**3. Statistical analysis**

Results are presented in the successive tables as percentages (%) and means (M) with corresponding standard deviations (s.d.) and confidence intervals (95% CI). The statistical analysis (descriptive statistics, Student's t-test, analysis of variance, Chi-square and multiple logistic regression analysis) was executed with the program *Statistical Packages for the Social Sciences* version 20.0 (Chicago, IL, USA). The statistical significance was reached with a P-value of 0.05.

This study was submitted and subsequently approved by the Ethics Committee for Human Investigation of the Navarra Hospital Complex, Pamplona, Spain (in compliance with the ethical standards of the 1964 Declaration of Hensinki and later amendments). Parents and/or legal guardians were aware of the characteristics and requirements of the study and provided acceptance for the participation in all cases.

#### **4. Results**

The sample of VLBW infants who have been recruited for this study consists of 170 children (82 boys and 88 girls). In the aggregate, 40.6% (n = 69) of the infants were included as small for gestational age (SGA subgroup) and the remaining 59.4% (n = 101) as appropriate for gestational age (AGA subgroup). In the SGA subgroup, 59.4% (n = 41) of children had a history of weight and height alterations at birth, while specific alterations of height (23.2%, n = 16) or weight (17.4%, n = 12) were less frequent (**Figure 1**).

Multiple pregnancies amount to 42.4% (n = 72), being twin pregnancies predominant, (**Figure 2**).

On the basis of gestational age, they have been subdivided into extremely preterm (n = 32, 18.8%), very preterm (n = 72, 42.4%) and late preterm (n = 66, 38.8%) (**Figure 3**). Thirty-seven (21.8%) infants were included as ELBW.

**Table 1** exposes and compares the values of the anthropometric measurements at birth of VLBW infants in the AGA and SGA subgroups and classified by sex. We do not appreciate statistically significant differences in the mean weight and height values at birth between the two groups. The values of gestational age were significantly higher in the SGA subgroup than in the AGA subgroup.

**Table 2** displays and compares the mean values for height, weight and growth rate in VLBW infants and the control group from birth to 10 years of age. Figures for height and weight were significantly lower in VLBW than in the control group. In contrast, growth rate in the first two years of life in was significantly higher in VLBW infants than in the individuals of the control group.

**Figure 1.**

*Classification of VLBW according to weight and/or height at birth.*

**Figure 2.** *Distribution of VLBW according to the type of pregnancy.*

*Characteristics of Catch-Up Growth in Very Low Birth Weight Infants (<1500 g) DOI: http://dx.doi.org/10.5772/intechopen.96933*

#### **Figure 3.**

*Distribution of VLBW according to the degree of prematurity.*


#### **Table 1.**

*Gestational age, weight and height data from VLBW infants at birth in both sexes (M ± SD).*

**Figure 4** shows the percentage of VLBW infants who reached normal height at the different stages that were evaluated in the study. At age 2, 4 and 10 years, 49.4%, 78.9% and 87.1%of infants, respectively, had gained normal height. In this sense, 8.2% of VLBW infants presented with normal height between ages 4 and 10 years.

The analysis reveals that 86% of VLBW infants that had gained normal weight after the first year of life reached normal height (*P* < 0.001) by age 2 years. Additionally, 98.6% of VLBW infants with normal weight at age 2 had reached normal height (*P* < 0.001) by age 4. In the same way, 97.2% of VLBW infants with normal weight at age 4 appear with normal values for height (*P* < 0.001) by age 10, 99.2% of VLBW infants with normal weight at age 6 showed normal values for height by age 8 (*P* < 0.001), and finally, all VLBW infants that presented with normal weight at age 10 had also normal height at this age (*P* < 0.001).

**Table 3** states the comparison of mean values for height, weight and growth rate between AGA y SGA subgroups from birth to 10 years of age. The AGA subgroup features significantly higher values for height with respect to SGA subgroup at age 1, 2, 3, 4 and 6, as well as higher values for weight at age 1, 2, 3 and 6. There were no statistically significant differences in growth rate between both groups in every stage evaluated.

**Figure 5** shows the figures of the percentages of infants in the AGA and SGA subgroups that gained normal size at the different stages under assessment. There were no statistically significant differences between the groups, except at age 10:


#### **Table 2.**

*Changes in the values of height, weight and growth rate of VLBW and control group (M ± SD).*

17% of children in the SGA subgroup (*n =* 12) and 10% of children in the AGA subgroup (*n =* 10) presented with low height values (*P* = 0.018).

**Table 4** describes the mean values for height, weight and growth rate in ELBW (<1000 g) and VLBW (1001–1500 g) infants from birth to 10 years. Mean values for weight and height were significantly lower in ELBW than in VLBW in every age considered except for 10 years. There were no significant differences in growth rate between both groups in any period of age.

**Figure 6** presents the percentages of VLBW (1000–1500 g; *n* = 133) and ELBW (<1000 g; *n* = 37) infants that reached normal height at the different ages under assessment. There were significant differences between groups at every age evaluated. In this way, 7% of VLBW infants (*n* = 9) and 35% of ELBW infants (*n* = 13) showed short stature (*P* = 0.001) at age 10.

