Neonatal Morbidities of Fetal Growth Restriction: Pathophysiology and Impact

Malhotra, Atul; Allison, Beth J.; Castillo-Melendez, Margie; Jenkin, Graham; Polglase, Graeme R.; Miller, Suzanne L.

doi:10.3389/fendo.2019.00055

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Front. Endocrinol., 07 February 2019

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Volume 10 - 2019 | https://doi.org/10.3389/fendo.2019.00055

This article is part of the Research Topic Causes and Consequences of Intrauterine Growth Restriction View all 22 articles

Neonatal Morbidities of Fetal Growth Restriction: Pathophysiology and Impact

$\r\nAtul Malhotra,,*&#x;$ Atul Malhotra^1,2,3^*^†

Beth J. Allison^2,4^†

Margie Castillo-Melendez^2,4

Graham Jenkin^2,4

Graeme R. Polglase^2,4

Suzanne L. Miller^2,4

¹Monash Newborn, Monash Children's Hospital, Melbourne, VIC, Australia
²The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, VIC, Australia
³Department of Paediatrics, Monash University, Melbourne, VIC, Australia
⁴Department of Obstetrics and Gynaecology, Monash University, Melbourne, VIC, Australia

Being born small lays the foundation for short-term and long-term implications for life. Intrauterine or fetal growth restriction describes the pregnancy complication of pathological reduced fetal growth, leading to significant perinatal mortality and morbidity, and subsequent long-term deficits. Placental insufficiency is the principal cause of FGR, which in turn underlies a chronic undersupply of oxygen and nutrients to the fetus. The neonatal morbidities associated with FGR depend on the timing of onset of placental dysfunction and growth restriction, its severity, and the gestation at birth of the infant. In this review, we explore the pathophysiological mechanisms involved in the development of major neonatal morbidities in FGR, and their impact on the health of the infant. Fetal cardiovascular adaptation and altered organ development during gestation are principal contributors to postnatal consequences of FGR. Clinical presentation, diagnostic tools and management strategies of neonatal morbidities are presented. We also present information on the current status of targeted therapies. A better understanding of neonatal morbidities associated with FGR will enable early neonatal detection, monitoring and management of potential adverse outcomes in the newborn period and beyond.

Overview and description

Fetal growth restriction (FGR) describes the fetus that does not grow to its expected biological potential in utero, and is a relatively common complication of pregnancy. True FGR, as compared to constitutional smallness, is a pathological condition wherein the placental fails to deliver an adequate supply of oxygen and nutrients to the developing fetus, termed placental insufficiency. As a consequence, fetal growth becomes stunted. It is only in the last several years that consensus definitions for pathological FGR have been developed (1), but it remains that many cases of FGR in utero remain undetected, and therefore the neonatal description of small for gestational age (SGA) continues to be a useful and necessary proxy for FGR (2). Traditionally, an estimated fetal weight or abdominal circumference of less than the 10th centile for the population at a given gestational age was considered highly suggestive of FGR. However this broad description of SGA includes the many infants (~20%) that are born small, but are otherwise healthy (2). Accordingly, consensus definitions for FGR now incorporate Doppler indices of placental function/ dysfunction during pregnancy (1), to provide a more robust assessment of pathological fetal growth restriction. Clear and well-defined guidelines for description of FGR subsequent to placental insufficiency are important for two broad reasons, (i) early identification of FGR flags infants who are at significantly elevated risk for neonatal complications, and (ii) early identification of infants with FGR who would benefit from intervention(s) to improve outcomes. The etiology of many adverse consequences of FGR arise in utero from fetal hypoxia and nutrient deprivation secondary to placental dysfunction, with fetal hemodynamic adaptations in utero laying the foundation for altered organ structure and function in the neonatal period and beyond.

Etiology and Uteroplacental Factors

The basic determinants of fetal growth are the individual's genetic makeup, nutrient availability from the mother, and environmental factors, coupled with the capacity of the placenta to adequately transfer nutrients and oxygen to the fetus, and endocrine modulation of these interactions (3, 4). Reduced fetal growth, and subsequent pathological FGR, can be caused by maternal factors (e.g., under nutrition, hypertension, preeclampsia), fetal (chromosomal abnormalities, multiple fetuses) or placental factors (5), however in the majority of cases, FGR results from placental dysfunction (6). Here, the term placental insufficiency is broadly used to describe reduced transfer of oxygen and nutrients to the fetus, with adverse effects on fetal development. Antecedents of placental insufficiency can include maternal malnutrition and hypertension, but in up to 60% of cases the placental insufficiency is idiopathic, wherein there is a physiological deficiency in the remodeling of uterine and placental spiral arteries resulting in restricted uteroplacental perfusion (7).

