarriage diagnosed with antiphospholipid syndrome in the index pregnancy. Of 64 women, 29 had received aspirin and 35 aspirin plus heparin. Pregnancy-induced hypertension, prematurity, intrauterine growth restriction and neonatal death were considered as maternal and fetal complications. There were no significant differences in antenatal and maternal complications between the groups. HOwever, there were significant differences in mean anticardiolipin IgG antibody levels. Aspirin alone or in combination with parin was equally efficacious in women with antiphospholipid syndrome and recurrent miscarriage.

Objective: The combination of heparin and aspirin was regarded as the 'standard therapy' for patients with recurrent pregnancy loss (RPL) and positive aPL antibodies to enhance live births, but it largely stems from expert opinion. We performed a meta-analysis of randomized controlled trials (RCTs) to assess whether this combination works better than aspirin alone., Methods: RCTs testing the efficacy of a combination of heparin and aspirin vs aspirin alone in patients with RPL and positive aPL antibodies were identified in electronic databases. Random effect meta-analysis was employed to pool relative risks (RRs) (with 95% CI) of live births as the primary outcome. RRs of obstetrical complications and standardized mean difference of birth weight were the secondary outcomes. Mixed-effects meta-regression was performed to identify factors associated with live births., Results: Data from five trials involving 334 patients were analysed. The overall live birth rates were 74.27 and 55.83% in the combination and aspirin alone groups, respectively. Patients who received heparin and aspirin had significantly higher live birth rate (RR 1.301; 95% CI 1.040, 1.629) than aspirin alone, with the number needed to achieve one live birth being 5.6. No significant differences in pre-eclampsia, preterm labour and birth weight were found between both the groups. Meta-regression using age at randomization, previous history of live births and episodes of miscarriages as covariates failed to predict the RR of live birth., Conclusions: The combination of heparin and aspirin is superior to aspirin alone in achieving more live births in patients with positive aPL antibodies and RPL.

Aim: To estimate the frequency of relapses of thrombotic and hemorrhagic complications during moderately intensive therapy for antiphospholipid syndrome (APS) with warfarin with and without aspirin., Subjects and Methods: Eighty-two patients diagnosed as having the antiphospholipid syndrome were examined. Group 1 patients (n = 49) received warfarin alone as an antithrombotic drug; Group 2 patients (n = 33) had a combination therapy with warfarin plus aspirin. The efficiency of therapy was evaluated from the number and rate of recurrences of thromboses and transient ischemic attacks (TIA) and its safety was assessed from the frequency and number of hemorrhages during the study. The genetic variants of cytochrome P450 CYP2C9 were determined in 52 of the 82 patients; mutations in the gene for vitamin K epoxide reductase complex 1 (VCORC1) were revealed in 22 patients., Results: During the follow-up, antithrombotic therapy was ineffective in 18.4 and 36.6% of the Groups 1 and 2 patients, respectively (p = 0.07). The rate of poor outcomes (thromboses and TIA) was 7 and 14.8 cases per 100 person-years, respectively. The first six months of warfarin therapy proved to be most risky for thrombotic events to occur--this period was responsible for 37% of bleedings. Hemorrhagic complications of antithrombotic therapy developed in 46.9 and 60.6% of Groups 1 and 2 patients, respectively (p = 0.26). Major hemorrhages were observed more frequently in the combination (warfarin plus low-dose aspirin) therapy group than in the warfarin monotherapy group. Mutant cytochrome P450 gene variants (CYP2C9*2 and CYP2C9*3) were present in 38.5% of the patients; VCORC1 gene mutations were observed in 27.3%. The number of nasal and gingival hemorrhages was increased in patients with CYP2C9*3 and homozygous VCORC1 gene mutations., Conclusion: Moderately intensive warfarin therapy (international normalized ratio 2.0-3.0) could generally reduce the frequency of recurrent thrombotic events by at least 2-fold as compared with that before warfarin administration. The efficiency of using warfarin alone or in combination with aspirin in APS was found to be similar; and its safety was higher during monotherapy therefore it is undesirable to combine warfarin with antiaggregants in real clinical practice. The determination of CYP2C9 and VCORC1 genotypes in patients with APS before warfarin use allows excessive hypocoagulation and related hemorrhages to be avoided.

