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* Hospital for Children and Adolescents, Helsinki University Central Hospital, Helsinki, Finland
National Research and Development Center for Welfare and Health, Helsinki, Finland
Turku University Central Hospital, Turku, Finland
|| Tampere University Hospital, Tampere, Finland
¶ Kuopio University Hospital, Kuopio, Finland
# Oulu University Central Hospital, Oulu, Finland
** Åbo Academi University, Turku, Finland
Department of Pediatrics, Lund University, Lund, Sweden
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Methods. Of all live-born ELBW infants (n = 351) who were delivered in the 2-year period 1996–1997 in Finland, 206 (59%) survived until the age of 5 years. Of these, 103 were born at <27 gestational weeks (GW). A total of 172 children were assessed with neurocognitive tests (Wechsler Preschool and Primary Scale of Intelligence–Revised and a Developmental Neuropsychological Assessment [NEPSY]). Nine children with cognitive impairment and inability to cooperate in testing were not assessed. Motor development was assessed with a modified Touwen test.
Results. The rate of cognitive impairment in the ELBW survivors was 9%. The rate of cerebral palsy was 14% (19% of ELBW infants who were born at <27 GW). The mean full-scale IQ of the assessed children was 96 ± 19 and in children of GW <27 was 94 ± 19. Attention, language, sensorimotor, visuospatial, and verbal memory values of NEPSY assessment were significantly poorer compared with normal population means. Four percent needed a hearing aid, and 30% had ophthalmic findings. Of 21 children who had been treated with laser/cryo for retinopathy of prematurity, 17 (81%) had abnormal ophthalmic findings. Of the whole cohort, 41 (20%) exhibited major disabilities, 38 (19%) exhibited minor disabilities, and 124 (61%) showed development with no functional abnormalities but subtle departures from the norm. Only 53 (26%) of the total ELBW infant cohort were classified to have normal outcome excluding any abnormal ophthalmic, auditory, neurologic, or developmental findings. Being small for gestational age at birth was associated with suboptimal growth at least until age 5.
Conclusions. Only one fourth of the ELBW infants were classified as normally developed at age 5. The high rate of cognitive dysfunction suggests an increased risk for learning difficulties that needs to be evaluated at a later age. Extended follow-up should be the rule in outcome studies of ELBW infant cohorts to elucidate the impact of immaturity on school achievement and social behavior later in life.
Key Words: extremely preterm infants • neurocognitive function • developmental follow-up • neurologic outcome • long-term outcome
Abbreviations: ELBW, extremely low birth weight • CP, cerebral palsy • GW, gestational weeks • SGA, small for gestational age • AGA, appropriate for gestational age • MND, minor neurological dysfunction • WPPSI-R, the Wechsler Preschool and Primary Scale of Intelligence–Revised • ROP, retinopathy of prematurity • NEPSY, Developmental Neuropsychological Assessment • CI, confidence interval • OR, odds ratio
The increasing survival of extremely low birth weight (ELBW; birth weight <1000 g) infants1,2 and in particular that of the extremely immature infants of gestational age <26 weeks has raised concerns as to the increasing prevalence of adverse neurodevelopmental outcome.3,4 The neurologic disability rate has remained similar or only slightly decreased, despite decreasing mortality.5 Severe handicaps, such as cerebral palsy (CP), deafness, blindness, and cognitive impairment, have occurred in as many as in 15% to 25% of infants who were born in the 1990s,5 with even higher prevalences of cognitive dysfunction and learning disability in cohorts of several nationalities who were born in the presurfactant era.6,7 Prevalences seem similar despite differing cultural environments.8 In addition, problems in behavior and social interaction in adolescence are common.9 These long-term follow-up studies have been conducted on premature infants who were born before present perinatal treatment strategies, which include antenatal steroids, optimal delivery planning, surfactant administration, new strategies of ventilatory assistance, individualized care, and avoidance of postnatal steroids. Several risk factors for adverse outcome have been identified, such as chorioamnionitis,10 intrauterine growth restriction,11 and delivery outside a tertiary center.12,13 For assessing the risks for sequelae in immature infants who are born nowadays, new and recent population-based cohorts should be studied during long-term follow-up.