Abnormalities in placental function provide a primary clinical indicator that transfer of oxygen and nutrients is suboptimal, and fetal growth may be adversely affected. In the fetus, placental insufficiency is characterized by preferential blood flow redistribution to the vital organs (brain, myocardium, and adrenal glands), while other organs, including the gastrointestinal tract, skin, and others may be deprived of sufficient blood flow. This fetal redistribution of blood flow occurs as a direct result of hypoxia, and can be detected as altered umbilical, uterine and/or middle cerebral artery Doppler flows (8). Large population studies of small but otherwise healthy infants at birth (Apgar ≥ 7 at 5 min of life) demonstrates that severely growth restricted infants at the third birth weight centile are indeed chronically hypoxic; umbilical vein median pO₂ 13 mmHg (FGR) versus 26 mmHg (normally grown infants), and median SaO₂ 16 vs. 55% respectively (9, 10).

In addition to the fundamental roles of oxygen and glucose for development, fetal growth is dependent on a number of key anabolic hormones—placental, pancreatic, thyroid, adrenal and pituitary hormones—any disruption in these can also lead to FGR (11, 12). The insulin-like growth factors -I and -II (IGF-I and IGF-II) are both proposed to play central roles in normal fetal growth, stimulating fetal cell proliferation, differentiation, protein and glycogen synthesis, where these actions are mediated via their receptors and the IGF-binding proteins (IGFBPs). The two IGFs are detected in the fetal circulation in early gestation, and in particular it is noted that decreased serum IGF-1 is correlated with reduced fetal growth (3, 13). IGF-1 also has a central role in brain growth, white matter development and brain connectivity (14). Pregnancy-associated plasma protein-A (PAPP-A), secreted by the placental decidua, cleaves IGFBP-4, which in turn is a potent inhibitor of IGF bioactivity. Accordingly, low levels of PAPP-A in early pregnancy are linked with an increased risk for FGR, although the predictive value of this biomarker still remains poor (15). A recent study has investigated whether administration of IGF-1 into the amniotic fluid can improve postnatal growth and metabolism in a sheep model of FGR, and results from this study look promising (16) (see Interventions for Improved Outcomes section). Glucocorticoid hormones play a central role in the development and maturation of fetal organs, while growth hormone, which is the major hormonal regulator of postnatal growth, has no demonstrable effect on fetal growth per se (17). Exogenous glucocorticoids are administered to pregnant women at imminent risk of preterm birth to mature the fetal lungs, and preterm birth is a common complication of FGR. Preclinical and clinical evidence demonstrates that antenatal steroids may exacerbate growth restriction (particularly repeat doses) (18) and that the FGR fetus differentially responds to antenatal steroids compared to appropriately-grown fetuses, likely mediated via altered placental response to steroids (19). Antenatal glucocorticoids may not significantly improve neonatal outcomes in FGR preterm infants (20), and indeed, may have adverse effects on brain development (21, 22). Further research is clearly needed in this area.

The fetus mounts a critical hemodynamic response to hypoxia, aimed at ensuring the most important fetal organs maximize their oxygen supply. This adaptive response redistributes blood flow away from peripheral vascular beds which is preferentially shunted toward essential organs, termed brain sparing (23). This results in preferential supply of blood flow to favor the brain, heart, and adrenals, at the expense of the gut, kidney, hematologic organs, and peripheral vascular beds. When fetal hypoxia is chronic in nature, as occurs with placental insufficiency, the persistent fetal hemodynamic shift has significant consequences for the fetus and neonate. Characteristically, prolonged fetal hypoxia reduces fetal weight overall, but also does so in an asymmetric manner, with relatively spared head size and a thin and/or shorter body length. While hemodynamic redistribution may be an attempt to protect vital organs from hypoxic injury, an adverse impact on fetal organ development and vascular remodeling is increasingly being recognized (23, 24). For example, the shunting of blood flow away from the kidneys is now recognized as contributing to suboptimal renal development with reduced nephron endowment (25). Further, sustained vasoconstriction of peripheral vascular beds alters local arterial wall properties including endothelial vasodilator dysfunction and sympathetic hyperinnervation, and consequently contributes to cardiac remodeling (26). The short and long-term consequences of sustained redistribution of cardiac output are profound, for both spared and non-spared organs, and these will be discussed in more detail below.

