Catch-up growth in low birth weight infants

INTRODUCTION

Growth is a complex process, regulated by genetic, environmental, and metabolic factors. Following birth, maximum growth is seen in infancy which paves the foundation for future growth and development. Linear growth velocity declines gradually from infancy to early adolescence, which is then followed by a pubertal growth spurt, and subsequent gradual cessation as the growth plates undergo fusion. Growth velocity of an individual is typically maintained within a narrow channel on growth charts from 3 years till puberty. While short-term fluctuations in growth can occur due to seasonal factors, over the long-term, an individual’s growth curve typically aligns with the centile curves of growth charts, a phenomenon known as “canalization”. Periods of illness or malnutrition can result in slowed growth and downward shifts on growth curves, acting as a physiological mechanism to conserve nutrients. However, once recovery occurs, growth velocity often rebounds, sometimes surpassing normal rates, leading to upward crossing of centiles, a phenomenon known as catch-up growth (CUG).^[1-4] While the advantages of CUG are evident, there are also some drawbacks, particularly concerning the rapid postnatal growth in infants with fetal growth restriction. Over the past several decades, both observational and experimental studies have enhanced our understanding of these adverse effects and highlighted the need for monitoring growth, especially when there is an upward crossing of centiles.^[5,6] Therefore, monitoring and implementing appropriate interventions to optimize growth during infancy and early childhood is crucial for improving long-term health outcomes. In this paper, we explore the definition, physiology, benefits, and drawbacks of CUG during infancy.

Case: A 10-year-old girl, presented to the clinic with concerns of early menarche and progressive weight gain since early childhood. The girl was the first-born child of a non-consanguineously married couple. The antenatal period was complicated by pregnancy-induced hypertension, and pregnancy was terminated at 35 + 5 weeks gestational age due to severe preeclampsia. The baby weighed 1.86 kg at birth, and had a smooth perinatal transition. She was exclusively breastfed for 6 weeks, after which supplementary feed was initiated as the mother perceived her milk to be insufficient for the baby. During her 6-months’ vaccination, the parents were reassured that the baby was growing well and the weight for length was at the 75^th percentile, as per the World Health Organization (WHO) 0–5 growth charts. From the age of 6 years, the parents observed that she was gaining weight excessively when compared to her peers; however, no medical opinion was sought at that point. She developed thelarche, axillary and pubic hair with apocrine body odor at 8 years of age. She was now brought to the clinic as she attained menarche about 1 month ago. On examination, her weight, height, and body mass index were 42 kg (+1.34 standard deviation score, SDS), 138 cm (+0.08 SDS), and 22 kg/m² (+1.67 SDS) respectively [Figure 1]. She had acanthosis nigricans, thelarche Tanner stage 4, pubic hair stage 5, blood pressure of 126/80 mmHg, and systemic examination was unremarkable.

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Figure 1:

Growth trajectory of the girl in Case 1 plotted on Indian Academy of Pediatrics (IAP) 2015 growth chart for girls.

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Laboratory investigations showed a fasting glucose level of 88 mg/dL, insulin level of 22 mU/mL, total cholesterol level of 176 mg/dL, low-density lipoprotein level of 132 mg/dL, and triglyceride level of 210 mg/dL. Alanine aminotransferase and aspartate aminotransferase levels were 72 U/L and 68 U/L, respectively, and an ultrasonogram of the abdomen showed grade I fatty liver.

The clinical scenario highlights the complex interplay between low birth weight (LBW), growth trajectory, and metabolic risk. Early nutritional excess during CUG could predispose the child to adiposity and insulin resistance, ultimately culminating in obesity and features of metabolic syndrome by adolescence. In girls, small for gestational age (SGA) with early CUG is often associated with early pubarche, thelarche, and menarche, and in a few girls, this may be associated with a higher risk of polycystic ovarian syndrome as well.

