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Objectives: An increased risk of adverse maternal and foetal pregnancy complications (including pre-eclampsia, intrauterine growth restriction, and small for gestational age) is well described in women with autoimmune rheumatic disease (ARD) compared with the general population (GenPop). It is less clear, however, whether this risk of adverse pregnancy outcome (APO) also exists in women with 'preclinical ARD' (pre-ARD) before they are diagnosed with an ARD many years post-partum. Therefore, we have undertaken a systematic review of the available evidence on APO in patients who subsequently were diagnosed with a rheumatic disease to identify whether there is an increased risk in pre-ARD., Methods: The present study was reported in accordance with the guidance of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standard. A systematic literature review was performed using the online PubMed database. Pre-SLE and pre-RA patients were defined as those who, over the subsequent years, developed SLE or RA according to international classification criteria., Results: A total of 176 articles were screened, and 27 original articles were selected for final analysis. Pre-RA was the most studied group, with 15 studies and a total of >1600 pregnancies, and pre-SLE was the second-most studied pre-ARD in pregnancy, with 14 studies and a total of >1000 pregnancies. We found that patients who subsequently developed SLE had an increased burden of poor pregnancy outcomes compared with pregnant women from the GenPop, but fewer APOs compared with pregnancies of women with SLE. In contrast, a similar rate of APOs was found when pre-RA pregnancies were compared with GenPop pregnancies., Conclusion: Our findings of an increased risk of APO in certain pre-ARDs highlights the relevance of taking an obstetric history during the first rheumatology appointment and the need for novel screening strategies for the prediction of APOs. Further research is required to elucidate the immune basis of APOs in preclinical and clinical ARD., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: To investigate the impact of thrombocytopenia on survival in patients with APS., Methods: Thrombocytopenia and other predictors of outcome were retrospectively evaluated in an aPL-positive and APS cohort with 38-year follow-up (1980-2018). Thrombocytopenia was defined as <150 × 109 platelets/l. Hazard ratios (HR) of mortality were calculated using Cox-regression models., Results: Among 114 patients, 64% had primary APS, 25% secondary APS and 10% asymptomatic aPL. Mean follow-up was 19 (range 5-38) years. ANA [hazard ratio (HR) 1.8, 95% CI 0.8, 3.6, P = 0.10], arterial thrombotic events (HR 7.0, 95% CI 1.4, 3.5, P = 0.016), myocardial infarction (HR 8.3, 95% CI 1.1, 59, P = 0.03), intracardiac thrombosis (HR 17, 95% CI 1, 279, P = 0.04) and thrombocytopenia (HR 2.9, 95% CI 1.4, 6.1, P = 0.004) were risk factors for all-cause mortality, but in multivariate analysis only thrombocytopenia (HR 2.7, 95% CI 1.3, 6.0, P = 0.01) remained significant. Persistent (HR 4.4, 95% CI 2.1, 9.2, P = 0.001) and low-moderate thrombocytopenia (HR 2.8, 95% CI 1.2, 6.4, P = 0.01) were associated with a significant increase in mortality compared with acute (HR 1.6, 95% CI 0.5, 5.3, P = 0.40) and severe (HR 2.1, 95% CI 0.5, 9.2, P = 0.30) forms. APS patients with vs without thrombocytopenia were more frequently male (58 vs 24%, P = 0.001) with arterial thrombosis (55 vs 32%, P = 0.04), LA positivity (100 vs 87%, P = 0.04), type I aPL profile (89% vs 71%, P = 0.05) and anticoagulant treatment (89 vs 63%, P = 0.01). Thrombosis caused 13% of deaths in thrombocytopenic patients and 1% in those without (P = 0.01)., Conclusion: Thrombocytopenia is an aPL-related manifestation that identifies patients with severe disease phenotype and high thrombotic risk. Persistent low-moderate thrombocytopenia is associated with a reduced long-term survival., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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.)

