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Extensive shift in placental transcriptome profile in preeclampsia and placental origin of adverse pregnancy outcomes.

ABSTRACT: One in five pregnant women suffer from gestational complications, prevalently driven by placental malfunction. Using RNASeq, we analyzed differential placental gene expression in cases of normal gestation, late-onset preeclampsia (LO-PE), gestational diabetes (GD) and pregnancies ending with the birth of small-for-gestational-age (SGA) or large-for-gestational-age (LGA) newborns (n?=?8/group). In all groups, the highest expression was detected for small noncoding RNAs and genes specifically implicated in placental function and hormonal regulation. The transcriptome of LO-PE placentas was clearly distinct, showing statistically significant (after FDR) expressional disturbances for hundreds of genes. Taqman RT-qPCR validation of 45 genes in an extended sample (n?=?24/group) provided concordant results. A limited number of transcription factors including LRF, SP1 and AP2 were identified as possible drivers of these changes. Notable differences were detected in differential expression signatures of LO-PE subtypes defined by the presence or absence of intrauterine growth restriction (IUGR). LO-PE with IUGR showed higher correlation with SGA and LO-PE without IUGR with LGA placentas. Whereas changes in placental transcriptome in SGA, LGA and GD cases were less prominent, the overall profiles of expressional disturbances overlapped among pregnancy complications providing support to shared placental responses. The dataset represent a rich catalogue for potential biomarkers and therapeutic targets.

SUBMITTER: Sober S

PROVIDER: S-EPMC4542630 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Extensive shift in placental transcriptome profile in preeclampsia and placental origin of adverse pregnancy outcomes.

Sõber Siim S Reiman Mario M Kikas Triin T Rull Kristiina K Inno Rain R Vaas Pille P Teesalu Pille P Marti Jesus M Lopez JML Mattila Pirkko P Laan Maris M

Scientific reports 20150813

One in five pregnant women suffer from gestational complications, prevalently driven by placental malfunction. Using RNASeq, we analyzed differential placental gene expression in cases of normal gestation, late-onset preeclampsia (LO-PE), gestational diabetes (GD) and pregnancies ending with the birth of small-for-gestational-age (SGA) or large-for-gestational-age (LGA) newborns (n = 8/group). In all groups, the highest expression was detected for small noncoding RNAs and genes specifically impl ...[more]

PMID: 26268791

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Project description:BACKGROUND:Abnormal placental cord insertion (PCI) includes marginal cord insertion (MCI) and velamentous cord insertion (VCI). VCI has been shown to be associated with adverse pregnancy outcomes. This systematic review and meta-analysis aims to determine the association of abnormal PCI and adverse pregnancy outcomes. METHODS:Embase, Medline, CINAHL, Scopus, Web of Science, ClinicalTrials.gov, and Cochrane Databases were searched in December 2016 (from inception to December 2016). The reference lists of eligible studies were scrutinized to identify further studies. Potentially eligible studies were reviewed by two authors independently using the following inclusion criteria: singleton pregnancies, velamentous cord insertion, marginal cord insertion, and pregnancy outcomes. Case reports and series were excluded. The methodological quality of the included studies was assessed using the Newcastle-Ottawa Scale. Outcomes for meta-analysis were dichotomous and results are presented as summary risk ratios with 95% confidence intervals. RESULTS:Seventeen studies were included in the systematic review, all of which were assessed as good quality. Normal PCI and MCI were grouped together as non-VCI and compared with VCI in seven studies. Four studies compared MCI, VCI, and normal PCI separately. Two other studies compared MCI with normal PCI, and VCI was excluded from their analysis. Studies in this systematic review reported an association between abnormal PCI, defined differently across studies, with preterm birth, small for gestational age (SGA), low birthweight (<?2500 g), emergency cesarean delivery, and intrauterine fetal death. Four cohort studies comparing MCI, VCI, and normal PCI separately were included in a meta-analysis resulting in a statistically significant increased risk of emergency cesarean delivery for VCI (pooled RR 2.86, 95% CI 1.56-5.22, P =?0.0006) and abnormal PCI (pooled RR 1.77, 95% CI 1.33-2.36, P <?0.0001) compared to normal PCI. CONCLUSIONS:The available evidence suggests an association between abnormal PCI and emergency cesarean delivery. However, the number of studies with comparable definitions of abnormal PCI was small, limiting the analysis of other adverse pregnancy outcomes, and further research is required.

