Outi Tammela

Neurodevelopmental outcome at 5 years of age of a national cohort of extremely low birth weight infants who were born in 1996-1997

Objective. Increasing survival of extremely low birth weight (ELBW; birth weight <1000 g) infants raises a concern regarding the risks of adverse long-term outcome such as cognitive dysfunction. Few studies have reported long-term follow-up of representative regional cohorts. The objective of this study was to assess the 5-year outcome of a prospectively followed national ELBW infant cohort. 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.

No improvement in outcome of nationwide extremely low birth weight infant populations between 1996-1997 and 1999-2000

OBJECTIVE. Our goal was to investigate whether outcome in extremely low birth weight infants changes over time in Finland. PATIENTS AND METHODS. All infants with a birth weight <1000 g born in Finland in 1996–1997 and 1999–2000 were included in the study. Perinatal and follow-up data were collected in a national extremely low birth weight infant research register. Data concerning cerebral palsy and visual impairment were obtained from hospitals, the national discharge, and visual impairment registers. RESULTS. A total of 529 and 511 extremely low birth weight infants were born during 1996–1997 and 1999–2000. No changes were detected in prenatal, perinatal, neonatal, and postneonatal mortality rates between the periods. The survival rates including stillborn infants were 40% and 44%. The incidence of respiratory distress syndrome and septicemia increased from 1996–1997 to 1999–2000 (75% vs 83% and 23% vs 31%). The overall incidence of intraventricular hemorrhage increased (29% vs 37%), but the incidence of intraventricular hemorrhage grades 3 through 4 did not (16% vs 17%). The rates of oxygen dependency at the age corresponding with 36 gestational weeks, retinopathy of prematurity stages 3 to 5, cerebral palsy, and severe visual impairment did not change. Mortality remained higher in 1 university hospital area during both periods compared with the other 4 areas, but no regional differences in morbidity were detected during the later period. CONCLUSIONS. No significant changes were detected in birth or mortality rate in extremely low birth weight infants born in Finland during the late 1990s, but some neonatal morbidities seemed to increase. Regional differences in mortality were detected in both cohorts. Repeated long-term follow-up studies on geographically defined very preterm infant cohorts are needed for establishing reliable outcome data of current perinatal care. Regional differences warrant thorough audits to assess causalities.

Outcome of patients operated on for esophageal atresia: 30 Years' experience

PURPOSE The aim of this study was to evaluate the outcome and late sequelae of patients with esophageal atresia or tracheoesophageal fistula. METHODS Sixty patients with esophageal atresia or tracheoesophageal fistula (EA-TEF) were treated in Tampere University Hospital in the years 1963 through 1993. Long-term outcome was evaluated with a questionnaire, pulmonary and esophageal function test results, 24-hour pH level monitoring, tracheobronchoscopy findings, and esophagogastroscopy with biopsy sections and samples for bacterial cultures. RESULTS One third of the respondents reported having impaired quality of life because of respiratory infections, dyspnea, and difficulties in swallowing and coughing at night. Eighteen percent had gastroesophageal reflux (GER) symptoms. The rate of symptoms decreased with age. Impaired pulmonary function, GER, abnormal esophageal peristalsis, and transit time were registered. Tracheobronchoscopy showed tracheal narrowing and inflammation in one third; in histopathologic analysis, however, the rate of inflammation was more than doubled. Histologically, esophageal inflammation was found in 51%, Barretts esophagus in 6%, and a Helicobacter pylori infection in 21% of cases. The severity of GER, esophageal peristaltic abnormality, tracheal inflammation, and impairment of pulmonary function seems to be alleviated with age. CONCLUSIONS Although the long-term outcome of EA-TEF patients seems to be favorable, respiratory and gastrointestinal symptoms as well as functional abnormalities remain frequent. Gastric metaplasia in the esophagus and the high rate of tracheal, esophageal, and gastric inflammation indicate a need for long-term follow-up.

