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Objective: This paper presents an analysis of the pregnancy trajectory and therapeutic regimen documentation of a primigravida with APSN. It aims at communicating the therapeutic approach and preventive measures for APSN in pregnancy. Case Presentation: This paper reports the trajectory and therapeutic regimen documentation of a primigravida with APSN. The APSN was discovered in a primigravida woman aged 26 years at 11 weeks of gestation. The initial therapy regimen consists of daily administration of prednisone 10 mg, hydroxychloroquine 200 mg, dapparin 5000 IU, and aspirin 50 mg. At a gestational age of 20 + 3 weeks, the dosage of dapparin was modified to 5000 IU/other day, along with a significant rise in urinary protein level seen at 30 + 3 weeks of gestational age. The initial dosage of dapanin sodium was renewed. The patient delivered at 38 + 3 weeks of gestation without other complications. Conclusion: It is imperative to acknowledge that altering the dosage and administration of medication should not be done haphazardly during pregnancy. [ABSTRACT FROM AUTHOR]

Recently, we read with great interest the papers by Kwak-Kim et al from "The 39th Annual Meeting of the American Society for Reproductive Immunology" (12-15 June 2019, Grand Rapids, Michigan, USA).[[1]] The authors investigated reproductive outcomes of women with recurrent pregnancy loss (RPL) and repeated implantation failure (RIF) who received intravenous immunoglobulin G (IVIg) infusion. The most commonly reported allergies were similar before and after IVIg treatment reaching a prevalence similar to general population estimates. Taken together, these indirect data clearly support the high success rate of IVIg-treated pregnancy in RPL women with APS or immunological disorders [[3], [6]] and highlight that RPL seems most likely associated with the occurrence of thyroid diseases.[[5], [8], [10]] Interestingly, for the first time, our data provide overall evidence for a successful very long-term outcome for both the IVIg-treated mothers and their living children who were in utero exposed to IVIg. [Extracted from the article]

Problem: To illustrate the clinical features, treatment strategy, and pregnancy outcome of patients with obstetric antiphospholipid syndrome (OAPS), non‐criteria obstetric antiphospholipid syndrome (NC‐OAPS) Method of study: A single‐center nested case‐control study was designed. Patients with a diagnosis of OAPS and NC‐OAPS were enrolled. The medical history, coagulation status, and antibody profile data were collected. Patients were given standard anticoagulation therapy with or without glucocorticoids (GC) and/or hydroxychloroquine (HCQ) during pregnancy and were observed for their pregnancy outcome. Results: A total of 47 patients with OAPS and 120 patients with NC‐OAPS were finally included, of whom 55 patients met the clinical criteria (subgroup C) and 65 met the laboratory criteria (subgroup L). Pregnancy morbidity showed significant differences: gravida, pregnancy loss in OAPS versus NC‐OAPS. The coagulation function was not significantly different between OAPS and NC‐OAPS groups, while TT and FIB were significantly higher in the subgroup C. Thromboelastography (TEG) results showed a significantly lower ANGEL in the NC‐OAPS group, a higher ANGEL and lower EPL, LY30 in the subgroup L. No differences between groups were observed in treatment strategy. The pregnancy outcomes were not significantly different between NC‐OAPS and OAPS groups. Conclusions: Clinical and laboratory differences were found between OAPS and NC‐OAPS groups in this study. Patients in different subgroups of NC‐OAPS could be identified with different clinical phenotypes. A relatively hypercoagulable status existed in the OAPS group compared to NC‐OAPS, and also in the subgroup L. [ABSTRACT FROM AUTHOR]

Reproductive failure (RF) is the inability to conceive or to carry a pregnancy to term, and its prevalence is not negligible. Pregnancy is a prothrombotic condition, which can be abnormally exaggerated in women with thrombophilia. Antiphospholipid syndrome is a cause of RF and effectively managed with heparin and aspirin. However, there are yet insufficient data in patients with RF and inherited thrombophilia. This review focuses on the significance of inherited thrombophilia and RF and the role of anticoagulants in pregnancy outcomes. A few randomized case‐control studies have investigated the effect of anticoagulation in RF with thrombophilia, and the results are yet debatable. Some inherited thrombophilia including mutations of factor V Leiden, prothrombin, and methylenetetrahydrofolate reductase and protein S deficiency are associated with RF and/or late pregnancy complications. There are several implications which influence the diagnosis and treatment. First, there is a lack of studies revealing appropriate thrombophilia markers and its cutoff values for RF specifically. Second, some thrombophilia markers change with sex and age. Lastly, the study designs of previous studies are heterogeneous in selecting the thrombophilia markers and drugs. Further studies to find adequate thrombophilia markers of RF are warranted and eventually elucidate the subgroups beneficial to anticoagulation treatment. [ABSTRACT FROM AUTHOR]