Project description:BackgroundThe Eunice Kennedy Shriver National Institute of Child Health and Human Development Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be was established to investigate the underlying causes and pathophysiological pathways associated with adverse pregnancy outcomes in nulliparous gravidas.ObjectiveThis study aimed to study placental physiology and identify novel biomarkers concerning adverse pregnancy outcomes, including preterm birth (medically indicated and spontaneous), preeclampsia, small-for-gestational-age neonates, and stillbirth. We measured levels of placental proteins in the maternal circulation in the first 2 trimesters of pregnancy.Study designMaternal serum samples were collected at 2 study visits (6-13 weeks and 16-21 weeks), and levels of 9 analytes were measured. The analytes we measured were vascular endothelial growth factor, placental growth factor, endoglin, soluble fms-like tyrosine kinase-1, A disintegrin and metalloproteinase domain-containing protein 12, pregnancy-associated plasma protein A, free beta-human chorionic gonadotropin, inhibin A, and alpha-fetoprotein. The primary outcome was preterm birth between 20 0/7 and 36 6/7 weeks of gestation. The secondary outcomes were spontaneous preterm births, medically indicated preterm births, preeclampsia, small-for-gestational-age neonates, and stillbirth.ResultsA total of 10,038 eligible gravidas were enrolled in the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be cohort, from which a nested case-control study was performed comparing 800 cases with preterm birth (466 spontaneous preterm births, 330 medically indicated preterm births, and 4 unclassified preterm births), 568 with preeclampsia, 406 with small-for-gestational-age birth, and 49 with stillbirth with 911 controls who delivered at term without complications. Although levels of each analyte generally differed between cases and controls at 1 or 2 visits, the odds ratios revealed a <2-fold difference between cases and controls in all comparisons. Receiver operating characteristic curves, generated to determine the relationship between analyte levels and preterm birth and the other adverse pregnancy outcomes, resulted in areas under the receiver operating characteristic curves that were relatively low (range, 0.50-0.64) for each analyte. Logistic regression modeling demonstrated that areas under the receiver operating characteristic curves for predicting adverse pregnancy outcomes were greater using baseline clinical characteristics and combinations of analytes than baseline characteristics alone, but areas under the receiver operating characteristic curves remained relatively low for each outcome (range, 0.65-0.78).ConclusionWe have found significant associations between maternal serum levels of analytes evaluated early in pregnancy and subsequent adverse pregnancy outcomes in nulliparous gravidas. However, the test characteristics for these analytes do not support their use as clinical biomarkers to predict adverse pregnancy outcomes, either alone or in combination with maternal clinical characteristics.