Respiratory outcome in school-aged, very-low-birth-weight children in the surfactant era

Aim. To assess respiratory outcome and its predictors during the surfactant era in very‐low‐birth‐weight (VLBW, birth weight <1500g) schoolchildren with and without bronchopulmonary dysplasia (BPD). Methods. At 7‐8 years of age, 34 VLBW children with BPD diagnosed at a postnatal age of 28 d underwent flow‐volume spirometry, metacholine challenge, bronchodilatation test, whole body plethysmography and diffusion capacity measurement. Fourteen of them had not recovered from BPD by a corrected gestational age of 36 wk (sBPD subgroup). The age‐ and sex‐matched control groups comprised 34 VLBW cases without BPD and 34 term children. Results. Current respiratory symptoms in contact with cold air and/or upon exercise were reported in one‐third of the VLBW children. Only half of the symptomatic VLBW cases without BPD had inhaled medications. Compared with term controls, the BPD cases had lower forced expiratory volume in 1 s (FEV1), higher ratio of residual volume to total lung capacity and higher airway resistance. Lower FEV1 and specific conductance were found in the sBPD subgroup compared to both control groups. Additionally, their vital capacity was lower than in term controls. A higher rate of bronchial hyper‐reactivity and lower diffusion capacity of the lungs were detected in VLBW as against term cases. Low birth weight, long duration of oxygen therapy, low socio‐economic status and exposure to animal dander emerged as predictors of poorer respiratory outcome.

Cerebral palsy is characterized by protein mediators in cord serum

Cerebral palsy (CP) is a major neurodevelopmental disability in childhood. An association between intrauterine infection and CP has been reported. We examined the relationship between inflammatory mediators in cord serum and CP in term and preterm children. Regional multicenter study was conducted on 19 CP children and 19 gestation‐matched paired controls. CP children (n = 27) were further compared with controls of similar gestation at birth (n = 25). Serum levels of 78 protein mediators were analyzed. Eleven analytes correlated with the length of gestation both in cases and controls. In paired analysis, B‐lymphocyte chemoattractant, ciliary neurotrophic factor, epidermal growth factor, interleukin (IL)–5, IL‐12, IL‐13, IL‐15, macrophage migration inhibitory factor, monocyte chemoattractant protein–3, monokine induced by interferon γ, and tumor necrosis factor–related apoptosis‐inducing ligand were higher in children with CP (p ≤ 0.05). Preterm infants with CP showed higher epidermal growth factor and lower levels of granulocyte‐macrophage colony‐stimulating factor, IL‐2, macrophage‐derived chemokine, and pulmonary and activation‐regulated chemokine than their paired controls. Inflammatory mediators and growth factors serve as a footprint of the fetal response to an insult manifesting after birth as a permanent brain damage. The cytokine patterns at birth differ between premature and term infants who develop CP.

Randomized Trial of a Single Repeat Dose of Prenatal Betamethasone Treatment in Imminent Preterm Birth

BACKGROUND. A single dose of prenatal betamethasone treatment decreases neonatal morbidity rates when administered within 7 days before preterm delivery. A single repeat dose or booster dose of betamethasone before delivery has been proposed to be effective, but its efficacy has not been subjected to a randomized, blinded trial. METHODS. Women with imminent delivery before 34.0 gestational weeks were eligible if they remained without delivery for >7 days after a single course of betamethasone. After stratification, a single repeat dose of betamethasone (12 mg) or placebo was administered. The primary outcome was survival without respiratory distress syndrome or severe intraventricular hemorrhage (grade 3 or 4). RESULTS. A total of 249 mothers had been enrolled by the time the study was discontinued. All of the 159 infants in the betamethasone group and 167 in the placebo group were born before 36 weeks of gestation. The intact survival rate was unaffected and was lower than anticipated, because the gestational age-adjusted incidence of respiratory distress syndrome was higher than the population incidence. The requirement for surfactant therapy in respiratory distress syndrome was increased in the betamethasone group. According to posthoc analysis of the data for 206 infants who were delivered within 1 to 24 hours, the betamethasone booster tended to increase the risk of respiratory distress syndrome and to decrease intact survival rates. CONCLUSIONS. According to this study, a single booster dose of betamethasone just before preterm birth may perturb respiratory adaptation. These results caution against uncontrolled use of a repeat dose of glucocorticoid in high-risk pregnancies.

