1 Introduction

Small for gestational age (SGA) is generally defined as the birth weight and/or birth length of infants that is less than 2 standard deviation scores (SDS) from the mean for gestational age [1]. Based on the reference data, neonates can be subdivided into SGA for weight, SGA for length, or SGA for both weight and length, which helps to understand the mechanisms and effects of being bore SGA [1]. Noteworthy, birth weight is currently the most often used reference data to define SGA newborns.

Catch-up growth in linear growth refers to “a height velocity above the statistical limits of normality for age and(or) maturity during a defined period, following a transient period of growth inhibition” [2]. The typical growth pattern of SGA children is defined as a period of accelerated linear growth, which occurs mainly in the first 12 months of life, with a complete recovery in height at the age of 2 years [3]. However, a landmark study by Karlberg et al. in 1995 reported that 10–15% of full-term SGA children lack catch-up growth, and most of these children remain short in adulthood [4]. For late preterm SGA children, one-third of them were below the 10th percentile for length at 36 months of corrected age [5]. Currently, the treatment of recombinant human growth hormone (rhGH) has been approved by many countries for short children born SGA. However, the treatment is less effective than in patients with growth hormone deficiency (GHD) [6]. In addition, the timing of initiating growth hormone therapy is controversial due to the uncertainty of spontaneous catch-up growth in children with SGA [32]. The rabbit model demonstrated that during catch-up growth, the proliferative zone, hypertrophic zone, and total growth plate all experienced a delayed decline in senescence. This suggests that, at least in part, the delay in growth plate senescence is what allows for greater proliferative capacity during linear catch-up growth. By modifying the cellular senescence process, it might be feasible to encourage catch-up growth in SGA children more successfully [33].

Recent studies suggested that SGA children with inadequate catch-up growth had abnormal skeletal development. SGA infants had significantly lower femur, tibia, humerus lengths and cortical bone mass than AGA infants [34]. When SGA children experience catch-up growth in height postnatally, they can reach the average long bone length and mineralization by 4 years of age [35, 36]. Still, SGA children who lack catch-up growth have insufficient bone mineral accumulation during growth and are at risk for low adult bone mass [37]. Cohort studies highlight the bone mineralization is the outcome of catch-up growth. Hormone level improvements alone, such as exogenous rhGH injection, are not sufficient to promote bone formation in short SGA cases. Research by Schweizer et al. revealed that rhGH treatment did not increase bone diameter in children with short SGA [38, 39]. The above-mentioned studies showed that regulatory problems at two levels—growth plate senescence control and endocrine system hormone regulation—are the cause of catch-up failure in SGA children. The limitation of the study is that the subjects were only full-term SGA children. In children with preterm SGA, a severe prenatal shock may have a direct impact not only on growth catch-up but also on bone formation.

2.3 Multiple influencing factors in inadequate catch-up growth in SGA children

2.3.1 Maternal factors

Maternal factors not only cause neonates to exhibit SGA at birth, but further affect postnatal catch-up growth in SGA children. These determinants cover not only maternal physiological characteristics (e.g., height, weight, weight gain during pregnancy, placental function, and illnesses during pregnancy), but also maternal psychological states (e.g., anxiety, depression) and breastfeeding behaviors. A study analyzing a subgroup of the Early Childhood Longitudinal Study Birth Cohort (ECLS-B) found that the effects of short maternal height, pre-pregnancy underweight, inadequate gestational weight gain, and smoking on poor catch-up growth before school age [91,92].

2.4.5 Reprogramming of the hypothalamic–pituitary–adrenal axis

A study of 49 children with IUGR suggested that catch-up growth in children with IUGR may be influenced by intrauterine reprogramming of the HPA axis, and children with increased cortisol secretion may have a higher likelihood of growth failure [93]. Factors including exposure to xenobiotics and psychosocial stress throughout pregnancy, may lead to intrauterine programming and change the hypothalamic–pituitary–adrenal (HPA) axis. Exogenous substances may cause programmed alterations in the fetal HPA axis via epigenetic modifications of essential genes or oxidative stress in the fetal adrenal glands [94]. However, cortisol which is lipophilic and can pass through the placenta, is usually considered the primary mediator. Excess maternal cortisol may continue to impair fetal HPA axis development and result in growth failure [94, 95]. In rats, maternal undernutrition could induce IUGR and overexpose the fetus to maternal corticosterone, leading to increased cortisol secretion in newborns and potential growth retardation [96]. In monkeys, dexamethasone treatment during pregnancy caused a reduction in hippocampal volume and an increase in postnatal plasma cortisol levels. The HPA axis was also enhanced postnatally in fetuses of ewes that were malnourished during the first half of gestation [93, 97]. Because of the hyperactivity of the HPA axis induced by numerous circumstances, elevated cortisol may act by limiting the proteolysis of IGFBP-3, thereby reducing the bioavailability of IGFs [93]. Through what molecular mechanisms intrauterine reprogramming of HPA axis regulates the IGF system to participate in postnatal growth retardation in SGA children will be the focus of future studies.

