Gene expression in term placentas is regulated more by spinal or epidural anesthesia than by late-onset preeclampsia or gestational diabetes mellitus

Abstract

Pre-eclampsia (PE) and gestational diabetes mellitus (GDM) are common complications of pregnancy, but the mechanisms underlying these disorders remain unclear. The aim was to identify the extent of altered gene expression in term placentas from pregnant women with late-onset PE and GDM compared to controls. RNAseq identified few significantly differentially regulated genes in placental biopsies between PE, GDM, or uncomplicated pregnancy (n = 10 each group). Five genes were altered in placentas from PE including 4 non-coding genes and Angiopoietin 2 (ANGPT2). No genes were significantly regulated by GDM. In contrast, many genes were significantly regulated by fetal, maternal and delivery-specific variables, particularly spinal and epidural anesthesia. We selected ANGPT2 and Chemokine (C-X-C motif) ligand 14 (CXCL14) to test with qPCR in a larger set of placentas (n = 475) and found no differences between the groups. However, regression analysis revealed a stronger association between placental ANGPT2 and CXCL14 mRNA expression and fetal, maternal and delivery-specific variables than diagnostic group. To conclude, the gene expression in term placentas are highly affected by fetal, maternal and delivery specific variables. Few regulated genes were found in late-onset PE and GDM placentas, which may suggest that these conditions could be more affected by maternal factors.The placenta is a composite structure of embryonic and maternal tissues that supplies nutrients and removes waste products from the developing embryo. It also has critical endocrine and immuno-modulatory properties. Up to 10% of pregnancies suffer from abnormal placental development and, as such, are at high risk for complications such as miscarriage, pre-eclampsia (PE), gestational diabetes mellitus (GDM), fetal growth restriction and preterm birth 1 . Pre-eclampsia is characterized by new-onset hypertension and end-organ damage after 20 weeks of gestation and affects 3-5% of all pregnancies 2 . PE has a multifactorial etiology and includes several subtypes 3 . Early-onset PE generally involves poor placental development, whereas late-onset PE is believed to arise from the interaction between a normal placenta and a damaged maternal microvasculature due, for example, to chronic hypertension or diabetes 4 . The late-onset form of PE may thus be more similar to GDM, in which pregnancy serves as a stress test in predisposed women 5,6 . GDM is defined as glucose intolerance of variable degrees first recognized during pregnancy. It may affect up to 20% of pregnant women depending on ethnicity and the diagnostic criteria used 7 .

A Review of Candidate Genes and Pathways in Preeclampsia–An Integrated Bioinformatical Analysis

“…Homogeneity of the selected studies was ensured by adhering to the defined study design in order to prevent sampling bias, as seen in an intervention study that could interfere with the selection of cases with PE. Notably, all of the reported studies were performed in European populations: Finland, Estonia, and Norway [6][7][8]. Moreover, all these high-throughput sequencing studies included a confirmatory method to validate the RNA sequencing results using real-time polymerase chain reaction (qPCR).…”

“…Moreover, all these high-throughput sequencing studies included a confirmatory method to validate the RNA sequencing results using real-time polymerase chain reaction (qPCR). Sample sizes for each study varied from 8-40 samples in RNA sequencing methods [6][7][8]. Whereas for validation they ranged from 39-475 samples [6][7][8].…”

“…Sample sizes for each study varied from 8-40 samples in RNA sequencing methods [6][7][8]. Whereas for validation they ranged from 39-475 samples [6][7][8]. Table 1 highlights the characteristics of these studies.…”

“…In another study by Sober, the main objective was to investigate the profile of differential gene expression in prevalent adverse pregnancy outcomes at term, focusing on maternal late-onset PE, gestational diabetes, and pregnancies ending with the birth of either small-for-gestational-age (SGA) or large-for-gestational age (LGA) [7]. Lekva and colleagues categorized their patients into late-onset PE and gestational diabetes mellitus (GDM) in third trimester pregnancies [8].…”

“…The dataset from Sober had five groups consisting of eight samples of each group: Normal placenta, late-onset PE placentae, gestational diabetes placentae, small-for-gestational-age placentae, and large-for-gestational-age placentae [7]. Lekva used 10 samples for each group: Normal placentae, gestational diabetes placentae, and preeclamptic placentae [8]. Using a p < 0.05 as a cut-off criterion, we extracted 53, 198, and 2 differentially expressed genes from the expression profile datasets Kaartokallio, Sober, and Lekva, respectively.…”