Factors Associated with Catch-up Growth in Term, Asymmetrical Small-for-Gestational Age Infants in the First Year of Life

Introduction Catch-up growth (CUG) in small-for-gestational age (SGA) infants is essential for their overall development. Knowledge about the factors influencing CUG might be critical in their effective management. Hence this study was performed with the aim of identifying factors that may influence CUG in SGA infants. Methods Asymmetrical SGA infants born at term were included in the study as per defined criteria, and their demographic details were recorded. Anthropometric data, feeding practice details, and intercurrent illnesses data were collected on follow-up at 6 weeks, 6 months, and 12–15 months of age. Catch-up growth weight was defined as improvement of weight to the normal range of −2 to +2 weight-for-age Z score (WAZ). Analysis was carried out using SPSS Expand 17 software. Chi-square test was used to find association between variables. Logistic regression analysis was used to measure effect. A P value of less than 0.05 was taken as significant. Results Out of 324 SGA infants born at term, 119 completed 12–15-month follow-up, of which 69.7% had achieved CUG weight. Exclusive breastfeeding >4 months, continued breastfeeding until 12–15 months, and absence of diarrheal episodes were positively associated with CUG. Pregnancy-induced hypertension, gestational diabetes, and maternal overweight/obesity were negatively associated with CUG. Maternal education status, conception age, gravida status, mode of delivery, vitamin D and iron supplementation, and intercurrent respiratory infections were not associated with CUG. On multivariate analysis, continued breastfeeding and absence of diarrheal episodes were independent factors associated with CUG. Conclusion Breastfeeding practice, especially continued breastfeeding, and the absence of diarrheal illness are the key determinants for achieving CUG weight in term SGA infants, particularly in settings where resources are limited.


INTRODUCTION
Catch-up growth (CUG) is the acceleration in growth that occurs postnatally in babies born small for gestational age (SGA). Weight catch-up is the decrease in the weight deficit between the individual and the reference mean for a healthy population that occurs over time. There are no international standards for definition of catch-up growth. 1 One of the relative definitions of catch-up is improvement of weight to the normal range of -2 to +2 weight-for-age Z score (WAZ). 2 Catch-up growth in SGA infants is associated with better neurobehavioral outcomes, 3 prevention of metabolic consequences of early intrauterine growth retardation, 4,5 prevention of persistent short stature, 6 and better immune function. 7 Correct understanding of the factors that positively and negatively influence CUG is vital for the appropriate management of SGA infants. The aim of this study was to follow up asymmetrical SGA babies born at term, once at 6-8 months, and again at 12-15 months of age, to identify factors associated with failure to achieve CUG.

METHODS
This prospective cohort study was done with the approval of the Institutional Ethics Committee in the well-baby clinic of the Department of Paediatrics in a university teaching hospital in South India. The parents of SGA term infants born between August 2015 and July 2016 signed a written informed consent when their infants were 6-8 weeks of age, and indicated a willingness for the infants to undergo follow-up until 12-15 months of age. Infants were excluded if they had congenital malformations, length for gestational age less than the 10th centile at birth, chronic systemic illness, and neonatal intensive care unit hospitalization for more than 2 days. The mothers' demographic and pregnancy details were obtained from their hospital records. Socioeconomic status was classified according to the Modified Kuppuswamy Scale. 8 Birth anthropometry was noted from the discharge summary. The infants were followed up at 6 months and 12-15 months of age.
At each follow-up visit, the infants' anthropometric measurements (weight, length, head circumference) were taken by a trained nurse in triplicate, and the average of the three readings was noted. Nude body weight was recorded using an electronic weighing scale to the nearest 5 g. Length was recorded using an infantometer to the nearest 0.1 cm, and the occipitofrontal circumference was measured using a non-stretchable tape measure. Anthropometry measurements were plotted on WHO growth charts. At 6 weeks, the infants were started on oral vitamin D drops (400 IU/day) and at 6 months on iron drops (elemental iron 1 mg/kg/day) and advised to continue until the final 12-15-month visit. At each subsequent visit, details regarding feeding, compliance to iron and vitamin D administration, and intercurrent illnesses were noted. The mothers' height and weight were also measured at the final 12-15month visit to assess the effect of maternal nutritional status in CUG of their infants.
Study definitions used were as detailed in Table 1.
Data were analyzed using SPSS Expand 17 software. Chi-square test was used to find associations between variables. Variables which had significant association with achievement of CUG were noted, and the odds ratio (OR) was calculated. Those with a significant association were then analyzed with logistic regression model, and adjusted odds ratio was calculated to identify the independent variables. A P value of less than 0.05 was taken as significant.