The overall incidence of FGR depends on the diagnostic criteria used, and the population being examined. It is estimated that between 3 and 9% of pregnancies in the developed world, and up to 25% of pregnancies in low-middle income countries are affected by FGR (27, 28). Factors that influence FGR rates in communities include maternal nutrition, maternal and paternal smoking rates, alcohol and drug addiction, socio-economic status, maternal activity, stress during pregnancy and genetic make-up (29). The incidence of FGR is significantly higher in low- and middle- income countries, compared to high-income countries, and this is notably contributed by a large number of FGR infants born in the Asian continent, which accounts for approximately 75% of all affected infants in the world, followed by Africa and South America (30).

Classification Types of FGR

FGR can be classified as early- or late-onset, reflecting the gestational age when growth restriction is diagnosed. Early onset FGR (<32 weeks gestation) is the more severe phenotype, associated with significant disruption to placental perfusion leading to chronic fetal hypoxia, and with subsequent fetal cardiovascular adaptation in utero (31). Fetuses with early-onset placental insufficiency are more likely to be born preterm, to deteriorate over weeks, and have a high risk of morbidity or mortality. Late onset FGR (≥32 weeks gestation) is the more common presentation of growth restriction (up to 80% of FGR cases), and is generally linked with a milder placental deficit, together with a lesser degree of fetal hemodynamic adaptation. Although placental dysfunction is mild, this group has a high risk of deteriorating rapidly, such that they have an elevated risk of stillbirth (31). This broad distinction between early- and late-onset FGR demonstrates that the timing when placental function becomes rate limiting for the fetus is a principal factor affecting outcome.

Advances in obstetric monitoring mean that it is increasingly likely that placental insufficiency and fetal growth restriction are detected during pregnancy. However, a significant proportion (up to 50%) of FGR fetuses remain undiagnosed, and are first recognized only very late in pregnancy or at birth (32–34). Furthermore, debate continues around the utility of third trimester ultrasound for the detection of late-onset FGR (35), with a recent study reporting that undiagnosed FGR does not lead to increased incidence of morbidity in neonates (36). These data likely reflect that it is predominantly the early-onset FGR infants with severe placental insufficiency, and worse neonatal outcomes, who are more straightforward to detect during pregnancy. Currently, no effective antenatal therapy exists for FGR, hence, delivery of the fetus remains the only viable option for a severely affected pregnancy; this often occurs preterm, introducing further risk of morbidity and mortality (37, 38). Together these data are indicative that the timing of the onset of placental insufficiency (early vs. late), gestation at birth, and severity of compromise/birth weight are the most predictive factors for neonatal outcomes (39) (Figure 1).

FIGURE 1

Figure 1. Factors that affect outcomes in FGR.

Perinatal Morbidities

A typical FGR infant at term age and an appropriately grown infant at term are shown in Figure 2. Key pathophysiological mechanisms driving fetal growth restriction and the resulting in-utero and postnatal consequences are highlighted in Figure 3. Placental pathology and FGR are strongly associated with fetal demise in utero, and stillbirth (40–42). FGR is the greatest risk factor for stillbirth; overall it is shown that up to 50% of infants who are stillborn were small for gestational age or growth restricted (43). The detection, early diagnosis, surveillance and delivery of the severely growth restricted fetus are paramount to decrease stillbirth, but it remains that 40% of severe FGR infants (<3rd centile for birth weight) remain undetected in utero (44).

FIGURE 2

Figure 2. Example of a FGR (2nd centile weight for age, yellow), and an appropriately grown (50th centile weight for age, blue) infant born at 37 weeks gestation.

FIGURE 3

Figure 3. In-utero and postnatal consequences of FGR and potential targeted therapies.

