Hypoxia: A teratogen underlying a range of congenital disruptions, dysplasias, and malformations

Abstract

In this review, we explore evidence that hypoxia in the developing human fetus can lead not only to the more commonly accepted disruptive-type defects, but also patterns of anomalies that suggest that hypoxia can exert a more classic teratogenic effect, using the brain as one example. We review neuropathology in the context of intrauterine hypoxia, particularly as it relates to carbon monoxide poisoning, in utero strokes, and homozygous alpha-thalassemia. In general, the associated brain injuries resemble those seen with other causes of hypoxic-ischemic injury. Fetal strokes during development usually lead to loss of brain tissue in areas that do not follow a typical embryologic pattern, and therefore are considered disruptions. However, there is also evidence that fetal brain ischemia can cause more classically recognized patterns of abnormal embryonic neuronal migration and organization such as polymicrogyria, cortical dysplasia, or dysgenesis, including select types of focal cortical dysplasia. This study summarizes available literature and evidence to raise clinicians' awareness regarding the association between hypoxia and congenital anomalies, including brain malformations.

Protocols for the Evaluation of Neurodevelopmental Alterations in Rabbit Models In Vitro and In Vivo

“…All tests presented in this collection have been used to evaluate the neurodevelopmental alterations induced by mild-hypoxic conditions during the prenatal period and some of them have been used by other authors to study the neurodevelopmental effects of caffeine exposure or maternal endotoxin exposure (Balakrishnan et al, 2013;Van der Veeken et al, 2020). The whole battery of tests has not been used to assess known neurotoxic compounds so far, but a broad definition of teratogen includes "any infection, physical, chemical, or environmental agent that can disrupt or disturb the development of a fetus or embryo (Adam, 2012)", and in fact, hypoxia is accepted as a teratogen agent (Adam et al, 2021). Hypoxia, or low oxygen levels, is a neurodevelopmental key event that can be triggered by multiple causes, including a reduction or lack of blood flow (as presented here), low oxygen levels in the blood, low levels of red blood cells and/or hemoglobin, but also by the inability of the tissues to utilize oxygen due to, for example, carbon monoxide poisoning (Adam et al, 2021).…”

“…The whole battery of tests has not been used to assess known neurotoxic compounds so far, but a broad definition of teratogen includes "any infection, physical, chemical, or environmental agent that can disrupt or disturb the development of a fetus or embryo (Adam, 2012)", and in fact, hypoxia is accepted as a teratogen agent (Adam et al, 2021). Hypoxia, or low oxygen levels, is a neurodevelopmental key event that can be triggered by multiple causes, including a reduction or lack of blood flow (as presented here), low oxygen levels in the blood, low levels of red blood cells and/or hemoglobin, but also by the inability of the tissues to utilize oxygen due to, for example, carbon monoxide poisoning (Adam et al, 2021). Therefore, as an illustrative case study, the results of this battery of tests after chronic hypoxia-ischemia insult during gestation induced in one of the uterus horns by ligation of 40-50% of uteroplacental vessels on day 25 of pregnancy are discussed here, to show the potential of the combination of the different tests described in these protocols.…”

Additional evidence for the vascular disruption defect hypothesis in a novel case of brainstem disconnection syndrome

“…In addition, no radiological manifestations of chondrodysplasia punctata were observed postnatally. Alternatively, an ischemic injury related to a maternal trauma or a severe hypotension causing a fetal stroke could be suggested (Adam, Payton, Sanchez‐Lara, Adam, & Mirzaa, 2021; Özduman et al, 2004). Even though a low placenta flow related to a severe maternal hypotension could be observed, no history of maternal trauma was recorded in the present case.…”