Low complement levels are related to poor obstetric outcomes in women with obstetric antiphospholipid syndrome. The EUROAPS Registry Study Group.

INTRODUCTION: Obstetric antiphospholipid syndrome (OAPS) is an autoimmune disease related to antiphospholipid antibodies (aPL) with primaryinflammatory injury followed by clot cascade activation and thrombus formation. Complement system activation and their participation in aPL-related thrombosis is unclosed. METHODS: We haveanalysed adverse pregnancy outcomes (APO) related to low complement (LC) levels in a cohort of 1048 women fulfilling classification criteria for OAPS. RESULTS: Overall, 223 (21.3%) women presented LC values, during pregnancy. The length of pregnancy was shorter in OAPS women with LC compared to those with normal complement (NC) (median: 33 weeks, interquartile range: [24-38] vs. 35 weeks [27-38]; p = 0.022). Life new-born incidence was higher in patients with NC levels than in those with LC levels (74.4% vs. 67.7%; p = 0.045). Foetal losses were more related to women with triple or double aPL positivity carrying LC than NC values (16.3% vs. 8.0% NC; p = 0.027). Finally, some placental vasculopathies were affected in OAPS patients with LC as late Foetal Growth Restriction (FGR >34 weeks) rise to 7.2% in women with LC vs. 3.2% with NC (p = 0.007). DISCUSSION: Data from our registry indicate that incidence of APO was higher in OAPS women with LC levels and some could be reverted by the correct treatment.

sFlt-1 to PlGF ratio cut-offs to predict adverse pregnancy outcomes in early-onset FGR and SGA: a prospective observational study.

This is a prospective, observational study, conducted in a tertiary referral hospital. We enrolled 175 singleton pregnancies with estimated foetal weight below the 10th centile between 20 + 0 and 31 + 6 weeks. Placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and fetoplacental circulation were assessed at the time of diagnosis. Receiver operating characteristic curves were used to assess the performance of sFlt-1/PlGF for predicting adverse perinatal outcomes (APO). The optimal cut-offs to predict each adverse outcome were calculated and the resulting areas under the curve (AUC) were compared to those calculated from the cut-off points of 38, 85 and 110. The need for delivery at <30 and <34 weeks and APO were the main outcome measures. The optimal cut-off points to predict APO, delivery <30 and <34 weeks were 24.9, 116.7 and 97.5, respectively. None of them proved to be superior to 38, 85 or 110 for predicting any adverse pregnancy outcome. Impact StatementWhat is already known on this subject? Soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) are biomarkers of placental dysfunction. High sFlt-1/PlGF values predict adverse perinatal outcomes in preeclampsia (PE).What do the results of this study add? No specific thresholds have been described to identify early-onset foetal growth restriction (FGR) and small for gestational age (SGA) foetuses at higher risk of adverse outcomes. This study describes these specific cut-offs and compares their predictive capacity to those described for PE.What are the implications of these findings for clinical practice and/or further research? The sFlt-1/PlGF cut-off points of 38, 85 and 110 might be useful for ruling out the occurrence of APO and the need for elective delivery at <30 and at <34 weeks from the moment of diagnosis in early-onset FGR and SGA. These cut-offs could aid Doppler studies in the distinction between FGR and SGA.

Angiogenic factors for planning fetal surveillance in fetal growth restriction and small-for-gestational-age fetuses: A prospective observational study.

