Human placentation is uniquely associated with physiological remodeling of the spiral arteries, with deep placentation involving their almost complete transformation. Defective deep placentation has been associated with the development of pre-eclampsia (PE) and fetal growth restriction (FGR), collectively termed ‘placental syndromes’. The clinical significance of PE and FGR and their deleterious effect on maternal, fetal and neonatal health are well accepted. This article attempts to highlight the importance of maternal hemodynamics and their relevance to placental syndromes.
A video podcast of the TED Talk of this article can be accessed from the following link: http://bit.ly/2i1SqDk
Implied causation of placental syndromes
A placenta is essential for PE and FGR to occur, and is therefore believed to be central in their pathogenesis. The cure for PE is delivery of the placenta, supporting its crucial role. The name ‘placental syndrome’ itself demonstrates the commonly accepted belief that the association between inadequate trophoblast invasion and the subsequent development of PE and/or FGR is causal in nature. Incomplete remodeling of uterine spiral arteries is thought to result in a placental ‘stress’ biochemical response, which can lead to the subsequent development of both FGR and endothelial cell dysfunction characteristic of PE.
A number of characteristic histological lesions have been associated with the development of both PE and FGR, especially in early or preterm gestations. Although several studies consistently demonstrate that these lesions occur more frequently in FGR and PE, the vast majority of cases of PE and FGR occur at term, when placental histology is predominantly normal. Furthermore, even though these characteristic histological placental lesions are more prevalent in pathological pregnancies, their overall incidence is higher in placentae from normal pregnancies because these outnumber pathological pregnancies several-fold. Importantly, the only lesions consistently seen more often in PE and FGR pregnancies at term are those associated with maternal underperfusion of the placenta, such as massive perivillous fibrin deposition.
An expected and anticipated consequence of poor placental development is impaired fetal growth; consistent with this, about 60% of early-onset PE cases exhibit FGR. However, over 80% of PE cases occur at term and the majority of the neonates in these pregnancies are of normal size, the remainder tending to be either slightly smaller or, even, larger than average-weight neonates. Normal and larger birth weights are not consistent with long-standing placental dysfunction.
First-trimester serum levels of pregnancy-associated plasma protein-A (PAPP-A) and placental growth factor (PlGF) are reduced in pregnancies destined to develop preterm FGR and PE. In the studies with the best-reported screening performance, for a 5% false-positive rate, the sensitivity for early-onset PE using PlGF was around 60%, falling to approximately 15% for term PE. These hormonal patterns support the placental origins hypothesis for early-onset, but not for late-onset, PE. In the later stages of pregnancy, an imbalance of the vasoactive angiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and PlGF is thought to affect adversely vascular homeostasis and to contribute to the development of PE signs and symptoms. These angiogenic factors were first recognized for their involvement in the development of cardiovascular disorders in the non-pregnant state.
Uterine artery Doppler
Uterine artery Doppler assessment in the first trimester has been shown to have good sensitivity and specificity (47.8% and 92.1%, respectively) for the detection of early-onset PE. Increased uterine artery resistance indices have long been presumed to be the consequence of incomplete trophoblast invasion of maternal spiral arteries, resulting in a high-resistance placental circulation and underperfused fetoplacental unit. However, ophthalmic artery Doppler assessment is as equally effective as uterine artery assessment in screening for FGR and/or PE. High ophthalmic artery resistance indices are unlikely to be explained by poor spiral artery conversion from impaired placentation, and more likely to be related to maternal cardiovascular performance. The reduced sensitivity of uterine artery Doppler indices for late-onset PE lends further support to the argument that the heterogeneity observed in PE is due to early-onset PE being related to a dysfunctional placenta, whilst late-onset PE may have to be explained by an alternative, possibly cardiovascular etiology. Corroborative evidence for this hypothesis is provided by magnetic resonance imaging studies showing that early-onset PE is associated with lower placental perfusion fractions compared with gestational age-matched controls. In contrast, late-onset PE had larger placental perfusion fractions, supporting the argument that late-onset PE is unlikely to be due to placental insufficiency.
Genetics of placental syndromes
Familial clustering has been reported in PE, supporting a genetic causality link. Many susceptibility genes for PE have been described; however, the function of the majority of these genetic loci remains unknown. The few PE genetic loci with known associations have been implicated in adult cardiovascular disease, suggesting a genetic link between PE and cardiovascular disease.
Maternal cardiovascular adaptation
It has been a long-standing belief that the placenta is a prerequisite for and crucial to the development of PE, as highlighted above. However, there are inconsistencies in the placental origins hypothesis, and the parallels between PE and gestational diabetes should be considered further. The placenta is required for the development of gestational diabetes, characteristic placental lesions are seen, fetal growth is affected and it is cured by interruption of pregnancy. In spite of these parallels with PE, gestational diabetes is not considered a placental disorder, and it is well accepted that the endocrine ‘stress’ of pregnancy results in the development of gestational diabetes when maternal pancreatic function is suboptimal.
