Sexually dimorphic patterns in maternal circulating microRNAs in pregnancies complicated by fetal growth restriction

Background: Current methods fail to accurately predict women at greatest risk of
developing fetal growth restriction (FGR) or related adverse outcomes, including
stillbirth. Sexual dimorphism in these adverse pregnancy outcomes is well documented
as are sex-specific differences in gene and protein expression in the placenta.
Circulating maternal serum microRNAs (miRNAs) offer potential as biomarkers that
may also be informative of underlying pathology. We hypothesised that FGR would be
associated with altered miRNA profile and would differ depending on fetal sex.
Methods: miRNA expression profiles were assessed in maternal serum (>36 weeks’
gestation) from women delivering a severely FGR infant (defined as an individualised
birthweight centile (IBC) <3 rd ) and matched control participants (AGA; IBC=20-80 th
), using miRNA arrays. qPCR was performed using specific miRNA primers in an
expanded cohort of patients with IBC < 5 th (n=15 males, n=16 females/group).
Maternal serum human placental lactogen (hPL) was used as a proxy to determine if
serum miRNAs were related to placental dysfunction. In-silico analyses were
performed to predict the potential functions of altered miRNAs. Results: Initial
analyses revealed eleven miRNAs were altered in maternal serum from FGR
pregnancies. In-silico analyses revealed all 11 altered miRNAs were located in a
network of genes that regulate placental function. Subsequent analysis demonstrated
four miRNAs showed sexually dimorphic patterns. miR-28-5p was reduced in FGR
pregnancies (p<0.01) only when there was a female offspring and miR-301a-3p was
only reduced in FGR pregnancies with a male fetus (p<0.05). miR-454-3p was
decreased in FGR pregnancies (p<0.05) regardless of fetal sex but was only positively
correlated to hPL when the fetus was female. Conversely, miR-29c-3p was correlated
to maternal hPL only when the fetus was male. Target genes for sexually dimorphic
miRNAs reveal potential functional roles in the placenta including angiogenesis,
placental growth, nutrient transport and apoptosis. Conclusions: These studies have
identified sexually dimorphic patterns for miRNAs in maternal serum in FGR. These
miRNAs may have potential as non-invasive biomarkers for FGR and associated
placental dysfunction. Further studies to determine if these miRNAs have potential
functional roles in the placenta may provide greater understanding of the pathogenesis
of placental dysfunction and the differing susceptibility of male and female fetuses to
adverse in-utero conditions.