OBJECTIVE: The aim of this study was to assess the added value of the soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) ratio for adjusting the periodicity of ultrasound examinations in early-onset fetal growth restriction (FGR) and small for gestational age (SGA). DESIGN: A prospective, observational study. SETTING: Tertiary referral hospital. POPULATION: One hundred and thirty-four single pregnancies with ultrasonographic estimated fetal weight (EFW) below the 10th centile between 20+0 and 31+6  weeks of gestation with antegrade umbilical artery flow. METHODS: The time from Doppler and sFlt-1/PlGF assessment to delivery was recorded and classified into four ranges: <1, <2, <3 and <4 weeks. MAIN OUTCOME MEASURES: Sensitivity (Sn), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) of sFlt-1/PlGF values to predict the time to delivery. RESULTS: In the SGA cohort, the NPV calculated for an sFlt-1/PlGF cut-off value of 38 was 100% for delivery before 3 weeks, and 98% for delivery before 4 weeks after diagnosis (95% CI 0.89-1.00). In the FGR cohort, the NPV calculated for an sFlt-1/PlGF cut-off value of 38 was 100% for delivery before 2 weeks after diagnosis (95% CI 0.92-1.00). By contrast, more than 50% of cases with an sFlt-1/PlGF value of >85 required an elective delivery before 1 week. CONCLUSIONS: sFlt-1/PlGF values in early-onset SGA and FGR are predictive of the time to delivery and could be used for planning fetal surveillance, by reducing the frequency of ultrasound in cases with sFlt-1/PlGF < 38 and by providing closer follow-up in cases with sFlt-1/PlGF >85. TWEETABLE ABSTRACT: sFlt-1/PlGF values in early-onset SGA/FGR could be used in addition to Doppler for planning fetal surveillance.

Bleeding and antithrombotic therapy during pregnancy in women with poor aPL-related obstetric outcomes: A survey of 1075 cases from EUROAPS registry∗.

BACKGROUND: The combination of low-dose aspirin (LDA) and low-molecular-weight heparin (LMWH) until the end of gestation are the currently the accepted standard of care for the treatment of antiphospholipid-related obstetric disorders. In refractory cases, hydroxychloroquine (HCQ) can be added to this standard of care. OBJECTIVE: To evaluate the haemostatic safety of LDA and LMWH (medium to high prophylactic doses) during pregnancy and the puerperium in women with both full-blown obstetric antiphospholipid syndrome (OAPS) (Sydney criteria) and noncriteria - incomplete - OAPS. STUDY DESIGN: Retrospective/prospective multicentre observational study. Obstetric background, laboratory categories, delivery mode, antithrombotic regimens and bleeding complications were compared. SETTING: A total of 30 tertiary European hospitals. PATIENTS: Mainly, Caucasian/Arian pregnant women were included. Other ethnicities were minimally present. Women were controlled throughout pregnancy and puerperium. MAIN OUTCOME MEASURES: The primary end-point was to evaluate the number of major and minor haemorrhagic complications in this cohort of women. Neuraxial anaesthetic bleeding complications were particularly assessed. Secondly, we aimed to compare local/general bleeding events between groups. RESULTS: We studied 1650 women, of whom 1000 fulfilled the Sydney criteria of the OAPS and 650 did not (noncriteria OAPS). Data on antithrombotic-related complications were available in 1075 cases (65.15%). Overall, 53 (4.93%) women had bleeding complications, with 34 being considered minor (3.16%) and 19 major (1.76%). Neither obstetric complications nor laboratory categories were bleeding-related. Assisted vaginal delivery and caesarean section were related to local haemorrhage. Heparin doses and platelet count were not associated with major bleeding. CONCLUSIONS: LDA and medium to high prophylactic LMWH during pregnancy in women with full-blown OAPS/noncriteria OAPS are safe. A slight increase in bleeding risk was noted in instrumental deliveries. No women who underwent spinal or epidural anaesthesia suffered bleeding complications. No haemorrhage was observed in cases where HCQ was added to standard therapy.

Immunological and physiopathological approach of COVID-19 in pregnancy.

