Head growth spurt in SGA infants started earlier than in AGA infants. Head growth from birth to 35 weeks PMA was associated with the neurodevelopmental outcomes. Similarly, the catch-up growth of HC at 4 months CA was significantly associated with better neurodevelopmental outcomes. Failed catch-up growth of any of the three growth parameters at 9 and 18 months CA showed worse neurodevelopmental outcomes. Antibiotics usage and feeding tolerance were significantly associated with subsequent head growth.
This study revealed different growth patterns between SGA and AGA infants from birth to 18 months CA(Fig. 2). Compared to AGA infants, the degree of postnatal HC Z score drop was less in SGA infants; additionally, Z-score of HC at 40 weeks PMA reached that at birth in SGA infants while it remained decreased in AGA infants. This suggests that there is an earlier spurt of head growth in SGA infants than in AGA infants, which was consistent with the study findings of Brandt et al. showing a sensitive period for catch-up growth of HC only during the phase of rapid growth in SGA preterm infants [14]. In the analysis of the relationship between growth failure and NDI at each time point, head growth failure from birth to PMA of 35 weeks was associated with more NDI. It can be interpreted that the characteristic early head growth observed in preterm SGA infants (Fig. 2) was related to subsequent neurodevelopment [19]. While head growth between birth and 35 weeks PMA exhibited overall downward growth, the trajectory was of relevance to neurodevelopment.
There have been debates on the significant timing of head growth, which affects neurodevelopment in SGA infants. Belfort et al. explored the associations of growth from 1 week of age to term, term to 4 months, and 4 to 12 months with Bayley Scales of Infant Development (2nd edition) at 18 months. Unlike our results, poor head growth had no effect on NDI at any time point in their SGA subgroup [8]. The SGA definition and the time point of neurodevelopmental assessment in their study were similar to those of our study; however, they used the previous version of Bayley Scales and included 50 SGA infants. Leppänen et al. observed that among seven periods within 2 years of age, only optimal head growth around term age was beneficial for SGA infants, which is similar to our results [2].
Similarly, the relationship between growth and development was analyzed regarding the attainment of the 10th percentile at a particular time point. By 4 months CA, only head growth that did not reach the 10th percentile was associated with worse neurodevelopmental outcomes (Table 3). By 9 months CA and onwards, failed catch-up growths in length, weight, and HC were all associated with poor outcomes. This information can aid the establishment of growth goals and the definition of the population with poor developmental prognosis by clinicians in the course of following up preterm SGA infants. It was difficult to compare the study results with those of previous studies because of variations in the definition of SGA, time points of growth assessment, and outcome. Frisk et al. observed that SGA infants with optimal postnatal head growth until 9 months CA demonstrated better cognitive development at 7–9 years [15]. Nine months CA was the first time point of growth assessment after term age, and the definition of SGA was less than 2SD. Brandt et al. showed that optimal head catch-up growth until 1 year showed benefits to the intelligence scores in SGA infants [14]. They explored longer-term cognitive outcomes; however, only 46 SGA infants were enrolled (< 10th percentile), and growth parameters before 1 year were not examined.
Because failed head growth catch-up was shown as a consistent risk factor for NDI after 4 months CA, the clinical factors during NICU stay, which were related to poor head growth by these time points, were sought. Days of antibiotics usage and days to full enteral feeding were associated with head growth (Table 4). Days of antibiotics usage may reflect the period during which the infants experienced inflammation. Inflammation is considered one of the important risk factors of growth restriction in the perinatal period. The growth rate was observed to be negatively correlated with C-reactive protein, erythrocyte sedimentation rate, and Interleukin (IL)-6. In a mice study, a decrease in insulin-like growth factor-1 (the synthesis of which is stimulated by growth hormones) was observed in transgenic IL-6 overproducing mice [25]. Similarly, inflammation is related to head growth. Elevated concentrations of inflammation-related proteins in early postnatal blood specimen provided information about an increased risk of microcephaly 2 years after [26] and impaired mental and motor development at 2 years of age in extremely preterm infants [27]. Days to full enteral feeding may indicate the general clinical complexities as well as the nutritional status of an infant. The duration (in days) of antibiotics usage and days to full enteral feeding could be potential targets for improving neurodevelopment in preterm SGA infants; however, a causal relationship between them cannot be concluded from this study.
The strengths of this study are as follows: we focused on the growth and development of preterm SGA infants; the growth was analyzed using both an absolute criterion, the attainment of 10th percentile and a relative criterion, Z-score changes. The growth parameters were examined at multiple time points before 1 year CA and information was provided on the contemporary preterm SGA population. On the contrary, the limitations of our study include its retrospective design, which led to the exclusion of many infants because of missing Bayley-III data. However, Bayley scales were recommended for preterm infants with gestational age < 32 weeks or birth weight < 1500 g in our follow-up clinic without any medical or social consideration.