Background: NETosis occurs in the context of infection or inflammation and results in the expulsion of decondensed DNA filaments called NETs (Neutrophil Extracellular Traps) into the extracellular environment. NETosis activates coagulation and contributes to the thrombotic risk of inflammatory diseases. To date, two mechanisms of NETosis have been identified: suicidal NETosis, in which neutrophils die after expelling the filaments; and vital NETosis, in which expulsion appears without altering the membrane. Human pregnancy is associated with a mild pro-inflammatory state, which is increased in the event of complications such as preeclampsia (PE). NETosis has been observed in these situations, but the mechanism of its production has not yet been studied. The aim of our study was to evaluate the balance of vital vs. suicidal NETosis in normal pregnancy and in PE.Patients/Methods: Neutrophils from healthy volunteers were stimulated with plasma from normal pregnancies (n = 13) and from women developing preeclampsia (n = 13). Immunofluorescent labelling was performed to determine the percentages and origin of NETs in both groups. Inhibition with suicidal or vital NETosis inhibitors was also performed to validate our results.Results: We found a significant increase in NETs in women with PE compared to women with normal pregnancies. We showed that vital and non-vital NETosis are present in normal and preeclamptic pregnancies. We demonstrated that the higher proportion of NETs observed in PE was due to non-vital NETosis whose main component is represented by suicidal NETosis.Discussion: These results suggest the important part of non-vital NETosis in the pathophysiology of PE.

Pregnancy and puerperium increase the relative risk of venous thromboembolism (VTE) and the absolute risk remains low, around 1 per 1,000, with induced mortality of around 1 per 100,000. Analysis of large databases has helped specify the modes of presentation and risk factors (RF) whose impact is greater after than before childbirth, since VTE during pregnancy and post-partum obey different RFs. The evolution of the population concerned (mostly women over 35, obese, of multi-ethnicity undergoing medically assisted reproduction) affects the frequency of these RFs. Pulmonary embolism (PE) is over-represented after childbirth, but 30% of PE in pregnancy occurs without any RFs. Recommendations for prevention, mainly from expert groups, are heterogeneous and often discordant. Low molecular weight heparins (LMWH) are the mainstay of pharmacological thromboprophylaxis, in a field where randomized controlled studies are definitely lacking. VTE risk assessment in pregnancy must be systematic and repetitive. Risk assessment methods and scores are beginning to emerge to guide thromboprophylaxis and should be used more systematically. In the future, analyzing observational data from huge, nationwide registries and prospective cluster clinical trials may bring to light clinically relevant outcomes likely to feed comprehensive guidelines.

Antiphospholipid antibodies (aPL Abs) have long been associated with the occurrence of certain specific pregnancy morbidities, affecting both mother and fetus. Antithrombotic-based prophylactic regimens are the standard of care. Their intensity is modulated by the thrombotic history and has greatly improved the prognosis related to spontaneous morbidity. Observational studies show that this treatment is still associated with the persistence of excess of late-pregnancy placental diseases, calling for new or complementary developments, yet to be validated. Rigorous prospective multicentric validation of clinical and laboratory parameters capable of identifying those women and fetuses at a risk of pejorative evolution, thus early prognosis, is a priority issue. These will make it possible to develop customized treatments and test them. Furthermore, there are still concerns, particularly neurodevelopmental ones, about children born to aPL Ab-positive mothers, and clarification based on regular, more systematic evaluations is required. Even after pregnancy, women with a pure obstetrical antiphospholipid syndrome are at a greater risk of venous and arterial thrombosis over time, and prevention needs to be improved. These women also appear to develop more psychiatric and mood disorders. Central nervous system imaging using high-resolution techniques has shown subtle impairments in the white matter, associated with the most pathogenic aPL Abs and the clinical significance of this is under investigation. These mothers also seem to develop an excess of cancers. The systemic impact of aPL Abs is gradually being suspected, although this requires further evidence, and prevention should be envisaged.

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