Pathophysiology of placental-derived fetal growth restriction

doi:10.1016/j.ajog.2017.11.577

American Journal of Obstetrics and Gynecology

Volume 218, Issue 2, Supplement, February 2018, Pages S745-S761

https://doi.org/10.1016/j.ajog.2017.11.577 Get rights and content

Placental-related fetal growth restriction arises primarily due to deficient remodeling of the uterine spiral arteries supplying the placenta during early pregnancy. The resultant malperfusion induces cell stress within the placental tissues, leading to selective suppression of protein synthesis and reduced cell proliferation. These effects are compounded in more severe cases by increased infarction and fibrin deposition. Consequently, there is a reduction in villous volume and surface area for maternal-fetal exchange. Extensive dysregulation of imprinted and nonimprinted gene expression occurs, affecting placental transport, endocrine, metabolic, and immune functions. Secondary changes involving dedifferentiation of smooth muscle cells surrounding the fetal arteries within placental stem villi correlate with absent or reversed end-diastolic umbilical artery blood flow, and with a reduction in birthweight. Many of the morphological changes, principally the intraplacental vascular lesions, can be imaged using ultrasound or magnetic resonance imaging scanning, enabling their development and progression to be followed in vivo. The changes are more severe in cases of growth restriction associated with preeclampsia compared to those with growth restriction alone, consistent with the greater degree of maternal vasculopathy reported in the former and more extensive macroscopic placental damage including infarcts, extensive fibrin deposition and microscopic villous developmental defects, atherosis of the spiral arteries, and noninfectious villitis. The higher level of stress may activate proinflammatory and apoptotic pathways within the syncytiotrophoblast, releasing factors that cause the maternal endothelial cell activation that distinguishes between the 2 conditions. Congenital anomalies of the umbilical cord and placental shape are the only placental-related conditions that are not associated with maldevelopment of the uteroplacental circulation, and their impact on fetal growth is limited.

Introduction

The kinetics of placental and fetal growth are closely interrelated, and are important features predicting postnatal health and in particular cardiovascular adaptations in childhood.1, 2 Fetal growth is dependent on nutrient availability, which in turn is related to the maternal diet, uteroplacental blood supply, placental villous development, and the capacity of the villous trophoblast and fetoplacental circulation to transport these nutrients. At birth, the fetoplacental weight ratio gives a retrospective indication of the efficiency of the placenta to support growth of the fetus, and estimates the potential risks for chronic diseases in later life through developmental programming.2, 3

Fetal growth restriction (FGR) is defined as the failure of the fetus to achieve its genetically determined growth potential.⁴ FGR can have many causes, but the majority of cases that are not associated with fetal congenital malformations, fetal genetic anomalies, or infectious etiology are thought to arise from compromise of the uterine circulation to the placenta. Sufficient dilatation of the uteroplacental circulation together with rapid villous angiogenesis are the key factors necessary for adequate placental development and function, and subsequent fetal growth.

The etiopathology of FGR due to abnormal development of the uteroplacental circulation and its impact on placental development and structure has been studied for >5 decades.⁵ Ultrasound imaging, and in particular color Doppler imaging, has allowed the study of both the umbilicoplacental and uteroplacental circulations from the first trimester of gestation onward.6, 7 These techniques have been used extensively in the screening of placental-related complications of pregnancy, such as preeclampsia,8, 9 and the management of a fetus presenting with primary or secondary FGR.¹⁰ More recently, 3-dimensional Doppler imaging11, 12 and magnetic resonance imaging (MRI)¹³ have been used to study the development of the placental and fetal circulations, but their use in clinical practice remains limited.

Placental-related complications of pregnancy that lead to FGR have their pathophysiological roots in the early stages of placentation and can manifest themselves from the end of the first trimester of pregnancy when the definitive placenta is forming.14, 15 Considerable remodeling of the placenta takes place toward the end of the first trimester/start of the second trimester, associated with onset of the maternal arterial circulation when the placenta becomes fully hemochorial. Events at this time potentially impact the final size of the placenta, and hence it functional capacity. This concept is supported by findings in utero showing that pregnancies complicated with FGR, with or without accompanying preeclampsia later in pregnancy, have a smaller placenta volume and higher uterine resistance to blood flow compared to healthy controls from the beginning of the second trimester.⁹

The relationships between abnormal placental development and FGR are complex. Isolating the placental causes of FGR can be difficult as many clinical studies are small, retrospective, and often multivariate with confounding factors such as maternal smoking and ethnicity. Also, many potential stressors converge on the same intracellular pathways, and separating the influence of, for example, glucose as compared to oxygen deprivation during periods of ischemia is impossible.

To provide a coherent account of how the FGR phenotype may arise we first consider the development of the normal placenta before discussing the molecular and clinical pathologies.

