Longitudinal reference ranges for maternal plasma laeverin, and its role as a potential biomarker of preeclampsia

Abstract

BackgroundLaeverin is a placenta-specific membrane-bound aminopeptidase. In this study we wanted to: 1) serially measure plasma levels of laeverin in healthy women during the second half of pregnancy and postpartum, 2) determine whether laeverin is differently expressed at 22–24 weeks in women who later develop preeclampsia compared to controls, 3) compare laeverin protein expression in placenta and umbilical vein serum in healthy and preeclamptic pregnancies at birth.MethodsPlasma was obtained serially, approximately every 4-weeks, from 53 healthy women with uncomplicated pregnancies during 22+0 to 39+6 weeks of gestation, and at 22–24 weeks from 15 women who later developed preeclampsia. Enzyme-linked immunosorbent assay was used to measure laeverin protein concentration. Serum from healthy non-pregnant premenopausal women (n = 10), menopausal women (n = 10) and men (n = 11) were used as negative controls. Protein extracts from placental tissue were obtained after birth from healthy- (n = 11) and preeclamptic women (n = 13). Paired umbilical artery and vein serum samples from the neonates (n = 10) of healthy mothers were also analyzed. Multilevel modeling was used to determine the reference centiles. Differences between groups were analyzed using Student’s t-test.ResultsHealthy pregnant women at term (37–40 weeks) had significantly higher plasma levels of laeverin (mean 4.95 ± 0.32 ng/mL; p < 0.0001) compared to men (mean 0.18 ± 0.31 ng/mL), non-pregnant premenopausal women (mean 0.77 ± 0.26 ng/mL) and postmenopausal women (mean 0.57 ± 0.40 ng/mL). Maternal plasma laeverin levels decreased with advancing gestation, from 6.96 ± 0.32 ng/mL at 22–24 weeks to 4.95 ± 0.32 ng/mL at term (p < 0.0001) in uncomplicated pregnancies. Half of the women who developed preeclampsia had plasma laeverin levels below the 5th percentile at 22–24 weeks gestation. However, laeverin levels were 1.6 fold higher in preeclamptic compared to healthy placentas (p = 0.0071). Umbilical venous samples of healthy neonates (n = 38) had higher (p = 0.001) mean levels of laeverin (16.63 ± 0.73 ng/mL), compared to neonates of preeclamptic (n = 14) mothers (12.02 ± 1.00 ng/mL). Postpartum plasma levels of laeverin decreased in healthy and preeclamptic women with a half-life of 3 and 5 days, respectively.ConclusionsMaternal plasma levels of laeverin decrease with advancing gestation during the second half of normal pregnancy and lower levels measured at 22–24 weeks might be associated with the development of preeclampsia later in gestation.

Maternal serum laeverin (aminopeptidase Q) measured in the first trimester of pregnancy does not predict preeclampsia

“…We found a positive correlation between maternal serum laeverin concentration and gestational age in the late first trimester, which is in contrast to the finding of negative correlation reported in the second and third trimester [7]. However, the median laeverin concentrations measured during 8-14 weeks were higher compared to the values reported during 22-40 weeks.…”

“…This is supported by the finding of laeverin gene being significantly upregulated (10 fold) in placentas from pregnancies complicated by severe PE [6]. Furthermore, in the second trimester, maternal plasma laeverin level was found to be reduced in pregnancies that later developed PE [7].…”

“…Maternal serum laeverin might be a biomarker of PE in the second and third trimester. In a recent study, Nystad et al [7] report that second trimester maternal plasma laeverin was significantly reduced in pregnancies that developed PE. It was speculated that the reduction in laeverin during the development of PE was caused by trapping of laeverin in the placenta or in microvesicles in the fetal capillaries [5].…”

Galectin-13 and Laeverin Levels Interfere with Human Fetoplacental Growth

“…An increasing amount of literature is reporting on the potential role of laeverin in the pathomechanisms of preeclampsia, since preeclamptic trophoblasts overproduce laeverin [ 17 , 18 , 19 ] and ectopic intracellular expression of the protein [ 20 ] could be observed in preeclamptic placenta. Laeverin can be detected in the maternal serum [ 19 , 21 ] since EVT releases it into the maternal circulation. A lower circulating level might be a prognosticator of preeclampsia since the abundant laeverin is entrapped in the placenta [ 19 ], a disease with impaired uterine vascularity and placentation.…”

“…Laeverin can be detected in the maternal serum [ 19 , 21 ] since EVT releases it into the maternal circulation. A lower circulating level might be a prognosticator of preeclampsia since the abundant laeverin is entrapped in the placenta [ 19 ], a disease with impaired uterine vascularity and placentation. Overexpression of laeverin disrupts the migratory capability of EVTs, resulting in shallow invasion and dysfunctional placental impairment [ 17 , 19 , 20 ].…”