Paediatric consequences of fetal growth restriction

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Abstract

The evidence for outcome following fetal growth restriction (FGR) has previously been inferred from studies, based on babies who were born small for gestational age (SGA). Great care is required when evaluating studies in this area due to a number of potential confounders. It does appear, however, that FGR is associated with an increased risk of poor neurological outcome. This includes an increased risk of cerebral palsy in babies greater than 32 weeks' gestation. Below 32 weeks, the effects of prematurity appear to negate the effects of FGR. FGR is also associated with cognitive deficit and behaviour problems. Babies with poor prenatal head growth appear to have a worse cognitive outcome. However, the role of ‘fetal brain sparing’ remains unclear, as impaired cognitive outcome is still evident in babies with appropriate head growth. Recent studies, which have identified FGR more accurately using fetal growth standards, have found an increased incidence of major intracranial injury and other adverse neonatal outcomes, which had previously been thought to occur less frequently in FGR babies. FGR is also associated with poor postnatal growth. The majority of children with FGR demonstrate catch-up growth in the first 2 years of life. Children who fail to demonstrate catch-up growth have a high risk of long-term growth problems. There is evidence of impaired growth hormone activity in some children with FGR who have persistent poor growth in the postnatal period.

Introduction

Our ability to accurately identify a fetus that is failing to thrive in utero is a relatively recent development. Most studies describing paediatric outcome in babies with what is often called ‘intra-uterine growth retardation’ (IUGR) have identified their subjects postnatally, using definitions of ‘light for dates’ or ‘small for gestational age’ (SGA), and a variety of cut-offs. This makes interpretation of the literature particularly difficult, as being SGA is different from birth following fetal growth restriction (FGR). The growth-restricted fetus is one that fails to grow at a predicted rate, usually due to environmental factors. In contrast, SGA is a statistical description of the birth weight of babies born at a particular gestational age. This definition will include babies who have appropriate intra-uterine growth but happen to be small due to the interplay of a number of genetic and physiological factors, such as their sex, maternal height and weight in early pregnancy, parity and ethnic group. Furthermore, some babies with growth restriction, who might otherwise have been relatively large, will miss detection because their birth weight remains above the arbitrarily chosen percentile, despite impaired growth.

The current techniques of fetal growth assessment and the use of customized fetal growth charts1 help to identify the babies with growth restriction more adequately. Future studies of childhood outcomes following FGR must address these methodological issues.

There are a number of other potential confounders to be considered when assessing the available data. Poor outcome can be underestimated significantly if associated mortality is not considered. Perinatal mortality is higher at each gestational age in SGA babies compared with ‘appropriate for gestational age’ (AGA) babies.2 Furthermore, obstetric interventions (i.e. delivery at different points in the evolution of FGR) may alter the balance of mortality in these groups. In the Growth Restriction Intervention Trial (GRIT), immediate delivery was associated with higher neonatal mortality and deferred delivery was associated with increased fetal death.3 Thus SGA survivors, being a mix of ‘small normal’ babies and babies exposed to an adverse intra-uterine environment, might represent a self-selected group and appear to do better than AGA babies. It is critical, therefore, that the appropriate denominator is chosen for sample groups in any study.

It is likely that FGR of different aetiologies will have different outcomes. Several studies seek to ensure they have comparable groups by excluding particular populations such as chromosomally abnormal children, multiple births or children with recognized congenital infection.4, 5 Systematic investigation of the ‘causes’ of being SGA is no longer fashionable because of poor return; exclusion in cohort studies can only be justifiable if such screening is undertaken.

Differences in perinatal care may also influence outcome. The timing of delivery with respect to the progression of FGR on mortality has been noted above. Very preterm fetuses with FGR are usually the subject of close obstetric surveillance, elective delivery and may be more likely to have received adequate predelivery treatment with steroids6 compared with an unselected preterm population.

Finally, the gestational age of a baby may be critical to the identification of adverse outcomes. Problems of prematurity, which are much more prevalent at lower gestations, may overwhelm less severe effects of FGR. Cohort studies that match by birth weight are thus fundamentally flawed, as the comparison of mature children who are SGA against preterm children of equivalent birth weight is inappropriate.

Against this background, great care is required when evaluating studies in this area. Due to the nature of the development of FGR, prospective cohort studies (with clear denominator definition) and randomized controlled trials of interventions are most likely to shed light on this complex area.