The aim of this prospective study was to assess the long-term outcome of a national population-based birth cohort of all ELBW infants who were born during the 2-year period of 1996–1997. The objectives were to assess the 5-year outcome, especially neurodevelopmental and cognitive outcome, in 3 groups: in all ELBW infants, in a subcohort born at <27 gestational weeks (GW), and in those who were small for gestational age (SGA) versus appropriate for gestational age (AGA).
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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A modified partial Touwen test17 was used for the neurologic assessment to detect minor neurologic dysfunction (MND) as well as major impairment. MND was defined as "developmental co-ordination disorder with normal intelligence and without evidence of major neurologic impairment or cognitive impairment."18 Findings of the neurologic examination were scored into 6 functional categories according to Hadders-Algra19: (1) mildly abnormal muscle tone regulation assessed from posture maintenance during standing, sitting, and walking; (2) mildly abnormal reflexes; (3) involuntary choreiform movements; (4) mild coordination problems in finger–nose and fingertip touching, diadochokinesis, walking a straight line, and standing on 1 leg; (5) mild abnormalities in fine manipulation; and (6) other miscellaneous abnormalities, such as brain nerve dysfunction or excess of associated movements. Results of the neurologic examination were classified as (1) normal outcome; (2) simple minor neurologic dysfunction (MND-simple), meaning that 1 or 2 of the 6 main categories were abnormal; (3) complex minor neurologic dysfunction (MND-complex) with 3 or more abnormal; and (4) CP.18
Cognitive development was assessed by the Wechsler Preschool and Primary Scale of Intelligence–Revised (WPPSI-R).20 Cognitive impairment was classified as severe when the IQ was <34, moderate at 35 to 49, and mild at 50 to 69.20 Borderline intelligence was defined at IQ of 70 to 80. Neuropsychological performance was assessed with a Developmental Neuropsychological Assessment (NEPSY) test.21,22 Mean scores were calculated from the following domains: attention and executive functions (the Auditory Attention and Response Set, Visual Attention, and Statue subtests), language (the Phonological Processing, Comprehension of Instructions, and Speeded Naming subtests), sensorimotor function (the Imitating Hand Positions, Visuomotor Precision, and Manual Motor Sequences subtests), visuospatial perception (the Design Copying and Block Construction subtests), and memory and learning (the Memory for Names, Narrative Memory, and Sentence Repetition subtests). Clinical diagnoses of attention deficit and hyperkinesia disorder and dysphasia were collected from patient files.
In the previous 1.5-year follow-up study, neurologic outcome was classified in 3 categories according to number of disabilities detected in the hearing, ophthalmic, motor, and speech assessments, defining normal as absence of impairments; mild as the presence of 1 or 2 impairments; and major as either 3 to 4 impairments or blindness, deafness, CP, or convulsions.15 In this 5-year follow-up, the overall disability was classified into 3 categories: development with no functional abnormalities but subtle departures from the norm; minor disability included mild CP causing motor clumsiness and nonfluent gait, mild neurologic dysfunction, mild cognitive impairment, borderline IQ, severe attention deficit and hyperkinesia disorder, dysphasia, and severe visuomotor dysfunction; major disability included CP except the mild category, severe visual impairment, hearing aid requirement, epilepsy, shunted hydrocephalus, and moderate to severe cognitive impairment. Severe visual impairment was defined as bilateral or unilateral amaurosis, or amblyopia, or a combination of myopia and severe astigmatism
BMI was calculated as usual (weight in kilograms divided by height2 in meters). Height SD z score was calculated from the following equation: observed height – mean height for age/SD (ie, the SD for the normal Finnish population of the same chronologic age and gender).23 Weight-for-height index as a percentage was calculated from the ratio of weight (kg) for height (cm) to the mean weight for height for the normal population of the same chronologic age and gender.23 High social class was defined as a family in which the mother belonged to the upper white-collar class at the time of delivery.24
