Circulating mRNAs are differentially expressed in pregnancies with severe placental insufficiency and at high risk of stillbirth.

Adult Cohort Studies Female Humans Infant, Newborn Placental Insufficiency / blood Pregnancy RNA, Messenger / metabolism Risk Factors Stillbirth / genetics
Circulating mRNA Fetal growth restriction Fetal hypoxia Pregnancy

Journal

BMC medicine
ISSN: 1741-7015
Titre abrégé: BMC Med
Pays: England
ID NLM: 101190723

Informations de publication

Date de publication:
22 05 2020
Historique:
received: 04 02 2020
accepted: 24 04 2020
entrez: 23 5 2020
pubmed: 23 5 2020
medline: 15 12 2020
Statut: epublish

Résumé

Fetuses affected by placental insufficiency do not receive adequate nutrients and oxygenation, become growth restricted and acidemic, and can demise. Preterm fetal growth restriction is a severe form of placental insufficiency with a high risk of stillbirth. We set out to identify maternal circulating mRNA transcripts that are differentially expressed in preterm pregnancies complicated by very severe placental insufficiency, in utero fetal acidemia, and are at very high risk of stillbirth. We performed a cohort study across six hospitals in Australia and New Zealand, prospectively collecting blood from 128 pregnancies complicated by preterm fetal growth restriction (delivery < 34 weeks' gestation) and 42 controls. RNA-sequencing was done on all samples to discover circulating mRNAs associated with preterm fetal growth restriction and fetal acidemia in utero. We used RT-PCR to validate the associations between five lead candidate biomarkers of placental insufficiency in an independent cohort from Europe (46 with preterm fetal growth restriction) and in a third cohort of pregnancies ending in stillbirth. In the Australia and New Zealand cohort, we identified five mRNAs that were highly differentially expressed among pregnancies with preterm fetal growth restriction: NR4A2, EMP1, PGM5, SKIL, and UGT2B1. Combining three yielded an area under the receiver operative curve (AUC) of 0.95. Circulating NR4A2 and RCBTB2 in the maternal blood were dysregulated in the presence of fetal acidemia in utero. We validated the association between preterm fetal growth restriction and circulating EMP1, NR4A2, and PGM5 mRNA in a cohort from Europe. Combining EMP1 and PGM5 identified fetal growth restriction with an AUC of 0.92. Several of these genes were differentially expressed in the presence of ultrasound parameters that reflect placental insufficiency. Circulating NR4A2, EMP1, and RCBTB2 mRNA were differentially regulated in another cohort destined for stillbirth, compared to ongoing pregnancies. EMP1 mRNA appeared to have the most consistent association with placental insufficiency in all cohorts. Measuring circulating mRNA offers potential as a test to identify pregnancies with severe placental insufficiency and at very high risk of stillbirth. Circulating mRNA EMP1 may be promising as a biomarker of severe placental insufficiency.

Sections du résumé

BACKGROUND
Fetuses affected by placental insufficiency do not receive adequate nutrients and oxygenation, become growth restricted and acidemic, and can demise. Preterm fetal growth restriction is a severe form of placental insufficiency with a high risk of stillbirth. We set out to identify maternal circulating mRNA transcripts that are differentially expressed in preterm pregnancies complicated by very severe placental insufficiency, in utero fetal acidemia, and are at very high risk of stillbirth.
METHODS
We performed a cohort study across six hospitals in Australia and New Zealand, prospectively collecting blood from 128 pregnancies complicated by preterm fetal growth restriction (delivery < 34 weeks' gestation) and 42 controls. RNA-sequencing was done on all samples to discover circulating mRNAs associated with preterm fetal growth restriction and fetal acidemia in utero. We used RT-PCR to validate the associations between five lead candidate biomarkers of placental insufficiency in an independent cohort from Europe (46 with preterm fetal growth restriction) and in a third cohort of pregnancies ending in stillbirth.
RESULTS
In the Australia and New Zealand cohort, we identified five mRNAs that were highly differentially expressed among pregnancies with preterm fetal growth restriction: NR4A2, EMP1, PGM5, SKIL, and UGT2B1. Combining three yielded an area under the receiver operative curve (AUC) of 0.95. Circulating NR4A2 and RCBTB2 in the maternal blood were dysregulated in the presence of fetal acidemia in utero. We validated the association between preterm fetal growth restriction and circulating EMP1, NR4A2, and PGM5 mRNA in a cohort from Europe. Combining EMP1 and PGM5 identified fetal growth restriction with an AUC of 0.92. Several of these genes were differentially expressed in the presence of ultrasound parameters that reflect placental insufficiency. Circulating NR4A2, EMP1, and RCBTB2 mRNA were differentially regulated in another cohort destined for stillbirth, compared to ongoing pregnancies. EMP1 mRNA appeared to have the most consistent association with placental insufficiency in all cohorts.
CONCLUSIONS
Measuring circulating mRNA offers potential as a test to identify pregnancies with severe placental insufficiency and at very high risk of stillbirth. Circulating mRNA EMP1 may be promising as a biomarker of severe placental insufficiency.