DEFINITION OF CUG

The term “catch-up growth” was coined by Prader et al. in 1963 to define the period of rapid linear growth that occurs in children following periods of growth inhibition due to illness or starvation.^[7] Although this term is mostly used for weight and length, CUG can be seen with other anthropometric parameters, fat and fat-free mass as well.^[8] CUG is generally defined as a physiological increase in the weight-for-age (WFA) Z-score following a period of “growth faltering”, eventually returning to the initial WFA Z-score.^[9] Recent consensus guidelines on long-term follow-up of infants born SGA define CUG as the growth rate (cm/year) of >0 SDS, i.e., more than the median for age and sex.^[10] The main purpose of CUG is to take the child toward his/her pre-retardation growth curve as per their genetic potential. It is a physiological phenomenon that is driven by inherent stimuli such as increased hunger during recovery from illness, or even better breastfeeding behavior in healthy full-term infants born SGA. However, in case of infants, especially those born LBW due to prematurity or even SGA, in whom feeding is primarily regulated by the caregivers, the nutritional guidelines are not well-defined. Well-meaning parents often end up top feeding and using calorie-dense feeds in their efforts to achieve a rapid increase in weight, often resulting in excessive CUG. There is some evidence to suggest that over-feeding in infancy may possibly lead to a programming effect that leads to habitual over-riding of hypothalamic satiety cues later.^[11,12] The recent consensus guidelines for SGA advise against excessive weight gain (defined as a change in weight-for-length [WFL] Z-score exceeding 0.67 SDS, which involves crossing of weight SDS lines upward), especially in early life.^[10]

CUG IN INFANCY

CUG in infancy or faster postnatal growth is often seen in infants born at a centile below their genetic potential. Although more often seen in babies born LBW due to prematurity or intrauterine growth restriction (IUGR),^[16-18] this phenomenon is not limited to these conditions alone. Jain et al., in a prospective cohort study of healthy term infants observed that approximately two-thirds of healthy term infants experienced either CUG or CDG in weight as well as length (defined as change in Z-score of >+0.67 or >−0.67, respectively) from birth to 2 years of age, with only a third maintaining a relatively stable growth pattern. The chief determinants of CUG or CDG in weight were birth weight and calorie intake, while for length, the main determinants were both parents’ height.^[14] The study highlighted that CUG may not be restricted to LBW infants, but may represent accelerated growth related to nutritional excess in a proportion of babies. Another conclusion was that genetic potential is an important determinant of length gain in the first 2 years.^[14] Similar conclusions were also drawn by other authors from Indian studies.^[19-22] Chrestani et al., in their systematic review, found that primiparity, LBW, early weaning, and formula feeding were significantly associated with postnatal growth acceleration.^[23]

BENEFITS OF CUG

CUG has been described not just in humans, but also in other mammals, birds, and fish as well, suggesting it to be an evolutionary adaptive response to environmental cues to improve survival and maximize reproductive fitness.^[24] CUG decreases the prevalence of undernutrition, stunting, and infections during early life. It has also been seen to improve neurocognitive outcomes in preterm infants.^[25] In a study by Victora et al., infants born SGA with catch-up weight gain of ≥0.66 Z-score had 65% lower hospital admissions rate at 20 months of age compared to infants with weight gain of ≤0.65 Z-score. Similarly, infants who showed good weight gain by 2 years of life were found to have 75% lower mortality by 5 years when compared to those infants who did not demonstrate similar weight gain.^[26] Takeuchi et al. found that term SGA infants with poor CUG were at increased risk of motor, language, and social developmental delay at 2.5 years of age, and aggressive behavior at school age.^[27] Similar findings have been reported by Varella et al., Yang et al. and Lei et al.^[28-30] Franz et al., in a longitudinal study in extremely preterm infants (<30 weeks and <1500 g), found that CUG in weight and head circumference from birth to hospital discharge was associated with better cognitive and motor development at 5 years of age.^[31] A systematic review by Ong et al. found a positive correlation between CUG in head circumference or weight and neurocognitive outcomes.^[32]

ADVERSE EFFECTS OF CATCH-UP GROWTH

Despite all its benefits, CUG has its downside too. The long-term adverse effects of postnatal growth acceleration were first described by McCay in 1930, when he demonstrated that postnatal growth acceleration in rats led to increased risk of chronic diseases and decreased their life span by 35%.^[33] Similar observations were reported by Eid in the 1970s in humans.^[34] Since then, multiple randomized controlled trials, systematic reviews, and meta-analyses have found the association between early postnatal growth acceleration and increased risk of obesity, metabolic syndrome, and cardiovascular events in adulthood in both high- and low-income countries. Such association has been seen in terms as well as preterm, small, as well as appropriate for gestational age (AGA), and breast-fed, as well as formula-fed babies.^[35-38]

Khandelwal et al., in a prospective study of term LBW infants, found that early CUG (in the first 6–12 weeks) was associated with higher body fat at 7 months of age.^[39] In another study by Jain et al., amongst term infants followed up till 2 years of age, those infants who had CUG in weight between 0 and 2 years had higher fat mass (FM) percentage (assessed by deuterium dilution technique) at 2 years compared to those who did not have CUG.^[40] Ou-Yang et al., in a systematic review, concluded that premature babies with accelerated weight gain during the first 2 years of life had a greater risk of childhood and adolescent obesity.^[41]