After birth, FGR infants are more likely to spend a significantly longer time in NICU compared to gestation age-matched infants (45). Accordingly, financial costs associated with the care of FGR infants are high, given that many of them will remain in NICU for prolonged periods (46, 47). FGR infants demonstrate elevated rates of intolerance to feeds/ milk, feeding difficulties and necrotizing enterocolitis (NEC). NEC is predominantly seen in infants who are born preterm, but late preterm infants are more likely to develop NEC if they were growth restricted (48). It is likely that in utero chronic fetal hypoxia and subsequent cardiovascular redistribution of blood flow away from the gastrointestinal tract contribute to immature gut development (49). FGR newborns, especially with abnormal flows in the umbilical artery prior to birth, are shown to have more feed intolerance when compared to their well-grown preterm counterparts (50). Superior mesenteric artery blood flows have been used as a marker for splanchnic perfusion in neonates and decreased flows correlate with feed intolerance (51). Application of near infra-red spectroscopy in the neonatal period as an assessment tool for monitoring gut perfusion can detect changes in splanchnic oxygen delivery, which may be reduced in FGR infants and may predict feeding intolerance and development of NEC (52). Studies have shown that preterm FGR infants do not tolerate enteral feeds in the first few days of life (53) but conversely there is evidence that delaying enteral feeds in preterm FGR infants does not confer any protection against feed intolerance or NEC (54). In fact, it may delay establishment of feeds and increase length of stay in the neonatal unit (55).

Malnutrition and low birth weight puts FGR infants at an increased risk of a number of transient neonatal morbidities including hypothermia, altered glucose metabolism (hypoglycemia, hyperglycemia), hypocalcemia, polycythemia, jaundice and sepsis (5). Increased risk of infection is also common, potentially related to depressed immunological state and competence (56). FGR infants born preterm also have an increased risk of retinopathy of prematurity (57). FGR is linked to altered nephrogenesis, due to suboptimal tubular development caused by intrauterine hypoxia (58), and in turn, urinary Cystatin-C excretion is increased in FGR infants compared to appropriately-grown infants which is seen to reflect reduced renal volume (59). It is therefore suggested that increased secretion of Cystatin-C signifies nephron loss as a result of the negative impact of FGR on kidney development. Factors involved in nephron loss may include intrauterine hypoxia, decreased antioxidant capacity, and altered levels of growth factors.

Specific Neonatal Morbidities (Table 1)

Cardiovascular Morbidity

Clinical Features

In addition to chronic hypoxia, placental insufficiency imposes other important stressors for the developing fetus, such as oxidative stress, inflammation and increased hemodynamic stress. This leads to elevated cardiac afterload due to high placental vascular resistance, which in turn directly and indirectly impacts on the developing cardiovascular system. It is now accepted that the fetal adaptations to these combined stressors sets the fetus, and future offspring, on a path of predetermined increased risk of cardiovascular disease (60, 61). It is also now apparent that subclinical or subtle evidence of cardiovascular dysfunction is present in fetal and/or early neonatal life, well before the onset of significant cardiovascular or metabolic disease in adulthood, supporting the notion of perinatal programming (60).

TABLE 1

Table 1. Neonatal morbidities in fetal growth restriction.

Advances in Doppler ultrasonography of the placental and fetal circulations provide a window of opportunity to observe and quantify fetal cardiovascular function, and early dysfunction. In early-onset FGR, severe placental insufficiency is characterized by high vascular resistance within placental vascular beds, resulting in absent or reversed diastolic umbilical artery flow, as well as high pulsatility index in the ductus venosus and increased dilation of cerebral vessels evident of fetal brain sparing (31). In late-onset FGR, umbilical artery flow may be normal, representing a milder placental insufficiency. Despite this, brain sparing is still evident, with increased cerebral to placental blood flow driven primarily by vasodilation within the middle cerebral artery in response to hypoxia (62). In both early- and late-onset FGR, increasing vasodilation within cerebral vascular beds is indicative of a worsening fetal state (63). Increased myocardial performance index, an index incorporating both diastolic and systolic function to assess global cardiac function/dysfunction, is evident from 24 weeks gestation in early onset-FGR fetuses (64). An increase in myocardial performance index is not indicative of improved performance, but rather demonstrates an increased time of systolic relaxation evident in early-onset FGR. Increased myocardial dysfunction is also present in late-onset FGR from >35 weeks gestation. In this population, late-onset placental insufficiency and FGR results in fetuses with larger, more globular hearts and early indices of functional deficits with impaired relaxation (65). This study is the first to show that late-onset placental insufficiency and FGR induces cardiac dysfunction that is detectable in the third trimester of pregnancy (~35 weeks gestation), indicating the presence of cardiac programming prior to birth. It has also been shown that cardiac dysfunction and markers of cardiac injury such as BNP and H-FABP become increasingly worse as the severity of fetal compromise progresses (66).