For statistical analyses, SPSS 12.0.1 for Windows (SPSS, Inc, Chicago, IL) was applied. Analysis of variance, 
2, Student’s independent t test, and Fisher’s exact test served to distinguish group differences of continuous and category variables. Multiple linear and binary logistic regression analyses allowed assessment of risk factors. Independent variables for risk analyses included multiparity, maternal smoking, high social class, preeclampsia, absence of antenatal steroids, multiple birth, gestational age, birth weight, gender, SGA, vaginal delivery, Apgar score <4 at 5 minutes of age, university hospital area (designated A, B C, D, and E providing tertiary care for geographically defined populations), birth outside a tertiary-level hospital, intraventricular hemorrhage grade 3 to 4, perforated necrotizing enterocolitis, oxygen dependency at 36 GW, and retinopathy of prematurity (ROP) grades 3 to 4. All variables were entered stepwise both forward and backward. P < .05 was considered statistically significant, and only significant risk factors are reported with 95% confidence intervals (CIs). This study was approved by the ethics committee of the Hospital for Children and Adolescents, Helsinki University Central Hospital (Helsinki, Finland), the National Research and Development Center for Welfare and Health, and the National Data Protection Ombudsman (Helsinki, Finland).
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Neurologic Outcome
CP was diagnosed in 28 (14%) children; diplegia in 19, tetraplegia in 3, hemiplegia in 2, dystonic CP in 3, and triplegia in 1. Ten (5%) children had epilepsy. In logistic regression analysis with parameters listed in the methods section, a significant risk factor for epilepsy was intraventricular hemorrhage grades 3 to 4 (odds ratio [OR]: 11.7; 95% CI: 2.4–57.8; P = .003). According to the neurologic assessment, 110 (57%) children had normal outcome, 41 (21%) had MND-simple, 14 (7%) had MND-complex, and 28 (14%) had CP. Abnormalities were common in the detailed Touwen functional categories: abnormal posture was evident in 37 (20%) children, abnormal reflexes in 33 (18%), exceptional involuntary movements in 31 (17%), coordination problems in 94 (51%), fine manipulative disorders in 28 (15%), and abnormal brain nerve findings in 20 (11%). In logistic regression analysis, a risk factor for MND (CP not included) was male gender (OR: 2.93; 95% CI: 1.1–7.6; P = .03), and a protective factor was delivery in the largest university hospital area (OR: 0.29; 95% CI: 0.11–0.74; P < .01).
Sensorineural Outcome
ROP had been diagnosed in 86 (42%) infants before term. Of all ELBW infants, 21 (10%) had ROP that needed laser or cryo treatment and that was a significant risk factor for later severe visual impairment (OR: 10.6; 95% CI: 3.2–31.5; P = .001; Fig 2). Of 173 assessed children, 17 (10%) had strabismus, 21 (12%) had myopia, 14 (8%) had astigmatism, 4 (2%) had hypermetropia, 7 (4%) had amblyopia, 4 (2%) had unilateral amaurosis, and 1 (0.6%) had bilateral amaurosis. Severe ophthalmic impairment correlated with verbal IQ (r = –0.25, P = .002), mean language scores in NEPSY (r = –0.24, P = .004), and MND-complex (r = 0.17, P = .03). Eight (4%) children needed a hearing aid, 4 of them having a specific contributory cause (hereditary hypacusis, cerebellar anomaly, ataxia and hypacusis, chromosome 8 inversion, or postnatal cytomegaloviremia).
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Overall Disability
According to the overall disability criteria, 124 (61%) children were considered as having no functional abnormalities, 38 (19%) had minor disabilities, and 41 (20%) had major disabilities. Comorbidity was frequent in the major impairment category; 13 (32%) children had 2 or more impairments of major disability severity. A completely normal outcome excluding any abnormal ophthalmic, auditory, neurologic, or psychological test findings was found in only 53 (26%) of the total ELBW infant cohort. Perinatal risk factors for major adverse outcomes are listed in Table 3. At the age of 1.5 years, 33 children were classified as having major impairments; at the age of 5, 2 of them were classified as developing with no functional abnormalities and 4 to have only minor impairments. Of the 157 (76%) children who were classified as developing with no functional abnormalities at age 1.5,15 1 had a major and 11 had minor disabilities at age 5.