Identifiants

DOI: 10.1186/s12916-020-01605-x PMID: 32438913 PMC: PMC7243334
pubmed: 32438913
doi: 10.1186/s12916-020-01605-x
pii: 10.1186/s12916-020-01605-x
pmc: PMC7243334
doi:

Substances chimiques

RNA, Messenger 0

Types de publication

Journal Article Multicenter Study Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

145

Subventions

Organisme : National Health and Medical Research Council of Australia
ID : 1028521;1183854;1055795;1146128;1159261;11364118
Pays : International
Organisme : FP7 Ideas: European Research Council ()
ID : 305823
Pays : International

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Auteurs

Natalie J Hannan (NJ)

Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Level 4, Studley Rd, Heidelberg, Victoria, 3084, Australia.
Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, 3084, Australia.
Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, 3010, Australia.

Owen Stock (O)

Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Level 4, Studley Rd, Heidelberg, Victoria, 3084, Australia.
Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, 3084, Australia.
Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, 3010, Australia.

Rebecca Spencer (R)

Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, WC1E 6BT, UK.
University of Leeds, Leeds, LS2 9JT, UK.

Clare Whitehead (C)

Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Level 4, Studley Rd, Heidelberg, Victoria, 3084, Australia.
Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, 3084, Australia.
Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, 3010, Australia.
The University of Sydney Northern Clinical School, Women and Babies Research, St Leonards, New South Wales, 2065, Australia.

Anna L David (AL)

Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, WC1E 6BT, UK.

Katie Groom (K)

Department of Maternal Fetal Medicine, Royal Women's Hospital, Parkville, Victoria, 3052, Australia.

Scott Petersen (S)

Liggins Institute, University of Auckland, Auckland, 1023, New Zealand.

Amanda Henry (A)

Centre for Maternal Fetal Medicine, Mater Mothers' Hospital, South Brisbane, Queensland, 4101, Australia.

Joanne M Said (JM)

Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, 3010, Australia.
School of Women's and Children's Health, UNSW Medicine, University of New South Wales, Sydney, Australia.

Sean Seeho (S)

Maternal Fetal Medicine, Joan Kirner Women's & Children's Sunshine Hospital, St Albans, Victoria, 3021, Australia.

Stefan C Kane (SC)

Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, 3010, Australia.
The University of Sydney Northern Clinical School, Women and Babies Research, St Leonards, New South Wales, 2065, Australia.

Lavinia Gordon (L)

University of Melbourne Centre for Cancer Research, Parkville, Victoria, 3010, Australia.

Sally Beard (S)

Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Level 4, Studley Rd, Heidelberg, Victoria, 3084, Australia.
Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, 3084, Australia.
Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, 3010, Australia.

Kantaraja Chindera (K)

Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, WC1E 6BT, UK.

Smita Karegodar (S)

Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, WC1E 6BT, UK.

Richard Hiscock (R)

Department of anesthesia, Mercy Hospital for Women, Heidelberg, Victoria, 3084, Australia.

Natasha Pritchard (N)

Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Level 4, Studley Rd, Heidelberg, Victoria, 3084, Australia.
Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, 3084, Australia.
Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, 3010, Australia.

Tu'uhevaha J Kaitu'u-Lino (TJ)

Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Level 4, Studley Rd, Heidelberg, Victoria, 3084, Australia.
Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, 3084, Australia.
Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, 3010, Australia.

Susan P Walker (SP)

Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Level 4, Studley Rd, Heidelberg, Victoria, 3084, Australia.
Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, 3084, Australia.
Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, 3010, Australia.

Stephen Tong (S)

Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Level 4, Studley Rd, Heidelberg, Victoria, 3084, Australia. stong@unimelb.edu.au.
Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, 3084, Australia. stong@unimelb.edu.au.
Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, 3010, Australia. stong@unimelb.edu.au.

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questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Circulating mRNAs are differentially expressed...
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questionsmedicales.fr › Personnes › Tranches d'âge › Nourrisson › Nouveau-né › Circulating mRNAs are differentially expressed...
questionsmedicales.fr › Maladies urogénitales › Maladies de l'appareil urogénital féminin et complications de la grossesse › Complications de la grossesse › Maladies du placenta › Insuffisance placentaire › Circulating mRNAs are differentially expressed...
questionsmedicales.fr › Phénomènes physiologiques des appareils urinaire et reproducteur › Phénomènes physiologiques de la reproduction › Reproduction › Grossesse › Circulating mRNAs are differentially expressed...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › ARN messager › Circulating mRNAs are differentially expressed...
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