Section snippets

Early development of the placenta

Initial development of the placenta takes place within the superficial layer of the endometrium, and by the end of the third week postconception villi have formed over the entire chorionic sac. This precocious growth is supported and stimulated by secretions from the underlying endometrial glands (Figure 1),16, 17 so-called histotrophic nutrition. The carbohydrate- and lipid-rich secretions are delivered through openings in the developing basal plate into the intervillous space, from where they

Development of the uteroplacental circulation

The human hemochorial form of placentation poses major hemodynamic challenges. In particular, a high volume of maternal arterial blood flow has to be delivered to the placenta at a sufficiently low pressure and velocity to prevent mechanical damage to the delicate villous trees.²⁴ In normal pregnancies, the arcuate and radial arterial components of the uterine vasculature dilate under the combined effects of estrogen, progesterone, human chorionic gonadotropin, and other hormones and factors

Placental remodeling

The early or primitive placenta undergoes extensive remodeling toward the end of the first trimester. Regression of villi starts over the superficial pole of the gestational sac (Figure 3, A) and gradually extends until only those villi covering the deep pole in contact with the placental bed remain as the definitive discoid placenta. This profound remodeling raises questions regarding how and when the size and shape of the placental disc are determined, and whether further expansion and

Deficient spiral artery remodeling

Deficiencies in extravillous trophoblast invasion and maternal arterial remodeling have been linked to the pathophysiology of the great obstetric syndromes, including growth restriction, through malperfusion of the placenta.⁴⁶ Studies have reported a gradient of effects, with absence of remodeling in the junctional zone and myometrial segment being associated with more severe growth restriction compounded with preeclampsia.46, 47, 48, 49, 50 Aberrant remodeling of the more proximal radial

Growth regulatory pathways

One of the principal features of the placenta in cases of FGR is the reduction in volume, surface area, and vascularization of the intermediate and terminal villi that mediate maternal-fetal exchange.76, 77, 78 This reduction appears to be due to excessive villous regression during placental remodeling, compounded by a slower rate of subsequent growth.⁷⁹

In the case of the placenta, members of the insulin-like growth factor family are particularly important regulators of cell proliferation.⁸⁰

Clinical placentology in FGR

Many, if not all, placental abnormalities have been found in association with FGR, but the results of most histopathological studies are hampered by a number of methodological factors. Most studies are retrospective based on case-series rather than case-control data and many have used different clinical definitions of FGR, mixing cases of fetuses constitutionally small (SGA) and/or born prematurely following inaccurate gestational dating or unknown gestational age (low birthweight). Specific

Abnormalities of placentation

Abnormal placental shapes, in particular those with irregular outlines (extrachorial and bilobate placenta) have been associated with poor obstetric outcome, in particular poor fetal growth.119, 120 These anomalies are difficult to diagnose in utero by ultrasound scanning and are not routinely investigated in pregnancies complicated by FGR.

Placental location is an important factor; for example, cases of lateral placentation are more likely to be associated with FGR. A case-control study of

Macroscopic vascular anomalies

Deficient remodeling of the spiral arteries is associated with greater pulsatility of the jets of maternal blood in SGA pregnancies, as expected.³⁴ More severe vasculopathies of the arteries are associated with a combination of secondary placental macroscopic lesions including intervillous and parabasal thrombi, hematomas, infarcts, and extensive fibrin deposition (Figure 8).116, 117 Placental thromboses and infarcts are the most commonly found lesions in pregnancies complicated by FGR with or

Microscopic lesions

Many different microscopic placental lesions have been described in pregnancies complicated by FGR. Most are nonspecific, have been found in villous tissue from uncomplicated pregnancies, and the terminology used to describe them has been highly variable. The distribution of these lesions depends on whether the restricted fetal growth is isolated or associated with preeclampsia, and on gestational age at onset, with late onset leading to a more heterogeneous group with less characteristic

Umbilical cord anomalies

FGR has been associated with abnormalities of the umbilical cord insertion, ie: eccentric, marginal, or velamentous.119, 162 These anomalies are rare and often associated with abnormalities of the placental shape. Thus, there are no data supporting a direct link between the location of the umbilical cord insertion and poor fetal growth.

The absence of 1 of the 2 normal umbilical arteries or single umbilical artery (SUA) cord is one of the most common congenital fetal malformations with an

Conclusion

The placental changes seen in cases of FGR of noninfective and nongenetic origin form part of a spectrum of pathology associated with different degrees of deficient remodeling of the uterine spiral arteries.46, 173 Deficient remodeling results in maternal blood entering the placental intervillous space in jetlike streams that carve large channels and lakes within the villous trees. The high velocity, uneven and, most likely, intermittent perfusion of the placenta causes oxidative stress and