PEDIATRICS Vol. 115 No. 5 May 2005, pp. 1289-1298 (doi:10.1542/peds.2004-1482)
Early Death, Morbidity, and Need of Treatment Among Extremely Premature Infants
* Department of Pediatrics, Haukeland University Hospital, Bergen, Norway
Department of Pediatrics, University Hospital of Northern Norway, Tromsø, Norway
Department of Pediatrics, Rikshospitalet University Hospital, Oslo, Norway
|| Department of Pediatrics, St Olavs' University Hospital, Trondheim, Norway
¶ Department of Pediatric Intensive Care, Ulleval University Hospital, Oslo, Norway
# Department of Pediatrics, Rogaland Central Hospital, Stavanger, Norway
** Medical Birth Registry of Norway, Locus of Registry-Based Epidemiology
Norwegian Institute of Public Health, Section for Epidemiology and Medical Statistics, University of Bergen, Bergen, Norway
 |
ABSTRACT |
|---|
 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Objective. To determine outcomes, in terms of perinatal and early death, need for treatment, and morbidity at the time of discharge home, among extremely preterm infants.
Design. A prospective observational study of all infants with a gestational age (GA) of 22 to 27 completed weeks or a birth weight of 500 to 999 g who were born in Norway in 1999 and 2000.
Results. Of 636 births, 174 infants (27%) were stillborn or died in the delivery room, 86 (14%) died in the NICU, and 376 (59%) were discharged from the hospital. The risk of being registered as stillborn or not being resuscitated increased with decreasing GA below 25 weeks. The survival rates for all births and for infants admitted to a NICU were, respectively, 0% for <23 weeks, 16% and 39% for 23 weeks, 44% and 60% for 24 weeks, 66% and 80% for 25 weeks, 72% and 84% for 26 weeks, 82% and 93% for 27 weeks, and 69% and 90% for >27 weeks. For the survivors, days of mechanical ventilation decreased from a median of 37 days to 3 days and the proportion in need of oxygen at 36 weeks’ postconceptional age decreased from 67% to 26% at 23 and 27 weeks’ GA, respectively. At 40 weeks’ postconceptional age, the respective figures were 11% and 6%. The proportion with retinopathy of prematurity (ROP) requiring treatment decreased from 33% for GA of 23 weeks to 0% for >25 weeks. Periventricular hemorrhage of more than grade 2 occurred for 6% of the survivors and significant periventricular leukomalacia occurred for 5%, with no significant association with GA. The proportion of survivors without severe neurosensory or pulmonary morbidity increased from 44% for 23 weeks’ to 86% for 27 weeks’ GA. Apart from ROP, the morbidity rate was not associated with GA.
Conclusions. The survival rate was high and the morbidity rate at discharge home was low in the present study, compared with previous population-based studies. With the exception of ROP, the morbidity rates among the survivors were not higher at the lowest GAs, possibly because withholding treatment was considered more acceptable for the most immature infants. The need for intensive care increased markedly for survivors with the lowest GAs.
Key Words: extremely low birth weight • extreme prematurity • perinatal outcome • neonatal death • morbidity
Abbreviations: GA, gestational age • BW, birth weight • LMP, last menstrual period • MBRN, Medical Birth Registry of Norway • OR, odds ratio • CI, confidence interval • PCA, postconceptional age • PVH, periventricular hemorrhage • PVL, periventricular leukomalacia • ROP, retinopathy of prematurity • ISS, illness severity score
The question of providing life support or not for premature infants at the threshold of viability is an important and ongoing debate. During the past 2 decades, survival rates have increased substantially because of advances in knowledge, medical technology, and therapeutic options (for review, see ref 1), but long-term morbidity rates continue to be high. 2, 3 Indeed, several studies have suggested that the incidences of long-term disease and neurodevelopmental disabilities may not have decreased among survivors. 1, 3–6 With respect to offering life support, various authors and societies conclude differently, on the basis of their interpretations of available data concerning cost of care, burdens to the patient, family, and society, and long-term outcomes. The American Academy of Pediatrics suggests that parental choice based on thorough information should be respected within the limits of what is medically feasible and appropriate, but definitions of those limits are vague, except that noninitiation of resuscitation is considered appropriate for newborns of <23 weeks of gestation and/or birth weight (BW) of <400 g. 7 In the Netherlands, long-term outcomes are interpreted as being very poor for gestational ages (GAs) of <25 weeks, 8 and Dutch centers find it inappropriate to offer life support for infants born before 25 to 26 weeks’ GA. 9 In Norway, a national consensus conference in 1998 concluded that the GA limit for offering resuscitation should be 23 to 25 completed weeks and that within this range an individual approach is appropriate. 10
Differences in reported short- and long-term outcomes may be attributable to selection bias, because many studies are not population based but are limited to treatment centers, to population differences (eg, between nations 1, 11), to differences in organization of care (eg, centralized versus decentralized care 3), or to attitudes toward resuscitation and continued care despite severe early morbidity. Also, differences in reporting results, such as GA based on last menstrual period (LMP) or ultrasound findings or on BW, may yield results that are difficult to compare. 1
In the Norwegian Extreme Prematurity Study, data were collected on all births in Norway of 22 to 27 completed weeks of gestation or a BW of 500 to 999 g, in 1999 and 2000. The purpose was to examine short-term and long-term physical and neurodevelopmental outcomes in a national birth cohort. The aim of the present study was to assess the effect of GA on survival rates, causes of death, early major morbidity, and need for treatment and to identify other prognostic factors with respect to early outcomes.
