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Outcome in preterm small for gestational age infants compared to appropriate for gestational age preterms at the age of 2 years: a prospective study
European Journal of Obstetrics & Gynecology and Reproductive Biology 110 (2003) S93–S97
Outcome in preterm small for gestational age infants compared to appropriate for gestational age preterms at the age of 2 years: a prospective study Ludwig Gortnera,*, Michael van Husenb, Ute Thyenb, Ulrich Gembruchc, Hans-Ju¨rgen Friedrichd, Eva Landmanna a
Department of Neonatology, Pediatric Center, Justus Liebig University, Feulgenstr. 12, Giessen D-35383, Germany b Pediatric University Hospital, Medical University, Luebeck, Germany c Department of Obstetrics and Gynecology, Medical University, Luebeck, Germany d Department of Medical Statistics, Medical University, Luebeck, Germany
Abstract Objectives: To investigate the effects of small for gestational age (SGA) in preterm infants on growth and development until the age of 22 months. Study design: Seventy-four preterm infants being born SGA (birth weight <10th percentile) were compared with 74 appropriate for gestational age (AGA) infants matched prospectively according to gestational age with respect to growth parameters and neurodevelopment (using Griffiths developmental scores) at the age of 22 months corrected age. Results: Birth weight was significantly lower in SGA-infants compared to AGA-infants (1503 g (430–2205 g) versus 1995 g (680–3300 g); P < 0:0001 (median and range)). There were no significant differences regarding the median gestational age (34 weeks), gender distribution, mode of delivery, umbilical artery pH, and APGAR-scores. Mean Griffiths-scores did not differ significantly between both groups (96.7% versus 97.6%). Developmental retardation was diagnosed in 9 SGA-infants versus 10 AGA-infants. Within the total group a positive correlation was observed between gestational age and developmental scoring. Body weight, head circumference, and height were significantly lower in SGA-infants at 22 months corrected age. Conclusion: No significant differences regarding neurodevelopmental outcome at 22 months were observed between SGA- and AGA-infants. SGA-infants did not show catch-up growth. # 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Intrauterine growth; Small for gestational age; Preterm neonate; Neonatal outcome; Neurodevelopmental outcome
1. Introduction Restricted intrauterine growth results from various maternal and fetal disorders. Underlying disorders largely depend on the population investigated and include starvation in Third World countries whereas in Western countries utero-placental insufficiency and substance abuse are considered to be the main factors influencing birth weight. Congenital malformations, chromosomal disorders, and intrauterine infections are less frequent causes of restricted intrauterine growth [1]. Restricted intrauterine growth is not only considered as a problem in neonatal medicine but also as a life-long risk factor for cardiac and metabolic disorders [2]. Focusing the neonatal period, restricted intrauterine growth is associated with an increased risk for neonatal *
Corresponding author. Tel.: þ49-641-99-43410; fax: þ49-641-99-43419. E-mail address: [email protected] (L. Gortner).
mortality and morbidity, especially in preterm infants [3,4]. Studies investigating the neurodevelopmental outcome of infants being born small for gestational age (SGA) compared with those being born appropriate for gestational age (AGA) show controversial results. This might be explained by different definitions of restricted intrauterine growth, by different time intervals of follow-up examinations, by different methods used to evaluate the neurodevelopmental outcome, and by different pathophysiologies underlying the restricted intrauterine growth. In order to obtain data on the prevalence of developmental delay in SGA-preterm infants compared with AGA-preterms, we conducted a prospective trial enrolling preterm newborns from a level-3 perinatal center in Germany. We hypothesized that at 20–22 months corrected postnatal age preterms being born SGA have a lower developmental performance than AGA-preterms. We further hypothesized that somatic growth of SGA-preterms is below the range observed in AGA-infants.