Recurrent miscarriage is frustrating for the physician and a heartbreaking experience for the patient. Approximately 5% of couples trying to conceive have two consecutive miscarriages. Despite a thorough study of patients, the aetiology of this common obstetric complication is unknown in 50% of cases. Known causes include abnormal chromosomes, endocrinological disorders and uterine abnormalities. Although antiphospholipid antibodies have been demonstrated in miscarriages, the role played by alloimmune mechanisms remains unclear. New immunological approaches such as natural killer cells, regulatory T cells, tumour necrosis factor α, cell-derived microparticles, leptin, certain glycoproteins and cytokines should be considered. The management of thyroid diseases and immunological disorders is continuously evolving. Several genetic diagnostic procedures such as parental karyotyping and preimplantation genetic screening should probably not be used routinely. Antiphopholipid syndrome and some recurrent miscarriage-related endocrinological disorders can be effectively treated. Finally, new therapeutic approaches and the pleiotropic effects of old ones have led to improved fetal-maternal outcomes., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Aims: Animal models showed that angiogenesis is related to abnormal heart development. Our objectives were to ascertain whether a relationship exists between congenital heart defects (CHDs) and angiogenic/anti-angiogenic imbalance in maternal and foetal blood and study the expression of angiogenic factors in the foetal heart., Methods and Results: Maternal and cord blood placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) were compared in 65 cases of CHD and 204 normal controls. Angiogenic factor expression and markers of hypoxia were measured in heart tissue from 23 CHD foetuses and 8 controls. In the CHD group, compared with controls, plasma PlGF levels were significantly lower (367 ± 33 vs. 566 ± 26 pg/mL; P < 0.0001) and sFlt-1 significantly higher (2726 ± 450 vs. 1971 ± 130 pg/mL, P = 0.0438). Foetuses with CHD had higher cord plasma sFlt-1 (442 ± 76 vs. 274 ± 26 pg/mL; P = 0.0285) and sEng (6.76 ± 0.42 vs. 4.99 ± 0.49 ng/mL, P = 0.0041) levels. Expression of vascular endothelial growth factor (VEGF), sFlt-1, markers of chronic hypoxia, and antioxidant activity were significantly higher in heart tissue from CHD foetuses compared with normal hearts (VEGF, 1.59-fold; sFlt-1, 1.92-fold; hypoxia inducible factor (HIF)-2α, 1.45-fold; HO-1, 1.62-fold; SOD1, 1.31-fold)., Conclusion: An intrinsically angiogenic impairment exists in CHD that appears to be present in both the maternal and foetal circulation and foetal heart. Our data suggest that an imbalance of angiogenic-antiangiogenic factors is associated with developmental defects of the human heart.

Background: The risk of pre-eclampsia (PE) increases in twin pregnancies, especially when assisted reproduction technologies (ART) are used. The aim of this study was to assess angiogenic/anti-angiogenic factors in maternal serum in the first trimester of twin pregnancies and establish if the mode of conception influences angiogenic status., Methods: This prospective study enrolled women with twin (n = 61) and singleton (n = 50) pregnancies. Dichorionic twin pregnancies were divided into two groups according to their mode of conception. Singleton pregnancies were used as the control group. Soluble fms-like tyrosine kinase (sFlt-1), free placental growth factor (PlGF) and soluble endoglin (sEng) concentrations were measured in the first trimester maternal serum., Results: In the first trimester, women with twin pregnancies had higher serum concentrations of the anti-angiogenic factor sFlt-1 than that with singleton pregnancies (3924 ± 250 versus 2426 ± 162 pg/ml, respectively; P < 0.001). Maternal serum PlGF concentrations were lower in singleton pregnancies than those in twin pregnancies (37 ± 3.7 versus 59 ± 5.6, respectively; P < 0.001). Serum concentrations of sFlt-1 were higher in twin pregnancies conceived by ART than those in spontaneous twin pregnancies (4313 ± 389 versus 3522 ± 300 pg/ml, respectively; P < 0.05). No differences between groups were observed for sEng., Conclusions: In the first trimester, twin pregnancies conceived using ART showed a heightened anti-angiogenic status that could explain the increased risk of PE in these cases.