|
METHODS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
All stillbirths and live births with a GA of 220 to 276 weeks or a BW of 500 to 999 g in Norway during the 2 years from January 1, 1999, to December 31, 2000, were eligible for the study. All obstetric and pediatric departments in Norway participated, and the study was coordinated by the Medical Birth Registry of Norway (MBRN). Data on maternal health, the pregnancy, the delivery, and the newborn period until the death of the infant or discharge home were collected consecutively by local obstetricians and neonatologists, with forms developed for the study. Completed forms returned to MBRN were scrutinized, to correct possible errors and to code open questions. Attempts were made to collect missing data by contacting the physician who had filled in the form. Because of long distances, infants were often transferred between neonatal and pediatric units, so that adequate treatment could be provided as close to home as possible; separate forms were completed for each unit. In Norway, all stillbirths and live births after 16 weeks of pregnancy are reported to the MBRN through compulsory notification. 12 On the basis of births reported to the MBRN, the coordinator identified neonates who fulfilled the inclusion criteria and then reported back to the local obstetricians and neonatologists, to ensure a high participation rate. The data collected on the study forms were linked with data from MBRN on maternal health, previous pregnancies, date of LMP, expected date of delivery based on ultrasound determinations, pregnancy complications, mode and complications of delivery, plurality, anthropometric measures, and health of the newborn.
Pregnancy care in Norway is highly standardized, with a standard pregnancy follow-up form, and virtually all pregnant women comply with this program, which is partly physician based and partly midwife based. Virtually all women also opt for ultrasound screening by specially trained personnel at 17 to 18 weeks of pregnancy, which is offered as part of this program. According to national consensus, the expected date of delivery is based on ultrasound findings if available. In the present study, GA at birth was calculated as completed weeks on the basis of ultrasound determinations. If ultrasound determinations were unavailable, then GA was based on the date of LMP, if consistent with clinical findings.
An index of early disease severity, the illness severity score (ISS), 13 was computed from 3 components of the Clinical Risk Index for Babies, 14 namely, the lowest and highest fractional oxygen requirements and the largest base deficit during the first 12 hours of life. The score was also used for infants who died within the first 12 hours. The other components of the Clinical Risk Index for Babies, namely, GA, BW, and malformations, were omitted because outcomes were related to GA and z score for BW and because lethal malformations were excluded in the statistical analyses. Periventricular hemorrhage (PVH) was graded as described by Papile et al 15 and retinopathy of prematurity (ROP) as described by the Committee for Classification of Retinopathy of Prematurity. 16 Estimates of ventricular dilation were not standardized. All survivors underwent regular follow-up monitoring by an ophthalmologist during the hospital stay and a hearing assessment with brainstem audiometry or otoacoustic emission testing before discharge. Routines regarding treatment and examinations of the newborns, such as cerebral ultrasonography, were left to the discretion of each neonatal unit, but the extent of such studies was recorded. Neurosensory deficits were defined as PVH of more than grade 2, bilateral periventricular leukomalacia (PVL) or >2 PVL cysts on 1 side, ventricular dilation requiring a ventriculoperitoneal shunt, ROP of more than stage 3 or treated with cryotherapy, deafness, or clinical signs of brain damage in clinical examination at discharge.
The study was approved by the Regional Committee on Medical Research Ethics and the Norwegian Data Inspectorate. Written informed consent for participation was required for infants transferred to a NICU but not for infants who were stillborn or died in the delivery room.
