We conducted a prospective longitudinal study in a cohort of 28 children born in the Hospital Clínico Universitario de Zaragoza between 1995 and 2009 with a diagnosis of SGA. Participants were included consecutively. There was no control group. The follow-up period was four years, and we compared the sample data for different points in time. Seventy-one percent of the sample completed the four-year followup, while the remaining 29% patients were in earlier stages of treatment by the end of the study, as they had been included at later times.

The patients included in the study fulfilled the criteria required by the Advisory Committee on Growth Hormone of the Ministry of Health, Social Services and Equality for its use in SGA children:

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  Birth length and/or weight at least 2 SDs below the reference standards.12

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  From age 4 years, stature at least 2.5 SDs below the reference standard.13

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  Lack of catch-up growth by age 4 years.

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  Ruling out of other medical problems or treatments as the cause of the growth disorder.

The exclusion criteria were the following:

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  Patients that did not meet the auxologic criteria for inclusion.

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  Presence of certain syndromes that may not benefit from the therapy.

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  Diabetes mellitus or other significant disorder of carbohydrate metabolism.

We collected the neonatal data of participants: birth weight and length (z-score)12 and gestational age in weeks. We calculated the genetic potential length (SD).

We collected data for the following variables before initiating treatment and in the four years of followup:

To describe the baseline characteristics of the sample, we performed a descriptive analysis of the quantitative variables (mean, standard deviation, minimum, maximum, median and interquartile range) and expressed qualitative variables as frequency distributions.

We performed comparisons with parametric tests after verifying the normality of the distributions by means of the Kolmogorov–Smirnov and Shapiro–Wilk tests, and the homogeneity of variance by means of Levene's test.

To describe the changes that occurred during the years of followup, we compared means by repeated measures ANOVA. When we found significant differences in the ANOVA, we used Student's t test to compare different ranges in order to determine the time at which the changes occurred. We used Student's t test for independent samples to make comparisons between the sexes. We defined statistical significance as P<.05 in any of these tests.

The statistical analysis was performed with the software SPSS version 20.0 for Windows.

The study was approved by the Clinical Research Ethics Committee of Aragón (Comité Ético de Investigación Clínica en Aragón [CEICA]) of the Department of Health and Consumer Affairs of the autonomous community of Aragón. We also obtained the informed consent of patients and family members.

The sample included twenty-eight participants: twenty-one female (75%) and seven male (25%). At the beginning of the study, 78.5% of the sample was in stage 1 of the Tanner scale, and 21.5% in stage 2. The bone age to chronological age ratio was 0.70±0.522. The mean administered dose of rhGH was 0.029mg/kg/day.

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  At birth: the mean gestational age was 38.29±3.46 weeks, and the mean auxologic measurements were 46.13±0.39cm for length (−2.42±0.20 SD) and 2575±85.63g for weight (−1.38±0.23 SD). The mean genetic potential length was −1.44±0.12 SD. We did not find significant differences in any of these variables based on sex. The documented aetiologies that may have contributed to intrauterine growth restriction were environmental factors in 35.7% (exposure to smoke and maternal employment), maternal factors in 10.7%, foetal factors in 10.7% and placental factors in 7.1%, with growth restriction considered idiopathic in 35.7%.

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  At treatment initiation: Table 1 presents the anthropometric, laboratory and body composition data. The mean age at initiation was 8.79±3.06 years. The mean height was −2.76±0.45 SD, with a growth velocity of −1.43±1.79 SD. Blood pressure and waist circumference values were within the normal range, as were the baseline blood test results. We only found increased insulin levels and HOMA indices in female participants, which did not reach the levels associated with insulin resistance (insulin in male patients, 5.07±2.42 vs female patients, 10.59±11.01 [P=.042]; HOMA index in male patients, 1.89±0.98 vs female patients, 4.13±4.32 [P=.037]). Table 2 shows that there were significant differences in these two variables when they were analysed taking pubertal maturation into account (prepubertal insulin, 6.51±4.98mIU/mL vs pubertal insulin, 19.13±16.41mIU/mL [P=.003]; prepubertal HOMA index, 2.54±2.09 vs pubertal HOMA index, 7.32±6.42 [P=.005]).

  Table 1.

  Anthropometric, clinical and laboratory data of the sample at baseline.

  	Mean (±SD)	Minimum	Maximum	Median	Q1	Q3	Pa
  Anthropometric data
  Age (years)	8.79±3.06	4.62	14.07	9.73	7.04	12.42	ns
  Weight (SD)	−1.50±0.50	−2.68	−0.83	−1.21	−1.52	−0.9	ns
  Height (SD)	−2.76±0.45	−4.90	−2.23	−2.77	−2.98	−2.56	ns
  BMI (SD)	−0.68±0.68	−1.89	−0.91	−0.68	−1.16	−0.20	ns
  GV (SD)	−1.43±1.79	−5.72	2.26	−1.47	−2.35	−0.59	ns
  Clinical data
  SBP (mmHg)	96.71±11.91	69	124	95	86.88	103.12	.022*
  SBP (SD)	0.20±1.21	−1.88	3.16	0.59	−0.15	1.33	.010*
  DBP (mmHg)	57.64±9.63	40	80	58	52	64	ns
  DBP (SD)	0.08±0.86	−1.50	2.14	0.08	−0.43	0.59	ns
  Waist circumference (cm)	60±11.01	44	85	55	47.50	62.50	ns
  Waist circumference (SD)	−0.22±1.46	−2.50	3.50	−0.51	−1.10	0.08	ns
  Laboratory data
  Glucose (mg/dL)	85.67±8.88	65	100	89	84	94	ns
  Glycosilated Hb (%)	5.01±0.49	4.00	6.50	5.10	4.80	5.40	ns
  Triglycerides (mg/dL)	60.11±21.90	31	115	63	46	80	ns
  Colesterol total/HDL	2.72±0.62	1.50	4.30	2.80	2.49	3.11	ns
  Insulin (mIU/mL)	9.33±11.26	2.00	40.07	7.79	2.66	12.92	.042*
  IGF1 (ng/mL)	232.82±166.66	59	601	206	72	340	ns
  IGF1BP3 (μg/mL)	4.77±1.31	2.79	7.13	5.09	3.85	6.33	ns
  IGF1/IGF1BP3	49.14±41.31	14.73	200.30	41.54	19.49	63.59	ns
  HOMA index	3.63±4.42	0.58	15.99	3.12	0.74	5.50	.037*
  DEXA
  Fat mass (g)	6214.27±4540.16	2581.00	18,832.60	5418.30	2508.70	8327.90	ns
  Fat mass (%)	25.94±6.09	16	40.80	24	19.5	28.5	ns
  Lean mass (g)	16,303±5686.05	8669.9	29,080.50	16,589.20	11,602.60	21,575.80	ns
  Lean mass (%)	70.75±6.09	55.90	80.70	72.70	68.40	77	ns
  FM/[FM+LM]	26.81±6.90	16.05	40.80	25.44	20.93	29.95	ns
  LM/[FM+LM]	73.19±6.90	59.20	83.95	74.56	70.05	79.07	ns

