SUBJECTS

National cohort

The national study population consisted of all infants with a birth weight below 1000 g and gestational age at least 22 full weeks born in Finland during a two year period from 1 January 1996 to 31 December 1997.⁸ Of the 529 ELBW infants (0.4% of all 121 330 infants born in Finland 1996–1997), 178 (34%) were stillborn and 351 (66%) liveborn. The neonatal survival rate was 62%; 211 (60%) ELBW infants survived until the age corresponding to 40 weeks gestation.⁸

Regional subcohort and controls

One third of the liveborn ELBW infants were born and treated in Helsinki University Hospital, serving a geographically defined region with neonatal intensive care, and formed the subcohort of the study. Of the 109 liveborn infants, 86 (79%) were alive at the age corresponding to 40 weeks gestation, and 78 had a neuropsychological assessment in the same hospital at the corrected age of 24 months. Of the remaining eight infants not screened at 24 months of age, two had died and six families lived outside the Helsinki region.

Full term infants born immediately after each ELBW infant in the same hospital (in 1996 one infant, in 1997 the next two infants) were eligible for the control group. The inclusion criteria for control infants were: gestational age ≥ 37 weeks; no requirement for medical care during the first three days; native language of parents Finnish, Swedish, or English. Four infants were excluded: two families had moved a long way from Helsinki, and in two cases the children did not live with their parents. A total of 75 of the 126 invited controls (60%) were entered into the study.

Table 1 summarises background information on all surviving ELBW infants of the subcohort and the control group. The controls who participated did not differ from those who did not with regard to the variables listed in table 1.

Infants with birth weight below −2 SD based on Finnish intrauterine growth charts were classified as small for gestational age.⁹ The estimation of gestational age was based on ultrasound examination before the end of 20 weeks (82%) or on the last menstrual period (18%). The criterion for septicaemia was a positive blood culture. International criteria were used to grade respiratory distress syndrome,¹⁰ intraventricular haemorrhage,¹¹ necrotising enterocolitis,¹² and retinopathy of prematurity.¹³ The diagnostic criterion for blindness was based on the specification of WHO.¹⁴ At the age corresponding to 36 weeks gestation, infants with muscular hypotonia or hypertonia or seizures were classified as neurologically abnormal.

METHODS

National follow up schedule

The national outcome data for ELBW infants were recorded from all five universities (the catchment areas of which were designated A–E for analysis and comparison) and 18 central or local hospitals up to the corrected age of 18 ± 2 months. A national neurological follow up programme included an ophthalmologic assessment at the corrected age of 12–18 months and examinations by a neurologist, psychologist, physiotherapist, and speech therapist¹⁵ at the corrected age of 18 months.

At the age of 18 months corrected for prematurity, cerebral palsy was defined as a non-progressive motor impairment with spastic or dystonic muscle tone, brisk tendon reflexes, positive Babinski’s sign, and persistent primitive reflexes. Four categories were used¹⁶: diplegia; hemiplegia; tetraplegia; ataxia or athetosis syndrome. Other motor impairments were defined as delay in motor development, hypotonia or hypertonia with a specific cause (trisomy 21, central nervous system malformation), or variable abnormalities in muscle tone without other features of cerebral palsy. The severity of the impairments was defined as follows: normal development (no impairments detected in the hearing, ophthalmological, motor, or speech assessment), mild impairment (one or two impairments detected in the above assessments, no blindness, hearing impairment, cerebral palsy, or convulsions), and severe impairment (three to four impairments in the above assessments or one of the following four impairments: blindness, hearing impairment, cerebral palsy, or convulsions).

The study population included 97% of all infants born before 27 weeks gestation, but of all infants born at 27 weeks gestation, the ELBW infants represented only 57%, of those born at 28 weeks gestation 34%, and of those born at 29 weeks gestation 16%. Above 29 weeks gestation, the proportion of ELBW infants born at each gestational week was much less than 10%. For this reason comparisons based on gestational age were made mainly in infants born at 26 weeks gestation or less, and thus included almost all infants per each gestational week. Comparisons based on birth weight were made at 100 g intervals.