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Growth
Adjusted by age and gender, the weight for height was –7 ± 11%, height SD z score was –1.0 ± 1.1, and head circumference SD z score was –1.2 ± 1.1 at 5 years of age. All of the mean growth values remained below the normal Finnish population mean with differences persisting between the SGA and the AGA groups (Table 4). Thirty-one (15%) children were underweight, ie, weight to height below 15%. The mean BMIs (kg/m2) at ages 1.5 and 5 were 15.1 ± 1.5% and 14.5 ± 1.8% in the whole cohort, 15.5 ± 1.2% and 14.8 ± 1.9% in the AGA children, and 14.8 ± 1.6% and 14.3 ± 1.7% in the SGA children, respectively. At both ages, difference in BMIs between the AGA and the SGA groups was significant (P = .003 and P = .03, respectively). SGA at birth was a risk factor for being short (height SD <–2) at age 5 (OR: 3.9; 95% CI: 1.3–11.5; P = .013). Mean growth velocity between 1.5 and 5 years remained slightly negative (
height SD: –0.085/3 years), slower than in the normal population. At 5 years, head circumference SD z score (n = 126) correlated positively with full-scale IQ (r = 0.25, P = .01), verbal IQ (r = 0.24, P = .01), and mean verbal memory (r = 0.25, P = .01). Mean head circumference SD of children with no functional abnormalities was –0.95 ± 1.1, of those with minor disability was –1.7 ± 0.1 (P = .005 compared with no functional abnormalities), and of those with major neurologic disability was –1.6 ± 1.1 (P = .013 compared with no functional abnormalities).
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ROP had been diagnosed in 63 (62%) infants, 21 (33%) of whom received laser or cryo treatment (mean GW: 25.5 ± 1; range: 23.7–26.9; mean birth weight: 761 ± 127 g). Of the treated children, 17 (81%) had abnormal ophthalmic findings at the age 5. Seven of 8 children who needed hearing aids were born before 27 GW, the difference compared with those with age >27 GW being significant (P = .03).
Mean full-scale IQ was 94 ± 19 (range: 50–138; median: 97; Table 2). Overall disability rate increased with decreasing gestational age (Fig 3). Larger proportions were classified at 5 years both as having no functional abnormalities and as having a major disability than in the classification at 1.5 years. The only survivor who was born at 22 GW had strabismus, hyperopia, and MND-complex. Only 1 of the survivors who were born at 23 GW was considered to have no functional abnormalities, and she had good cognitive function but slight myopia after ROP treatment.
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Regional Outcomes
The largest regional university hospital area, A (n = 85 survivors at age 5), had significantly better outcome than did the 4 smaller areas, B to E, each of the same size. In area A, the severe disability rate was 13% compared with 30% (8 of 26) in area B (P = .02). The means of full-scale and verbal IQ and mean attention value were higher in area A than in area C, and the cognitive impairment rate was lower (3% vs 8%; P = .047). Areas A and D differed significantly from each other in mean attention and mean sensorimotor values and in cognitive impairment rate (3% vs 16%; P = .021). Areas A and E had the largest number of statistically significant differences: in means of full-scale and performance IQs; in mean attention; and in frequencies of cognitive impairment (3% vs 16%; P = .018), CP (9% vs 29%; P = .008), MND-complex (12% vs 29; P = .036), and major disability rate (13% vs 31%; P = .021). In logistic regression analysis, the largest area, A, seemed to be a protective factor against CP and MND (OR: 0.29; 95% CI: 0.11–0.74; P < .01).
