Chronic Inflammation Offers Hints About Viable Therapeutic Targets for Preeclampsia and Potentially Related Offspring Sequelae

Abstract

The combination of hypertension with systemic inflammation during pregnancy is a hallmark of preeclampsia, but both processes also convey dynamic information about its antecedents and correlates (e.g., fetal growth restriction) and potentially related offspring sequelae. Causal inferences are further complicated by the increasingly frequent overlap of preeclampsia, fetal growth restriction, and multiple indicators of acute and chronic inflammation, with decreased gestational length and its correlates (e.g., social vulnerability). This complexity prompted our group to summarize information from mechanistic studies, integrated with key clinical evidence, to discuss the possibility that sustained or intermittent systemic inflammation-related phenomena offer hints about viable therapeutic targets, not only for the prevention of preeclampsia, but also the neurobehavioral and other developmental deficits that appear to be overrepresented in surviving offspring. Importantly, we feel that carefully designed hypothesis-driven observational studies are necessary if we are to translate the mechanistic evidence into child health benefits, namely because multiple pregnancy disorders might contribute to heightened risks of neuroinflammation, arrested brain development, or dysconnectivity in survivors who exhibit developmental problems later in life.

Keywords: autism; cerebral palsy; chorioamnionitis; disability; hypertension; intrauterine growth restriction; neurodevelopmental; small for gestational age; social vulnerability.

Figure 1

Conceptual Model Linking Preeclampsia Risk Factors, Chronic Inflammation and Potentially Related Sequelae in Offspring. [Chronic inflammation related risk factors for PE (*) might impact fertility or otherwise limit growth/maturation in ways that affect implantation (red numbers 1–3) or distrupt typical developmental processes (red numbers 4–6) that can increase the risk of downstream placental dysfunction (red numbers 7–8) and related clinical diagnoses after the 20th week of gestation. The conceptus is believed to be supported by histotrophic nutrition in early gestation before developing its placenta [11,12,13,14,15,16,17,18,19,20,21,22,23,24]. Around 7–12 weeks, placentation occurs by way of a complex network of interactions between uterine, decidual, and fetal cell populations [25,26,27,28,29,30,31,32]. Disruption of these developmental processes appears to limit trophoblast invasiveness, particularly before the 12th week of pregnancy when markers of trophoblast stemness decline rapidly [33], resulting in shallow placentation and inadequate remodeling of the spiral arteries [34,35,36,37,38,39,40,41], thereby reducing the flow of nutrients in maternal blood to the intervillous space [34,35,36,37,38,39,40,41], where oxygen and nutrients are transported to the fetus [42,43,44,45]. This, in turn, seems to raise the risk of downstream pregnancy and offspring developmental disorders that are associated with sustained systemic inflammation and white matter damage or dysfunction (e.g., PE, FGR, and autism). Thus, early gestation (or even prior to that) might present new opportunities to develop therapeutic interventions not only for PE, but also for optimizing fetal growth and the prevention of related neurobehavioral (and possibly cardiovascular and pulmonary) deficits in offspring [46]. (The ‘Week 1’ portion of the figure was adapted nder an extended license agreement [#505384740] from an Adobe Stock image created by udaix, while the images to the right were created by the authors using BioRender under an Academic License.)].