0301-2115/$ – see front matter # 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/S0301-2115(03)00178-7
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2. Materials and methods All preterm infants with a gestational age below 36 weeks being born from October 1995 to December 1997 and discharged from Luebeck University Pediatric Hospital, Luebeck, Germany, were enrolled in the study. Parents were provided with a standardized questionnaire in order to evaluate the milestones of development. Infants with a birth weight below the 10th percentile [5] were classified as SGA-infants. Exclusion criteria included gross chromosomal abnormalities, syndromal disorders, and SGA secondary to proven intrauterine infections (positive TORCH serology). SGA-infants were matched to infants whose birth weight was between the 10th and the 90th percentile who were born within the same year and whose gestational age was as close as possible to the respective SGA-infant. We prospectively recorded the following variables: gestational age (according to the last maternal menstrual period), growth parameters, mode of delivery, APGAR-score, umbilical artery pH, number of nucleated red blood cells, oligohydramnios, preeclampsia, preterm labor, prenatal administration of corticosteroids (12 mg of betamethasone administered twice within more than 24 h and less than 7 days before birth), maternal drug abuse, respiratory distress syndrome (diagnosed on the basis of radiographic criteria), need for intubation and mechanical ventilation, bronchopulmonary dysplasia at day 28 (supplemental oxygen at day 28 for pulmonary reasons and pathologic chest X-ray [6]), oxygen dependency on discharge, intraventricular hemorrhage [7], periventricular leukomalacia [8], patent ductus arteriosus [9], necrotizing enterocolitis (stage IIa according to Bell [10]), retinopathy of prematurity, and the number of days in the neonatal intensive care unit. Each child was seen at the corrected postnatal age of 20– 22 months. At this appointment the parents reported about
milestones of development, diseases requiring in-patientcare and growth parameters at 6 and 12 months documented within the regular postnatal follow-up appointments of the German Postnatal Care System using the above-mentioned questionnaire. Griffiths developmental scale testing was performed after a standardized physical and neurological examination [11], which included examination of muscle tone, deep tendon reflexes, motor skills, and coordinative capacities as well as an evaluation of hearing and of eye function. If necessary, otolaryngological or ophthalmologic testing was performed. Griffiths scoring was performed in a standardized way according to the German adaptation [12]. Subscale A represents motor skills, subscale B social abilities, subscale C cognitive abilities, subscale D eye-hand coordination, and subscale E adaptive skills. A moderate developmental delay was diagnosed if the mean result was below 89% (1 S.D.), a moderate to severe developmental retardation was diagnosed if the mean result was below 78% (2 S.D.). If study infants presented later than 24 months corrected postnatal age, the Mu¨ nchener Developmental Scoring System was used [13].
3. Statistical methods Categoric variables were compared by using the w2-test whereas for continuous variables the Mann–Whitney test was used. In order to prove correlations between test results and basic characteristics of study infants the Spearman rank correlation coefficient was used. Differences in terms of developmental testing were proved for their predictive value using the ROC analysis according to Hanley and McNeil. Data were analyzed using SPSS statistical software (SPSS Inc., Chicago, Illinois, USA). A difference in statistical significance was considered if the P-value was <0.05. The study was approved by the Committee on Investigations in Human Subjects at the University of Luebeck.
Table 1 Basic prenatal and neonatal characteristics of study infants
Maternal diabetes, n (%) Chorioamnionitis, n (%) Oligohydramnios, n (%) Preeclampsia, n (%) Prenatal steroids, n (%) Maternal substance abusea, n (%) Gestational age (weeks and days) Gender (male/female) Birth weight (g) Height (cm)b Head circumference (cm) Multiple births n.s.: not significant. a Incomplete data. b Median and range.
SGA-infants (n ¼ 74)
AGA-infants (n ¼ 74)
P
2 (2.7) 9 (12.2) 19 (25.7) 25 (33.8) 21 (28.2) 21 (29.2) 33 þ 6.5 (24 þ 4 36 þ 6)b 36/38 1502.5 (430–2205)b 41 (26–47)b 29.5 22
1 (1.4) 22 (29.7) 6 (8.1) 7 (9.5) 14 (18.9) 17 (23.6) 34 þ 0 (24 þ 2 36 þ 5)b 43/31 1995 (680–3300)b 44 (32–52)b 31 26
n.s. 0.014 0.008 0.001 n.s. n.s. n.s. n.s. <0.0001 <0.0001 <0.0001 n.s.
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neonatal period. An overview is given in Table 2. A total of 127 study infants could be included in the follow-up examination at a corrected median age of 22 months. Body weight, body length and the head circumference were significantly lower in SGA-neonates compared to AGA-infants at the time of the follow-up examination as well as at the age of 6 and 12 months. An overview is given in Table 3. No statistically significant differences could be observed between SGA- and AGA-infants regarding the following milestones of development: eye-hand coordination (3 months versus 2 months), creeping or crawling (median 8 months each), sitting up alone (median 8 months each), first words (median 11 months each), and walking alone (median 14 months versus 13 months). The rate of need for hearing aids, ophthalmologic treatment, physiotherapy, and hospitalization was similar in both groups. There was a tendency towards a higher rate of the diagnosis of failure to thrive in the SGA group. Statistical analysis of the Griffiths-testing for the different items is given in Table 4. A complete
4. Results A total of 74 SGA-infants were enrolled and matched with 74 AGA-infants. Prenatal and basic neonatal characteristics of study infants are given in Table 1. As expected the incidence of preeclampsia and HELLP-syndrome as well as oligohydramnios was higher in SGA-infants. Birth weight, length, and head circumference were significantly lower in SGA-infants. Three infants in the SGA group and eight infants in the control group were outborn. Numbers of nucleated red blood cells were increased (P < 0:0001) in SGA-infants. All other neonatal variables including umbilical artery pH and APGAR-scores at 1, 5, and 10 min were without any statistical difference. During the neonatal period no differences were observed concerning the incidence of neurological complications, the incidence of respiratory distress syndrome and its complications as well as the incidence of bronchopulmonary dysplasia and other complications of prematurity diagnosed during the Table 2 Complications during the neonatal period
SGA-infants (n ¼ 74) Neurological complications Intraventricular hemorrhage (total), n (%) Intraventricular hemorrhage III, n (%) Periventricular leukomalacia, n (%) Posthemorrhagic hydrocephalus, n (%) Pulmonary and extrapulmonary complications Respiratory distress syndrome (total), n (%) Respiratory distress syndrome III, n (%) Mechanical ventilation, n (%) Pneumothorax, n (%) Surfactant administration, n (%) Ventilation >7 days, n (%) Oxygen dependency at discharge, n (%) Bronchopulmonary dysplasia (day 28), n (%) Patent ductus arteriosus, n (%) Necrotizing enterocolitis (IIa), n (%) Nosocomial sepsis, n (%) Retinopathy of prematurity III, n (%)
4 (5.4) 0 0 0 35 9 17 4 12 5 3 7 2 1 3 3
(47.3) (12.2) (23.0) (5.4) (16.2) (6.8) (4.1) (9.5) (2.7) (1.4) (4.1) (4.1)
AGA-infants (n ¼ 74)
P
6 4 1 3
(8.1) (5.4) (1.4) (4.1)
n.s. n.s. n.s. n.s.