Magnitude of maternal cardiovascular adaptation
Just as gestational diabetes occurs as a consequence of the pancreas being unable to deal with the excessive glucose metabolic load of pregnancy, if PE were a cardiovascular disorder, pregnancy must present a significant strain on the maternal cardiovascular system. Indeed, studies have demonstrated that normal pregnancy results in an excessive increase in left ventricular mass, adverse ventricular remodeling and even overt diastolic dysfunction in a proportion of apparently healthy women at term[11, 12]. These changes are an order of magnitude greater than those observed in elite athletes and in some pathological conditions in non-pregnant individuals.
Evidence of cardiovascular maladaptation
There is evidence of impaired myocardial relaxation and diastolic dysfunction at diagnosis of PE and, to a lesser extent, FGR. Mild-to-moderate left ventricular diastolic dysfunction is seen in approximately half of women with early-onset PE, with one in five having biventricular systolic dysfunction. This impairment in cardiac function is likely to be related to increase in cardiac afterload (high systemic vascular resistance) and abnormal left ventricular remodeling/hypertrophy[13, 14]. The abnormal pattern of remodeling observed in PE is similar to that observed in non-pregnant individuals with essential hypertension and is consistent with an impairment that is afterload-induced.
Risk factors for cardiovascular maladaptation
Both PE and FGR have predisposing clinical risk factors, such as increased maternal age, ethnic origin, increased body mass index, diabetes and other maternal comorbidities. These predisposing risk factors have been taken to imply a deleterious impact on trophoblast development. However, it is important to acknowledge that these risk factors have long been associated with the development of cardiovascular disease in the non-pregnant population.
Late uteroplacental dysfunction
A recent large, population-based study demonstrated a 2% increase in risk of delivery of a term small-for-gestational-age infant for every 1-mmHg increase in maternal blood pressure within the normotensive range. The authors suggested that the observed maternal prehypertension is a response to impaired placental function; however, consideration should be given to the possibility that the placenta is a perfusion-dependent organ and that impaired cardiovascular function may cause placental dysfunction, rather than the other way round[17, 18]. In support of the latter hypothesis, previous work has demonstrated maternal ventricular remodeling and diastolic dysfunction as well as significantly poorer placental perfusion in normotensive FGR pregnancies. This is supported by the characteristic histological findings of placental hypoperfusion in cases of FGR. Such evidence suggests that term FGR may well occur as a consequence of secondary placental dysfunction caused by impaired maternal cardiovascular function. This is in contrast to preterm FGR, in which placental cause is unchallenged, and implies that both impaired maternal perfusion of the placenta (an extrinsic defect) and impaired placental development (an intrinsic defect) may lead to FGR.
Postpartum cardiovascular legacy
The parallels between placental syndromes and gestational diabetes can also be extended to the postpartum period. Women whose pregnancies were complicated by gestational diabetes have a 50% risk of developing diabetes in the subsequent decade. Similarly, women whose pregnancies were complicated with PE and/or FGR are predisposed to increased postpartum cardiovascular morbidity and mortality, including chronic hypertension, myocardial infarction, heart failure, stroke and death. In fact, even in apparently healthy women, postpartum follow-up after pregnancies complicated by placental syndromes has demonstrated persistent remodeling and left ventricular dysfunction. Population studies have suggested that the association of PE with adverse cardiovascular outcome postpartum may be due largely to shared prepregnancy risk factors rather than reflecting a direct influence of PE.
Clinical relevance of maternal hemodynamics
Although it is certainly plausible that the placenta causes PE and FGR in the minority of cases that constitute early-onset disorder, consistent and emerging evidence suggests otherwise for the development of late-onset PE and FGR. The inconsistencies and discrepancies of the placental origins hypothesis have been attributed to ‘heterogeneity’ or explained as the ‘maternal form’ of the disorder, neither one of these terms being an adequate or actual explanation of the causality of PE and FGR at term. A stronger argument can be made for the role of the maternal cardiovascular system in the development of PE and FGR. The evidence cited here and within this issue of the Journal supports maternal cardiovascular involvement in the etiology of placental syndromes, especially the late-onset variety. Whilst intrinsic placental dysfunction and the subsequent maladaptation of the maternal cardiovascular system leads to early-onset PE and FGR, late-onset disorders are more likely to be associated with an acquired placental dysfunction as a result of the maternal heart not being able to meet the excessive hemodynamic and metabolic demands of an advanced or overgrown pregnancy. Both intrinsic and acquired placental dysfunction result in placental stress, leading to the cluster of maternal signs and symptoms that we recognize as PE and/or FGR. It is possible that the lack of progress in improving outcomes of placental syndromes may be linked to the inaccurate assignment of disease causality in PE and FGR. Gaining a better understanding of the precise etiology of placental syndromes is critical for the development of accurate diagnostic aids, improved screening, better triage according to disease severity and offering targeted preventative and therapeutic measures. Research on maternal hemodynamic alteration in pregnancy will be critical to progress further in this arena.