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Angiogenic Factor Profiles in Pregnant Women With a History of Early-Onset Severe Preeclampsia Receiving Low-Molecular-Weight Heparin Prophylaxis

Lecarpentier, Edouard, MD, PhD; Gris, Jean, Christophe, MD, PhD; Cochery-Nouvellon, Eva, PharmD, PhD; Mercier, Erick, MD; Touboul, Cyril, MD, PhD; Thadhani, Ravi, MD; Karumanchi, S., Ananth, MD; Haddad, Bassam, MD

doi: 10.1097/AOG.0000000000002380
Contents: Original Research

OBJECTIVE: To evaluate whether daily low-molecular-weight (LMW) heparin prophylaxis during pregnancy alters profile of circulating angiogenic factors that have been linked with the pathogenesis of preeclampsia and fetal growth restriction.

METHODS: This is a planned ancillary study of the Heparin-Preeclampsia trial, a randomized trial in pregnant women with a history of severe early-onset preeclampsia (less than 34 weeks of gestation). In the parent study, all women were treated with aspirin and then randomized to receive LMW heparin or aspirin alone. In this study, we measured serum levels of circulating angiogenic factors (soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin by immunoassay) at the following gestational windows: 10–13 6/7 weeks, 14–17 6/7 weeks, 18–21 6/7 weeks, 22–25 6/7 weeks, 26–29 6/7 weeks, 30–33 6/7 weeks, and 34–37 6/7 weeks.

RESULTS: Samples were available from 185 patients: LMW heparin+aspirin (n=92) and aspirin alone (n=93). The two groups had comparable baseline characteristics and had similar adverse composite outcomes (35/92 [38.0%] compared with 36/93 [38.7%]; P=.92). There were no significant differences in serum levels of soluble fms-like tyrosine kinase-1, placental growth factor, and soluble endoglin in the participants who received LMW heparin and aspirin compared with those who received aspirin alone regardless of gestational age period. Finally, women who developed an adverse composite outcome at less than 34 weeks of gestation demonstrated significant alterations in serum angiogenic profile as early as 10–13 6/7 weeks that was most dramatic 6–8 weeks preceding delivery.

CONCLUSION: Prophylactic LMW heparin therapy when beginning from before 14 weeks of gestation with aspirin during pregnancy is not associated with an improved angiogenic profile. This may provide a molecular explanation for the lack of clinical benefit noted in recent trials.


Prophylactic low-molecular-weight heparin started at less than 14 weeks of gestation in women with a history of severe preeclampsia and on aspirin is not associated with improved circulating angiogenic factor profile.

University Paris Est Créteil and CHI Créteil, Créteil, France; the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts; the Department of Hematology, University Hospital Caremeau, Nîmes UPRES EA2992, and faculty of pharmaceutical and biological sciences, University of Montpellier, Montpellier, France; and the Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

Corresponding author: Bassam Haddad, MD, Department of Obstetrics–Gynecology and Reproductive Medicine, University Paris Est Créteil, Centre Hospitalier Inter-Communal de Créteil, 40 Avenue de Verdun, 94000 Créteil, France; email:

Supported by the Programme Hospitalier de Recherche Clinique National- PHRC-DRCD-APHP France.

Financial Disclosure Drs. Thadhani and Karumanchi are coinventors on patents related to preeclampsia biomarkers that are held at Harvard Hospitals, have financial interest in Aggamin LLC, and serve as consultants to Roche Diagnostics and Thermofisher Scientific. The other authors did not report any potential conflicts of interest.

The authors thank Mme Fatiha Aced-Djennaoui for her assistance for data collection.

Each author has indicated that he or she has met the journal's requirements for authorship.

© 2018 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.