Interpretation
Previous studies have demonstrated an association between placental
pathology and increased postpartum maternal cardiovascular health
risk.21-25 One study found that in normotensive women
who experienced placental abruption during pregnancy, CVRs were
significantly altered 6-9 months postpartum compared to women without
uncomplicated pregnancies.25 Lesions of maternal
vascular maldevelopment (defined as mural hyperplasia, unaltered
decidual vessels and decidual atherosis) are associated with maternal
hypertension 7 to 15 years after pregnancy.35 Catov et
al. reported that in normotensive women who delivered preterm without
fetal growth restriction, those who had placental lesions of MVM and
inflammation had significantly elevated atherogenic profiles assessed
4-12 years after delivery.21 Our findings are line
with this study in which the cumulative severity of placental lesions
may be important for identifying women at highest cardiovascular risk
following pregnancy. Together with our current findings, significant
placental pathology may be indicative of greater risk for CVD
postpartum.
The mechanisms linking PE and postpartum maternal cardiovascular risk
have yet to be fully elucidated. The most commonly held hypothesis to
explain this link proposes that pre-pregnancy maternal CVRs including
both clinically-diagnosed and subclinical risk factors, may contribute
to the development of PE, including abnormal placental development, and
predispose women to CVD after pregnancy. Placentation requires the
invasion of fetal trophoblast cells into the maternal decidua, resulting
in conversion of the maternal uterine spiral arteries to high capacity,
venous-like conduits to increase blood flow into the uteroplacental unit
to support fetal growth and development.36 This
physiological remodeling of the uterine spiral arteries is known to be
defective in PE and the two-stage model of pathogenesis proposes that
this failed remodeling leads to placental ischemia, oxidative stress and
placental dysfunction which stimulates the release of angiogenic
factors, pro-inflammatory cytokines, syncytiotrophoblast vesicles and
other factors from the placenta.1 These processes
result in characteristic histopathological lesions observed in placentas
from pregnancies complicated by PE, particularly lesions of
MVM.37 Placenta-derived circulating factors interact
with the maternal endothelium at the systemic level, leading to the
end-organ dysfunction observed in the clinical manifestation of the
disorder. The maternal environment, including subclinical CVRs common to
PE and CVD, may directly contribute to impaired trophoblast invasion and
defective spiral artery conversion and its downstream effects.
Dyslipidemia including elevated pre-pregnancy levels of serum
triglycerides, cholesterol, LDL and non-HDL cholesterol have been
associated with increased risk of developing PE and are known
contributors to CVD.38 Studies have shown that lipids
modulate human trophoblast invasion and alterations in maternal lipid
profiles could potentially contribute to abnormal trophoblast invasion
and spiral artery remodelling. 39,40 Systemic (often
subclinical) inflammation, common in obesity and other cardiometabolic
conditions, may also play a role in limited trophoblast invasion and
spiral artery conversion during placentation in
PE.41,42 Pro-inflammatory cytokines are known to
inhibit trophoblast invasion by increasing apoptosis and decreasing
proliferation.43 Cytokine imbalance prior to pregnancy
may alter the maternal inflammatory milieu over and above the
physiological immune/inflammatory changes that occur in pregnancy,
however, exactly how this imbalance contributes to altered placentation
is unknown.
PE and placental dysfunction, reflected as MVM lesions in the placenta,
may also cause lasting damage to the maternal cardiovascular system that
results in altered cardiovascular health trajectories. Circulating
levels of inflammatory cytokines such as tumor necrosis factor-a (TNF-a)
and interleukin-6 (IL-6) are elevated in PE and interfere with the
maternal endothelium to produce systemic endothelial dysfunction. Women
diagnosed with PE have been found to have chronically altered
circulating levels of these cytokines >20 years after
pregnancy suggesting that PE may program the maternal cardiovasculature
such that there is persistent cardiovascular dysregulation and
precipitating CVD in later life. 44 Anti-angiogenic
imbalance in the maternal circulation, including elevated soluble
Fms-like tyrosine kinase-1 (sFlt-1) and reduced placental growth factor
(PlGF), may contribute to lasting cardiovascular dysfunction after PE.
Alternations in circulating angiogenic factors during pregnancy are
associated with cardiovascular changes including increased blood
pressure 6 to 12 years after pregnancy.45,46 Although
angiogenic factors levels significantly drop following delivery, a
recent study suggests that angiogenic imbalance may persistent in the
postpartum period.47 While the mechanisms of
angiogenic factors on cardiovascular health are not fully known, sFlt-1
and PlGF have been shown to influence vasodilatory function in
preclinical models.48,49
It is plausible that a combination of the pre-pregnancy maternal
environment and persistent alterations to the maternal cardiovascular
system from placental dysfunction contribute to future CVD risk.
Placental pathology, particularly lesions of MVM, may reflect both
abnormalities in the maternal milieu as well as the significant
cardiovascular burden from abnormal placentation, thereby identifying
patients at particularly increased risk of postpartum CVD. As such,
placental lesions identified at the time of delivery, could provide a
modality to triage PE women for cardiovascular health screening
postpartum. Future studies are required to confirm the utility of
placental pathology in this capacity, but it may offer a unique
opportunity to extend the clinical benefits of the placenta pathology
exam while targeting postpartum resource-intensive cardiovascular
screening to the most vulnerable patients.