In the SGA subgroup, 7 out of the 12 children that presented with short stature at age 10 (7 of whom were ELBW) had reached normal values in height by age 14 (6 of them had taken treatment with recombinant human growth hormone [rhGH]); the remaining 5 (3 of whom were ELBW) maintained short stature (3 of them had treatment with rhGH). Treatment with rhGH was started between ages 6.5

#### *Characteristics of Catch-Up Growth in Very Low Birth Weight Infants (<1500 g) DOI: http://dx.doi.org/10.5772/intechopen.96933*

#### **Figure 4.**

*Percentages of adequate catch-up growth in height in VLBW infants.*


#### **Table 3.**

*Changes in the values of height, weight and growth rate of VLBW (AGA and SGA subgroups. (M ± SD).*

#### **Figure 5.**

*Percentages of adequate catch-up growth in height in AGA and SGA groups (chi-square).*


#### **Table 4.**

*Changes in the values of height, weight and growth rate of VLBW (1000–1500 g) and ELBW (< 1000 g). (M ± SD).*

*Characteristics of Catch-Up Growth in Very Low Birth Weight Infants (<1500 g) DOI: http://dx.doi.org/10.5772/intechopen.96933*

#### **Figure 6.**

*Percentages of adequate catch-up growth in height in ELBW and VLBW infants (chi-square).*


*VLBW: very low birth weight. ELBW: extremely low birth weight. AGA: appropriate for gestational age. SGA: small weight for gestational age. LPT: late preterm. VPT: very preterm. EPT: extremely preterm.*

#### **Table 5.**

*Logistic regression analysis of factors associated with inadequate catch-up growth.*

and 8.3 years. In the AGA subgroup, 2 of the 10 children that presented with short stature at age 10 (7 of whom were ELBW) had reached a normal height at 14 years (1 of them had received rhGH therapy at age 8.9 years) and 8 (6 of them ELBW) kept in short stature (1 of them started rhGH therapy at age 7.8 years, and 7 of them were not entitled to receive treatment due to normal responses in growth hormone stimulation tests).

**Table 5** displays the results of the multiple logistic regression analysis conducted to study the association of neonatal clinical history with inappropriate catch-up growth in height at ages 2, 4, and 10. The analysis shows that the conditions of ELBW, SGA for height and preterm birth before 28 weeks of gestation were associated with inadequate catch-up growth in height at 2, 4, and 10 years. On the other side, SGA for

both weight and height was associated with inadequate catch-up growth only at age 10, whereas preterm birth between 28 to 32 weeks of gestation was associated with inadequate catch-up growth only at ages 2 and 4. Additionally, multiple birth was not associated with inadequate catch-up growth at ages 2, 4 or 10 years.

## **5. Discussion**

The terms "intrauterine growth restriction" (IUGR) and "small for gestational age" (SGA) newborn are not strictly equivalent concepts [30], since they are related to different chronological stages (fetal growth and anthropometric measurements at birth, respectively). Nevertheless, they refer to failure to reach the genetic growth potencial during the prenatal period as an adaptive response to an adverse uterine environment. In any way, both terms are used indistinctly in daily clinical practice in order to cluster those newborns whose weight and/or height at birth are equal to/ below 2 standard deviations under the average of a reference population on the basis of gestational age and sex. In this case, the majority of children included in the socalled SGA group presented with a combined alteration in weight and height, whilst the proportion of children with exclusive weight or height disorder was slightly lower.

This definition requires a precise diagnosis of gestational age and the registration of anthropometric measurements after birth, whose values should be contrasted with reference standards for gestational age and sex. The choice of reference patterns is a determining factor in the assessment of newborn growth [31]. In fact, the variability of the anthropometric variables in relation to racial, genetic, social, environmental and maternal lifestyle factors make it advisable to use local or national growth reference charts. The charts from Lubchenco et al. [32], which were published in the 60s, have been widely used and are characterized by a contrasted clinical utility. At present, the most qualified local (Spanish) reference charts, which have been used in the present study, are the newborn (26–42 weeks of gestational age) weight and height charts from the anthropometric growth patterns of preterm from Carrascosa et al. [28].

Fetal development and intrauterine growth are complex processes in which continuous and harmonious cellular proliferation and differentiation take place. Multiple factors (maternal, fetal, placental and environmental) have been mentioned to have a negative impact on the fetus and set off a series of functional and structural adaptive changes that conclude in fetal growth restriction (in the so-called "thrifty phenotype hypothesis"). They are linked to different changes in hormone sensitivity and/or secretion that entails an increased risk of developing metabolic and/or endocrine disorders in adult life [33, 34]. In any way, most term newborns with previous intrauterine growth restriction manifest a compensatory growth (catch-up growth) after birth, mainly in the first year of life, that enables approximately 90% of the individuals to surpass the threshold of 2 SDs under the average in the reference population, or, in other words, to get normal height [2–4]. Even so, whenever this compensatory growth does not occur, a normal final height in adulthood is not likely to be reached. By knowing so, this event is considered one of the indications for rhGH therapy approved by the United States Food and Drug Administration (FDA), the European Medicines Agency (EMA) and the Growth Hormone Research Society, with the intention to boost the initial compensatory growth and/or to keep normal growth velocity [3, 35, 36].

