Problems of definition and interpretation

One of the major reasons for the controversy surrounding the relationship of SGA to adverse neurologic outcomes is that infants who are considered SGA in one study are not deemed SGA in other studies (Goldenberg et al, 1989). In addition, some studies include only the most severely SGA infants, while in others the entire spectrum of SGA infants is included in the analysis. These differences in study population definitions are potentially magnified by the fact that even though most authors define SGA as including infants born below the tenth percentile birth weight for gestational age, the standards used to define this tenth percentile cutoff are very different from one study to the next. In addition, not only are different cutoffs used, but some standards are race- or sex-specific while others are not. Because female infants generally weight less than male infants do, studies not using sex-specific standards will have a larger proportion of the female population and a smaller proportion of the male population. Similarly, since black infants tend to weigh less than white infants, using standards that are not race-specific will identify more black infants than white infants as SGA. Not only are the standards different, but the gestational ages of the infants studied are often different as well. Since it is likely that preterm SGA infants will have different outcomes than term SGA infants, it is important to define the gestational age ranges in populations under study.

Infants with various types of chromosomal or structural anomalies tend to weigh less than normal infants (Jones, 1978). The SGA infant population, therefore, potentially includes more infants with chromosomal and structural anomalies than the control population. When studying neurologic outcome associated with SGA, it is important to define whether these infants are included or excluded from the study population. Similarly, it is important to determine whether infants who are severely disabled were included or not. As an example, infants with severe disabilities are often excluded from the population when minor neurologic disabilities or IQ scores are presented - potentially giving a falsely high impression of the cognitive or neurologic capacity of the entire SGA population.

Many study designs have been used to evaluate neurodevelopment outcome in SGA infants. One of the most common is a cohort study in which the entire birth population is evaluated prospectively and the outcome associated with being in the lower tenth percentile birthweight for gestational age is compared to either the entire non-SGA population or a representative sample. This type of study is labor-intensive, in that only 10% of the children are SGA, and the outcomes of interest, which may include cerebral palsy or some other relatively rare outcome, occur only occasionally. Therefore, these studies generally do not have sufficient power to define significant relationships between SGA and major but rare outcomes, which are dichotomous in nature. Instead, many of these cohort studies tend to look at continuous outcomes such as the mean IQ score.

A retrospective case control study is another type of study used to determine adverse outcomes associated with SGA status. In these studies, children with the outcome of interest such as mental retardation or cerebral palsy are first identified. Then the rate of SGA in the cases is compared to the rate of SGA in the control group, and the relative risk of the association between SGA and the neurodevelopment handicap is determined. This type of study provides much of the evidence for the relationship between cerebral palsy and SGA.

One major difficulty in dealing with adverse neurologic outcomes related to SGA is that the outcomes are not necessarily stable over the child's lifetime. As an example, minimal neurologic dysfunctions such as hyperactivity and poor concentration are not apparent early in the child's life, and poor school performance obviously cannot be determined until the child enters school. Some poor outcomes, such as hyperactivity, may improve over time. It is, therefore, very important to specify the age at which an adverse outcome is observed, and to make sure the study age is comparable between the SGA infants and their controls.

There are many neuro-development outcomes one could assess in relationship to SGA. The most frequently measured outcome is cognitive function, which is usually determined by an IQ test. The outcome of interest is either dichotomized into mental retardation defined by an IQ below 70 or 75, or is presented as the continuous variable of IQ. Abnormalities of motor function include cerebral palsy as well as various measurements of decreased fine and gross motor skills and clumsiness. Minimal neurologic dysfunction is often defined as a combination of hyperactivity, poor attention span, and clumsiness, often associated with poor school performance. Finally, another outcome of some interest is sensory impairment, particularly related to vision and hearing. Each of these outcomes, except cognitive function (which will be discussed in McGregor's paper), will be evaluated for its association with SGA status.