Anti‐phospholipid syndrome (APS) recapitulates the link between autoimmunity and pregnancy failure: Acquired anti‐phospholipid antibodies (aPL) play a pathogenic role in pregnancy complications. The diagnosis of obstetric APS can easily be pursued when women present with laboratory and clinical features fulfilling the international classification criteria. Standard therapeutic approach to obstetric APS consists in the association of anti‐platelet agents and anticoagulants. Most patients achieve a live birth thanks to conventional treatment; however, approximately 20% fail to respond and are managed with additional therapeutic tools added on the top of conventional treatment. Surely, a refinement of risk stratification tools would allow early identification of high‐risk pregnancies that warrant tailored treatment. In real life, obstetricians and rheumatologists face complex diagnostic scenarios including women with pregnancy morbidities other than those mentioned in classification criteria such as one or two early losses and premature birth after 34 weeks due to preeclampsia or placental insufficiency, women with low‐titer aPL not fulfilling criteria laboratory requirements, women with positive non‐criteria aPL, asymptomatic aPL carriers, and infertile women found to be aPL‐positive. This review focuses on some of the several unanswered questions related to diagnostic, prognostic, and therapeutic aspects in obstetric APS. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Problem: The association of low molecular weight heparin (LMWH) with low‐dose aspirin (LDASA) provides the therapeutic cornerstone of obstetric anti‐phospholipid syndrome (APS). This combo approach is not effective in all patients, and few women still experience recurrences. Method of Study: In an elegant in vitro study, Chiombori Quao and colleagues demonstrated that anti‐phospholipid antibodies (aPL) affect the functionality of endometrial endothelial cells interfering with angiogenesis. LMWH and LDASA, in combination or alone, did not display any protective activity but exacerbated aPL‐mediated effects. Results: The above data were advocated as a demonstration of the inefficacy of LMWH and LDASA in obstetric APS. Given the lack of thrombotic lesions in APS placentae, this treatment is mainly empirical. However, clinical practice clearly shows that LMWH and LDASA are effective in most patients. Non‐responsive women represent a peculiar subgroup, with a high‐risk aPL profile. All experimental models, including in vitro models of obstetric APS, display limitations that should be considered before translating data to patients. In particular, the use of a monoclonal antibody specific for Domain (D) 5 does not fit with the evidence that anti‐D1, but not anti‐D4,5, are associated with both vascular and obstetric APS manifestations. Conclusion: The association of LMWH and LDASA is the most effective therapeutic option for pregnant aPL‐positive women. The lack of a clear demonstration of the pharmacological action of LMWH/LDASA should urge to further invtrestigate the pathophysiology of aPL‐associated miscarriages. [ABSTRACT FROM AUTHOR]

Problem Some patients with antiphospholipid syndrome (APS) suffer pregnancy morbidity (PM) but not vascular thrombosis (VT), whilst others suffer VT only. Therefore, we compared the effects of IgG from VT+/PM− and VT−/PM+ subjects on human first-trimester trophoblast (HTR8) cells. Method of study HTR-8 cells were incubated with APS VT+/PM−, APS VT−/PM+ or healthy control (HC) IgG. We measured trophoblast invasion by cell invasion assay; mRNA expression of TLR4 and adaptor proteins; phosphorylation of p38 MAPK, NFκB and ERK; and expression of interleukin (IL)-8 and IL-6. Results VT−/PM+ IgG, but not VT+/PM− IgG significantly reduced HTR-8 invasion. The effects on invasion were blocked by TLR-4 inhibition. Neither VT+/PM− nor VT−/PM+ IgG altered MyD88 mRNA expression, phosphorylation of signalling molecules or cytokine expression. Conclusions VT−/PM+ IgG exert functionally relevant effects on human trophoblast cells but VT+/PM− IgG do not. [ABSTRACT FROM AUTHOR]

The article focuses on a study that examined the influence on the induced pathology of the genetic background of the immune system and the type of animal model of antiphospholipid syndrome (APS) used. The results of the induction of APS by tetanus toxoid (TTd) hyperimmunization in mice are described. The role of TTd immunization and intravenous application of monoclonal antibody 26 in inducing the reproductive pathology is also discussed.