2.5 Potential therapeutic approaches

Several studies showed that rhGH therapy effectively induced catch-up growth in children with SGA, accompanied by normal body proportions, and improved adult height in the majority of short SGA children [98,99,100]. However, the growth response to GH was highly variable in all clinical trials involving short children born SGA, and this variability may be attributable, at least in part, to multiple genetic variations [8].

Currently, few studies address the treatment of inadequate catch-up growth among SGA children due to the unknown mechanism behind it. Some animal studies, however, have focused on providing additional nutrients in food restriction models to induce catch-up growth. Based on the similarities in GH resistance and abnormal growth plate development between the food restriction model and the SGA model lacking catch-up growth, these treatments may be applicable to SGA children lacking catch-up growth [101]. Various studies revealed that additional nutritional supplements could lead to catch-up growth in refed animal models by promoting bone growth. In the nutritional restriction and refed rat model, the height of the growth plate fed with casein and whey protein was higher than that provided with a regular diet, and the bone strength and growth rate of rats fed with casein were higher than those fed with whey protein. Higher calcium absorption, induction of IGF-1 secretion, alteration in amino acid profile and digestion velocity may account for this phenomenon [102]. For instance, β Palmitate, the most abundant saturated fatty acid in human milk, was also reported to increase the tibia length and growth plate in refed rats [103]. In addition, a slowly digestible carbohydrate (SDC) diet can improve bone mineral density (BMD), bone mineral content (BMC), growth plate width of limbs, and middle axis bone in a refed rat model [104]. These results suggested that specific dietary patterns and additional nutritional supplements could promote the effects of catch-up growth.

Pharmaceuticals targeting specific protein or gene could be beneficial for SGA children with genetic defects. Recombinant human C-type natriuretic peptide (CNP) analogs are currently authorized in the European Union to treat chondrodysplasia [105]. The fibroblast growth factor receptor three gene (FGFR3), a negative bone growth regulator that signals through several different pathways, is the cause of chondrodysplasia. A signaling through the MAPK pathway appears to be the most significant factor in the inhibition of bone growth [106]. CNP is a selective agonist of the natriuretic peptide receptor (NPR2). NPR2 predominantly inhibits MAPK signaling in the growth plate, which speeds up chondrocyte division, matrix production, and cellular hypertrophy [106]. In order to address the decreased chondrogenesis observed in individuals with short stature, Lui et al. created a cartilage-targeted single-chain human antibody fragment (CaAb) designed to deliver therapeutic molecules to the growth plate. In a mouse model with GHD, the subcutaneous injection of the CaAb-IGF-1 fusion protein resulted in an overall increase in growth plate height, while not affecting the proliferation of renal cortical cells, thus minimizing off-target effects on non-cartilage tissues [107]. Given that some short SGA children have similar pathway abnormalities, the therapeutic effect of pharmaceuticals targeting treatments on short SGA children warrants deeper study.

3 Conclusions

The mechanisms underlying the absence of catch-up growth in children born with SGA still need to be better understood—several maternal, perinatal and fetal factors affect the ability of SGA infants to catch up. Genetic defects are the most important explanation for the absence of catch-up growth, with signaling pathways in skeletal development, GH resistance, reprogramming of the hypothalamic–pituitary–adrenal axis, epigenetics, and the gut microbiome as possible mechanisms. Ultimately, SGA offspring have impaired postnatal catch-up growth, which increases the risk of dwarfism in adulthood.

Although GH therapy is currently effective in reducing the risk of stunting in most cases of short SGA, the response to GH varies greatly across all clinical trials, and the optimal time to begin GH therapy is debatable due to the uncertain timing of catch-up growth [7,8,9]. In order to intervene earlier and reduce the likelihood of insufficient catch-up growth, more study on the etiology is required. In terms of other prospective treatment techniques, the idea of translating data from animal trials to clinical application should be pursued.

For decades, there has been little research into the causes and potential mechanisms of catch-up development failure in SGA children. Understanding the etiology and probable causes of catch-up growth failure in SGA children is therefore critical for early detection and treatment options.