30 8 24 3 16 7 0 2 2 1 2 2
(40.5) (10.8) (32.4) (4.1) (21.6) (9.5)
n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s.
(2.7) (2.7) (1.4) (2.7) (2.7)
Table 3 Somatic growth in study infants at follow-up Age
Variable
SGA-infants (n ¼ 74)
AGA-infants (n ¼ 74)
P
6 months (median)
Body weight (kg) Body height (cm) Head circumference (cm)
6.535 (3.16–8.43) 64 (51–69) 42.35 (37–45)
7.45 (4.25–11) 67 (53–74) 43 (37–48)
<0.0001 <0.0001 0.026
12 months (median)
Body weight (kg) Body height (cm) Head circumference (cm)
8.08 (5.68–10.55) 72 (64–79) 45 (40.5–49)
9.285 (6.45–13) 74.25 (65–84) 45.5 (42–50)
<0.0001 0.001 0.036
22 months (median)
Body weight (kg) Body height (cm) Head circumference (cm)
10.5 (4.66–16.3) 83.5 (62–97.4) 47.85 (38–55)
12.2 (7.4–16.4) 86 (76.3–94) 48.5 (42.5–53)
<0.0001 0.005 0.016
All values are given as median and ranges.
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Table 4 Griffiths scores in study infants
Developmental Developmental Developmental Developmental Developmental
score—subscale score—subscale score—subscale score—subscale score—subscale
A (%) B (%) C (%) D (%) E (%)
Overall developmental rate Corrected postnatal age at follow-up (months)
SGA-infants (n ¼ 63)
AGA-infants (n ¼ 64)
P
97.7 (93.5–102.4) 97.6 (92–102.2) 91.7 (82.2–100) 97.7 (93–102.6) 100 (94.4–106.7)
97.7 (93.2–102.4) 96.65 (90.9–104.8) 94.5 (81.98–102.38) 97.65 (93.3–102.4) 100 (92.98–109.1)
n.s. n.s. n.s. n.s. n.s.
SGA-infants (n ¼ 64)
AGA-infants (n ¼ 64)
P
96.67 (92.78–100.78) 22 (21–23)
97.56 (92.61–103.03) 22 (21–24.125)
n.s. n.s.
All values are given as median and ranges.
Griffiths scale was performed in 63 SGA-infants and 64 AGA-infants. No differences were observed throughout the subscales with a tendency towards an improved performance in the AGA group in subscale C (cognitive abilities). In one infant, no Griffiths-testing was possible as neurological examination revealed severe cerebral palsy. The analysis of the subgroups of very preterm infants of <30 weeks gestational age revealed no differences between both groups in all Griffiths-subsets; in infants >30 weeks gestational age, only a marginal significant difference was observed in subscale B (social abilities). Ten infants in each study group were seen at an age of more than 24 months corrected postnatal age and were examined by using the Mu¨ nchener developmental score: eight infants in both groups were classified as normal, two as mildly developmentally retarded. The neurological examination revealed a moderately reduced function in two infants versus four infants, a severe neurological impairment was observed in two infants versus three infants (SGA versus AGA each). Correlation of basic neonatal variables and Griffiths subscale results versus birth weight, respectively, gestational age showed positive correlation for subscales A, B, and E in SGA-infants and A, B, and E in AGA-infants (P < 0:001). None of the study infants died during the follow-up period. One study SGA-infant was still on supplemental oxygen at follow-up examination.