  Data available for 28 patients.

  BMI, body mass index; DBP, diastolic blood pressure; DEXA, body composition; FM, total fat mass; GV, growth velocity; LM, total lean mass; ns, not significant; SD, standard deviation; SBP, systolic blood pressure.

  a

  Student's t test for significant differences based on sex.

  *

  P<.05.

  **P<.01.
  Table 2.

  Laboratory results at baseline by stage of pubertal development.

  	Prepubertal (Tanner I)	Pubertal (Tanner II)	Pa
  	n=22	n=6
  Sex
  % male	27.27	16.66
  % female	72.72	83.33
  Laboratory test results at baseline
  Glucose (mg/dL)	85.32±8.31	85.17±6.40	ns
  Glycosilated Hb (%)	4.97±0.54	5.15±0.26	ns
  Triglycerides (mg/dL)	58.36±16.47	64.67±28.64	ns
  Total cholesterol/HDL	2.74±0.62	2.58±0.47	ns
  Insulin (mIU/mL)	6.51±4.98	19.13±16.41	.003**
  IGF1 (ng/mL)	213.96±136.66	305.17±177.95	ns
  IGF1BP3 (μg/mL)	4.62±1.22	5.22±1.16	ns
  IGF1/IGF1BP3	48.04±37.97	54.86±24.99	ns
  HOMA index	2.54±2.09	7.32±6.42	.005**

  Data available for 28 patients.

  a

  Student's t test for significant differences based on stage of pubertal development.

  *P<.05.

  **

  P<.01.

Table 3 shows the evolution of the different variables.

Anthropometric variables (Fig. 1): there was a gradual increase in height through time (from −2.76±0.45 SD to −1.53±0.62 SD; P=.000), with significant differences between all studied years. Fig. 2 shows how actual height gradually approached the genetic potential, and how the largest height gain occurred in the first year of treatment.

Figure 1.

Changes in anthropometric variables during treatment with growth hormone.

(0.1MB).

Figure 2.

Changes in height (SD) relative to genetic potential (SD) during followup.

(0.09MB).

Weight improved as years passed (from −1.50±0.50 SD to −1.21±0.49 SD; P=.016). Growth velocity increased progressively (from −1.43±1.79 SD to 0.41±1.52 SD; P=.009). We found no changes in body mass index.

There were no differences between sexes in any of the variables.

Clinical data: we found no changes in systolic blood pressure with time, although we did find significant changes in diastolic blood pressure, which decreased in the second year of treatment (−0.16±0.13 SD vs −0.26±0.13 SD; P=.037). There were no changes in waist circumference. We found no differences in the variables based on sex.

Laboratory data: the percent glycosilated haemoglobin increased significantly, although it remained within the normal range, with a baseline of 5.01±0.49% and a value of 5.30±0.30% in the fourth year (P=.002). The largest increase occurred in the first year of treatment.

The plasma insulin levels increased significantly with the years, with levels of 9.33±11.26mIU/mL at baseline and of 16.55±6.22mIU/mL in the fourth year (P=.044), which were within normal ranges. We did not observe differences based on sex during the followup, as had been the case of the baseline levels.

The values of IGF1, IGF1BP3 and their ratio increased significantly, with the increase occurring in the first and second years.

The HOMA index increased significantly from 3.63±4.42 to 6.43±2.55 (P=.042), probably due to the increase in plasma insulin, as we did not observe any changes from baseline in glucose levels. We observed no changes in triglyceride levels during the followup. There were no differences between the sexes in any of the analysed variables.

Body composition data: lean mass increased significantly during the followup (from 16 303±5686.05g to 31 153.61±7214.24g; P=.000). There was a progressive increase in lean mass due to the growth of the patients, but there were no significant changes. Furthermore, we observed a significant increase of the percent lean mass attributable to changes that occurred in the first year of treatment (from 70.75%±6.09% to 74.92%±4.62%; P=.0034) as well as a decrease in the percent fat mass (from 25.94%±6.09% to 21.04±4.81%; P=.015).

The LM/[LM+FM] ratio increased during the followup from 73.19±6.90 to 78.74±4.33 (P=.037), a trend that was more pronounced in male patients. Since they are complementary, the FM/[LM+FM] decreased. When we analysed by time range, we found that the statistically significant differences were due to the changes that occurred in the first year of treatment.