Coronavirus disease-2019 (COVID-19) related to Coronavirus-2 (SARS-CoV-2) is a worldwide health concern. Despite the majority of patients will evolve asymptomatic or mild-moderate upper respiratory tract infections, 20% will develop severe disease. Based on current pathogenetic knowledge, a severe COVID-19 form is mainly a hyperinflammatory, immune-mediated disorder, triggered by a viral infection. Due to their particular immunological features, pregnant women are supposed to be particularly susceptible to complicate by intracellular infections as well as immunological disturbances. As an example, immune-thrombosis has been identified as a common immune-mediated and pathogenic phenomenon both in COVID-19, in obstetric diseases and in COVID-19 pregnant women. According to extensive published clinical data, is rationale to expect an interference with the normal development of pregnancy in selected SARS-CoV-2-infected cases, mainly during third trimester.This manuscript provides insights of research to elucidate the potential harmful responses to SARS-CoV-2 and /or other coronavirus infections, as well as bidirectional interactions between COVID-19 and pregnancy to improve their respective management.

Evaluating the Effect of Pravastatin in Early-Onset Fetal Growth Restriction: A Nonrandomized and Historically Controlled Pilot Study.

OBJECTIVE: This study aimed to analyze the effect of pravastatin on angiogenic factors, feto-maternal Doppler findings and pregnancy outcomes in women with early-onset fetal growth restriction (FGR) treated with pravastatin compared with nontreated controls. STUDY DESIGN: This was a pilot study conducted between March 2016 and September 2017. Women with single pregnancies and FGR diagnosed at ≤ 28 weeks of gestation were offered 40 mg of pravastatin daily. Doppler progression, soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) values, and pregnancy outcomes were assessed and compared with consecutive historical controls. Controls were matched to treated women for gestational age, maternal characteristics, maternal and obstetric history, Doppler severity classification, and angiogenic factors at diagnosis. The sFlt-1/PlGF was measured in maternal serum at two different times: before pravastatin was started (ratio M0) and during pravastatin treatment (ratio M1). Doppler severity was classified into four categories: normal, mild, moderate, and severe. RESULTS: A total of 38 women were enrolled in this study. No differences were observed in baseline characteristics between groups. However, when compared with the ratio M0, M1 was increased by a median (interquartile range) of 67.0 (-34.8 to 197.3) in the control group but decreased by a median (interquartile range) of -10.1 (-53.1 to -0.07) in the pravastatin treated group (p < 0.001). No significant differences were observed in Doppler progression throughout pregnancy. Median interval from diagnosis to delivery was extended by 16.5 days, the median newborn birthweight was increased from 1,040 to 1,300 g, and the number of women with preeclampsia decreased from 9 (47.4%) to 6 (31.6%) in treated women; however, these trends were not statistically significant. CONCLUSION: In women with early-onset FGR, treatment with pravastatin 40 mg daily was associated with significant improvement in the angiogenic profile. Additionally, median pregnancy duration and median birthweight increased and the incidence of PE was reduced in treated women. Nevertheless, since this pilot study was underpowered, none of these differences were statistically significant. KEY POINTS: · Pravastatin improves sFlt-1/PlGF in FGR.. · Pregnancy duration tended to be greater in treated women.. · Birthweight tended to be greater in treated women..

Comparative study of obstetric antiphospholipid syndrome (OAPS) and non-criteria obstetric APS (NC-OAPS): report of 1640 cases from the EUROAPS registry.

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.

EULAR recommendations for the management of antiphospholipid syndrome in adults.