Project description:ObjectiveCurrently, no investigations reliably identify placental dysfunction in late pregnancy. To facilitate the development of such investigations we aimed to identify placental features that differ between normal and adverse outcome in late pregnancy in a group of pregnancies with reduced fetal movement.MethodsFollowing third trimester presentation with reduced fetal movement (N = 100), placental structure ex vivo was measured. Placental function was then assessed in terms of (i) chorionic plate artery agonist responses and length-tension characteristics using wire myography and (ii) production and release of placentally derived hormones (by quantitative polymerase chain reaction and enzyme linked immunosorbant assay of villous tissue and explant conditioned culture medium).ResultsPlacentas from pregnancies ending in adverse outcome (N = 23) were ~25% smaller in weight, volume, length, width and disc area (all p<0.0001) compared with those from normal outcome pregnancies. Villous and trophoblast areas were unchanged, but villous vascularity was reduced (median (interquartile range): adverse outcome 10 (10-12) vessels/mm2 vs. normal outcome 13 (12-15), p = 0.002). Adverse outcome pregnancy placental arteries were relatively insensitive to nitric oxide donated by sodium nitroprusside compared to normal outcome pregnancy placental arteries (50% Effective Concentration 30 (19-50) nM vs. 12 (6-24), p = 0.02). Adverse outcome pregnancy placental tissue contained less human chorionic gonadotrophin (20 (11-50) vs. 55 (24-102) mIU/mg, p = 0.007) and human placental lactogen (11 (6-14) vs. 27 (9-50) mg/mg, p = 0.006) and released more soluble fms-like tyrosine kinase-1 (21 (13-29) vs. 5 (2-15) ng/mg, p = 0.01) compared with normal outcome pregnancy placental tissue.ConclusionThese data provide a description of the placental phenotype of adverse outcome in late pregnancy. Antenatal tests that accurately reflect elements of this phenotype may improve its prediction.

Project description:BackgroundProteinuria is one of the common manifestations of patients with preeclampsia (PE), but whether the severity of proteinuria is related to the pregnancy outcome of patients with preeclampsia remains controversial. The present study aimed to determine the relationship between 24-h proteinuria and adverse outcomes in patients with preeclampsia.MethodsThe present retrospective study included 329 pregnant women in Chongqing, China. Patients were divided into PE group and non-PE group. PE group was stratified into three subgroups based on the level of 24-h proteinuria. Correlation analysis was used to analyze the correlation between biochemical indexes and adverse pregnancy outcome, and Logistic regression analysis was used to analyze the risk factors of adverse pregnancy outcome. The receiver operating characteristic curve (ROC) was used to evaluate the ability of 24-h urinary protein to distinguish the adverse pregnancy outcome in patients with preeclampsia.Results(1) Between PE and non-PE group, cesarean section rate in PE group was significantly higher than that in non-PE group (84.4% vs. 25.9%, p < 0.001). Laboratory findings such as uric acid and creatinine level in PE group were higher than those in non-PE group. (2) Among mild (proteinuria < 0.3 g/24 h), moderate (0.3 g/24 h ≦ proteinuria < 2 g/24 h) and massive (proteinuria ≧ 2 g/24 h) groups, the frequencies of induced labor (p = 0.006) and stillbirth (p = 0.002) increased with the increase of 24-h proteinuria. (3) Adverse outcomes were positively correlated with 24-h proteinuria (adverse maternal outcomes: r = 0.239, p = 0.002; adverse fetal outcomes: r = 0.336, p < 0.001). (4) The best 24-h proteinuria cutoff values to determine stillbirth, premature and fetal distress were 3965.0 mg/24 h, 984.75 mg/24 h and 1503.85 mg/24 h and their odds ratio (95% confidence interval) were 12.46 (3.46-44.88), 2.48 (1.15-5.37) and 10.02 (2.14-46.80), respectively.ConclusionsThe severity of 24-h proteinuia may forecast adverse outcomes in women with preeclampsia. We suggest proteinuria should be retained as one of the monitoring indexes in patients with preeclampsia.Trial registrationRetrospectively registered. (LTMCMTS202001).