5. Discussion The diagnosis and consequences of intrauterine growth restriction resulting in the birth of an SGA-infant has been debated in the past. The most commonly used definition for SGA is birth weight below the 10th percentile for the corresponding gestational age. We used percentiles that were derived from newborns from various German federal states at the beginning of the 90’s [5]. It must be emphasized that some infants classified as SGA-infants are healthy normal infants. These neonates are at the lower end of the normal distribution of birth weights due to constitutional
reasons. Thus not each SGA-infant is the result of restricted intrauterine growth. Intrauterine growth restriction in sensu strictu implies the deviation from the genetically programmed growth potential leading to a deviation from the respective percentile. We could not demonstrate statistically significant differences between SGA- and AGA-infants with respect to developmental test results and neurological outcome. As we matched infants of the same gestational age the factor of different degrees of immaturity in both groups has been excluded. Comparable results have been obtained by Robertson et al. [14] who compared preterm SGA-infants with preterm AGA-infants of the same gestational age at the age of 8 years. Our results are not consistent with two North American studies. Sung et al. [15] showed SGA-infants to score lower on developmental tests at 1–3 years than gestation-matched AGA-infants. McCarton et al. showed SGAinfants to have significantly poorer cognitive scores at 1–3, 5 and/or 6 years of age when compared with AGA-infants of similar gestational ages [16]. Differences in study results may in part be explained by the number of infants lost to follow-up during the study period and by different developmental tests. We used a commonly accepted developmental scale as well as an internationally used classification of the neurological examination [11] in order to be able to compare our results to other studies. As only a very small percentage of initially enrolled babies was lost on follow-up this factor is not likely to influence the results of our study. Our results on developmental and neurological outcome are in accordance with a recently published study from the Netherlands [17]. This study showed restricted intrauterine growth not to be a risk factor for adverse developmental outcome. This study further showed that low gestational age and low birth weight are major predictive factors for adverse neurological and developmental outcome which is consistent with our results. No clear conclusion can be drawn from animal models with respect to the impact of restricted intrauterine growth on fetal central nervous system development. In a lamb model restricted intrauterine growth could be shown to lead to a reduced birth weight with reduced weight of the heart,
L. Gortner et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 110 (2003) S93–S97
the thymus, the liver, and the lung [18]. However, the weight of the brain of growth-restricted lambs did not differ from that of control animals [18]. In a rat model of intrauterine growth retardation abnormal cerebral neuronal migration could be demonstrated [19]. In our study, the incidences of neonatal neurological complications attributable to prematurity, i.e. intraventricular hemorrhage and periventricular leukomalacia did not differ significantly between SGA- and AGA-preterms. Thus, these risk factors for poor neurological and developmental outcome were equally distributed. Similar rates of neonatal neurological complications attributable to prematurity were shown in very preterm neonates enrolled in a German multicenter trial [4] and in an epidemiological study [20]. Our study showed a poor postnatal growth until the age of 20–22 months corrected age in the SGA group. Thus, catchup growth resulting in growth parameters comparable to those of the AGA group could not be demonstrated. Our findings suggest a successful compensation of neurological development to intrauterine growth restriction whereas there is no compensation with respect to growth. In conclusion, we were unable to confirm the hypothesis that SGA-infants have a higher risk for adverse neurological and developmental outcome compared with AGA-infants. These data should be considered for prenatal counseling. As low gestational age and low birth weight were demonstrated to be main factors for impaired neurodevelopmental outcome prevention of preterm delivery of low birth weight babies still represents a major tool in perinatal medicine.
References [1] Resnik R. Intrauterine growth restriction. Obstet Gynecol 2002; 99(3):490–6. [2] Barker DJ. In utero programming of chronic disease. Clin Sci (Colch) 1998;95(2):115–28. [3] Wang KG, Chen CP, Yang JM, Su TH. Impact of reverse end-diastolic flow velocity in umbilical artery on pregnancy outcome after the 28th gestational week. Acta Obstet Gynecol Scand 1998;77(5): 527–31. [4] Gortner L, Wauer RR, Stock GJ, Reiter HL, Reiss I, Jorch G, et al. Neonatal outcome in small for gestational age infants: do they really better. J Perinat Med 1999;27(6):484–9.