The objective was to develop evidence-based recommendations for the management of antiphospholipid syndrome (APS) in adults. Based on evidence from a systematic literature review and expert opinion, overarching principles and recommendations were formulated and voted. High-risk antiphospholipid antibody (aPL) profile is associated with greater risk for thrombotic and obstetric APS. Risk modification includes screening for and management of cardiovascular and venous thrombosis risk factors, patient education about treatment adherence, and lifestyle counselling. Low-dose aspirin (LDA) is recommended for asymptomatic aPL carriers, patients with systemic lupus erythematosus without prior thrombotic or obstetric APS, and non-pregnant women with a history of obstetric APS only, all with high-risk aPL profiles. Patients with APS and first unprovoked venous thrombosis should receive long-term treatment with vitamin K antagonists (VKA) with a target international normalised ratio (INR) of 2-3. In patients with APS with first arterial thrombosis, treatment with VKA with INR 2-3 or INR 3-4 is recommended, considering the individual's bleeding/thrombosis risk. Rivaroxaban should not be used in patients with APS with triple aPL positivity. For patients with recurrent arterial or venous thrombosis despite adequate treatment, addition of LDA, increase of INR target to 3-4 or switch to low molecular weight heparin may be considered. In women with prior obstetric APS, combination treatment with LDA and prophylactic dosage heparin during pregnancy is recommended. In patients with recurrent pregnancy complications, increase of heparin to therapeutic dose, addition of hydroxychloroquine or addition of low-dose prednisolone in the first trimester may be considered. These recommendations aim to guide treatment in adults with APS. High-quality evidence is limited, indicating a need for more research.

The European Registry on Obstetric Antiphospholipid Syndrome (EUROAPS): A survey of 1000 consecutive cases.

AIM: To analyse the clinical features, laboratory data and foetal-maternal outcomes, and follow them up on a cohort of 1000 women with obstetric antiphospholipid syndrome (OAPS). METHODS: The European Registry of OAPS became a registry within the framework of the European Forum on Antiphospholipid Antibody projects and was placed on a website in June 2010. Thirty hospitals throughout Europe have collaborated to carry out this registry. Cases with obstetric complaints related to antiphospholipid antibodies (aPL) who tested positive for aPL at least twice were included prospectively and retrospectively. The seven-year survey results are reported. RESULTS: 1000 women with 3553 episodes were included of which 2553 were historical and 1000 were latest episodes. All cases fulfilled the Sydney classification criteria. According to the laboratory categories, 292 (29.2%) were in category I, 357 (35.7%) in IIa, 224 (22.4%) in IIb and 127 (12.7%) in IIc. Miscarriages were the most prevalent clinical manifestation in 386 cases (38.6%). Moreover, the presence of early preeclampsia (PE) and early foetal growth restriction (FGR) appeared in 181 (18.1%) and 161 (16.1%), respectively. In this series, 448 (44.8%) women received the recommended OAPS treatment. Patients with recommended treatment had a good live-birth rate (85%), but worse results (72.4%) were obtained in patients with any treatment (low-dose aspirin (LDA) or low-molecular-weight heparin (LMWH) not on recommended schedule, while patients with no treatment showed a poor birth rate (49.6%). CONCLUSION: In this series, recurrent miscarriage is the most frequent poor outcome. To avoid false-negative diagnoses, all laboratory category subsets were needed. OAPS cases have very good foetal-maternal outcomes when treated. Results suggest that we were able to improve our clinical practice to offer better treatment and outcomes to OAPS patients.

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.

Comparative study between obstetric antiphospholipid syndrome and obstetric morbidity related with antiphospholipid antibodies / Estudio comparativo entre síndrome antifisfolipídico obstétrico y morbilidad obstétrica relacionada con anticuerpos antifosfolípido

Background and objectives: To compare clinical, laboratory, treatment and live birth rate data between women with aPL-related obstetric complications (OMAPS) not fulfilling the Sydney criteria and women fulfilling them (OAPS). Materials and methods: Retrospective and prospective multicentre study. Data comparison between groups from The European Registry on Antiphospholipid Syndrome included within the framework of the European Forum on Antiphospholipid Antibody projects. Results: 338 women were analysed: 247 fulfilled the Sydney criteria (OAPS group) and 91 did not (OMAPS group). In the OMAPS group, 24/91 (26.37%) fulfilled laboratory Sydney criteria (subgroup A) and 67/91 (74.63%) had a low titre and/or non-persistent aPL-positivity (subgroup B). Overall, aPL laboratory categories in OAPS vs. OMAPS showed significant differences: 34% vs. 11% (p<0.0001) for category I, 66% vs. 89% (p<0.0001) for category II. No differences were observed when current obstetric complications were compared (p=0.481). 86.20% of OAPS women were treated vs. 75.82% of OMAPS (p=0.0224), particularly regarding the LDA+LMWH schedule (p=0.006). No differences between groups were observed in live births, gestational, puerperal arterial and/or venous thrombosis. Conclusions: Significant differences were found among aPL categories between groups. Treatment rates were higher in OAPS. Both OAPS and OMAPS groups had similarly good foetal-maternal outcomes when treated. The proposal to modify OAPS classification criteria, mostly laboratory requirements, is reinforced by these results

