Molecular subtyping of hypertensive disorders of pregnancy

Michal A. Elovitz; Elaine P.S. Gee; Nathaniel Delaney-Busch; Alison B. Moe; Mitsu Reddy; Arkady Khodursky; Johnny La; Ilma Abbas; Kay Mekaru; Hunter Collins; Farooq Siddiqui; Rory Nolan; Rupsa C. Boelig; Daniel G. Kiefer; Pamela M. Simmons; George R. Saade; Antonio Saad; Ebony B. Carter; Thomas F. McElrath; Stephen R. Quake; Mark A. DePristo; Carrie Haverty; Manfred Lee; Eugeni Namsaraev; Vincenzo Berghella; Ai ris Y. Collier; Antonia I. Frolova; Esther Park-Hwang; Luis D. Pacheco; Elizabeth F. Sutton; Maneesh Jain; Kara Rood; William A. Grobman; Joseph R. Biggio; Cynthia Gyamfi-Bannerman; Arun Jeyabalan; Morten Rasmussen

doi:10.1038/s41467-025-58157-y

Molecular subtyping of hypertensive disorders of pregnancy

Michal A. Elovitz
, Elaine P.S. Gee
, Nathaniel Delaney-Busch
, Alison B. Moe
, Mitsu Reddy
, Arkady Khodursky
, Johnny La
, Ilma Abbas
, Kay Mekaru
, Hunter Collins
, Farooq Siddiqui
, Rory Nolan
, Rupsa C. Boelig
, Daniel G. Kiefer
, Pamela M. Simmons
, George R. Saade
, Antonio Saad
, Ebony B. Carter
, Thomas F. McElrath
, Stephen R. Quake

Mark A. DePristo, Carrie Haverty, Manfred Lee, Eugeni Namsaraev, Vincenzo Berghella, Ai ris Y. Collier, Antonia I. Frolova, Esther Park-Hwang, Luis D. Pacheco, Elizabeth F. Sutton, Maneesh Jain, Kara Rood, William A. Grobman, Joseph R. Biggio, Cynthia Gyamfi-Bannerman, Arun Jeyabalan, Morten Rasmussen

Obstetrics & Gynecology

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

Hypertensive disorders of pregnancy (HDP), including preeclampsia, affect 1 in 6 pregnancies, are major contributors to maternal morbidity and mortality, yet lack precision medicine strategies. Analyzing transcriptomic data from a prospectively-collected diverse cohort (n = 9102), this study reveals distinct RNA subtypes in maternal blood, reclassifying clinical HDP phenotypes like early/late-onset preeclampsia. The placental gene PAPPA2 strongly predicts the most severe forms of preeclampsia in individuals without pre-existing high risk factors, months before symptoms, and its overexpression correlates with earlier delivery in a dose-dependent manner. Further, molecular subtypes characterized by immune genes are upregulated in less severe forms of HDP. These results reclassify HDP clinical phenotypes into two distinct molecular subtypes, placental-associated or immune-associated. Validation performance for placental-associated HDP yields an AUC of 0.88 in the advanced maternal age population without pre-existing high risk factors. Molecular subtypes create new opportunities to apply precision-based medicine in maternal health.

Original language	English (US)
Article number	2948
Journal	Nature communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-58157-y
State	Published - Dec 2025

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General
General Physics and Astronomy

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10.1038/s41467-025-58157-y

Cite this

Elovitz, M. A., Gee, E. P. S., Delaney-Busch, N., Moe, A. B., Reddy, M., Khodursky, A., La, J., Abbas, I., Mekaru, K., Collins, H., Siddiqui, F., Nolan, R., Boelig, R. C., Kiefer, D. G., Simmons, P. M., Saade, G. R., Saad, A., Carter, E. B., McElrath, T. F., ... Rasmussen, M. (2025). Molecular subtyping of hypertensive disorders of pregnancy. Nature communications, 16(1), Article 2948. https://doi.org/10.1038/s41467-025-58157-y

Elovitz, MA, Gee, EPS, Delaney-Busch, N, Moe, AB, Reddy, M, Khodursky, A, La, J, Abbas, I, Mekaru, K, Collins, H, Siddiqui, F, Nolan, R, Boelig, RC, Kiefer, DG, Simmons, PM, Saade, GR, Saad, A, Carter, EB, McElrath, TF, Quake, SR, DePristo, MA, Haverty, C, Lee, M, Namsaraev, E, Berghella, V, Collier, ARY, Frolova, AI, Park-Hwang, E, Pacheco, LD, Sutton, EF, Jain, M, Rood, K, Grobman, WA, Biggio, JR, Gyamfi-Bannerman, C, Jeyabalan, A & Rasmussen, M 2025, 'Molecular subtyping of hypertensive disorders of pregnancy', Nature communications, vol. 16, no. 1, 2948. https://doi.org/10.1038/s41467-025-58157-y

