Abstract
Preterm birth is recognized as the primary cause of infant mortality worldwide. Twin pregnancies are significantly more at risk of preterm birth than singleton pregnancies. A greater understanding of why this is and better modes of treatment and prevention are needed. Key to this is determining the differing pathophysiological mechanisms of preterm birth in twins, including the role of the myometrium and premature uterine contraction.We performed RNA sequencing (RNA-Seq) of human myometrium from singleton and twin pregnancies at term (> 37+0 weeks) and preterm (< 37+0 weeks), collected during pre-labour Caesarean Section. RNA-Seq libraries were prepared from polyA-selected RNA and sequenced on the Illumina HiSeq 4000 platform. Differentially expressed genes (DEGs), GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment were conducted using R software. Significance was determined with a false discovery rate–adjusted P value of <0.05. Only 3 DEGs were identified between gestational age-matched singleton and twin myometrium and only 1 DEG identified between singleton term and twin preterm tissues. Comparison of singleton preterm myometrium with twin term myometrium however, revealed 75 down-regulated and 24 up-regulated genes in twin myometrium. This included genes associated with inflammation and immune response, T cell maturation and differentiation and steroid biosynthesis. GO and KEGG enrichment analyses for biologically relevant processes and functions also revealed several terms related to inflammation and immune response, as well as cytokine-cytokine receptor interaction and chemokine receptor signalling. Data indicate that little or no differences exist in the transcriptome of singleton and twin myometrium when matched for gestational age. The significant up- and down-regulation of genes identified between preterm singleton and twin myometrium at term may point to transcriptome changes associated with the chronic levels of uterine stretch in twin pregnancy or genes associated with the myometrium transitioning to labour onset.
Highlights
Preterm birth is defined as delivery before 37 weeks gestation and occurs at a rate of around 11% of all births worldwide [1]
We examined for the first time, the human myometrial transcriptome from singleton and twin pregnancies at two gestational time points using high throughput RNA sequencing
When matched for gestational age, we find only a few genes which are differentially expressed between groups which implies that there is little or no difference in the myometrial transcriptome of singleton and twin pregnancies, at least when length of pregnancy is controlled for
Summary
Preterm birth is defined as delivery before 37 weeks gestation and occurs at a rate of around 11% of all births worldwide [1]. It is the single biggest cause of neonatal mortality and morbidity with almost half of preterm births being preceded by preterm labour (PTL). Infection or short cervix are known risk factors for preterm birth [5] and are likely to be common to both pregnancies, whilst others such as uterine (over) distension and early activation of contractile pathways may be more significant in twins. Endocrine differences may exist, resulting in part from double the quantity of fetal hormones from having more than one fetus, each producing hormones in the fetal hypothalamic-pituitary-adrenal-placental axis and in the case of dichorionic twins, the effects of increased overall placental mass [3]
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