Citation Mulla MJ, Myrtolli K, Brosens JJ, Chamley LW, Kwak-Kim JY, Paidas MJ, Abrahams VM. Antiphospholipid antibodies limit trophoblast migration by reducing IL-6 production and STAT3 activity. Am J Reprod Immunol 2010 Problem Women with antiphospholipid antibodies (aPL) are at risk of recurrent miscarriage and pre-eclampsia. aPL target the placenta by binding to β2-glycoprotein I (β2 GPI) expressed by the trophoblast. The objective of this study was to evaluate if and how aPL affect first trimester trophoblast migration. Method of study First trimester trophoblast cells were treated with anti-β2 GPI monoclonal antibodies. Migration was determined using a two-chamber assay. Interleukin (IL)-6 production was evaluated by RT-PCR and enzyme-linked immunosorbent assay, and signal transducer and activator of transcription 3 (STAT3) activation was assessed by western blot. Results Trophoblast cells constitutively secreted IL-6 in a time-dependent manner and this directly correlated with STAT3 phosphorylation. In the presence of anti-β2 GPI Abs, trophoblast IL-6 mRNA levels and secretion was downregulated in a Toll-like receptor 4/MyD88-independent manner and this correlated with a reduction in phosphorylated STAT3 levels. In addition, the anti-β2 GPI Abs reduced the migratory potential of trophoblast. Heparin was able to reverse aPL-dependent inhibition of trophoblast IL-6 secretion and migration. Conclusion This study demonstrates that aPL limit trophoblast cell migration by downregulating trophoblast IL-6 secretion and STAT3 activity. As heparin was unable to prevent these effects, our findings may explain why women with antiphospholipid syndrome, treated with heparin, remain at risk of developing obstetrical syndromes, associated with impaired deep placentation, such as pre-eclampsia. [ABSTRACT FROM AUTHOR]

Problem Women with antiphospholipid antibodies (aPL) are at risk for recurrent miscarriage, pre-eclampsia, and pre-term labor. aPL target the placenta directly by binding to beta2-glycoprotein I (β2GPI) expressed on the surface of trophoblast cells. The objective of this study was to determine the effects of aPL on trophoblast function and the mechanisms involved. Method of study First trimester trophoblast cells were treated with anti-β2GPI monoclonal antibodies and patient-derived aPL, after which cell survival and function was evaluated. Results We report that anti-β2GPI antibodies trigger an inflammatory response in trophoblast, characterized by increased secretion of interleukin (IL)-8, MCP-1, GRO-α, and IL-1β, and that this occurs in a TLR-4/MyD88-dependent manner. At high concentrations, these antibodies also induce caspase-mediated cell death. This was attenuated upon disabling of the MyD88 pathway, suggesting that anti-β2GPI-induced inflammatory mediators compromise trophoblast survival by acting in an autocrine/paracrine manner. Enhanced IL-8, GRO-α, and IL-1β secretion also occurred when trophoblast cells were incubated with antibodies from patients with antiphospholipid syndrome. Heparin, which acts as a pro-survival factor in human trophoblast, attenuated the anti-β2GPI antibody-mediated cell death, and also the pro-inflammatory response, but only at high concentrations. Conclusion These findings demonstrate that aPL triggers a placental inflammatory response via the TLR-4/MyD88 pathway, which in turn compromises trophoblast survival. Thus, the TLR-4/MyD88 pathway may provide a new therapeutic target to improve pregnancy outcome in antiphospholipid syndrome patients. [ABSTRACT FROM AUTHOR]

Problem Anti-beta2-Glicoprotein-1 antibodies (anti-β2GPI-ab) have been related to recurrent miscarriage (RM) with conflicting results. The aim was to evaluate the role of anti-β2-GPI-ab as unique biological marker in RM related to antiphospholipid (aPL). Method of study A cohort study that included 59 cases, divided in two groups, was designed: group 1 comprised 43 pregnant women with ‘obstetric’ antiphospholipid syndrome (APS) and group 2 included 16 cases with similar complaints but only having repeatedly anti-β2-GPI-ab. Previous thrombosis and/or inherited thrombophilia were excluded. Lupus anticoagulant, anticardiolipin antibodies (aCA), anti-β2-GPI-ab, and other autoantibodies were analyzed. Miscarriages, premature births, pre-eclampsia, live births, placental and systemic thromboses were studied. Results No differences in previous obstetric complications were detected ( P = 1.00–0.164). After the treatment, differences in number of obstetric complications were not seen ( P = 1.00). Live births were similar in two groups (88.4% and 93.7%; P = 1.00). Placental thrombosis was equal in both groups, 93.3% versus 80% ( P = 1.00). Conclusion These results suggest that anti-β2-GPI-ab may be considered a biological marker for obstetric APS. [ABSTRACT FROM AUTHOR]

A letter to the editor is given in response to article "Inherited thrombophilia in women with poor aPL-related obstetric history: prevalence and outcomes. Survey of 208 cases from the European Registry on Obstetric Antiphospholipid Syndrome cohort" by Alijotas-Reig J. and workers in a 2016 issue.