Pathophysiology

In the presence of very high placental resistance associated with a sub-optimal pregnancy, the fetal heart contracts against an increased afterload, thereby increasing the work required to contract with each beat, resulting in increased heart wall stress and hypertrophy (65). Over a sustained period, hypertrophy increases wall thickness altering ventricular compliance. Increased afterload is evidenced by the presence of increased serum B-natriuretic peptide in infants born growth restricted (67).

Where placental insufficiency is present, the fetal heart must also adapt to a reduced supply of glucose, with the fetal heart producing ATP from glycolysis and oxidation of lactate. Despite this, cardiac glucose consumption is not altered in growth restriction due to increase in insulin receptor GLUT4 in the heart, which increases insulin transport to maintain glucose consumption (68). Thus, glucose availability is not considered a primary limiting factor for fetal cardiac function. More in-depth analysis of the effects of suboptimal oxygen and glucose supply to the developing heart can be examined in animal studies of FGR (69). These studies show that the fetal heart is remodeled in a manner similar to that seen in dilated cardiomyopathy. Cardiomyocyte development is adversely affected and programmed cell death is increased in growth restricted fetal guinea pigs and sheep, with a persistence of the mononucleated, primitive cell type (70, 71). Permanent alterations in heart morphology are detected into adulthood, as evidenced by persistence in the deficits in cardiomyocyte number and cardiac hypertrophy (70).

The transition to ex utero represents a particularly critical period where the heart must rapidly adapt to new pressure and flow demands. After birth, the external pressures around the heart are reduced, due to alleviation of the liquid-filled lungs and amniotic fluid. Concurrently, the low resistance placental circulation is removed, temporarily decreasing cardiac output and increasing afterload, and thus heart rate, end-diastolic pressure and stroke volume must all be increased to maintain adequate cardiac output. In response to these altered pressure demands throughout the transition to ex-utero life, the myocardium undergoes rapid changes in cardiac muscle protein expression (72). One critical change precipitated by such pressure changes at birth is a shift in the fibrous component of sarcomeres toward smaller isoforms, which increase the passive tension within with postnatal heart (72). It is postulated that the growth-restricted fetus undergoes these changes in utero, due to the presence of increased afterload secondary to high placental resistance, and resulting in altered cardiac compliance (73). In human infants and in experimental animal models of FGR, the heart is shown to have shorter sarcomeres, which likely contributes to decreased contractile strength (73, 74). Further, changes in the large sarcomere protein titin are described in the FGR heart, reflecting a shift from a large compliant isoform toward a small and stiff isoform (73). As titin is a major determinant of sarcomere length, this change in isoform is consistent with overall reduction in sarcomere length in the hearts of growth-restricted fetuses, and has consequences for cardiac development and function.

Changes in the hearts of growth-restricted fetuses are directly coupled with changes in the wider cardiovascular system, notably the vasculature. It is now well described that vascular responses to placental insufficiency and chronic hypoxia are vascular bed-dependent. In peripheral vascular beds, human and animal data show that sustained vasoconstriction and peripheral vascular resistance in response to chronic hypoxia induces arterial stiffness and elevated central pulse pressure (75–77). Growth restriction induced via chronic hypoxia increases peripheral vascular tone via numerous methods, including endothelial dysfunction (76), increased sympathetic nervous system activation (69) and oxidative stress (78). Oxidative stress, induced via increased reactive oxygen species generation, quenches nitric oxide (NO), thereby reducing its bioavailability and increasing peripheral vascular tone. We have previously described an increase in plasma urate levels arising from chronic fetal hypoxia (78) suggesting activation of a potent oxidative enzyme, xanthine oxidase. Importantly, it is this altered vascular tone in fetal life that sets up developmental programming for future hypertension, as evidenced in both FGR animals (79) and human cohorts (61). Central vessels, such as the aorta and carotid arteries, have increased wall thickness (80) and increased stiffness (81) in FGR humans and animals. The vascular changes described above persist into adulthood, however, they are more pronounced in peripheral vascular beds compared to central vascular bed (82).

