Research Article: Micro RNA clusters in maternal plasma are associated with preterm birth and infant outcomes

Date Published: June 27, 2018

Publisher: Public Library of Science

Author(s): Joel C. Wommack, Jerome P. Trzeciakowski, Rajesh C. Miranda, Raymond P. Stowe, R. Jeanne Ruiz, Pierre Busson.


The current study examined micro RNA (miRNAs) clusters from the maternal plasma to determine their association with preterm birth (PTB) and infant birth outcomes. A subsample of 42 participants who spontaneously delivered either preterm (≤37 weeks) or term was selected from a parent sample of 515 pregnant Mexican American women. Plasma samples and prenatal data were collected at a single mid-gestation time point (22–24 weeks’ gestation) and birth outcomes were obtained from medical records after delivery. Circulating miRNAs were analyzed by qPCR. When miRNAs were grouped according to chromosomal cluster rather than expression level, individual miRNAs correlated strongly with other individual miRNAs within their respective genomic locus. miRNAs from the c19mc cluster negatively correlated with c14mc miRNAs, and this relationship was more pronounced in PTB. Clusters c14mc was negatively associated with length of gestation; while the c19mc was positively associated with length of gestation and infant head circumference. Together, these findings suggest that groups of miRNAs from common chromosomal clusters, rather than individual miRNAs, operate as co-regulated groups of signaling molecules to coordinate length of gestation and infant outcomes. From this evidence, differences in cluster-wide expression of miRNAs are involved in spontaneous PTB.

Partial Text

Preterm birth (PTB), or gestational length ≤37 weeks, is probably the most significant obstetrical problem we currently face. Babies born too soon and too small often have multiple problems such as respiratory problems, intraventricular hemorrhages, necrotizing colitis and neurodevelopmental delays [1]. PTB is currently the primary reason for newborn mortality [2]. The primary monetary costs of PTB total to approximately $26 billion per year in the U.S. [1]. However, the secondary burdens of PTB may be even greater due to the lifelong health impact of premature birth [3]. Thus despite ongoing research, further understanding of the multifactorial etiologies that may affect PTB and related poor birth outcomes is still vitally needed. Scientists need to contemplate multiple risk factors and pathways leading to PTB—as well as their interactions [4]. One particular area of interest related to the etiology of PTB has recently been focused on epigenetics (for which microRNAs are a portion) [4,5]. The origins of PTB may be from complex gene-environment interactions. We present our results using a new methodology to examine microRNAs (miRNAs) as part of a pathway related to gestational age, PTB, and deleterious infant outcomes such as low birth weight and smaller head circumference.

The current study was conducted in a subset of a parent study (n = 515) on pregnant Hispanic women recruited at two obstetrical clinics in the Houston metropolitan areas from 2008–2012 [24]. The subsample (n = 42) consisted of patients who spontaneously delivered before the completion of 37 gestational weeks (PTB; n = 21) and patients who spontaneously delivered after 37 weeks (Term; n = 21). Selected cases of PTB and term pregnancy were matched for age, gravidity, and BMI. Enrollment criteria included patients who: were between the ages 19 and 39; self-identified as Hispanic; had the ability to read and speak English and/or Spanish; were born in the U.S. or had lived in the U.S. for 10 or more years; were covered by self-pay, state funded or private insurance. Exclusion criteria included: pregnancies with twins or multiple fetuses; medical risk factors such as chronic hypertension, type I or II diabetes, gestational diabetes with insulin treatment, thyroid disorder; major psychiatric disorders (e.g. Bipolar Disorder, Schizophrenia); use of steroids or antidepressants one month prior to enrollment; fetal or uterine anomalies as determined by ultrasound; fetal demise; placenta previa, preeclampsia at time of data collection; cerclage.

The first major finding of our current study is that pregnancy specific miRNAs within the maternal plasma are co-regulated based on chromosomal clustering at distinct genomic loci. Previous studies into PTB and other prenatal medical complications that focused on individual miRNAs or groups of miRNAs sorted by expression levels rather than genomic location have produced disparate results. Findings from the current study provide a novel perspective by examining cluster-wide associations between circulating miRNAs and birth outcomes. Still, our results are consistent with previous studies that have identified individual miRNAs or groups of miRNAs from the c14mc, c19mc, and miR-17/92 chromosomal clusters that are associated with pregnancies disorders, including PTB [5], pre-eclampsia [8, 23], and FAS-D [9].




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