The recent advances in obstetric and perinatal care have led to a considerable decrease in VLBW infants mortality; despite this, and owing to the potential sensorineural morbidity in this children, these patients are usually enlisted in

#### *Characteristics of Catch-Up Growth in Very Low Birth Weight Infants (<1500 g) DOI: http://dx.doi.org/10.5772/intechopen.96933*

follow-up programmes whose goal is the early detection of neurodevelopmental problems [1, 37]. The improvement of these programmes has eased the standardization of dietary and nutritional advices, and enabled growth monitoring in the first years of life. It also facilitates the analysis, as we performed in this study, of the evolution of anthropometric variables in VLBW infants [38].

The results obtained in this study confirm that, on one side, the VLBW newborns undergo a postnatal compensatory growth that is maximum during the first year of life, as it occurs in term newborns that are SGA. As a matter of fact, growth velocity during the first 12 months of life in VLBW was considerably higher than in the control group; this explains, to a great extent, the noticeably proportion of individuals in this group that reach normal height by age 2 years [39]. On the other side, this study remarks that VLBW infants have a lower rate and/or delay in the catch-up growth in height when comparing to that observed in full-term SGA infants [4, 16–18, 24, 25]. In point of fact, 50.6%, 21.1% and 12.9% of individuals, maintained short stature at age 2, 4 and 10, respectively; in other words, these individuals reached normal height in a similar percentage than that for full-term SGA infants at age 2. Additionally, barely 8.2% of children reached normal height between ages 4 to 10. Despite current data are inconsistent, these results are somehow congruent with those exposed by the different authors that previously noticed that catch-up in VLBW infants could be delayed [12, 15, 40–44]. Nevertheless, none of the authors cited has screened the influence of catch-up growth in weight, which is concurrent with the catch-up in height and, in accordance to the data collected, plays a decisive role [24, 25]. In effect, a great majority of individuals who present with normal height at age 2, 4 and 10 have gained an adequate catch-up growth in weight in the previous evaluations. For this reason, these individuals should follow a strict nutritional control in order to raise an issue on the prescription of nutritional supplements with the challenge to get weight recovery as fast as possible [26, 45–47].

The findings of our study have direct implications on clinical practice. First of all, the assessment and comparison of the patterns of catch-up height gain in AGA and SGA groups present only small variances in the age range under consideration, except at age 10. At age 10, only 1 out of the 10 children did not register normal height in the AGA group, whilst approximately 1 in 5 children in the SGA subgroup still had short stature. In other words, the lower rate of catch-up growth in VLBW infants is slightly further reduced or delayed in SGA infants. On the other hand, it is important to emphasize that 1 in 3 children get normal height in both the AGA and the SGA groups between ages 2 and 4 years. This fact suggests that the implementation of the recommendation of the EMA and the Growth Hormone Research Society to postpone the beginning of rhGH therapy until the age of 4 years would be more applicable than implementing the recommendation of the FDA, which recommends the beginning of treatment at age 2 years.

The analysis of catch-up growth in ELBW infants merits particular attention. First, we detected that the majority of children that had not attained normal height by age 10 years in both the AGA and the SGA subgroups were infants born with ELBW. Second, there was a noticeable amount of children in the AGA subgroup that were not considered for hormone therapy when the response to growth hormone stimulation test was normal, in accordance with the current recommendations of the FDA, the EMA and the Growth Hormone Research Society. This fact fully explains the reason why children in the AGA subgroup with short stature at age 10 years (the majority of them were VLBW) remained in the same situation at age 14 and, presumably, in adulthood. Since current guidelines do not give consideration to the option of beginning growth hormone therapy in AGA infants with normal GH secretion, we should reckon if these criteria should be revised in the case of children born with VLBW and, especially, those with ELBW.

#### *Current Topics in Caesarean Section*

The multiple logistic regression analysis corroborated that ELBW and EPT infants were at higher risk of inadequate catch-up in height at 2, 4, and 10 years of age; additionally, they have an increased risk of short stature in adulthood. These results sustain the hypothesis of a potential benefit from GH treatment, independently of the adequacy of their birth weight and/or length for gestational age [18, 48–50].

In conclusion, the growth pattern of children born preterm has particular features. Approximately 85% and 53% of VLBW and ELBW infants, respectively, will attain normal height by 4 years of age. In contrast, those individuals with short stature at age 4 years are not likely to attain normal height in childhood. Catch-up in weight appears to be a decisive factor for catch-up in height, and, on this basis, we recommend a rigorous nutritional follow-up in these individuals. If these measures do not help improve catch-up in height, they may be eligible for the establishment of rhGH therapy.
