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

Abstract 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 an 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) < 3rd) and matched control participants (AGA; IBC = 20–80th), using miRNA arrays. qPCR was performed using specific miRNA primers in an expanded cohort of patients with IBC < 5th (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 11 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.

Download Full-text

Metabolomics Identifies Placental Dysfunction and Confirms Flt-1 (FMS-Like Tyrosine Kinase Receptor 1) Biomarker Specificity

Hypertension ◽

10.1161/hypertensionaha.119.13184 ◽

2019 ◽

Vol 74 (5) ◽

pp. 1136-1143 ◽

Cited By ~ 1

Author(s):

Marie Austdal ◽

Gabriela Brettas Silva ◽

Sophie Bowe ◽

Liv Cecilie Vestrheim Thomsen ◽

Line Haugstad Tangerås ◽

...

Keyword(s):

Tyrosine Kinase ◽

Fetal Growth ◽

Fetal Growth Restriction ◽

Magic Angle Spinning ◽

Maternal Serum ◽

Growth Restriction ◽

Tyrosine Kinase Receptor ◽

Resonance Spectroscopy ◽

Magic Angle ◽

Placental Dysfunction

Clinical end-stage parameters define the pregnancy disorders preeclampsia and fetal growth restriction while classification of the underlying placental dysfunction is missing and urgently needed. Flt-1 (FMS-like tyrosine kinase receptor 1) is the most promising placenta-derived predictive biomarker for preeclampsia. We aimed to classify placental dysfunction in preeclampsia and fetal growth restriction at delivery by metabolic profiling and authenticate the biomarker Flt-1 for placental dysfunction. We studied 143 pregnancies with or without preeclampsia and/or fetal growth restriction delivered by cesarean section. Metabolic placenta profiles were created by high-resolution magic angle spinning nuclear magnetic resonance spectroscopy and the resulting placental phenotypes obtained by hierarchical clustering. Placental Flt-1 expression (membrane-bound and soluble isoforms combined) and maternal serum Flt-1 expression (soluble isoforms) were analyzed by immunohistochemistry and ELISA, respectively. We identified 3 distinct placenta groups by 21 metabolites and diagnostic outcome parameters; normal placentas, moderate placental dysfunction, and severe placental dysfunction. Increased placental Flt-1 was associated with severe placental dysfunction, and increased serum Flt-1 was associated with moderate and severe placental dysfunction. The preeclamptic pregnancies with and without placental dysfunction could be distinguished by 5 metabolites and placental Flt-1. Placental Flt-1 alone could separate normal pregnancies with and without placental dysfunction. In conclusion, metabolomics could classify placental dysfunction and provide information not identified by traditional diagnostics and metabolites with biomarker potential were identified. Flt-1 was confirmed as precision biomarker for placental dysfunction, substantiating its usefulness for identification of high-risk pregnancies for preeclampsia and fetal growth restriction with placental involvement.

Download Full-text

Maternal serum concentrations of proteins linked to angiogenesis and cardiovascular disease are associated with placental histomorphometry in severe early-onset fetal growth restriction, with effect modification by fetal sex and aspirin use.

Placenta ◽

10.1016/j.placenta.2021.07.190 ◽

2021 ◽

Vol 112 ◽

pp. e59

Author(s):

Elena Piscitelli ◽

Katarzyna Maksym ◽

Neil Sebire ◽

Anna David ◽

Rebecca Spencer

Keyword(s):

Cardiovascular Disease ◽

Fetal Growth ◽

Fetal Growth Restriction ◽

Early Onset ◽

Effect Modification ◽

Maternal Serum ◽

Growth Restriction ◽

Serum Concentrations ◽

Fetal Sex

Download Full-text

Risk stratification for early-onset fetal growth restriction in women with abnormal serum biomarkers: a retrospective cohort study

Scientific Reports ◽

10.1038/s41598-020-78631-5 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

L. Ormesher ◽

L. Warrander ◽

Y. Liu ◽

S. Thomas ◽

L. Simcox ◽

...