The aim of this retrospective, observational study was to determine the impact of low-dose enoxaparin (20 mg) in conjunction with low-dose aspirin on the pregnancy outcome of women with antiphospholipid syndrome and recurrent miscarriage. The study was conducted in a tertiary referral teaching hospital. A total of 35 women with antiphospholipid syndrome were treated with low-dose enoxaparin and aspirin as soon as pregnancy was confirmed. The outcome of pregnancy was analysed. The miscarriage rate was 7/35 (20%) whereas the live birth rate was 28/35 (80%). In conclusion, low-dose (20 mg) enoxaparin in conjunction with low-dose aspirin treatment produced encouraging results. The findings in this study suggest that there is a case for randomized controlled trials to compare low-dose (20 mg) enoxaparin with higher doses.

There is consensus in treating patients with antiphospholipid syndrome (APS) and first venous thrombosis with oral anticoagulation to a target international normalized ratio of 2.0 - 3.0. A recent systematic review recommended a target international normalized ratio > 3.0 in the group of patients with APS and arterial thrombosis. The approach for women with obstetric manifestations of APS is based on the use of aspirin plus heparin. In addition, we summarize the evidence-based information about management of catastrophic APS and some difficult cases, such as 'seronegative' APS, patients who do not display formal classification criteria for APS, and recurrent thrombotic events despite optimal anticoagulation.

Objective: To compare low-molecular-weight (LMW) heparin plus low-dose aspirin with intravenous immunoglobulin (IVIG) in the treatment of antiphospholipid antibody syndrome in women with recurrent spontaneous abortions before 10 weeks of gestation., Method: This prospective, multicenter trial conducted between 2002 and 2006 included 85 patients aged 18-39 years. The women were allocated randomly to receive LMW heparin plus low-dose aspirin, or IVIG. Data were compared using the t test and Fisher exact test., Results: The women treated with LMW heparin plus low-dose aspirin had a higher rate of live births than those treated with IVIG (P=0.003). Of those who completed the study, 29/40 (72.5%) and 15/38 (39.5%), respectively, had live births. Intent-to-treat analysis revealed a significant difference between the 2 groups (OR 1.802; 95%CI, 1.14-2.84; P=0.007)., Conclusions: LMW heparin plus low-dose aspirin resulted in a higher live birth rate than IVIG in the treatment of antiphospholipid antibody syndrome in women with recurrent abortion.

Objective: To compare live birth rates in women with recurrent pregnancy loss (RPL) and either autoantibodies or a coagulation abnormality, treated with low molecular weight heparin plus aspirin (LMWH/ASA) or ASA alone, and to place our results in context with other randomized clinical trials (RCT) with similar cohorts., Methods: The HepASA Trial was an RCT including patients with a history of RPL and at least 1 of the following: antiphospholipid antibody (aPL), an inherited thrombophilia, or antinuclear antibody. Treatment groups were stratified by aPL status and history of early versus late pregnancy losses. Patients received either LMWH/ASA or ASA alone. The primary outcome was live birth; secondary outcomes included adverse events and bone loss at the spine and femoral neck. Literature over the past 20 years was reviewed to identify comparable RCT., Results: Over 4 years, 859 women with RPL were screened: 88 (10.2%) fulfilled inclusion criteria, became pregnant and were randomized to receive either LMWH/ASA or ASA alone. aPL were present in 42 (47.7%) patients in each group. The trial was stopped after 4 years when an interim analysis showed no difference in live birth rates in the 2 groups, and a lower rate of pregnancy loss in the ASA only group than expected. In the LMWH/ASA group, 35/45 (77.8%) had a live birth versus 34/43 (79.1%) in the ASA only group (p = 0.71). Neither number of prior losses nor aPL status was correlated with pregnancy outcome. There were no cases of pregnancy related thrombosis in either group. Mean change in BMD did not differ by treatment group at either the lumbar spine (p = 0.57) or femoral neck (p = 0.15). RCT since 2000 for aPL positive women with RPL and similar inclusion criteria report a mean live birth rate of 75% with either LMWH or ASA., Conclusion: LMWH/ASA did not confer incremental benefit compared to ASA alone for this population. Regardless of treatment regimen, number of prior losses, or aPL positivity, almost 80% of women in our RPL cohort had a successful pregnancy outcome. These findings contribute to a growing body of literature that contests the emerging standard of care comprising LMWH/ASA for this population.