Systems biology evaluation of cell-free amniotic fluid transcriptome of term and preterm infants to detect fetal maturity.
BACKGROUND
Amniotic fluid (AF) is a proximal fluid to the fetus containing higher amounts of cell-free fetal RNA/DNA than maternal serum, thereby making it a promising source for identifying novel biomarkers that predict fetal development and organ maturation. Our aim was to compare AF transcriptomic profiles at different time points in pregnancy to demonstrate unique genetic signatures that would serve as potential biomarkers indicative of fetal maturation.


METHODS
We isolated AF RNA from 16 women at different time points in pregnancy: 4 from 18 to 24 weeks, 6 from 34 to 36 weeks, and 6 from 39 to 40 weeks. RNA-sequencing was performed on cell-free RNA. Gene expression and splicing analyses were performed in conjunction with cell-type and pathway predictions.


RESULTS
Sample-level analysis at different time points in pregnancy demonstrated a strong correlation with cell types found in the intrauterine environment and fetal respiratory, digestive and external barrier tissues of the fetus, using high-confidence cellular molecular markers. While some RNAs and splice variants were present throughout pregnancy, many transcripts were uniquely expressed at different time points in pregnancy and associated with distinct neonatal co-morbidities (respiratory distress and gavage feeding), indicating fetal immaturity.


CONCLUSIONS
The AF transcriptome exhibits unique cell/organ-selective expression patterns at different time points in pregnancy that can potentially identify fetal organ maturity and predict neonatal morbidity. Developing novel biomarkers indicative of the maturation of multiple organ systems can improve upon our current methods of fetal maturity testing which focus solely on the lung, and will better inform obstetrical decisions regarding delivery timing.
Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Beena.Kamath-Rayne@cchmc.org.
Beena D
BD
Kamath-Rayne
Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Yina.Du@cchmc.org.
Yina
Y
Du
Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. marhughes2010@gmail.com.
Maria
M
Hughes
Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Erin.Wagner@cchmc.org.
Erin A
EA
Wagner
Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Louis.Muglia@cchmc.org.
Louis J
LJ
Muglia
Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Emily.DeFranco@ucmail.uc.edu.|Maternal-Fetal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA. Emily.DeFranco@ucmail.uc.edu.
Emily A
EA
DeFranco
Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Jeffrey.Whitsett@cchmc.org.
Jeffrey A
JA
Whitsett
Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Nathan.Salomonis@cchmc.org.
Nathan
N
Salomonis
Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Yan.Xu@cchmc.org.|Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Yan.Xu@cchmc.org.
Yan
Y
Xu
D000653:Amniotic Fluid / Q000166:cytology / Q000378:metabolism*; D015897:Comorbidity; D005260:Female; D005325:Fetal Organ Maturity / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D007234:Infant, Premature; D008297:Male; D011247:Pregnancy; D017423:Sequence Analysis, RNA; D049490:Systems Biology; D047929:Term Birth / Q000235:genetics*