Keyword(s):

Fetal Growth ◽

Fetal Growth Restriction ◽

Early Onset ◽

Late Onset ◽

Area Under The Curve ◽

Maternal Serum ◽

Serum Biomarkers ◽

Growth Restriction ◽

Aneuploidy Screening ◽

Internal Validation

AbstractAbnormal maternal serum biomarkers (AMSB), identified through the aneuploidy screening programme, are frequent incidental findings in pregnancy. They are associated with fetal growth restriction (FGR), but previous studies have not examined whether this association is with early-onset (< 34 weeks) or late-onset (> 34 weeks) FGR; as a result there is no consensus on management. The aims of this study were to determine the prevalence and phenotype of FGR in women with AMSB and test the predictive value of placental sonographic screening to predict early-onset FGR. 1196 pregnant women with AMSB underwent a 21–24 week “placental screen” comprising fetal and placental size, and uterine artery Doppler. Multivariable regression was used to calculate a predictive model for early-onset FGR (birthweight centile < 3rd/< 10th with absent umbilical end-diastolic flow, < 34 weeks). FGR prevalence was high (10.3%), however early-onset FGR was uncommon (2.3%). Placental screening effectively identified early-onset (area under the curve (AUC) 0.93, 95% confidence interval (CI) 0.87–1.00), but not late-onset FGR (AUC 0.70, 95% CI 0.64–0.75). Internal validation demonstrated robust performance for detection/exclusion of early-onset FGR. In this cohort, utilisation of our proposed algorithm with targeted fetal growth and Doppler surveillance, compared with universal comprehensive surveillance would have avoided 1044 scans, potentiating significant cost-saving for maternity services.

Download Full-text

Placental Dysfunction Underlies Increased Risk of Fetal Growth Restriction and Stillbirth in Advanced Maternal Age Women

Scientific Reports ◽

10.1038/s41598-017-09814-w ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 30

Author(s):

Samantha C. Lean ◽

Alexander E. P. Heazell ◽

Mark R. Dilworth ◽

Tracey A. Mills ◽

Rebecca L. Jones

Keyword(s):

Fetal Growth ◽

Fetal Growth Restriction ◽

Maternal Age ◽

Advanced Maternal Age ◽

Growth Restriction ◽

Placental Dysfunction ◽

Increased Risk

Download Full-text

Evaluating the Effect of Pravastatin in Early-Onset Fetal Growth Restriction: A Nonrandomized and Historically Controlled Pilot Study

American Journal of Perinatology ◽

10.1055/s-0040-1713651 ◽

2020 ◽

Cited By ~ 1

Author(s):

Manel Mendoza ◽

Raquel Ferrer-Oliveras ◽

Erika Bonacina ◽

Pablo Garcia-Manau ◽

Carlota Rodo ◽

...

Keyword(s):

Pilot Study ◽

Fetal Growth ◽

Pregnancy Outcomes ◽

Fetal Growth Restriction ◽

Early Onset ◽

Maternal Serum ◽

Angiogenic Factors ◽

Interquartile Range ◽

Growth Restriction ◽

Control Group

Objective This study aimed to analyze the effect of pravastatin on angiogenic factors, feto–maternal Doppler findings and pregnancy outcomes in women with early-onset fetal growth restriction (FGR) treated with pravastatin compared with nontreated controls. Study Design This was a pilot study conducted between March 2016 and September 2017. Women with single pregnancies and FGR diagnosed at ≤ 28 weeks of gestation were offered 40 mg of pravastatin daily. Doppler progression, soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) values, and pregnancy outcomes were assessed and compared with consecutive historical controls. Controls were matched to treated women for gestational age, maternal characteristics, maternal and obstetric history, Doppler severity classification, and angiogenic factors at diagnosis. The sFlt-1/PlGF was measured in maternal serum at two different times: before pravastatin was started (ratio M0) and during pravastatin treatment (ratio M1). Doppler severity was classified into four categories: normal, mild, moderate, and severe. Results A total of 38 women were enrolled in this study. No differences were observed in baseline characteristics between groups. However, when compared with the ratio M0, M1 was increased by a median (interquartile range) of 67.0 (−34.8 to 197.3) in the control group but decreased by a median (interquartile range) of −10.1 (−53.1 to −0.07) in the pravastatin treated group (p < 0.001). No significant differences were observed in Doppler progression throughout pregnancy. Median interval from diagnosis to delivery was extended by 16.5 days, the median newborn birthweight was increased from 1,040 to 1,300 g, and the number of women with preeclampsia decreased from 9 (47.4%) to 6 (31.6%) in treated women; however, these trends were not statistically significant. Conclusion In women with early-onset FGR, treatment with pravastatin 40 mg daily was associated with significant improvement in the angiogenic profile. Additionally, median pregnancy duration and median birthweight increased and the incidence of PE was reduced in treated women. Nevertheless, since this pilot study was underpowered, none of these differences were statistically significant. Key Points

Download Full-text