1. Introduction
Preeclampsia (PE) is a hypertensive disease that complicates
approximately 3-5% of all pregnancies, being one of the leading causes
of maternal morbidity and mortality1–10, as well as
adverse perinatal and neonatal outcomes11–14. This
condition is part of the most important obstetrical
syndromes15,16 and multiple
etiologies17–23 have been proposed to play a role in
its pathophysiology, including an imbalance of angiogenic and
anti-angiogenic factors24–40, systemic maternal
inflammation 41–43, endothelial
dysfunction44,45, metabolic
syndrome46–51, vascular disorders of the
placenta52–54, abnormal
placentation55–58, and utero-placental
ischemia59–61. Indeed, PE is characterized by a
systemic maternal vascular dysfunction associated with an abnormal
placentation that is, in part, attributable to abnormal remodeling of
the spiral arteries during early pregnancy62–69. An
abnormal placentation is associated with the increased release of
cellular debris from the trophoblast into the maternal circulation that
contributes to systemic inflammation, endothelial dysfunction, and the
clinical manifestation of the disease70–75. The only
effective treatment of PE is the delivery of the fetus, thus removing
the deleterious effects of the placenta on maternal
physiology67,76.
Early identification of women at risk for PE would allow for the
development and evaluation of timely and appropriate intervention
strategies to limit short- and long-term adverse
outcomes77,78. Given that interventions such as
aspirin administration during the first trimester of pregnancy, have
demonstrated a reduction of its incidence, the development of accurate
methods for identifying women at risk of developing PE is a recognized
clinical need79–82. Several multiparametric
predictive algorithms have been previously reported in
literature83,84, and are based on several combinations
of maternal risk factors, uterine artery Doppler pulsatility indices,
and different blood-borne biomarkers85–87; however,
these algorithms have not been universally adopted and accepted for
routine obstetric clinical care78,88–94. The
development of more accurate, inexpensive and effective risk assessment
algorithms may increase the adoption of such testing in clinical care
and improve patient management and disease outcome.
Recently, we have identified gingival crevicular fluid (GCF) as a source
of surrogate biomarkers of placental function95–97.
GCF is a serum exudate that originates in the gingival sulcus as a
result of periodontal inflammation and contains a variety of biological
cell types and molecular markers of systemic and local
origin98. Thus, the determination of the concentration
of such biomarkers in GCF may serve as a minimally invasive source of
biomarkers for the prediction of placenta-originated
diseases99,100. Among those biomarkers, placental
alkaline phosphatase (PLAP) has been linked to perinatal diseases such
as preterm delivery and PE101,102. PLAP is a
membrane-bound glycoprotein expressed by the maternal microvillous
membrane of the syncytiotrophoblast103–105. The
concentration of PLAP in maternal blood increases throughout gestation
in normal pregnancy103, and has been implicated in
regulating fetal/maternal metabolism, the transport of nutrients, and
placental differentiation106,107. Moreover, in a
recent case-control study, we reported a significantly higher
concentrations of GCF-PLAP in pregnant women with PE compared to those
with a normal pregnancy, even after adjusting for smoking status, body
mass index, and periodontal diagnosis99.
The rationale to utilize GCF for the prediction of PE also relies on the
association between periodontal disease and development of hypertensive
disorders of pregnancy108–111. A recent overview of
systematic reviews suggested an association between periodontal disease
and PE development (odds ratio [OR] 2.2; 95% confidence interval
[CI], 1.4 to 3.4), after the analysis of 15 studies that comprised
5,111 pregnant women112. In addition, periodontal
bacteria, such as Porphyromona gingivalis , Fusobacterium
nucleatum , and Treponema denticola , have been found to be
significantly enriched in the placentae of women affected by
hypertensive disorders compared to those of healthy
controls113–115, with increased expression of
Toll-like receptor 2 in the placentae of patients with
PE115; this finding suggests that periodontal
bacteremia could stimulate the placental tissue, inducing the systemic
release of pro-inflammatory cytokines.
Based on this previous considerations, the aims of the present study are
(1) to determine whether GCF-PLAP concentrations are increased during
early pregnancy in patients who will subsequently develop PE and (2) to
assess the diagnostic performance of GCF-PLAP concentrations when
combined with other maternal clinical parameters for the identification
of patients who will develop PE.