Fundamento Y objetivos: Comparar características clínicas, analíticas, tratamiento y tasa de hijos vivos entre gestantes con Síndrome Antifosfolípido Obstétrico (SAFO) y gestantes con morbilidad obstétrica relacionada con el síndrome que no cumplen los criterios de clasificación actuales. Material Y métodos: Estudio observacional retrospectivo y prospectivo multicéntrico: datos de once hospitales terciarios europeos recogidos en el European Registry on Antiphospholipid Syndrome. Resultados: Se analizaron 338 mujeres: 247 cumplían criterios de Sydney para SAFO (grupo OAPS), y 91 no (grupo OMAPS). En el grupo OMAPS, 24/91(26.37%) cumplían criterios analíticos, pero no clínicos para SAFO (subgrupo A) y 67/91(74.63%) presentaban títulos medio-bajos o títulos positivos no persistentes de anticuerpos antifosfolípido, con o sin cumplir criterios clínicos (subgrupo B). Se observaron diferencias significativas entre los 2 grupos en cuanto a las categorías analíticas: 34% vs. 11% (p<0.0001) para la categoría I y 66% vs. 89% (p<0.0001) para la categoría II, OAPS vs OMAPS, respectivamente. No se observaron diferencias significativas en cuanto a las complicaciones obstétricas (p=0.481). El 86.20% del grupo OAPS recibió tratamiento vs.el 75.82% del grupo OMAPS (p=0.0224). No se observaron diferencias en la tasa de hijos vivos, ni en la tasa de trombosis arterial y/o venosa gestacional y/o puerperal. Conclusiones: Ambos grupos fueron muy homogéneos, excepto en cuanto a la distribución de las categorías analíticas y en la tasa de tratamiento. Ambos grupos mostraron buenos resultados al ser tratados. Los resultados respaldan la opinión de muchos expertos de tener que revisar los criterios de clasificación actuales del Síndrome Antifosfolípido Obstétrico

Pravastatin for Preventing and Treating Preeclampsia: A Systematic Review.

IMPORTANCE: We have performed a systematic search to summarize the role of statins for preventing and treating severe preeclampsia. OBJECTIVE: The aim of this study was to examine whether pravastatin is a useful and safe alternative for treating preeclampsia during pregnancy. EVIDENCE ACQUISITION: A systematic MEDLINE (PubMed) search was performed (1979 to June 2017), which was restricted to articles published in English, using the relevant key words of "statins," "pregnancy," "preeclampsia," "obstetrical antiphospholipid syndrome," and "teratogenicity." RESULTS: The initial search provided 296 articles. Finally, 146 articles were related to the use of statins during pregnancy, regarding their effect on the fetus and the treatment of preeclampsia. Ten studies were related to in vitro studies, 25 in animals, and 24 in humans (13 case report series and 11 cohort studies). We found 84 studies on reviews of such guidelines on cardiovascular disease (35 studies), use of statins in the antiphospholipid syndrome (25 studies), statin's specific use during pregnancy (13 studies), or preeclampsia treatment (11 studies). CONCLUSIONS: Although the studies are of poor quality, the rate of major congenital abnormalities in the newborn exposed to statins during pregnancy is no higher than the expected when compared with overall risk population. The review shows a potential beneficial role of statins in preventing and treating severe preeclampsia that needs to be evaluated through well-designed clinical trials. RELEVANCE: This update could influence positively the clinical practice, giving an alternative therapy for clinicians who treat preeclampsia, particularly in severe cases.