Vascular compensation is observed in FGR offspring, wherein remodeling of the arterial wall, collagen and elastin content contribute to altered vascular mechanics (83). Rodent and guinea pig studies show that interruption of fetal growth in mid gestation coincides with a crucial period of elastin production within vasculature, attenuating elastin deposition and subsequently content, such that elastin is reduced and collagen increased (84, 85). This remodeling greatly impacts on vascular mechanics, as collagen is 100-times stiffer than elastin and, as a consequence, vascular stiffness is significantly increased (85). These changes in vessel biomechanics are most notably in the lower body arteries of growth-restricted offspring (83). Following low protein diet restriction, the aorta from adolescent rodents are not only stiffer, they also have increased fibrotic tendency, despite being normotensive (67). However, a more profound effect on vascular extracellular matrix remodeling is seen with placental dysfunction-induced growth restriction, compared to other factors such as diet (high fat) or fetal sex. These data are suggestive that vascular remodeling occurs primarily in response to changes in pressure and flow caused by chronic hypoxia and adaptive hemodynamic redistribution, rather than metabolic or hormone alterations.

Impact

The evidence presented above all indicates that exposure to placental insufficiency and chronic hypoxia significantly alters fetal development of the cardiovascular system. Unsurprisingly, the fetal cardiovascular alterations subsequent to placental insufficiency persist into clearly detectable structural and functional changes in the early postnatal period. After birth, tissue Doppler imaging (TDI) has allowed detection of persistent sub-clinical changes in movement and timing of the myocardium throughout the cardiac cycle, in particular during myocardial relaxation (86). In the first days of life, infants who were growth restricted show altered cardiac structure detectable on ultrasound with decreased sphericity index (a more globular shape), together with increased interventricular septum and left ventricle wall thickness (77). Further, load-dependent diastolic function is impaired (77, 87) this often represents impaired cardiac relaxation resulting in the transition from contraction to relaxation occurring prior to aortic valve opening, a situation which is common in hearts exposed to chronically high afterload. Frequently, FGR does not alter overall cardiac output, however components of cardiac output are altered with decreased stroke volume and increased heart rate often presenting in the FGR newborn (86). With increasing severity of FGR there is increased biomarkers of myocardiac cell damage, such as heart fatty acid binding protein (H-FABP), and incremental worsening of both systolic and diastolic dysfunction and in particular heart relaxation is altered (66). These alterations are indicative of hemodynamic compromise and are linked to worsening outcomes including fetal demise (88). Early signs of alteration in blood pressure in association with FGR remains contentious—we have documented increased blood pressure in the early postnatal period (80), whilst others show no change in blood pressure (82); these differences may reflect the difference between clinical and pre-clinical studies or the severity of the growth restriction induced.

In turn, in utero cardiac and vascular remodeling in FGR neonates programs for cardiovascular disease into adulthood. Indeed, the consequences of growth restriction on adult cardiovascular function are now well studied, and are central to the Developmental Origins of Health and Disease (DOHAD) hypothesis. These findings are apparent from both human epidemiological and experimental paradigms in growth-restricted offspring (76, 85) and adults (60). Long-term evidence of the link between low birth weight and developmental programming is available in the infants born in famine conditions in Europe in the 1900s wherein SGA is linked with significantly higher blood pressure in later life (89), and with increased risk of ischemic heart disease and cerebrovascular disease (90). Precursors of long-term suboptimal outcomes such as stroke and hypertension (91) have been proposed to be evident in growth restriction offspring as pre-atherosclerotic vascular damage in both newborns (92) and 18 month old FGR offspring (93).

Despite excellent evidence of the link between FGR and adult cardiovascular disease, there is some difficulty in dissociating the potentially separate effects of placental insufficiency/FGR and preterm birth. Growth restricted fetuses are often born preterm, particularly early-onset severe FGR infants, and preterm birth is also associated with adverse effects on the developing cardiovascular system (94). A recent study by Cohen et al. (87) followed both preterm and preterm FGR infants to 6 months of age to determine cardiac morphology. They found that changes in cardiac structure and function associated with preterm birth alone were sub-clinical, and normalized in childhood, while only thickened ventricular walls persisted into 6 months of age in FGR infants (87). This study goes some way to delineate the separate effects of prematurity and growth restriction and suggests a possible persistence of structural changes in FGR over and above the effects of prematurity.