Few authors have found a significant link between early CUG in terms of LBW infants and increased incidence of wheezing in childhood. It is hypothesized that a lag in growth of lungs as compared to somatic growth, and the adverse effects of pro-inflammatory cytokines released from excessive adipose tissue, might lead to airway remodeling and hypersensitivity.^[42] Den Dekker et al., in their systematic review, found that LBW, prematurity, and CUG in infancy were associated with poor lung function and risk of childhood asthma. They observed that infants with faster weight gain in infancy had higher forced expiratory volume in 1 s (FEV1), but lower FEV1/forced vital capacity ratio and forced expiratory flow after exhaling 75% of vital capacity in childhood.^[43]

PATHOPHYSIOLOGY BEHIND THE ADVERSE EFFECTS OF CUG IN INFANCY

Conventionally, CUG has been viewed from the context of meeting anthropometric targets and their outcomes with respect to metabolic disease. However, with advancements in body composition measurement techniques and biomarkers for the measurement of adiposity and inflammation, our understanding of the adverse effects of accelerated CUG in infancy has evolved over the last two decades.

Based on animal models, several mechanisms have been proposed to explain the pathophysiology behind these adverse effects. The thrifty catch-up fat hypothesis, the role of insulin-like growth factor-I (IGF-1) in the development of insulin resistance, the role of beta-3 adrenoreceptors in adipose tissue, and epigenetic alterations in genes modulating lipogenesis give some foundational evidence to our understanding of the etiological basis of poor metabolic outcomes in children experiencing accelerated CUG in infancy.

STRATEGIES FOR OPTIMIZING CUG

To effectively address growth faltering that occurs during the fetal period and infancy, strategies for achieving an appropriate CUG must be comprehensive and primarily depend on the timing (prenatal/postnatal) and the underlying causes of growth deceleration. Therefore, we discuss management strategies in the context of infants born SGA/ LBW and those experiencing growth deceleration in the postnatal period. During infancy, errors in infant feeding may occur at two critical junctures. The first is within the initial 6 months, a period during which exclusive breastfeeding is recommended, and, second is during the subsequent 6 months, when complementary feeding is introduced.

A significant contributor to reduced weight gain in early infancy is inadequate breastfeeding, and premature introduction of complementary feeding using improperly diluted formula. In addition, bottle feeding, unsanitary feeding practices resulting in frequent diarrheal illnesses, and misconceptions about complementary feeding further complicate the situation. Therefore, educating families about the importance of breastfeeding and appropriate feeding practices from the antenatal period is essential. A clear communication strategy during immunization and postnatal follow-up visits about breastfeeding and weaning diets in keeping with the cultural and social contexts needs to be carried out.

Given higher nutrient requirement of preterm infants, the current recommendation is to fortify expressed breast milk or donor human milk with standard human milk fortifiers or multi-nutrient fortification in preterm LBW infants with birth weight <1800 g and receiving enteral feeds of at least 50–80 mL/kg/day to achieve optimal weight gain (15–20 g/kg/day).^[63,64] In resource-limited settings, fortification should focus on preterm LBW infants who fail to gain weight despite adequate breastfeeding. In terms of LBW infants, WHO recommends exclusive breastfeeding or standard formula feeding rather than nutrient-enriched formulas till 6 months of age. Human milk fortifiers (preferably human milk-based) should be considered for term babies with birth weight <1500 g, who fail to gain weight despite adequate breastfeeding, as this intervention reduces malnutrition, infections, and mortality in infancy.^[64,65]

The initiation of weaning at 6 months presents a challenge for parents regarding appropriate dietary choices for their infants. Frequently, parents encounter a multitude of opinions from relatives and social media concerning suitable and unsuitable foods for their child. This confusion often results in mothers resorting to commercially packaged infant supplementary feeds for weaning, even in economically constrained circumstances. Parents need to be educated about various recommended complementary food group options, such as combinations of cereals and pulses, fruits, and milk-based cereal preparations. In addition, it is crucial to emphasize the importance of avoiding packaged food items, including biscuits, fruit juices, and commercial breakfast cereals. The Indian Academy of Pediatrics offers a comprehensive guideline for parents on complementary feeding recommendations for infants over 6 months, specifically tailored to the Indian context.^[66]

Proper infant nutrition during the early stages of life also requires avoiding overfeeding of the baby. Infants born LBW are particularly susceptible to overfeeding, the use of commercial infant formula for supplementary feeding, and the premature introduction of complementary foods. It is imperative that parents are informed that commercial infant formula and cereal preparations do not confer additional benefits in enhancing growth or long-term developmental outcomes in infants. The recent controversy regarding the inclusion of added sugar beyond permissible limits in infant formula marketed in India and other developing countries highlights the potential risks to which infants may be exposed on the introduction of such feeds.