Regional programme

In addition to the national follow up programme, two psychologists carried out developmental assessments on the subcohort and their controls at a corrected age of 24 months using the Bayley infant scale 2nd edition (mental section).¹⁷

Statistical analysis

Statistical analysis was performed using the SPSS program. Mantel-Haenzel, Pearson’s χ², and Fisher’s exact tests were used to distinguish differences in binary or category variables and Student’s t test to distinguish differences in continuous variables. Logistic regression analysis was used to detect risk factors for cerebral palsy for any motor impairment. The perinatal and neonatal variables included in each logistic regression analysis were multiparity, pre-eclampsia, premature rupture of membranes, maternal infection, antenatal steroid treatment, hyperstimulation or in vitro fertilisation, maternal age below 20 or above 40, smoking, marital status, social class 1–4,¹⁸ birth in secondary level hospital, birth in the university hospital area A, B, C, D, or E, vaginal delivery, birth weight (100 g groups), intrauterine growth retardation, gestational age (full weeks), male, multiple birth, anomalies, respiratory distress syndrome, septicaemia, necrotising enterocolitis with perforation, and intraventricular haemorrhage grades 2–4. All variables were entered stepwise both forwards and backwards. A linear regression model was used to find risks for poor performance in Bayley assessment in the Helsinki ELBW subgroup and in their controls with the following variables included: prematurity, intrauterine growth retardation, sex, primiparity, vaginal delivery, multiple birth, mother’s age, social class, smoking, marital status, examiner, day of birth—that is, number of days counted from 1 January 1996 to the birth to evaluate possible improvement over time—and the assessment age. In addition to the above factors, antenatal steroid treatment, maternal infection, pre-eclampsia, premature rupture of membranes, gestational age, birth weight, anomalies, respiratory distress syndrome, intraventricular haemorrhage grades 2–4, necrotising enterocolitis with perforation, septicaemia, and examiner were included when the risks for poor scores in Bayley assessment were analysed in the ELBW infant subgroup. In linear regression analyses, variables were entered stepwise.

In all analyses, p < 0.05 was considered significant.

Ethical consent

The study was approved by the ethics committee of the Hospital for Children and Adolescents of Helsinki University Hospital and by the National Data Ombudsman.

RESULTS

The national cohort

Mortality

Of the 211 ELBW infants who survived until the age corresponding to 40 weeks gestation, three (1.4%) died before or at the corrected age of 24 months: one from chronic lung disease, one accidentally, and one multiply disabled infant from pneumonia. None was lost to follow up.

Ophthalmological examination at the age of 12 months

Vision was assessed by a paediatrician, neurologist, or ophthalmologist on 197 (93%) children at the corrected age of 12–18 months. Ophthalmic status was considered normal in 151 (77%) children. The most common abnormality was strabismus (n = 23, 12%), myopia was found in 15 (8%) and astigmatism, hyperopia, or retinal scars after treatment for retinopathy of prematurity in 10 (5%) children. Two children had both strabismus and myopia. A total of 14 (8%) children needed spectacles. One child was legally blind (0.5%), and two (1%) had lost vision in one eye.

Neurological outcome

Neurological outcome was recorded in 90.3% of infants at 18 ± 2 months of corrected age. In 4.4%, the follow up examinations were performed at the corrected age of 12–15 months, and in 5.3% at the corrected age of 20–24 months.

Completely normal motor development was found in 157 (76%) cases. The prevalence of cerebral palsy was 23/208 (11%). Diplegia, the most common form of cerebral palsy, affected 15 (7%), tetraplegia affected four (2%), hemiplegia affected two (1%), and ataxia or athetosis affected two (1%) children. A total of 27 (13%) children had motor impairment other than cerebral palsy: 16 (8%) showed a delay in the normal age specific developmental milestones, three (1.5%) had congenital anomaly affecting the central nervous system (trisomy 21, meningomyelocele, or atrophy of cerebellum), and eight (3%) children suffered from clumsiness, hypotonia, rigidity, or difficulty in controlling movement. A total of 3% of all infants needed anticonvulsive treatment. Three children with otherwise normal motor development had congenital (two amnion strictures, one clubfoot) and one acquired (arterial thrombosis and amputation of one leg) anomaly affecting lower extremities. For analysis, they were included in the group of neurologically normal children.

In the verbal assessments, performed on 195 (94%) children, mild developmental delay was found in 70 (36%) cases and severe developmental delay in 12 (6%) cases. Hearing was assessed by otoacoustic emission or brainstem auditory evoked potential measurement in 184 (89%) infants: the hearing of 18 children was considered normal and the data for six children were missing. Six subjects suffered from hearing impairment necessitating hearing rehabilitation or the use of a hearing aid.

Figure 1 presents the prevalence of abnormalities in motor or verbal development and ophthalmic assessment in different birthweight groups. Table 2 shows motor impairment, cerebral palsy, and ophthalmic abnormality rates in infants born at 22–26 weeks gestation. In infants born after 26 weeks gestation, the prevalence of abnormalities in the vision assessment was 15% (16/105), cerebral palsy was found in 10%, and any motor abnormality in 23%. No infant born at 27 weeks gestation or more was blind or had hearing impairment necessitating a hearing aid.