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title = "Molecular subtyping of hypertensive disorders of pregnancy",

abstract = "Hypertensive disorders of pregnancy (HDP), including preeclampsia, affect 1 in 6 pregnancies, are major contributors to maternal morbidity and mortality, yet lack precision medicine strategies. Analyzing transcriptomic data from a prospectively-collected diverse cohort (n = 9102), this study reveals distinct RNA subtypes in maternal blood, reclassifying clinical HDP phenotypes like early/late-onset preeclampsia. The placental gene PAPPA2 strongly predicts the most severe forms of preeclampsia in individuals without pre-existing high risk factors, months before symptoms, and its overexpression correlates with earlier delivery in a dose-dependent manner. Further, molecular subtypes characterized by immune genes are upregulated in less severe forms of HDP. These results reclassify HDP clinical phenotypes into two distinct molecular subtypes, placental-associated or immune-associated. Validation performance for placental-associated HDP yields an AUC of 0.88 in the advanced maternal age population without pre-existing high risk factors. Molecular subtypes create new opportunities to apply precision-based medicine in maternal health.",

author = "Elovitz, \{Michal A.\} and Gee, \{Elaine P.S.\} and Nathaniel Delaney-Busch and Moe, \{Alison B.\} and Mitsu Reddy and Arkady Khodursky and Johnny La and Ilma Abbas and Kay Mekaru and Hunter Collins and Farooq Siddiqui and Rory Nolan and Boelig, \{Rupsa C.\} and Kiefer, \{Daniel G.\} and Simmons, \{Pamela M.\} and Saade, \{George R.\} and Antonio Saad and Carter, \{Ebony B.\} and McElrath, \{Thomas F.\} and Quake, \{Stephen R.\} and DePristo, \{Mark A.\} and Carrie Haverty and Manfred Lee and Eugeni Namsaraev and Vincenzo Berghella and Collier, \{Ai ris Y.\} and Frolova, \{Antonia I.\} and Esther Park-Hwang and Pacheco, \{Luis D.\} and Sutton, \{Elizabeth F.\} and Maneesh Jain and Kara Rood and Grobman, \{William A.\} and Biggio, \{Joseph R.\} and Cynthia Gyamfi-Bannerman and Arun Jeyabalan and Morten Rasmussen",

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doi = "10.1038/s41467-025-58157-y",

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AU - Elovitz, Michal A.

AU - Gee, Elaine P.S.

AU - Delaney-Busch, Nathaniel

AU - Moe, Alison B.

AU - Reddy, Mitsu

AU - Khodursky, Arkady

AU - La, Johnny

AU - Abbas, Ilma

AU - Mekaru, Kay

AU - Collins, Hunter

AU - Siddiqui, Farooq

AU - Nolan, Rory

AU - Boelig, Rupsa C.

AU - Kiefer, Daniel G.

AU - Simmons, Pamela M.

AU - Saade, George R.

AU - Saad, Antonio

AU - Carter, Ebony B.

AU - McElrath, Thomas F.

AU - Quake, Stephen R.

AU - DePristo, Mark A.

AU - Haverty, Carrie

AU - Lee, Manfred

AU - Namsaraev, Eugeni

AU - Berghella, Vincenzo

AU - Collier, Ai ris Y.

AU - Frolova, Antonia I.

AU - Park-Hwang, Esther

AU - Pacheco, Luis D.

AU - Sutton, Elizabeth F.

AU - Jain, Maneesh

AU - Rood, Kara

AU - Grobman, William A.

AU - Biggio, Joseph R.

AU - Gyamfi-Bannerman, Cynthia

AU - Jeyabalan, Arun

AU - Rasmussen, Morten

PY - 2025/12

Y1 - 2025/12

N2 - Hypertensive disorders of pregnancy (HDP), including preeclampsia, affect 1 in 6 pregnancies, are major contributors to maternal morbidity and mortality, yet lack precision medicine strategies. Analyzing transcriptomic data from a prospectively-collected diverse cohort (n = 9102), this study reveals distinct RNA subtypes in maternal blood, reclassifying clinical HDP phenotypes like early/late-onset preeclampsia. The placental gene PAPPA2 strongly predicts the most severe forms of preeclampsia in individuals without pre-existing high risk factors, months before symptoms, and its overexpression correlates with earlier delivery in a dose-dependent manner. Further, molecular subtypes characterized by immune genes are upregulated in less severe forms of HDP. These results reclassify HDP clinical phenotypes into two distinct molecular subtypes, placental-associated or immune-associated. Validation performance for placental-associated HDP yields an AUC of 0.88 in the advanced maternal age population without pre-existing high risk factors. Molecular subtypes create new opportunities to apply precision-based medicine in maternal health.

AB - Hypertensive disorders of pregnancy (HDP), including preeclampsia, affect 1 in 6 pregnancies, are major contributors to maternal morbidity and mortality, yet lack precision medicine strategies. Analyzing transcriptomic data from a prospectively-collected diverse cohort (n = 9102), this study reveals distinct RNA subtypes in maternal blood, reclassifying clinical HDP phenotypes like early/late-onset preeclampsia. The placental gene PAPPA2 strongly predicts the most severe forms of preeclampsia in individuals without pre-existing high risk factors, months before symptoms, and its overexpression correlates with earlier delivery in a dose-dependent manner. Further, molecular subtypes characterized by immune genes are upregulated in less severe forms of HDP. These results reclassify HDP clinical phenotypes into two distinct molecular subtypes, placental-associated or immune-associated. Validation performance for placental-associated HDP yields an AUC of 0.88 in the advanced maternal age population without pre-existing high risk factors. Molecular subtypes create new opportunities to apply precision-based medicine in maternal health.

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VL - 16

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 2948

ER -

Molecular subtyping of hypertensive disorders of pregnancy

Abstract

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