Circulating maternal placental growth factor responses to low molecular weight heparin in pregnant patients at risk of placental dysfunction

McLaughlin, K., Hobson, S. R., Ravi Chandran, A., Agarwal, S., Windrim, R. C., Parks, W. T., Bowman, A. W. , Sovio, U., Smith, G. C. and Kingdom, J. C. (2022) Circulating maternal placental growth factor responses to low molecular weight heparin in pregnant patients at risk of placental dysfunction. American Journal of Obstetrics and Gynecology, 226(2S), S1145-S1156.e1. (doi: 10.1016/j.ajog.2021.08.027) (PMID:34461078)

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Abstract

Background: Patients at high risk of severe preeclampsia and/or fetal growth restriction have low circulating levels of placental growth factor (PlGF) and features of maternal vascular malperfusion placental pathology at delivery. Multi-modal screening and commencement of aspirin prophylaxis at 11-13 weeks’ gestation significantly reduces the risk of preterm delivery with preeclampsia. However, the additional role of low molecular weight heparin (LMWH) and mechanisms of action remain uncertain. Since LMWH augments the production and release of PlGF in-vitro by both placental villi and vascular endothelium, it may be effective to suppress the risk of severe preeclampsia in a niche group of high-risk patients with low circulating PlGF in the early second trimester. Objectives: The purpose of the study was to define a gestational age-specific reference range for PlGF and to test the hypothesis that prophylactic LMWH administered in the early second trimester may restore deficient circulating PlGF levels and thereby prolong pregnancy. Study Design: Centile curves for circulating PlGF levels from 12-36 weeks’ gestation were derived using quantile regression of combined data from a published cohort of 4207 unselected nulliparous patients in Cambridge, U.K. at four sampling time points (12, 20, 28, 36 weeks’ gestation) and the Caucasian majority (n= 531) of a healthy nulliparous cohort in Toronto, Canada at 16 weeks’ gestation using the same test platform. Within a specialty high-risk clinic in Toronto, a niche group of seven patients with a circulating PlGF <10th centile in the early second trimester received daily prophylactic LMWH (enoxaparin; 40mg subcutaneously) and were followed until delivery (Group 1). Their baseline characteristics, delivery details and placental pathologies were compared with five similar patients who did not receive LMWH during the observation period (Group 2), and with a further 21 patients delivered with severe preeclampsia (Group 3) in the same institution. Results: A gestational age-specific reference range for PlGF levels at weekly intervals between 12-36 weeks was established for Caucasian women with singleton pregnancies. Within Group 1, five of seven patients demonstrated a sustained increase in circulating PlGF levels, while PlGF levels did not increase in Group 2 or Group 3 patients that did not receive LMWH. Group 1 patients receiving LMWH therapy exhibited a later gestation at delivery, relative to Groups 2 and 3 (36 weeks [33–37] versus 23 weeks [22–26] and 28 weeks [27-31], respectively), and consequently had higher birthweights (1.93 kg [1.1–2.7] versus 0.32 kg [0.19–0.39] and 0.73 kg [0.52-1.03], respectively). The incidence of stillbirth was lowest in Group 1 (14% (1/7)), relative to Groups 2 and 3 (80% (4/5) and 29% (6/21), respectively). Maternal vascular malperfusion was the most common placental pathology found in association with abnormal uterine artery Doppler. Conclusions: In patients at high risk of a serious adverse pregnancy outcome due to placental disease, the addition of LMWH to aspirin prophylaxis in the early second trimester may restore deficient circulating PlGF to mediate an improved perinatal outcome. These data support the implementation of a multicenter pilot randomized control trial where patients are recruited primarily based on the assessment of placental function in the early second trimester.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Bowman, Prof Adrian
Authors: McLaughlin, K., Hobson, S. R., Ravi Chandran, A., Agarwal, S., Windrim, R. C., Parks, W. T., Bowman, A. W., Sovio, U., Smith, G. C., and Kingdom, J. C.
College/School:College of Science and Engineering > School of Mathematics and Statistics
Journal Name:American Journal of Obstetrics and Gynecology
Publisher:Elsevier
ISSN:0002-9378
ISSN (Online):1097-6868
Published Online:27 August 2021
Copyright Holders:Copyright © 2021 Elsevier Inc.
First Published:First published in American Journal of Obstetrics and Gynecology 226(2 Supplement): S1145-S1156.e1
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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