SAS and SPSS statistical packages were used for analyses. Rates are presented as percentages with 95% confidence intervals (CIs). Continuous variables were described as medians with interquartile ranges and were compared with the Mann-Whitney test. Rates were compared with 
2 or logistic regression analyses, as appropriate, and are presented as odds ratios (ORs) and 95% CIs. Major outcomes were (1) stillbirth or not resuscitated, (2) postnatal death before discharge home, (3) major morbidities among survivors, described as neurosensory deficits, ileostomy at discharge, or requirement for oxygen or assisted ventilation at 36 and 40 weeks’ postconceptional age (PCA), and (4) indices of extent of treatment, ie, duration of mechanical ventilation, assisted ventilation (which is the sum of mechanical ventilation and nasal continuous positive airway pressure ventilation), oxygen supplementation, and hospital stay. Independent variables were GA and BW.
|
RESULTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
Study Group
Of 119611 births, 638 infants (0.53%) fulfilled the inclusion criteria. Of these, 174 (27%) were stillborn or died in the delivery room, whereas 464 (73%) were admitted to a NICU. Data on all infants were registered in the MBRN. Additional data were collected for 161 of the 174 infants (93%) not transferred to the NICU and for 462 of 464 of those transferred to a NICU (99.6%). The remaining 2 infants were excluded because the parents refused to participate. The infants were treated at 15 different NICUs, and 95% of them received their initial NICU treatment at the hospital where they were born. The median number of admissions of study infants per NICU was 26 for the 2 years (13 per year), the range was 1 to 94, and 148 infants (32%) received their treatment in NICUs with <20 admissions a year. GA was based on ultrasound findings in 598 cases (94%) and on LMP in the remaining. For 536 infants (84%), GA results based on both LMP and ultrasound findings were available. For 220 of those infants (41%), there was full agreement in GA results, whereas GA based on LMP was 1 week shorter than ultrasound findings for 52 (10%) and 1 week longer for 151 (28%). For 113 infants (21%), there were >1-week deviations in estimates.
Mortality Rates
The distributions of births, survival rates to discharge home, and BW according to GA are described in Table 1. Only 2 infants born at 22 weeks were resuscitated and transferred to a NICU, and none with a GA of <23 completed weeks survived. The survival rates based on all births increased from 16% for 23 weeks to 82% for 27 weeks. The respective survival rates based on infants admitted to a NICU increased from 39% to 93% (Table 1). If GA was calculated from LMP, then the survival rates according to GA of admitted infants were almost identical, although the number of infants within each GA category differed somewhat. The median BW for each GA week was significantly higher for the infants who were admitted to the NICU (Table 2), but values did not differ significantly between those who survived and those who died after transfer to the NICU, except that infants of 27 weeks who died were significantly lighter than the respective survivors (Table 2).
|
|
On the basis of BW, the rates of transfer to a NICU were 18% for BWs of <500 g, 63% for 500 to 749 g, and 90% for greater weights (Table 3). Survival rates until discharge home, based on all births, increased from 10% for those <500 g to 78% for those with a BW of 750 to 999 g (Table 3). The respective survival rates of transferred infants increased from 54% to 88% (Table 3).
|
For those who were not admitted to a NICU, the time of death was registered for 160 of the 174 infants (Table 4). With GA of <24 weeks, the majority died in utero after admission to the obstetric department or resuscitation was not attempted. For those with greater GA, the majority died in utero before admission.
|
There were no significant differences between those who were admitted and those who were not admitted to a NICU with respect to gender, single or multiple birth, maternal illness, or pregnancy disorders, except that preeclampsia was less common among those who were not admitted (OR: 0.3; 95% CI: 0.2–0.6). Below 25 weeks, a positive association was observed between GA and rate of admission to a NICU (Table 5).
|
Altogether 86 of the 462 infants who were transferred to the NICU died (19%). The median age of death was 2 days, with an interquartile range of 8 days, and there was no significant association between age of death and GA. Three infants died as a result of lethal malformations (1 diaphragmatic hernia, 1 trisomy 18, and 1 trisomy 13), 10 as a result of acute complications related to ventilator treatment, mainly pulmonary air leaks (7 infants), and 5 as a result of other acute complications. The others died as a result of 1 or combinations of the following: persistent respiratory failure (34 infants), cerebral complications (25 infants), sepsis (15 infants), necrotizing enterocolitis (7 infants), and other or combined complications (20 infants).
Prenatal steroid administration was registered for 147 (85%) of the stillbirths or infants not resuscitated and for 435 (94%) of the infants admitted to a NICU. For the stillbirths or infants not resuscitated, steroids were given to 41%, 45%, 33%, 25%, and 19% of the infants born at 23, 24, 25, 26, and 27 weeks’ GA, respectively. For those admitted to the NICU, prenatal steroids were given to 80%, and the proportion did not vary with GA. Sixty-nine percent of the mothers of admitted infants received the first dose >24 hours before delivery and the percentage did not vary significantly with GA, although it was somewhat lower for infants born at 23 weeks (44%; OR: 2.4; 95% CI: 0.8–6.5).