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[5] Voigt M, Schneider KT, Jahrig K. Analysis of a 1992 birth sample in Germany. Part 1. New percentile values of the body weight of newborn infants. Geburtshilfe Frauenheilkd 1996;56(10):550–8. [6] Toce SS, Farrell PM, Leavitt LA, Samuels DP, Edwards DK. Clinical and roentgenographic scoring systems for assessing bronchopulmonary dysplasia. Am J Dis Child 1984;138(6):581–5. [7] Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1500 g. J Pediatr 1978;92(4):529–34. [8] Hill A, Melson GL, Clark HB, Volpe JJ. Hemorrhagic periventricular leukomalacia: diagnosis by real time ultrasound and correlation with autopsy findings. Pediatrics 1982;69(3):282–4. [9] Gersony WM. Patent ductus arteriosus in the neonate. Pediatr Clin North Am 1986;33:545–60. [10] Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg 1978;187(1):1–7. [11] Hagberg G, Olow I. The changing panorama of cerebral palsy in Sweden 1954–1970. Part II. Analysis of the various syndromes. Acta Paediatr Scand 1975;64(2):193–200. [12] Griffiths R. Griffiths Entwicklungsskalen (GES) zur Beurteilung der Entwicklung in den ersten beiden Lebensjahren. Weinheim-Basel: Beltz; 1983. [13] Hellbru¨ gge T. Mu¨ nchener funktionelle Entwicklungsdiagnostik fu¨ r das 2. und 3. Lebensjahr. 4 ed. Mu¨ nchen: Deutsche Akademie fu¨ r Entwicklungsrehabilitation. [14] Robertson CM, Etches PC, Kyle JM. Eight-year school performance and growth of preterm, small for gestational age infants: a comparative study with subjects matched for birth weight or for gestational age. J Pediatr 1990;116(1):19–26. [15] Sung IK, Vohr B, Oh W. Growth and neurodevelopmental outcome of very low birth weight infants with intrauterine growth retardation: comparison with control subjects matched by birth weight and gestational age. J Pediatr 1993;123(4):618–24. [16] McCarton CM, Wallace IF, Divon M, Vaughan HG. Cognitive and neurologic development of the premature, small for gestational age infant through age 6: comparison by birth weight and gestational age. Pediatrics 1996;98(6 Pt 1):1167–78. [17] Vermeulen GM, Bruinse HW, de Vries LS. Perinatal risk factors for adverse neurodevelopmental outcome after spontaneous preterm birth. Eur J Obstet Gynecol Reprod Biol 2001;99(2):207–12. [18] Lang U, Baker RS, Khoury J, Clark KE. Effects of chronic reduction in uterine blood flow on fetal and placental growth in the sheep. Am J Physiol Regul Integr Comp Physiol 2000;279(1):R53–9. [19] Sasaki J, Fukami E, Mimura S, Hayakawa M, Kitoh J, Watanabe K. Abnormal cerebral neuronal migration in a rat model of intrauterine growth retardation induced by synthetic thromboxane A(2). Early Hum Dev 2000;58(2):91–9. [20] Reiss I, Landmann E, Heckmann M, Misselwitz B, Gortner L. Increased risk of bronchopulmonary dysplasia and increase mortality in very preterm infants being small for gestational age. Arch Gynecol Obstet 2003 [in press].
Outcome in preterm small for gestational age infants compared to appropriate for gestational age preterms at the age of 2 years: a prospective study Ludwig Gortnera,*, Michael van Husenb, Ute Thyenb, Ulrich Gembruchc, Hans-Ju¨rgen Friedrichd, Eva Landmanna a
Department of Neonatology, Pediatric Center, Justus Liebig University, Feulgenstr. 12, Giessen D-35383, Germany b Pediatric University Hospital, Medical University, Luebeck, Germany c Department of Obstetrics and Gynecology, Medical University, Luebeck, Germany d Department of Medical Statistics, Medical University, Luebeck, Germany
Abstract Objectives: To investigate the effects of small for gestational age (SGA) in preterm infants on growth and development until the age of 22 months. Study design: Seventy-four preterm infants being born SGA (birth weight <10th percentile) were compared with 74 appropriate for gestational age (AGA) infants matched prospectively according to gestational age with respect to growth parameters and neurodevelopment (using Griffiths developmental scores) at the age of 22 months corrected age. Results: Birth weight was significantly lower in SGA-infants compared to AGA-infants (1503 g (430–2205 g) versus 1995 g (680–3300 g); P < 0:0001 (median and range)). There were no significant differences regarding the median gestational age (34 weeks), gender distribution, mode of delivery, umbilical artery pH, and APGAR-scores. Mean Griffiths-scores did not differ significantly between both groups (96.7% versus 97.6%). Developmental retardation was diagnosed in 9 SGA-infants versus 10 AGA-infants. Within the total group a positive correlation was observed between gestational age and developmental scoring. Body weight, head circumference, and height were significantly lower in SGA-infants at 22 months corrected age. Conclusion: No significant differences regarding neurodevelopmental outcome at 22 months were observed between SGA- and AGA-infants. SGA-infants did not show catch-up growth. # 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Intrauterine growth; Small for gestational age; Preterm neonate; Neonatal outcome; Neurodevelopmental outcome
1. Introduction Restricted intrauterine growth results from various maternal and fetal disorders. Underlying disorders largely depend on the population investigated and include starvation in Third World countries whereas in Western countries utero-placental insufficiency and substance abuse are considered to be the main factors influencing birth weight. Congenital malformations, chromosomal disorders, and intrauterine infections are less frequent causes of restricted intrauterine growth [1]. Restricted intrauterine growth is not only considered as a problem in neonatal medicine but also as a life-long risk factor for cardiac and metabolic disorders [2]. Focusing the neonatal period, restricted intrauterine growth is associated with an increased risk for neonatal *
Corresponding author. Tel.: þ49-641-99-43410; fax: þ49-641-99-43419. E-mail address: [email protected] (L. Gortner).
mortality and morbidity, especially in preterm infants [3,4]. Studies investigating the neurodevelopmental outcome of infants being born small for gestational age (SGA) compared with those being born appropriate for gestational age (AGA) show controversial results. This might be explained by different definitions of restricted intrauterine growth, by different time intervals of follow-up examinations, by different methods used to evaluate the neurodevelopmental outcome, and by different pathophysiologies underlying the restricted intrauterine growth. In order to obtain data on the prevalence of developmental delay in SGA-preterm infants compared with AGA-preterms, we conducted a prospective trial enrolling preterm newborns from a level-3 perinatal center in Germany. We hypothesized that at 20–22 months corrected postnatal age preterms being born SGA have a lower developmental performance than AGA-preterms. We further hypothesized that somatic growth of SGA-preterms is below the range observed in AGA-infants.