Comparative study between obstetric antiphospholipid syndrome and obstetric morbidity related with antiphospholipid antibodies.

BACKGROUND AND OBJECTIVES: To compare clinical, laboratory, treatment and live birth rate data between women with aPL-related obstetric complications (OMAPS) not fulfilling the Sydney criteria and women fulfilling them (OAPS). MATERIALS AND METHODS: Retrospective and prospective multicentre study. Data comparison between groups from The European Registry on Antiphospholipid Syndrome included within the framework of the European Forum on Antiphospholipid Antibody projects. RESULTS: 338 women were analysed: 247 fulfilled the Sydney criteria (OAPS group) and 91 did not (OMAPS group). In the OMAPS group, 24/91 (26.37%) fulfilled laboratory Sydney criteria (subgroup A) and 67/91 (74.63%) had a low titre and/or non-persistent aPL-positivity (subgroup B). Overall, aPL laboratory categories in OAPS vs. OMAPS showed significant differences: 34% vs. 11% (p<0.0001) for category I, 66% vs. 89% (p<0.0001) for category II. No differences were observed when current obstetric complications were compared (p=0.481). 86.20% of OAPS women were treated vs. 75.82% of OMAPS (p=0.0224), particularly regarding the LDA+LMWH schedule (p=0.006). No differences between groups were observed in live births, gestational, puerperal arterial and/or venous thrombosis. CONCLUSIONS: Significant differences were found among aPL categories between groups. Treatment rates were higher in OAPS. Both OAPS and OMAPS groups had similarly good foetal-maternal outcomes when treated. The proposal to modify OAPS classification criteria, mostly laboratory requirements, is reinforced by these results.

Refractory obstetrical antiphospholipid syndrome: Features, treatment and outcome in a European multicenter retrospective study.

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.

Tumor Necrosis Factor-Alpha and Pregnancy: Focus on Biologics. An Updated and Comprehensive Review.

Tumor necrosis factor-α (TNF-α) is a central regulator of inflammation, and TNF-α antagonists may be effective in treating inflammatory disorders in which TNF-α plays a major pathogenic role. TNF-α has also been associated with inflammatory mechanisms related to implantation, placentation, and pregnancy outcome. TNF-α is secreted by immune cells and works by binding to TNFR1 and TNFR2 cell receptors. TNF-α is also related to JAK/STAT pathways, which opens up hypothetical new targets for modifying. The accurate balance between Th1 cytokines, mainly TNF-α, Th17, and Th2, particularly IL-10 is essential to achieve good obstetric outcomes. TNF-α targeted therapy could be rational in treating women with obstetric complication related to overproduction of TNF-α, such as recurrent pregnancy loss, early and severe pre-eclampsia, and recurrent implantation failure syndrome, all "idiopathic" or related to aPL positivity. Along the same lines, Th1 cytokines, mainly TNF- α, play a leading pathogenic role in rheumatic and systemic autoimmune diseases occurring in women and, to a lesser extent, in men of reproductive age. These disorders have to be clinically silent before pregnancy can be recommended, which is usually only possible to achieve after intensive anti-inflammatory and immunosuppressive treatment, TNF-α blockers included. Physicians should be aware of the theoretic potential but low embryo-fetal toxicity risk of these drugs during pregnancy. From an updated review in May 2016, we can conclude that TNF-α blockers are useful in certain "refractory" cases of inflammatory disorders related to poor obstetric outcomes and infertility. Furthermore, TNF-α blockers can be safely used during the implantation period and pregnancy. Breastfeeding is also permitted with all TNF-α inhibitors. Since data on the actual mechanism of action of JAK-STAT in inflammatory obstetric disorders including embryo implantation are scarce, for the time being, therapeutic interventions in this setting should be discouraged. Finally, adverse effects on sperm quality, or causing embryo-fetal anomalies, in men treated with TNF inhibitors have not been described.