The Effect of Birth in Secondary- or Tertiary-Level Hospitals in Finland on Mortality in Very Preterm Infants: A Birth-Register Study

OBJECTIVE. Our goal was to test the hypothesis that the level of the delivery hospital affects 1-year mortality of very preterm infants in Finland. PATIENTS AND METHODS. This retrospective national medical birth-register study included 2291 very preterm infants (gestational age of <32 weeks at birth or birth weight of ≤1500 g) born in 14 level II (central) and 5 level III (university) hospitals in 2000–2003. The main outcome measures were adjusted total mortality (including stillbirths) and mortality of live-born infants until the age of 1 year. RESULTS. Both the total 1-year mortality and the 1-year mortality of live-born infants were higher in level II hospitals compared with level III hospitals. Total mortality was higher in very preterm infants who were not born during office hours. In theory, delivery of all very preterm infants in level III instead of level II hospitals translates into an annual prevention of 69 of the 170 total deaths and prevention of 18 of the 45 deaths of live-born infants. CONCLUSIONS. Resources in neonatal intensive care should be increased, especially during non–office hours, to have an equally distributed service through the 24-hour day. More efficient regionalization of very preterm deliveries may improve 1-year survival of very preterm infants in Finland.

Short versus prolonged indomethacin therapy for patent ductus arteriosus in preterm infants

OBJECTIVE To evaluate whether a prolonged low-dose course of indomethacin would produce an improved closure rate and have fewer side effects compared with a short standard dosage schedule in the management of patent ductus arteriosus (PDA) in preterm infants. STUDY DESIGN Sixty-one infants of gestational ages 24 to 32 weeks with a PDA confirmed with echocardiography were randomized to receive 0.2 to 0.1 to 0.1 mg/kg indomethacin in 24 hours (short course, n = 31) or 0.1 mg/kg every 24 hours 7 times (long course, n = 30). Echocardiography was done 3, 9, and 14 days after the treatment was started, and side effects were monitored. RESULTS Primary PDA closure occurred more often in the short course group (94% vs 67%, P =.011), but the sustained closure rates were not different (74% vs 60%). Surgical PDA ligations were less frequent in the short course group than in the long course group. The short course group had a shorter duration of oxygen supplementation, less frequent symptoms of necrotizing enterocolitis, and a lower rate of urea retention. Mortality and other neonatal morbidity rates were similar. CONCLUSION A prolonged low-dosage indomethacin regimen offers no advantage compared with a standard-dosage short course in the management of a hemodynamically significant PDA in preterm infants.

Cerebral Palsy Among Children Born Moderately and Late Preterm

OBJECTIVE: To compare the incidence of and risk factors for cerebral palsy (CP) in moderately preterm (MP) (32+0–33+6 weeks) and late preterm (LP) (34+0–36+6 weeks) infants with those in very preterm (VP) (<32+0 weeks) and term infants (≥37 weeks). METHODS: The national register study included all live-born infants in Finland from 1991 to 2008. Infants who died before the age of 1 year, had any major congenital anomaly, or had missing data were excluded. A total of 1 018 302 infants were included in the analysis and they were analyzed in 4 subgroups (VP, MP, LP, and term) and 3 time periods (1991–1995, 1996–2001, and 2002–2008). RESULTS: By the age of 7 years, 2242 children with CP were diagnosed (0.2%). CP incidence was 8.7% in the VP, 2.4% in the MP, 0.6% in the LP, and 0.1% in the term group. The risk of CP was highest in the study period 1991–1995 in all groups. Factors predictive of an increased CP risk in the MP and LP groups included resuscitation at birth (odds ratio 1.60; 95% CI 1.01–2.53 and 1.78; 1.09–2.90), antibiotic treatment during the first hospitalization (1.63; 1.08–2.45 and 1.67; 1.13–2.44), 1-minute Apgar score <7 (1.70; 1.15–2.52 and 1.80; 1.21–2.67) and intracranial hemorrhage (7.18; 3.60–14.3 and 12.8; 5.58–29.2). CONCLUSIONS: The incidence of CP is higher in LP and MP infants compared with term infants. There is a nonlinear decrease in incidence over time and with increasing gestational age.

Frequency of and risk factors for necrotizing enterocolitis in infants born before 33 weeks of gestation

Aim: To investigate the frequency of and risk factors for necrotizing enterocolitis (NEC) among infants of <33 wk of gestation. Methods: Prospective follow‐up of 140 inpatients. Results: 26 (18.6%) subjects developed NEC stage I‐III and 12 (8.6%) severe NEC (stage II‐III). Breast milk fortifier and duration of morphine infusion emerged as the statistically significant factors associated with NEC stage I‐III, but only the latter had a significant association with severe NEC.