0301-2115/$ – see front matter # 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/S0301-2115(03)00178-7
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2. Materials and methods All preterm infants with a gestational age below 36 weeks being born from October 1995 to December 1997 and discharged from Luebeck University Pediatric Hospital, Luebeck, Germany, were enrolled in the study. Parents were provided with a standardized questionnaire in order to evaluate the milestones of development. Infants with a birth weight below the 10th percentile [5] were classified as SGA-infants. Exclusion criteria included gross chromosomal abnormalities, syndromal disorders, and SGA secondary to proven intrauterine infections (positive TORCH serology). SGA-infants were matched to infants whose birth weight was between the 10th and the 90th percentile who were born within the same year and whose gestational age was as close as possible to the respective SGA-infant. We prospectively recorded the following variables: gestational age (according to the last maternal menstrual period), growth parameters, mode of delivery, APGAR-score, umbilical artery pH, number of nucleated red blood cells, oligohydramnios, preeclampsia, preterm labor, prenatal administration of corticosteroids (12 mg of betamethasone administered twice within more than 24 h and less than 7 days before birth), maternal drug abuse, respiratory distress syndrome (diagnosed on the basis of radiographic criteria), need for intubation and mechanical ventilation, bronchopulmonary dysplasia at day 28 (supplemental oxygen at day 28 for pulmonary reasons and pathologic chest X-ray [6]), oxygen dependency on discharge, intraventricular hemorrhage [7], periventricular leukomalacia [8], patent ductus arteriosus [9], necrotizing enterocolitis (stage IIa according to Bell [10]), retinopathy of prematurity, and the number of days in the neonatal intensive care unit. Each child was seen at the corrected postnatal age of 20– 22 months. At this appointment the parents reported about
milestones of development, diseases requiring in-patientcare and growth parameters at 6 and 12 months documented within the regular postnatal follow-up appointments of the German Postnatal Care System using the above-mentioned questionnaire. Griffiths developmental scale testing was performed after a standardized physical and neurological examination [11], which included examination of muscle tone, deep tendon reflexes, motor skills, and coordinative capacities as well as an evaluation of hearing and of eye function. If necessary, otolaryngological or ophthalmologic testing was performed. Griffiths scoring was performed in a standardized way according to the German adaptation [12]. Subscale A represents motor skills, subscale B social abilities, subscale C cognitive abilities, subscale D eye-hand coordination, and subscale E adaptive skills. A moderate developmental delay was diagnosed if the mean result was below 89% (1 S.D.), a moderate to severe developmental retardation was diagnosed if the mean result was below 78% (2 S.D.). If study infants presented later than 24 months corrected postnatal age, the Mu¨ nchener Developmental Scoring System was used [13].
3. Statistical methods Categoric variables were compared by using the w2-test whereas for continuous variables the Mann–Whitney test was used. In order to prove correlations between test results and basic characteristics of study infants the Spearman rank correlation coefficient was used. Differences in terms of developmental testing were proved for their predictive value using the ROC analysis according to Hanley and McNeil. Data were analyzed using SPSS statistical software (SPSS Inc., Chicago, Illinois, USA). A difference in statistical significance was considered if the P-value was <0.05. The study was approved by the Committee on Investigations in Human Subjects at the University of Luebeck.
Table 1 Basic prenatal and neonatal characteristics of study infants
Maternal diabetes, n (%) Chorioamnionitis, n (%) Oligohydramnios, n (%) Preeclampsia, n (%) Prenatal steroids, n (%) Maternal substance abusea, n (%) Gestational age (weeks and days) Gender (male/female) Birth weight (g) Height (cm)b Head circumference (cm) Multiple births n.s.: not significant. a Incomplete data. b Median and range.
SGA-infants (n ¼ 74)
AGA-infants (n ¼ 74)
P
2 (2.7) 9 (12.2) 19 (25.7) 25 (33.8) 21 (28.2) 21 (29.2) 33 þ 6.5 (24 þ 4 36 þ 6)b 36/38 1502.5 (430–2205)b 41 (26–47)b 29.5 22
1 (1.4) 22 (29.7) 6 (8.1) 7 (9.5) 14 (18.9) 17 (23.6) 34 þ 0 (24 þ 2 36 þ 5)b 43/31 1995 (680–3300)b 44 (32–52)b 31 26
n.s. 0.014 0.008 0.001 n.s. n.s. n.s. n.s. <0.0001 <0.0001 <0.0001 n.s.