Project description:BACKGROUND:Malaria in pregnancy has been associated with maternal morbidity, placental malaria, and adverse birth outcomes. However, data are limited on the relationships between longitudinal measures of malaria during pregnancy, measures of placental malaria, and birth outcomes. METHODS:This is a nested observational study of data from a randomized controlled trial of intermittent preventive therapy during pregnancy among 282 participants with assessment of placental malaria and delivery outcomes. HIV-uninfected pregnant women were enrolled at 12-20 weeks of gestation. Symptomatic malaria during pregnancy was measured using passive surveillance and monthly detection of asymptomatic parasitaemia using loop-mediated isothermal amplification (LAMP). Placental malaria was defined as either the presence of parasites in placental blood by microscopy, detection of parasites in placental blood by LAMP, or histopathologic evidence of parasites or pigment. Adverse birth outcomes assessed included low birth weight (LBW), preterm birth (PTB), and small for gestational age (SGA) infants. RESULTS:The 282 women were divided into three groups representing increasing malaria burden during pregnancy. Fifty-two (18.4%) had no episodes of symptomatic malaria or asymptomatic parasitaemia during the pregnancy, 157 (55.7%) had low malaria burden (0-1 episodes of symptomatic malaria and < 50% of samples LAMP+), and 73 (25.9%) had high malaria burden during pregnancy (? 2 episodes of symptomatic malaria or ? 50% of samples LAMP+). Women with high malaria burden had increased risks of placental malaria by blood microscopy and LAMP [aRR 14.2 (1.80-111.6) and 4.06 (1.73-9.51), respectively], compared to the other two groups combined. Compared with women with no malaria exposure during pregnancy, the risk of placental malaria by histopathology was higher among low and high burden groups [aRR = 3.27 (1.32-8.12) and aRR = 7.07 (2.84-17.6), respectively]. Detection of placental parasites by any method was significantly associated with PTB [aRR 5.64 (1.46-21.8)], and with a trend towards increased risk for LBW and SGA irrespective of the level of malaria burden during pregnancy. CONCLUSION:Higher malaria burden during pregnancy was associated with placental malaria and together with the detection of parasites in the placenta were associated with increased risk for adverse birth outcomes. Trial Registration Current Controlled Trials Identifier NCT02163447.

Project description:BackgroundMalaria during pregnancy is a major contributor to the global burden of adverse birth outcomes including fetal growth restriction, preterm birth, and fetal loss. Recent evidence supports a role for angiogenic dysregulation and perturbations to placental vascular development in the pathobiology of malaria in pregnancy. The Angiopoietin-Tie2 axis is critical for placental vascularization and remodeling. We hypothesized that disruption of this pathway would contribute to malaria-induced adverse birth outcomes.MethodsUsing samples from a previously conducted prospective cohort study of pregnant women in Malawi, we measured circulating levels of angiopoietin-1 (Angpt-1) and Angpt-2 by Luminex (n=1392). We used a preclinical model of malaria in pregnancy (Plasmodium berghei ANKA [PbA] in pregnant BALB/c mice), genetic disruption of Angpt-1 (Angpt1+/- mice), and micro-CT analysis of placental vasculature to test the hypothesis that disruptions to the Angpt-Tie2 axis by malaria during pregnancy would result in aberrant placental vasculature and adverse birth outcomes.FindingsDecreased circulating levels of Angpt-1 and an increased ratio of Angpt-2/Angpt-1 across pregnancy were associated with malaria in pregnancy. In the preclinical model, PbA infection recapitulated disruptions to the Angiopoietin-Tie2 axis resulting in reduced fetal growth and viability. Malaria decreased placental Angpt-1 and Tie2 expression and acted synergistically with reduced Angpt-1 in heterozygous dams (Angpt1+/-), to worsen birth outcomes by impeding vascular remodeling required for placental function.InterpretationCollectively, these data support a mechanistic role for the Angpt-Tie2 axis in malaria in pregnancy, including a potential protective role for Angpt-1 in mitigating infection-associated adverse birth outcomes.FundingThis work was supported by the Canadian Institutes of Health Research (CIHR), Canada Research Chair, and Toronto General Research Institute Postdoctoral Fellowship Award. The parent trial was supported by the European & Developing Countries Clinical Trials Partnership and the Malaria in Pregnancy Consortium, which was funded by the Bill & Melinda Gates Foundation. The funders had no role in design, analysis, or reporting of these studies.

Dataset Information

Extensive shift in placental transcriptome profile in preeclampsia and placental origin of adverse pregnancy outcomes.

Publications

Extensive shift in placental transcriptome profile in preeclampsia and placental origin of adverse pregnancy outcomes.

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