Keeping in mind the short- and long-term effects of CUG, there is no ‘one size fits all’ solution for the postnatal growth trajectory and pattern for LBW infants. While the disadvantages of accelerated weight gain and excess CUG have been discussed in this review, it is also important to recognize that in developing countries, adequate weight gain during infancy and childhood is necessary, as it has a direct bearing on survival. In the recent paper by Jana et al. performing modeling studies on data obtained from the National Family Health Survey-5 (India) estimated that infants born LBW were more likely to be stunted (odds ratio [OR] 1.46; 95% confidence interval [CI]: 1.41–1.50) and underweight (OR = 1.33; 95%CI: 1.27–1.37),^[67] with a 53% higher risk of mortality,^[68] underlining that the need for fine balanced growth that that protects against infections and death while minimizing future adverse cardio-metabolic outcomes [Figure 2].

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Figure 2:

Pathophysiology and outcomes of catch-up growth (CUG) in low birth weight (LBW) infancy.

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Irrespective of the etiology, the cornerstone of ensuring appropriate CUG relies on consistent monitoring of anthropometric parameters. The recent consensus guidelines (2023) on the management of infants born SGA recommend measurement of weight, length, head-circumference, and weight/length or body mass index every 3 monthly for the first 1^st year, 6 monthly in the 2^nd year, and annually thereafter until the child has attained their genetic height potential. It is important to note that some deviation in growth patterns is expected in the first 3 years, a sudden upstroke in the child’s weight for height with crossing of centile should be a clue that corrective measures need to be taken.^[10]

FUTURE DIRECTIONS

In recent decades, we have advanced our understanding of CUG, including its benefits and potential drawbacks. However, various aspects of CUG remain inadequately elucidated. Future research should focus on elucidating the molecular and endocrine mechanisms that underpin CUG.

Similarly, the various factors that determine the rate of gain of weight in early infancy (e.g., how frequently an infant demands milk), as well as its partitioning into lean and fat compartments, are not fully understood. Further research is needed to understand the optimal CUG patterns for preterm and term SGA infants, the determinants of the CUG in early life, its consequences over the life-course, and strategies for optimizing the lean and FM gain during CUG. There also needs to be a focus on the impact of nutritional interventions at both individual and community levels on CUG, and exploring personalized approaches to optimize CUG. Finally, studies addressing disparities in CUG between high- and low-income countries should be regarded as a priority for upcoming research initiatives.

CONCLUSION

CUG in the postnatal period has several benefits in terms of decreased infection, stunting, hospital admissions and mortality. However, if excessive, it also exacts a long-term cost in the form of increased risk of obesity and metabolic syndrome in adulthood. The current policy is to promote adequate postnatal growth in LBW preterm infants by providing nutrient-enriched feeds whenever needed, as improved neurocognitive outcomes outweigh risks. However, there is a need for proper monitoring of growth and avoiding rapid crossing of weight centiles. In addition, the applicability of the same principles in larger preterm infants is still controversial and needs further research and understanding.

KEY POINTS

1. Catch-up growth is defined as a physiological increase in the weight-for-age Z-score following a period of “growth faltering,” eventually returning to the initial WFA Z-score.

2. Recent consensus guidelines on long-term follow-up of infants born SGA define CUG as the growth rate (cm/ year) of >0 SDS, i.e., more than the median for age and sex.

3. Catch-up growth can occur in various anthropometric parameters, including weight, height, and body composition, including fat and fat-free mass as well.

4. Catch-up growth in the postnatal period is a result of being born at a centile that is lower than the genetic potential of a child.

5. Adequate CUG decreases the prevalence of undernutrition, stunting, and infections during early life and also improves neurocognitive outcomes in preterm infants.

6. Current data suggest excessive CUG increases the risk of obesity and metabolic syndrome in preterm and SGA infants later in their lives.

7. Insulin resistance has been found to be higher in IUGR infants who show early and excessive CUG compared to the infants with adequate CUG.

8. Exclusive breastfeeding and timely initiation of appropriate complementary feeds ensure adequate growth during infancy.

9. Breastmilk fortification with human milk fortifiers is recommended for preterm babies with birth weight less than 1800 g and receiving enteral feeds of at least 50– 80 mL/kg/day.

10. Term very low birth weight (VLBW) babies who fail to achieve appropriate weight gain on breastmilk or formula feed should be considered for human milk fortification.

11. Growth monitoring and an appropriate diet during infancy are essential for managing babies born LBW.