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neonatal period. An overview is given in Table 2. A total of 127 study infants could be included in the follow-up examination at a corrected median age of 22 months. Body weight, body length and the head circumference were significantly lower in SGA-neonates compared to AGA-infants at the time of the follow-up examination as well as at the age of 6 and 12 months. An overview is given in Table 3. No statistically significant differences could be observed between SGA- and AGA-infants regarding the following milestones of development: eye-hand coordination (3 months versus 2 months), creeping or crawling (median 8 months each), sitting up alone (median 8 months each), first words (median 11 months each), and walking alone (median 14 months versus 13 months). The rate of need for hearing aids, ophthalmologic treatment, physiotherapy, and hospitalization was similar in both groups. There was a tendency towards a higher rate of the diagnosis of failure to thrive in the SGA group. Statistical analysis of the Griffiths-testing for the different items is given in Table 4. A complete
4. Results A total of 74 SGA-infants were enrolled and matched with 74 AGA-infants. Prenatal and basic neonatal characteristics of study infants are given in Table 1. As expected the incidence of preeclampsia and HELLP-syndrome as well as oligohydramnios was higher in SGA-infants. Birth weight, length, and head circumference were significantly lower in SGA-infants. Three infants in the SGA group and eight infants in the control group were outborn. Numbers of nucleated red blood cells were increased (P < 0:0001) in SGA-infants. All other neonatal variables including umbilical artery pH and APGAR-scores at 1, 5, and 10 min were without any statistical difference. During the neonatal period no differences were observed concerning the incidence of neurological complications, the incidence of respiratory distress syndrome and its complications as well as the incidence of bronchopulmonary dysplasia and other complications of prematurity diagnosed during the Table 2 Complications during the neonatal period
SGA-infants (n ¼ 74) Neurological complications Intraventricular hemorrhage (total), n (%) Intraventricular hemorrhage III, n (%) Periventricular leukomalacia, n (%) Posthemorrhagic hydrocephalus, n (%) Pulmonary and extrapulmonary complications Respiratory distress syndrome (total), n (%) Respiratory distress syndrome III, n (%) Mechanical ventilation, n (%) Pneumothorax, n (%) Surfactant administration, n (%) Ventilation >7 days, n (%) Oxygen dependency at discharge, n (%) Bronchopulmonary dysplasia (day 28), n (%) Patent ductus arteriosus, n (%) Necrotizing enterocolitis (IIa), n (%) Nosocomial sepsis, n (%) Retinopathy of prematurity III, n (%)
4 (5.4) 0 0 0 35 9 17 4 12 5 3 7 2 1 3 3
(47.3) (12.2) (23.0) (5.4) (16.2) (6.8) (4.1) (9.5) (2.7) (1.4) (4.1) (4.1)
AGA-infants (n ¼ 74)
P
6 4 1 3
(8.1) (5.4) (1.4) (4.1)
n.s. n.s. n.s. n.s.
30 8 24 3 16 7 0 2 2 1 2 2
(40.5) (10.8) (32.4) (4.1) (21.6) (9.5)
n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s.
(2.7) (2.7) (1.4) (2.7) (2.7)
Table 3 Somatic growth in study infants at follow-up Age
Variable
SGA-infants (n ¼ 74)
AGA-infants (n ¼ 74)
P
6 months (median)
Body weight (kg) Body height (cm) Head circumference (cm)
6.535 (3.16–8.43) 64 (51–69) 42.35 (37–45)
7.45 (4.25–11) 67 (53–74) 43 (37–48)
<0.0001 <0.0001 0.026
12 months (median)
Body weight (kg) Body height (cm) Head circumference (cm)
8.08 (5.68–10.55) 72 (64–79) 45 (40.5–49)
9.285 (6.45–13) 74.25 (65–84) 45.5 (42–50)
<0.0001 0.001 0.036
22 months (median)
Body weight (kg) Body height (cm) Head circumference (cm)
10.5 (4.66–16.3) 83.5 (62–97.4) 47.85 (38–55)
12.2 (7.4–16.4) 86 (76.3–94) 48.5 (42.5–53)
<0.0001 0.005 0.016
All values are given as median and ranges.
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Table 4 Griffiths scores in study infants
Developmental Developmental Developmental Developmental Developmental
score—subscale score—subscale score—subscale score—subscale score—subscale
A (%) B (%) C (%) D (%) E (%)
Overall developmental rate Corrected postnatal age at follow-up (months)
SGA-infants (n ¼ 63)
AGA-infants (n ¼ 64)
P
97.7 (93.5–102.4) 97.6 (92–102.2) 91.7 (82.2–100) 97.7 (93–102.6) 100 (94.4–106.7)
97.7 (93.2–102.4) 96.65 (90.9–104.8) 94.5 (81.98–102.38) 97.65 (93.3–102.4) 100 (92.98–109.1)
n.s. n.s. n.s. n.s. n.s.
