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 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 Saade, Antonio Saad, Ebony B. Carter, Thomas F. McElrath, Stephen R. QuakeMark 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

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 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., 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, G, 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 George Saade 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

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.

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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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