Serum leukotriene B4 and hydroxyeicosatetraenoic acid in the prediction of pre-eclampsia
Introduction
Pre-eclampsia (PE) is a leading cause of maternal and perinatal morbidity and mortality and affects 2–8% of pregnancies worldwide [1]. To date, there is no definitive treatment except the delivery of the baby and placenta. The severity of PE and fetal maturity are important considerations in the timing of the delivery and, as such, prediction of disease onset and intervention to prevent the development of severe PE are paramount to improve maternal and perinatal outcomes.
The current best available test for first trimester prediction of PE combines maternal characteristics and history with the results of mean arterial pressure (MAP), mean uterine artery pulsatility index (UtA-PI) and serum placental growth factor (PlGF) and/or serum pregnancy-associated plasma protein-A (PAPP-A) and detects about 75% of preterm PE at a 10% false positive rate; however, the detection rate of this combined multimarker screening test for term PE is lower at about 45%, and term PE accounts for two thirds of all cases [2,3]. Similarly, studies have investigated potential biomarkers for the prediction of PE at the second trimester. These include MAP, UtA-PI, PIGF and serum soluble fms-like tyrosine kinase-1 (sFlt-1) and in late third trimester MAP, PIGF and sFlt-1 [[4], [5], [6], [7]]. For the screening of asymptomatic women during the second and third trimesters, the Fetal Medicine Foundation (FMF) algorithm showed the best predictors to be MAP, UtAPI and PlGF [8] with sFlt-1 performing similarly to PIGF in predicting mid pregnancy PE. In the early and late third trimester, MAP, PIGF and sFlt-1 have been useful predictors [4,5,7,9].
Identification of other potential biomarkers to add to the current screening panel may add the extra value required to further improve accuracy. The eicosanoids leukotriene B4 (LTB4) and hydroxyeicosatetraenoic acid (HETE) have long been studied in PE but their potential as useful predictors of the disease is yet to be fully realised [10]. These molecules are derived from arachidonic acid via the lipoxygenase (LOX) pathway, are operative during inflammation to promote bronchoconstriction and are potent immunoregulatory lipid mediators of immune responses [[11], [12], [13]] with additional roles in vascular function and angiogenesis [13,14]. These properties and the contribution of excessive systemic inflammation to PE make these metabolites potential candidates as biomarkers for PE.
The objective of this study is to compare serum levels of LTB4 and 15(S)-HETE in asymptomatic women who later developed preterm or term PE with those of unaffected pregnancies in the second and third trimesters of pregnancy.
Section snippets
Study design and population
This is a case-control study drawn from a prospective cohort study of screening for adverse pregnancy outcomes. Informed consent was obtained from women with singleton pregnancies attending routine second and third trimester hospital visits at the Harris Birthright Unit for Fetal Medicine, King's College Hospital, London, between July 2011 and January 2016. The study was approved by the UK National Research Ethics Committee (reference number: 02-03-033).
The following maternal characteristics
Results
The baseline characteristics of the study population are listed in Table 1. Compared to normotensive controls, women who later developed PE had significantly higher maternal body weight, had more commonly a history of PE in a previous pregnancy, as well as higher rates of chronic hypertension.
Main findings
Serum LTB4 levels increased with gestational age in normal pregnancies but remained stable in women who developed PE. Women with preterm PE had significantly higher LTB4 at 19–24 weeks and a trend to higher levels at 30–34 weeks, and in the second trimester these levels seem to correlate with the severity of disease. In women with term PE, LTB4 levels were comparable to those of normotensive controls. Serum 15(S)-HETE levels remained stable during gestation in normotensive controls and in women
Conclusion
Serum LTB4 is increased during the second and early third trimester in women who will develop preterm PE and is a potentially useful predictive biomarker in the prediction for PE. Serum 15(S)-HETE is not altered in pregnancies affected by PE in the second or in the third trimester before disease onset and is unlikely to be useful in PE prediction.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
ED was supported by a senior research fellowship from the National Health and Medical Research Council of Australia (grant numbers 1117033 and 1098332). DW was supported by a grant from the Paracelsus Medical University Salzburg, Austria (PMU Research Fund – PMU FFF Number: L-18/02/006-WET) and by Drs Haackert Foundation, Germany.
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LLS and DW contributed equally to this study.