SGA-infants (n ¼ 64)
AGA-infants (n ¼ 64)
P
96.67 (92.78–100.78) 22 (21–23)
97.56 (92.61–103.03) 22 (21–24.125)
n.s. n.s.
All values are given as median and ranges.
Griffiths scale was performed in 63 SGA-infants and 64 AGA-infants. No differences were observed throughout the subscales with a tendency towards an improved performance in the AGA group in subscale C (cognitive abilities). In one infant, no Griffiths-testing was possible as neurological examination revealed severe cerebral palsy. The analysis of the subgroups of very preterm infants of <30 weeks gestational age revealed no differences between both groups in all Griffiths-subsets; in infants >30 weeks gestational age, only a marginal significant difference was observed in subscale B (social abilities). Ten infants in each study group were seen at an age of more than 24 months corrected postnatal age and were examined by using the Mu¨ nchener developmental score: eight infants in both groups were classified as normal, two as mildly developmentally retarded. The neurological examination revealed a moderately reduced function in two infants versus four infants, a severe neurological impairment was observed in two infants versus three infants (SGA versus AGA each). Correlation of basic neonatal variables and Griffiths subscale results versus birth weight, respectively, gestational age showed positive correlation for subscales A, B, and E in SGA-infants and A, B, and E in AGA-infants (P < 0:001). None of the study infants died during the follow-up period. One study SGA-infant was still on supplemental oxygen at follow-up examination.
5. Discussion The diagnosis and consequences of intrauterine growth restriction resulting in the birth of an SGA-infant has been debated in the past. The most commonly used definition for SGA is birth weight below the 10th percentile for the corresponding gestational age. We used percentiles that were derived from newborns from various German federal states at the beginning of the 90’s [5]. It must be emphasized that some infants classified as SGA-infants are healthy normal infants. These neonates are at the lower end of the normal distribution of birth weights due to constitutional
reasons. Thus not each SGA-infant is the result of restricted intrauterine growth. Intrauterine growth restriction in sensu strictu implies the deviation from the genetically programmed growth potential leading to a deviation from the respective percentile. We could not demonstrate statistically significant differences between SGA- and AGA-infants with respect to developmental test results and neurological outcome. As we matched infants of the same gestational age the factor of different degrees of immaturity in both groups has been excluded. Comparable results have been obtained by Robertson et al. [14] who compared preterm SGA-infants with preterm AGA-infants of the same gestational age at the age of 8 years. Our results are not consistent with two North American studies. Sung et al. [15] showed SGA-infants to score lower on developmental tests at 1–3 years than gestation-matched AGA-infants. McCarton et al. showed SGAinfants to have significantly poorer cognitive scores at 1–3, 5 and/or 6 years of age when compared with AGA-infants of similar gestational ages [16]. Differences in study results may in part be explained by the number of infants lost to follow-up during the study period and by different developmental tests. We used a commonly accepted developmental scale as well as an internationally used classification of the neurological examination [11] in order to be able to compare our results to other studies. As only a very small percentage of initially enrolled babies was lost on follow-up this factor is not likely to influence the results of our study. Our results on developmental and neurological outcome are in accordance with a recently published study from the Netherlands [17]. This study showed restricted intrauterine growth not to be a risk factor for adverse developmental outcome. This study further showed that low gestational age and low birth weight are major predictive factors for adverse neurological and developmental outcome which is consistent with our results. No clear conclusion can be drawn from animal models with respect to the impact of restricted intrauterine growth on fetal central nervous system development. In a lamb model restricted intrauterine growth could be shown to lead to a reduced birth weight with reduced weight of the heart,
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the thymus, the liver, and the lung [18]. However, the weight of the brain of growth-restricted lambs did not differ from that of control animals [18]. In a rat model of intrauterine growth retardation abnormal cerebral neuronal migration could be demonstrated [19]. In our study, the incidences of neonatal neurological complications attributable to prematurity, i.e. intraventricular hemorrhage and periventricular leukomalacia did not differ significantly between SGA- and AGA-preterms. Thus, these risk factors for poor neurological and developmental outcome were equally distributed. Similar rates of neonatal neurological complications attributable to prematurity were shown in very preterm neonates enrolled in a German multicenter trial [4] and in an epidemiological study [20]. Our study showed a poor postnatal growth until the age of 20–22 months corrected age in the SGA group. Thus, catchup growth resulting in growth parameters comparable to those of the AGA group could not be demonstrated. Our findings suggest a successful compensation of neurological development to intrauterine growth restriction whereas there is no compensation with respect to growth. In conclusion, we were unable to confirm the hypothesis that SGA-infants have a higher risk for adverse neurological and developmental outcome compared with AGA-infants. These data should be considered for prenatal counseling. As low gestational age and low birth weight were demonstrated to be main factors for impaired neurodevelopmental outcome prevention of preterm delivery of low birth weight babies still represents a major tool in perinatal medicine.
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