Overall outcome

Complete data on hearing disability necessitating a hearing aid, verbal, motor, and ophthalmic impairments were available for 186 (88%) children. Figure 2 shows data on mortality and severity of impairments in infants born at 22–26 weeks gestation.

Risk factors

A significant decrease in ophthalmic abnormalities was found in all surviving infants with increasing birth weight (p = 0.010), and in infants born at 22–26 weeks gestation with increasing gestational age (p = 0.040). However, no significant differences in prevalence of cerebral palsy, any motor impairment, verbal impairment, or hearing impairment necessitating a hearing aid were found between the birthweight groups or between the gestational age groups 22–26 weeks. Intrauterine growth retardation or birth outside of a tertiary care centre did not seem to be risks for any of these impairments in surviving ELBW infants.

Table 3 lists significant risk factors found in logistic regression analysis for cerebral palsy or for any motor impairment in surviving infants, and for motor impairment or death in liveborn infants.

The second logistic regression analysis included outcome measures at the age corresponding to 36 weeks gestation (retinopathy of prematurity, neurological status, or need for extra oxygen) as explanatory factors. An abnormal neurological status (hypotonia or hypertonia, or seizures) at the age corresponding to 36 weeks gestation was a risk for cerebral palsy (odds ratio (OR) = 4.3, p = 0.005) and for overall motor impairment (OR = 4.3, p = 0.002). Oxygen dependency was a risk factor for motor impairment (OR = 2.1, p = 0.038) and for ophthalmic problems (OR = 2.6, p = 0.014), whereas retinopathy of prematurity grade 3–5 was a risk for ophthalmic abnormalities (OR = 16.5, p < 0.001) in the surviving children.

The regional subcohort

Four infants were excluded from the Bayley infant scale mental assessment, performed on the subcohort at a mean age of 2.0 years (range 1.84–2.26); the assessment of two children was impossible because of a combination of language, social, and developmental problems. Two otherwise normal children were not examined because of exhaustion after other assessments during the same day or because the parents withdrew them from the study. One ELBW child did not pass the test because of severe mental retardation. All participating controls were assessed at the mean age of 2.2 years (range 1.91–2.73).

The ELBW children had significantly lower mean (SD) Bayley mental scores than controls (95.1 (12.9) v 106.3 (9.6); p < 0.001). Seventeen ELBW infants (22%) had Bayley scores below 85, and one (1%) below 70. One of the control infants had Bayley scores below 85.

In a linear regression analysis comparing ELBW infants with controls, prematurity decreased the Bayley mental score by 10.4 points (SE = 1.8, p < 0.001) and male sex by 5.6 points (SE = 1.8, p = 0.002); the scores seem to improve by 0.013 point per birth day (counted from 1 January 1996) during the two year study period (SE = 0.004; p = 0.004). When the ELBW infants and the control group were analysed separately, the only significant factor for the ELBW infants was the number of days counted from 1 January 1996 to the birth; the scores seem to improve 0.024 point per day (SE = 0.007, p = 0.001). In the control group, no such improvement over time was found, and the only significant risk factor for poor outcome in linear regression analysis was male sex, which seemed to reduce the scores by 6.3 points (SE = 2.133, p = 0.005).

The correlation between Bayley scores and the day of birth was 0.388 (p = 0.001) in the ELBW infant group. No such correlation was found in the control group (r = 0.072; p = 0.537).

DISCUSSION

By establishing a national ELBW infant research register with detailed background and follow up information, we could satisfactorily evaluate outcome in the study cohort at 18 months of age. Although 23 hospitals participated in the prospective data collection, 75% of the data came from the five university clinics responsible for the study design. However, using data gathered from the national healthcare system caused some limitations—for example, the neurological assessments were performed by several clinicians. The possible bias resulting from many investigators may have been avoided by performing a centralised study, but this kind of study does not usually extend to all inclusive follow up rate. In our study, no infant was lost to follow up, but the data were nevertheless not fully comprehensive. The classification of impairment severity used only those with complete data available and may be somewhat overstated because it seems that missing data mostly resulted from the practice not to perform some assessments on children with apparently normal development.

Mortality in ELBW children during the first two years after discharge was comparable to that in other studies^19,20; however, none of the infants in our study population died from sudden infant death syndrome, for which prematurity is thought to be a risk factor.

