L6 PE & Offspring Neurodevelopment Flashcards
PE risk factors
obesity, advanced maternal age, diabetes, chronic hypertension, history of PE in a previous pregnancy
PE symptoms
- onset of chronic hypertension on or after week 20 of gestation
- proteinuria
- placental insufficiency
- endothelial dysfunction
- systemic inflammation
PE treatment
No effective treatment except for the immediate delivery of the baby & placenta
Untreated PE can lead to…
- liver, kidney or brain damage
- eclampsia
- death
Children born to a mother with PE have an increased risk of…
CVD, obesity, asthma, stroke
The risk for which brain disorders is increased by about 30-35% in children born to a mother with PE?
ASD, ADHD, ID
Neuroimaging studies in offspring of women who had PE
- altered regional grey matter volumes
- altered structural and functional connectivity
- reduced white matter maturation
Findings from animal studies of PE
- behavioural deficits
- altered regional brain volumes
- reduced neurogenesis and oligodendrogliogenesis
- altered brain transcriptome
Known risk genes for PE are mostly involved in…
endothelial cell function (VEGF) or cytokine signalling (TNFα & ERAP1)
Most common risk genes for ASD
synapse proteins (Shank & Neuroligin genes)
transcription factors that regulate neurodevelopment (FoxP1 & MeCP2)
A study that controlled for genetic factors by comparing PE-exposed children to their unexposed siblings found that PE, independent of sibling matching, increased the risk of…
ASD and ADHD
Potential mechanisms (interconnected) that could link PE with neurodevelopmental disorders
- altered placental nutrient transfer
- impaired angiogenesis
- perturbed placental signalling systems
- inflammation
- oxidative stress
- epigenetics
- microbiota
2 of the earliest and most well-characterised events in PE
- shallow trophoblast invasion
- failure to remodel the spiral arteries of the myometrium
(lead to placental insufficiency)
Nutrient levels in PE newborns
- altered placental expression of nutrient transporters
- higher total amino acids
- lower DHA levels
- higher homocysteine levels
- lower nervonic acid levels (esp males)
The effect of PE on angiogenic factors
Decrease in pro-angiogenic factors (PlGF & VEGF), and a large increase in anti-angiogenic factors (sFlt-1 & sENG) in both maternal & fetal circulation
What does impaired development of the cerebrovasculature affect?
- oxygen & nutrient supply to developing brain
- BBB development & permeability
Women with PE exhibit __ levels of stress
increased
Excessive cortisol affects genes involved in neurodevelopment, such as…
BDNF and Shh
Expression of what placental enzyme is reduced in PE?
HSD11β2
Dysregulation of which neurotransmitter is involved in PE pathophysiology
Serotonin
What drives the increase in 5-HT in PE?
Altered placental tryptophan metabolism i.e. decreased catabolism & increased availability of tryptophan precursor
How are neurotrophins affected in PE?
Decreased BDNF and increased NGF in the placenta and fetal circulation
How does exaggerated oxidative stress in PE affect the placenta?
It causes the placenta to secrete unknown molecules into fetal circulation, which can adversely affect neuronal development
Examples of neurodevelopmental processes that ROS regulate
NPC proliferation and differentiation, axonal guidance
What is observed in animal models of oxidative stress?
sub-optimal neurodevelopment
What are epigenetic modifications?
Heritable changes to gene expression which do not affect the actual DNA sequence e.g. DNA methylation
Example of where epigenetic changes have been observed in a neurodevelopmental disorder
Some ASD risk genes are for chromatin-remodelling enzymes (e.g. ACTL6B)
Epigenetic modifications in PE
Babies born to a PE pregnancy have altered DNA methylation in their circulation (no study has yet examined histone modifications)
Microbiota changes in PE
It has been reported that women with PE have an altered gut and vaginal microbiota composition. Women with PE are also much more likely to delivery via C-section, thereby colonising the baby with distinctly different microbes
How is breast milk composition altered in PE?
increased DHA and nervonic acid, decreased BDNF, altered metabolites (influenced by maternal microbiome)
Conclusion of paper by Scott et al. (2018)
Pre-eclamptic placentae release factors that affect neuronal development - largely mediated through astrocytes and glutamate signalling
In the paper by Scott et al. (2018), how did pre-eclamptic placenta medium affect neurite length and astrocyte numbers?
- decreased neurite length
- altered neurotransmitter receptor expression
- increased astrocyte numbers
In the paper by Scott et al. (2018), what’s the role of MK801?
MK801 is a glutamate NMDA receptor antagonist that prevents PE-induced neurite growth deficits
What are responsible for the effects of PE placenta media on neurons (Scott et al., 2018)?
Astrocytes, via glutamate NMDA signalling
