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Perinatal inflammation and placental programming of neonatal stroke

Rare diseases share many challenges, most notably a poor understanding of their determinants and causes, which results in delay in the implementation of targeted interventions. A solution to this lies in exploiting databases that include a suitable number of thoroughly selected cases and controls. However, in rare diseases, even multisite epidemiological studies take a long time to be completed. With a birth prevalence of 6 to 17 per 100 000, neonatal arterial ischemic stroke (NAIS) is no exception. Two main mechanisms of NAIS are suspected, but rarely demonstrated in clinical practice: a thrombus embolizing from the placenta and, less commonly, a craniocervical arterial injury occurring during the birthing process. Our inability to assign the right explanation often leaves parents with uncertainty and potential culpability. Sorg et al. are to be commended for investigating 134 neonates with arterial ischemic stroke, matched with four controls per case. (The authors use the generic appellation perinatal arterial ischemic stroke, but because all infants were diagnosed within the neonatal period and almost 90% were symptomatic during this time, we can infer that the population is representative of NAIS). Patients were consecutively recruited over 3 years by a nationwide network of 345 hospitals in Germany, with monthly recall notices and centralized case ascertainment. Multiple obstetric and neonatal variables were compared between cases and appropriate controls, with few missing data. This state-of-the-art methodology strengthens the significance of the study. By multiplying the risk of NAIS by 10, Sorg et al. reveal that chorioamnionitis far outweighs other identified determinants. Furthermore, perinatal inflammation was a constant independent risk factor in previous case–control studies of NAIS. Because inflammation and thrombotic processes are intimately linked, the placental–cerebral embolic hypothesis seems to be supported. Nevertheless, other issues, not mutually exclusive, merit discussion. The placenta plays a key role in brain development, with a constant resonance between both organs during pregnancy and consequences over the lifespan. Inflammatory mediators act as messengers of this interaction and, experimentally, neonatal vasculitis of the median cerebral artery is a remote consequence of chorioamnionitis. The visual presentation of the causal pathway of NAIS by a directed acyclic graph is an additional merit of the Sorg et al. study. This approach allows for delineating independent risk factors from confounders/statistical predictors and consequences of the stroke; a linear distinction that is not always obvious with multivariable analysis. Nonetheless, the approach also requires a priori considerations. In agreement with previous studies, biomarkers of peripartum hypoxia increased the risk of stroke in the Sorg et al. univariable analysis. However, the authors assumed that these biomarkers were consequences of stroke and did not include them in the main multivariable model. This is why ‘factors related to asphyxia at delivery’ are drawn with the temporal arrow pointing from NAIS to them. Regardless, this unidirectionality can be challenged. We agree that a low Apgar score, need for resuscitation, or acidosis shows only that something (e.g. a stroke) has occurred. Yet, the reverse hypothesis (defined in the authors’ second sensitivity analysis) is also arguable, namely peripartum hypoxia as causing or precipitating the NAIS. This hypothesis is supported by animal models in which hypoxia needs to be combined with carotid occlusion to lead to NAIS. Further, in such experimental models, chorioamnionitis as well as postnatal exposure to bacterial components sensitize the brain to the occurrence of NAIS. Hence, this experimental, triple-encounter among perinatal inflammation, focal ischemia, and global hypoxia, clinically supported by current and pre-existing clinical data, generates not only a third kind of pathophysiological hypothesis for NAIS but also provides compelling evidence for the need to design innovative, preventive, and curative trials combining anti-inflammatory molecules with posthypoxic neuroprotectants. Treatments such as erythropoietin, interleukin-1 receptor antagonists, and therapeutic hypothermia are already used in neonates and repurposing of their indication for NAIS could be a potentially costeffective and efficient strategy.