RESULTS
There were 3,113 live births in the enrollment period, of which 324 were term SGA (10.4%). Of these, 180 SGA infants (104 boys, 76 girls) were enrolled at 6-8 weeks; 143 (86 boys, 57 girls) completed the 6-8-month follow-up, and 119 (62 boys, 57 girls) completed the 12-15-month follow-up ( Figure 1). A WAZ score greater than -2 was achieved by 6 weeks in 41%, at 6 months in 79.8%, and by 12-15 months in 69.7% of the study group. Throughout the followup period, all children had a length and head circumference for age Z score of +2 to -2; at no time did the Z score exceed +2.
The clinico-sociodemographic factors associated with weight for age catch-up at 1 year were analyzed ( Table 2).
Among the mothers, 55.5% were less than 25 years of age at the time of conception, 79.8% had a graduate education, 67.2% were primipara, and 62.2% had a normal vaginal delivery. There was no significant relationship between any of these factors and CUG in their infants. Overall, 32.8% mothers were either overweight or obese at infant age 12-15 months. Maternal overweight/obesity was significantly higher in the failed versus achieved CUG infants (50% versus 25.3%, respectively; P value 0.008). Respiratory infection Based on both clinical findings and official diagnosis Small for gestational age (SGA) Birth weight less than 10th percentile for gestation as per Intergrowth-21st charts 10,11 Term 37 completed weeks as assessed by pregnancy dating scan The occurrence of pregnancy-induced hypertension (PIH) was higher among the failed versus achieved CUG infants (27.8% versus 12%, respectively; P value 0.035), as was gestational diabetes mellitus (GDM) (25% versus 10.8%, respectively; P value 0.048), and the difference was statistically significant.
Overall, exclusive breastfeeding (EBF) for less than 4 months was found in 70 infants (58.8%). Only 12 infants (overall 10.1%) were maintained on EBF for 6 months. The prevalence of EBF for >4 months was significantly greater in achieved versus failed CUG infants (50.6% versus 19.4%, respectively; P value 0.002). Breastfeeding together with complementary feeds was continued through to the 12-15month follow-up visit by 74 mothers (62.2%). This practice of continued breastfeeding was significantly associated with CUG in the achieved versus failed infants (86.7% versus 5.6%; P value <0.0001, re-spectively). Although there was good compliance to vitamin D and iron supplementation in 33.6% and 36.9% of infants, respectively, there was no significant association between good compliance and CUG. Anemia was found in 66.4% of the children at the 12-15-month visit, with no significant association between anemia and CUG. By 12-15 months of age, 73.1% of the children had experienced one or more episodes of diarrhea; the proportion of children with diarrhea was significantly lower in achieved versus failed CUG (63.9% versus 94.4%), respectively; P value 0.001). However, there was no significant difference in the proportion of infants with respiratory infection in either group (P=0.07) ( Table 2).
On multivariate analysis of risk factors, continued breastfeeding until 12-15 months and absence of diarrheal episodes were found to be independent factors associated with CUG (Table 3). On further

DISCUSSION
In the present study, 69.7% of SGA infants achieved CUG in weight at 12-15 months of age. We also studied the maternal-infant factors associated with weight CUG. Absence of antenatal risk factors, EBF for 4 months, continued breastfeeding until 12-15 months, and fewer diarrheal episodes in the first 12-15 months were favorably associated with CUG. However, on multivariate analysis, continued breastfeeding until 12-15 months and absence of diarrheal episodes were the only two independent factors associated with CUG.
There was no significant association between CUG and other maternal factors (mother's age at conception, education, gravida status, and mode of delivery) or infant factors such as gender, mode of delivery, or number of respiratory infections during infancy.
Maternal PIH or GDM were more prevalent in the failed CUG infants. Previous studies have shown that CUG is not influenced by antenatal factors. 12,13 The association found in our study may be attributed to the severity of antenatal medical conditions and other confounding factors such as maternal age, pregnancy weight gain, or parity, although no significance was noted via multivariate analysis. Similar observations of breastfeeding being a key factor influencing CUG, independently of confound-ing factors, have been made in previous studies. [14][15][16] This breastfeeding practice also influences the incidence of intercurrent infections, particularly diarrheal episodes. It is well known that diarrheal episodes have a negative impact on the nutritional status of infants. 17 The overall EBF rate until 6 months in our study group was 10.1% as compared to the national average of 50%. 18 This may be due to maternal anxiety regarding low birth weight and postnatal weight gain, which prompted early introduction of complementary feeds. However, this is purely conjectural as we did not probe into the reasons for early initiation of complementary feeds in our study.
Vitamin D and iron supplementation did not have an impact on CUG. It is well established that these are type 1 nutrients which, when deficient, cause characteristic clinical symptoms associated with the dysfunction of a particular biochemical pathway, and are unrelated to growth failure. 19 Growth restriction in SGA can occur in the first or later trimesters. Restricted growth in the later trimester is mainly due to maternal factors and an unfavorable intrauterine environment. This pattern of growth restriction results in asymmetrical intrauterine growth restriction. After delivery these babies are expected to achieve CUG. However, multiple external factors may influence it.
The demographic profile and socioeconomic and cultural factors for all study participants who completed final follow-up were similar and did not change during follow-up. A major limitation of the study was the attrition rate and failure to follow up all recruited infants, which can be considered as attrition bias. However, we assume that this bias might not have affected the study results as attrition was for social reasons and not intentional. The primary reason for follow-up failure was migration of the mother-infant duo owing to the local cultural practice of having the delivery in the mother's place of pre-marriage residence, and moving back to her husband's residence after 3-5 months. Another limitation is that this observation was made in a developing country, with most of the families belonging to the lower middle socioeconomic class, and the results cannot be generalized for developed countries.

CONCLUSION
Overall, 69.7% of term SGA babies showed CUG according to the WAZ score at 12-15 months. The independent factors associated with CUG were continued breastfeeding until 12-15 months and the absence of diarrheal episodes during the study period. These findings are from a resource-limited setting and cannot be generalized for all countries.