Ophthalmic problems are relatively common in ELBW children. Compared with most previous studies, in which visual impairment rates varied between 6% and 9%,^20,21 ophthalmic abnormalities in our study were more common (23%). The difference may be partly explained by the fact that we included even mild cases without visual impairment or need for treatment. However, similar high rates of ocular abnormalities were found in the study of Pennefather et al.²² The prevalence of blindness was comparable to numerous follow up studies (0.5–3.6%),^1,20–25 and our study also confirms the finding of Emsley et al²⁶ that infants born extremely prematurely are at particular risk of visual disabilities.

The prevalence of cerebral palsy in the whole country is comparable to recent results from Sweden, the United States, Australia, and Canada, where the detected prevalence of cerebral palsy at the age of 1–3 years varied between 7% and 17%.^{1,20,23,24,27,28} When the results of the subcohort of our study were compared with those of an earlier regional cohort born in 1991–1994 in the same area, neonatal mortality seemed to have decreased from 31% to 21% (p = 0.046) and the prevalence of cerebral palsy from 17% to 4% (p = 0.002).²⁹ Thus, despite the increased survival rate of ELBW infants, the prevalence of cerebral palsy did not increase in the region. In logistic regression analysis, detected differences in mortality and cerebral palsy prevalence also indicate that decreased mortality is not always associated with increased morbidity. As previously reported,³⁰ this study showed that regional differences occur in mortality and morbidity even in a country with a homogeneous population and social security and that both morbidity and mortality should be included when quality of care is analysed to avoid the effect of selection by outcome.

Kitchen et al³¹ suggested that neurological findings at 2 years of age are too pessimistic, and that 33% of children had a poorer diagnosis at that age than at 5, and in only 4% was the outcome at 2 years of age better than at 5. However, in comparison with normal weight children, Halsey et al³² has shown that ELBW children classified as non-disabled at an early age show a significantly poorer performance on cognitive, verbal, perceptual, motor, and visual-motor measures at preschool age, a finding also supported by Saigal et al.³³ The rate of normal development in our study (42%) was lower than that found in some previous studies,^{19–21,28,34,35} but we also recorded minor, non-disabling impairments. The prognostic value of these minor impairments in later development is an important subject for subsequent studies, for which a uniform classification of disabilities, such as the recently published Health Status Questionnaire,³⁶ would provide even more generalisable results.

The effect of gestational age on neurological development in ELBW infants is contradictory. Several investigators have found no independent effect of gestational age on later outcome,^35,37,38 whereas others report an effect.^1,6,39,40 In our study population, which included virtually all infants born in Finland at 26 weeks gestation, gestational age was not an independent risk factor for later impairments (cerebral palsy, motor and hearing impairments, speech delays), not even in a multivariate logistic regression analysis. Abnormal ophthalmological status was more common in children born extremely prematurely, at the limit of viability 22–24 weeks. In a previous study, we found gestational age and birth weight to be significant risks for death.⁸ Thus, we assume that the majority of the most immature infants died, and the infants who survived had as favourable a prognosis as the more mature ones in all other domains except visual acuity.

Poorer cognitive skills in ELBW children compared with full term controls has been a universal finding.^{32,33,41–43} The ELBW infants in our study population differed from their controls in that their mothers were more likely to belong to a lower social class. Although a lack of maternal education and low social class have been shown to be risk factors for poor cognitive development of premature children,^{1,20,35,37,39,41} in our study population deficient maternal education was not a risk factor for poor outcome.

The effect of the date of birth on Bayley scores of ELBW children was an unexpected finding. The same two well trained investigators examined the ELBW and control children. No such correlation was found in the controls, confirming the reliability of the method. Neither could the result be explained by selection by outcome, because neonatal mortality in ELBW infants did not change during the study period. It may be that the outcome improved because of improved perinatal and neonatal care. Which factors were improved and whether the improvement is permanent remains to be seen.

In conclusion, at the corrected age of 18 months, no outcome differences were detected between birthweight groups or in ELBW infants born at 22–26 weeks gestation in sensory-motor outcome except for ophthalmic abnormalities, the rate of which declined significantly with increasing birth weight and gestational age. In the Helsinki University Hospital, the scores from the Bayley mental test seemed to improve during the short study period, but this needs to be confirmed. Our results also show that, even in a country with a uniform healthcare system, some regional differences in early neurological outcome of ELBW children exist, which warrants continuous quality control and audit. Major disabilities—that is, cerebral palsy, blindness, deafness, and mental retardation—are usually discovered at the age of 2 years. However, follow up should be continued to at least preschool age to detect cognitive disabilities such as problems in learning, behaviour, and attention.