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.