Tratamiento de las gestantes con enfermedades reumáticas o autoinmunitarias sistémicas con fármacos inmunodepresores y biológicos / Treatment with immunosuppressive and biologic drugs of pregnant women with systemic rheumatic or autoimmune disease

Las enfermedades reumáticas y autoinmunitarias afectan a mujeres y, en menor medida, también a hombres en edad fértil. Estas deben estar sin actividad clínica antes de la concepción, lo que suele conseguirse con fármacos inmunodepresores/antiinflamatorios. Un 50% de los embarazos en este colectivo no serán planificados. Los profesionales debemos conocer los efectos embrio/fetotóxicos de estos fármacos, así como sus consecuencias negativas sobre la gestación y la lactancia. Esta revisión actualizada hasta enero de 2016 permite concluir que la mayoría de los inmunodepresores disponibles, incluidos los inhibidores del TNF, se pueden utilizar antes y durante la gestación, con la excepción de ciclofosfamida, metotrexato, micofenolato y leflunomida. Se puede lactar exceptuando si se usa metotrexato, leflunomida, micofenolato y ciclofosfamida. Parece que abatacept, belimumab, rituximab, tocilizumab y anakinra son seguros durante la gestación y la lactancia. Exceptuando ciclofosfamida y sulfasalazina, no se han comunicado efectos sobre la calidad espermática ni un aumento de embriofetopatías en hombres tratados con inmunodepresores (AU)

Rheumatic and systemic autoimmune diseases occur in women and, to a lesser degree, men of reproductive age. These disorders have to be clinically nonactive before conception, which is usually only possible after anti-inflammatory and immunosuppressive treatment. We must be alert since 50% of pregnancies are unplanned. Physicians should know the embryo-foetal toxicity of these drugs during pregnancy and lactation. This January 2016-updated review allows us to conclude that the majority of immunosuppressives available -anti-TNF inhibitors included- can be used before and during pregnancy, with the exception of cyclophosphamide, methotrexate, mycophenolate and leflunomide. Lactation is permitted with all drugs except methotrexate, leflunomide, mycophenolate and cyclophosphamide. Although data on abatacept, belimumab, rituximab, tocilizumab and anakinra are scant, preliminary reports agree on their safety during pregnancy and, probably, lactation. Cyclophosphamide and sulfasalazine apart, no negative effects on sperm quality, or embryo-foetal anomalies in men treated with immunosuppressives have been described (AU)

[Treatment with immunosuppressive and biologic drugs of pregnant women with systemic rheumatic or autoimmune disease]. / Tratamiento de las gestantes con enfermedades reumáticas o autoinmunitarias sistémicas con fármacos inmunodepresores y biológicos.

Rheumatic and systemic autoimmune diseases occur in women and, to a lesser degree, men of reproductive age. These disorders have to be clinically nonactive before conception, which is usually only possible after anti-inflammatory and immunosuppressive treatment. We must be alert since 50% of pregnancies are unplanned. Physicians should know the embryo-foetal toxicity of these drugs during pregnancy and lactation. This January 2016-updated review allows us to conclude that the majority of immunosuppressives available -anti-TNF inhibitors included- can be used before and during pregnancy, with the exception of cyclophosphamide, methotrexate, mycophenolate and leflunomide. Lactation is permitted with all drugs except methotrexate, leflunomide, mycophenolate and cyclophosphamide. Although data on abatacept, belimumab, rituximab, tocilizumab and anakinra are scant, preliminary reports agree on their safety during pregnancy and, probably, lactation. Cyclophosphamide and sulfasalazine apart, no negative effects on sperm quality, or embryo-foetal anomalies in men treated with immunosuppressives have been described.