Delivery outside a tertiary-level hospital had occurred for 21 children, ie, 10% of all ELBW infants (mean birth weight: 868 ± 83 g; range: 710–990 g; mean GW: 28.4 ± 3.1; range: 24.4–34.9). Four (20%) children had cognitive impairment, a difference that was nonsignificant (P = .086) compared with the rate of those who were born in a tertiary-level hospital. Two children had hearing aids, and 2 had CP.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Use of birth weight as the inclusion criterion has both advantages and disadvantages. Cohorts have been based on birth weight, because weight seems more reliable than gestational age estimations, making comparison of our results with population-based cohorts from previous time periods possible. Another strength in the design of this study is the inclusion of all deliveries, providing a more realistic prognosis of the extremely preterm deliveries than when the denominator is only live-born infants. A disadvantage of using birth weight as an inclusion criterion is the increasing frequency of growth-retarded infants at the higher gestational ages. This was obvious in our cohort.14 Intrauterine growth restriction may have been associated with infants’ underlying disease, thus explaining the high rate of comorbidity and syndromes that affect outcome. With routine use of early ultrasound assessment of gestational age in almost all pregnancies in the Nordic countries, the accuracy of gestational age determination can be considered highly satisfactory,13 because only a small proportion of intrauterine growth restriction starts during the first trimester.25 Thus, we analyzed the outcome separately for the subgroup born before 27 GW, in which all infants were included.14 Perinatal management in 1996–1997 of extremely preterm infants at the border of viability was generally restrictive toward active obstetric intervention on fetal indication below 24 GW. From 24 completed weeks, proactive management was the rule in the tertiary perinatal centers. In the mid-1990s, antenatal steroids, early surfactant administration, and new ventilatory models were in common use in NICUs, and this cohort reflects the results of these new strategies.
The dropout rate in our follow-up was low, 1%, and an additional 5% were only locally assessed. Because some follow-up information was available in all cases, our nonattending children most likely represent those with good outcome, like in a previous study.26 In other countries with different health service organizations, however, dropouts may have worse outcome.27 Although the tests used have been standardized in the same national population, comparison with normal reference values may have been more precise had we included a comparable group of control subjects who were born after normal pregnancies and deliveries in the same hospitals, as was the design in the previous regional follow-up subcohort.15
Survival and Morbidity
The stillborn rate increased with decreasing gestational age,14 suggesting a gray zone between life and death at the limit of viability. A recent retrospective study showed that proactive management at the limit of viability led to an increased incidence of live birth at 22 to 25 GW.13 The 5-year survival rate in our study increased as gestational age and birth weight increased and was of the same magnitude as reported in the mid-1990s.1,3,5,28 The postneonatal mortality was 2.4%, mainly as a result of complications of prematurity. Likewise, considerable complications of neonatal care were noted in 2%. The almost 10% prevalence of congenital disorders and syndromes that were not evident in the neonatal period but successively were diagnosed during the first years of life indicates that underlying disorders may be associated with premature delivery. Birth at 22 to 23 GW was associated with higher mortality than at 24 weeks, and adverse outcome at 5 years of age was the rule. This may be a result of less active treatment of the most immature infants. Whether proactive management is advisable in these deliveries should be assessed in prospective studies with clear strategies for perinatal care and extended follow-up.
Neurosensory Impairment
The cognitive impairment rate may not be determined at 1.5 years of age but is assessed reliably at 5 years. Our cognitive impairment prevalence of 9% is slightly less than the 12% to 15% reported in infants who were born in the early 1990s.5,29 Advanced ROP that required laser or cryo treatment was a significant risk for later visual impairment, in accordance with findings that ROP treatment reduces the incidence of poor visual outcome without an increase in the rate of normal visual acuity.30 Ophthalmic impairment has been correlated with lower scores on visual-motor integration and intelligence testing.31 In this study, severe visual impairment was associated with poor language skills.
Four percent needed a hearing aid. In other ELBW infant cohorts of the 1990s, the range of hearing deficits has largely varied, from 9%32 down to <1% in infants of GW <27.5 In this study, in which birth weight was the inclusion criterion without exclusion of any syndromes, approximately half of the children who were using a hearing aid seemed to have some underlying cause other than prematurity for the hearing deficit. Population selection, in addition to differences in treatment strategies, may account for the differences between studies.