Section snippets

Neurological outcome

Most studies assessing neurological outcome in the growth-restricted or SGA population are retrospective. Adverse neurological outcomes, such as cerebral palsy (CP), occur infrequently and cannot be diagnosed reliably until children are several years old. To investigate these outcomes by prospective studies requires large sample sizes and long-term follow-up and so are often prohibited by cost. Retrospective studies on the other hand, although good for investigating rare specific outcomes, are

Risk of CP

Several studies have found an association between low birth weight for gestational age and an increased risk of CP. Studies vary in the way they define CP. Some studies have looked at specific types of CP only, whilst others have used a wider definition. The risk of CP appears to be highest in preterm SGA children whose gestation at birth was greater than 33 weeks.7, 8

In the classic prospective National Collaborative Perinatal Project (NCPP) in the USA, 54 000 children born between 1959 and

Type of CP

In the NCPP data reported by Ellenberg and Nelson, the increased risk of CP in term SGA infants was only significant for the spastic diplegia type.9 The SCPE group, however, reported an increased risk of all types of CP (unilateral or bilateral spasticity, dyskinetic and ataxic CP) in term SGA children. Despite the small number of cases of dyskinetic or ataxic CP, they found the same pattern of increasing prevalence with decreasing birth weight Z score for all types of CP.11 Uvebrant and

Incidence of major intracranial injury

Early studies evaluating the effect of IUGR on major intracranial injury such as intraventricular haemorrhage (IVH) or periventricular leucomalacia in preterm infants suggested that SGA was associated with a reduced incidence of these complications compared with AGA.13, 14 However, more recent studies have either shown no difference15, 16 or an increased incidence of IVH.17 The study by Zaw et al.17 used fetal growth standards to identify infants who were SGA. When they used neonatal growth

Cognitive/neurodevelopmental outcome

There is evidence to suggest an association between poor prenatal head growth (symmetric IUGR) and poor developmental outcome.19, 20, 21 The neurodevelopmental outcome for children with what is euphemistically known as ‘fetal brain sparing’ (asymmetrical IUGR) is less clear cut. Using data from the NCPP (1959–1976), a total of 2719 term infants whose birth weight was less than 2500 g (SGA) were compared with the remaining population of 43 104 term infants who were not small for dates. The

Behavioural problems

Hawdon et al.33 assessed a group of 38 singleton males of 36–42 weeks' gestation at birth and birth weight below the second percentile in a 10–11-year outcome study. They used similar assessment techniques to a previous study by Neligan et al.34 that also assessed a cohort of SGA children in the Newcastle area. When compared with controls who were matched for social class, they found a significant increase in behavioural problems of the attention-deficit-hyperactivity type in the SGA children.

Causes of poor neurological outcome in FGR

Although there is good evidence to suggest an increased risk of poor neurological outcome due to FGR, the mechanisms by which this occurs are less well understood.

  • It is plausible that growth restriction mediates a poor outcome through a direct effect on brain growth or through some other intervening factor.

  • Alternatively, damage to the developing brain might induce an abnormal growth pattern through endocrine or other pathways.36

  • It is also possible that growth restriction increases a child's

Effects on childhood growth

Studies of outcome in children known to have been SGA show that they have a high incidence of failure to thrive. In one series of 914 preterm infants with low birth weight, the reported incidence of failure to thrive was 19.7% at 30 months of age.39 It is also estimated that about 15–20% of infants with growth restriction have short stature at the age of 4 years40 and 7.9% are still short at 18 years of age.41 It is usual for SGA infants born at term to experience catch-up growth during the

Causes of poor postnatal growth in infants with FGR

The mechanisms by which catch-up growth occurs or the factors associated with a failure of catch-up growth are not fully understood. SGA infants have been found to have high serum growth hormone levels.46 Moreover, a significant proportion of children (up to 60%) who fail to achieve catch-up growth have disturbed growth hormone (GH) secretion and low serum IGF-1 concentrations.47 It is thus likely that catch-up growth may result from increased production of growth factors. A number of

Conclusions

Outcome studies of FGR suggest an association with neurodevelopmental disability including CP, cognitive deficit and behavioural problems. The group most at risk of CP appears to be term or moderately preterm babies (over 32 weeks of gestation). Outcome for more preterm children who are exposed to FGR is complicated by the high prevalence of adverse outcome for the population as a whole, from which it appears to be difficult to separate out the effects of FGR.

Infants with IUGR can be expected

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