Before evaluating the specific outcomes associated with SGA, it is important to emphasize that many of the factors associated with, or causative for, SGA may have a direct effect on neurologic or sensory development, independent of their effect on fetal growth. As an example, many babies with chromosomal abnormalities are small for gestational age (Breart and Poisson-Salomon, 1988). These infants also have several different types of neuro-development handicaps, but it would seem inappropriate to consider their being SGA as causative for the neurodevelopment handicaps. Instead, the chromosome anomaly itself is likely responsible for both the SGA and the neuro-development handicap. Several other risk factors, such as congenital infection, various types of structural abnormalities, drug use, alcohol use, and smoking all may cause growth retardation and may cause neurodevelopment problems, but the growth retardation itself may not be in the causative pathway for the neurologic dysfunction.

Finally, it is extremely important to understand that being born SGA is only one factor of many which may contribute to neurodevelopment variability in childhood. These factors may include maternal intelligence, maternal education, socioeconomic status, home environment and attendance at preschool (Chard et al, 1993; Aylward et al, 1989; Breart and Poisson-Salomon, 1988; Allen, 1984; Goldenberg, 1996). Since at least some of the factors associated with the baby being born SGA also may influence the child's neurodevelopment functioning after birth independently of the risk factor's effect on infant size, understanding the direct causative relationship between being born SGA and a neurodevelopment problem later in life is often very difficult.

One of the very difficult issues dealing with adverse neurologic outcome in SGA infants is the relationship among SGA, hypoxia, and the adverse outcome. For example, it is often not clear if any specific poor neurologic outcome is related to the SGA or to an associated hypoxia. Conceptually, chronically poor placental function, is a cause of at least a portion of the SGA. If the SGA is caused by poor transport of essential nutrients and oxygen across the placenta, one can picture that poor fetal oxygenation, especially during labor, is a likely phenomenon. What is known, is that poor oxygenation and the resultant acidemia is seen more frequently in SGA infants than in other infants (Low et al, 1972). However, there is not a universally agreed upon definition for hypoxia, asphyxia, or acidemia. The nature of the association between these conditions and cerebral palsy, as well as other neurologic outcomes, is therefore currently under debate. The question that naturally arises is whether SGA infants who are not subject to decreased oxygenation in the perinatal period are at risk for poor neurologic performance.

In a study which addressed this issue, Berg (1989), using data from the National Collaborative Perinatal Project, found that in the absence of hypoxia-related factors, neither symmetric nor asymmetric IUGR children were at higher risk for neurologic morbidity compared to non-IUGR children at seven years of age. However, in the presence of perinatal hypoxia-related factors, IUGR children were more likely to be neurologically abnormal compared to non-IUGR children. Similar conclusions have been reached by a number of other authors, including Uvebrant and Hagberg (1992), who agreed that at least part of the increase in cerebral palsy in term SGA infants was associated with asphyxia. Other authors have confirmed that low ponderal index SGA infants generally had normal outcomes unless they were asphyxiated at birth (Low et al, 1978; 1982; 1992). Asphyxia more commonly occurred in primiparous women who develop severe preeclampsia and poor uterine blood flow, especially prior to term. This may be the reason that in certain studies SGA infants born in association with maternal hypertension were more likely to have low IQs and mild neurologic handicaps than were other SGA infants. Ounsted et al (1984) evaluated neurologic outcome in SGA infants at seven years of age or more, and noted that given good obstetric and neonatal care and a favorable environment in which to grow up, the outlook for normal development of SGA infants born in the 1970's was much improved over that for SGA children born earlier. At least part of this improvement has been associated with less asphyxial injury in infants born to preeclamptic mothers.

A related issue is whether SGA, which occurs solely on the basis of acute maternal nutritional deprivation, is associated with long-term neurologic deficiencies. One of the few natural experiments in which this issue can be evaluated, the Dutch famine during World War II, showed that there was no increase in adverse neurologic outcomes with nutritional deprivation alone (Susser and Stein, 1977). These data suggest that most of the adverse neurologic outcomes associated with SGA in otherwise healthy populations are due to non-nutritional causes.