More than one third of our follow-up cohort had either CP or minor neurologic dysfunction at age 5, illustrating the vulnerability to developmental coordination disorder in ELBW infants. MND is supposed to reflect the nonoptimal neural connections, which are considered to be of perinatal origin.33 Comparison of a regional 4-year ELBW infant cohort born from 1991 to 1994 from the Helsinki University Hospital area34 to the corresponding regional subcohort of this study revealed a reduction in motor impairment: the CP rate fell from 19% to 9% and the MND rate from 37% to 27%. Male gender is a risk factor for CP in very immature infants.28 Our study showed no gender differences in the subgroup born before 27 GW, possibly because of the small sample size. Our risk factor analysis showed, however, an increased risk for MND in boys.
Cognitive Outcome
The mean full-scale, verbal, and performance IQs of the tested children were within normal limits, but the means were lower than in the normal population. In ELBW infants who were born in the beginning of the 1990s, full-scale IQ at school age was significantly lower than for normal birth weight (
2.5 kg) control subjects.35 In another follow-up study, ELBW infants performed poorly on mathematic tasks and were at increased risk for school difficulties compared with control children.7
In the EPICure 6-year follow-up study, including all infants who were <26 GW and born in the United Kingdom and Ireland in 1995, a cognitive score of 39 was given to children with severe cognitive impairment; thus, the overall cognitive mean score was 82 ± 19.2 in their cohort.36 This is less than the full-scale IQ in our children who were born before 27 GW, who had a mean IQ of 94 ± 19 and a median value of 97, when no value was assigned for severe cognitive impairment. However, when these children are included, the median full-scale IQ is only slightly lower, 95. The cognitive outcome seems to be superior in our cohort, but the comparison should be interpreted with caution, because the gestational ages and test methods were different.
Learning difficulties, according to a recent review, seem mainly to be related to low overall IQ.37 Verbal IQ and NEPSY language were particularly poor in our SGA children, a type of impairment that may be a significant risk for learning disabilities at school. Our findings suggest that despite improved treatment and survival, the risk for cognitive and achievement deficits are considerable and similar to those in other population-based ELBW infant cohorts.8
All domains of neurocognitive function, as measured by NEPSY, were significantly below the normal age-correlated mean and corresponded to a low average. The domains that were most affected were sensorimotor and visuospatial performance. Correspondingly, the performance IQ in WPPSI-R was also relatively poor, whereas verbal IQ was not significantly poorer than normal. The NEPSY language domain was poorer than were the results from the attention and memory tasks; however, the latter type of tasks may represent activities not yet as relevant at the 5-year age level as at school age. To reveal learning disabilities and behavioral disorders, the follow-up age needs to be extended beyond 5 years, up to school age and adolescence.
Overall Disability
Both major neurologic disability rates and rates of development with no functional abnormalities increased significantly in our children from 1.5 to 5 years of age. That the CP rate increased with increasing age is in line with the recommendation by Hagberg et al38 that definite CP can reliably be diagnosed first at 4 years of age. One study showed major disability to be overestimated in some infants and underestimated in some others at the age of 2 compared with 55 as in our study, too. Some of the infants who were classified with major or minor disability at 1.5 years of age turned out to be developing slowly but with a normal preschool outcome, and some later received a diagnosis as having cognitive impairment or CP, thus joining the major disability outcome group.
Criteria for disability in preterm cohort follow-up studies vary, hampering comparisons even regarding major neurologic disabilities,39 which traditionally include CP, moderate and severe cognitive impairment, blindness, and deafness. Minor disability comprises mild motor dysfunction and mild cognitive impairment. Social behavioral dysfunction and severe attention deficit and hyperkinesia disorder are more common in ELBW infants than in control subjects9 and may have a major impact on normal everyday life, although cognitive capacity and motor performance may fall within normal test limits. In the present study, minor disability criteria also included severe attention deficit and hyperkinesia disorder, dysphasia, and severe visuomotor integration disorders. Assessment of these disorders requires careful neuropsychological testing.
In Finland, the intervention rate for children with disabilities is high, but the effect of regular therapy on development is unclear. A case-control study of ELBW infants with early occupational therapy intervention from 6 to 12 months of age showed no noticeable benefit at the age of 240 or 4 years.41 However, studies are needed on the influence of more target-oriented rehabilitation; the infant group that would benefit from rehabilitation should be defined as well as the right time window for therapy.
Risk Factors
The majority of the risk factors for adverse 5-year outcome were related to immaturity and perhaps could be treated or ameliorated in the future. Absence of antenatal steroids as a primary risk factor may be ascribed not only to lack of steroidal effects but also to an acute delivery situation’s allowing no time for drug administration.
Like in a recent study,42 vaginal delivery was a risk factor for adverse outcome. However, this may not only be ascribed to the delivery mode but also to parturition triggering factors, such as chorioamnionitis.10 Unfortunately, no reliable assessment of intrauterine infections was performed in our cohort.
That the largest university hospital was a protective factor for CP as compared with the other university hospitals may be more related to the size of the tertiary center than to population or treatment-strategy differences. Several studies have shown better outcomes in centers with a sufficient patient volume, usually defined as a patient census of at least 15 per day.43 No evidence-based recommendations for the size of a tertiary unit, however, are available. Regional differences in outcome have been ascribed to differences in treatment strategies in other countries.13
Like in the EPICure study36 male gender was an important risk factor for adverse outcome. In addition, intrauterine growth restriction had a negative effect on long-term outcome, both on motor skills and neurocognition, especially language skills, and on postnatal growth. Many children with major disabilities experience severe comorbid conditions, because perinatal brain damage affects many sensorineural areas, resulting in multiple handicaps.29 Perinatal complications may result in chronic comorbidity, further highlighting the need for centralization of pregnancies and parturitions of the most vulnerable infants in tertiary-level perinatal units.12
Growth
BMI and weight for height both can aid in assessing nutritional status; BMI has been shown to represent especially well body fat composition.44 Despite that weight for height increased over time, the mean BMI of our ELBW infant cohort at 1.5 and 5 years remained at the 10th percentile as compared with American standardized BMI percentile curves.45 We noted that in the SGA children, the height z score decreased from age 1.5 to age 5 in line with previously observed prolonged growth disturbance, although catch-up growth of ELBW infants may take place even from school age up to adolescence.46 In a very low birth weight infant cohort, a gender difference appeared in growth until adolescence, showing girls to have a greater ability to catch up later.47 Our study revealed no gender-specific growth changes until age 5. Antenatal corticosteroids did not turn out to be a risk factor for later growth. An association appeared between head circumference at birth and cognitive outcome in those who were born before GW 27, which was not the case at 30 months of age in the EPICure study for their infants who were born before 26 GW.48 Poor catch-up growth in other studies49 as well as in this one pinpoints the importance of top-level postnatal care, including good nutrition in these immature infants, and warrants future nutritional and endocrinologic study.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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ACKNOWLEDGMENTS |
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The additional co-authors of the Finnish ELBW infant cohort study group were Leena Haataja, MD, PhD, Turku University Central Hospital, Turku; Manta Tolvanen, MD; Outi Saarenpää-Heikkilä, MD, PhD, Tampere University Hospital, Tampere; Kirsti Heinonen MD, PhD, Kuopio University Hospital, Kuopio; and Marja-Leena Pokela, MD, PhD, Oulu University Central Hospital, Oulu.
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FOOTNOTES |
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Address correspondence to Kaija Mikkola, MD, Hospital for Children and Adolescents, Helsinki University Central Hospital, Lastenlinnantie 11 C 29, PB 280, 00029 Helsinki, Finland. E-mail: kaija.mikkola{at}hus.fi
No conflict of interest declared.
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