Of the infants admitted to a NICU, the proportions delivered through cesarean section increased from 0% at 23 weeks’ GA to 21% at 24 weeks’ GA, 38% at 25 weeks’ GA, 64% at 26 weeks’ GA, and 75% at 27 weeks’ GA. Whether surfactant was given in the delivery room was registered for 446 of the infants (97%). Fifty-four percent of all infants and 69% of those with GA of <26 weeks received surfactant in the delivery room, and all of them were admitted subsequently to a NICU. Rupture of membranes for >6 days, vaginal delivery (as opposed to cesarean section), and, in particular, high ISS values were associated with increased risk of death, whereas various pregnancy complications were associated with reduced risk (Table 6). The risk of death was lowest for 27 weeks and increased markedly for the lowest GAs (Table 7). After adjustment for relevant factors, the OR related to GA increased slightly (Table 7). The z score for BW was not adjusted for because only a few infants born at 23 and 24 weeks had z scores below the second quartile, whereas the proportion with low z scores increased markedly with increasing GA. If BW z scores were included for GA of >24 weeks, the adjusted scores were 4.3 (95% CI: 1.4–13.6) for 25 weeks, 3.0 (95% CI: 1.0–8.8) for 26 weeks, and 1.1 (95% CI: 0.4–3.6) for >27 weeks.
|
|
ISS data were available for 454 of the 462 infants admitted to a NICU. Of these infants, 146 (32%) had a score of 0, which indicates base excess of better than –7.1, highest fractional oxygen requirement of <0.41, and lowest fractional oxygen requirement of <0.41 during the first 12 hours of life. Another 147 infants (32%) had a score of 1, whereas 14 had scores in the highest 5% range of 10 to 12 (all except 1 died).
Morbidity Among Survivors
Cerebral ultrasonography was performed at 
1 week of age for all surviving infants and was repeated at least once at 3 weeks of age for the majority of the infants (Table 8). PVH of more than grade 2 occurred for 6% of the infants, and PVL with bilateral cysts or >1 to 2 cysts on 1 side occurred for 5% of the infants (Table 8). ROP treated with cryotherapy occurred only for infants with a GA of <26 weeks (Table 8). Of the survivors, 87% did not have findings suggesting severe neurosensory deficits, as defined in Table 8, and 79% did not experience severe complications, defined as free of severe neurosensory deficits, no requirement for oxygen or assisted ventilation at 40 weeks’ PCA, and no ileostomy at discharge home (Table 8). Of the perinatal factors listed in Table 6, only vaginal delivery was associated with an increased risk of complications (OR: 2.0; 95% CI: 1.2–3.4). In a logistic regression model, the risk of severe illness increased with decreasing GA below 26 weeks (Table 9). ORs decreased slightly after adjustment for a set of relevant variables (Table 9). At discharge, no infant had more severe ROP than stage 3. If ROP was omitted as a severe complication, then there was no significant association between GA and risk of severe illness, except for a slight increase for 24 weeks’ GA (OR: 3.6; 95% CI: 1.3–10.0) and a similar tendency for 25 weeks (OR: 2.2; 95% CI: 0.9–5.5). The OR for 23 weeks was 1.1 (95% CI: 0.2–6.8).
|
|
Nineteen of all infants (4%) were treated for proven necrotizing enterocolitis, and another 10 (2%) were treated for suspected necrotizing enterocolitis. Thirteen had surgery. Seventeen of the survivors (4.5%) had suspected (8 infants) or proven (9 infants) necrotizing enterocolitis, and 9 of them had surgery (Table 10). Seven of the survivors had ileostomies, and 4 of them were discharged from the hospital with ileostomies.
|
For the survivors, the durations of assisted ventilation and of hospital stay until discharge home increased with decreasing GA for GAs of <26 weeks (Table 10). On average, one third were still dependent on assisted ventilation or oxygen at 36 weeks’ PCA and 9% were dependent at 40 weeks. Dependency at 40 weeks was not more frequent among infants with lesser GAs.
|
DISCUSSION |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
Interpretation of Outcomes
In this national cohort of extremely premature infants, none with a GA of <23 completed weeks survived. From 23 weeks on, however, the likelihood of being resuscitated increased markedly until 24 weeks and that of survival increased until 26 to 27 weeks. Before 24 weeks, most deaths occurred in utero after admission to an obstetric unit or because of omission of resuscitation at birth. From 24 weeks onward, deaths occurred mainly as stillbirths before admission to an obstetric department or postnatal deaths in the NICU. This pattern may at least partly reflect differences in attitudes toward life-saving interventions according to GA in early gestation and a much more optimistic attitude to resuscitation from
24 weeks. This assumption is supported by the findings that greater proportions of infants who were stillborn or not resuscitated received prenatal steroids at 23 and 24 weeks than at later GA, indicating that they were alive at entry into the obstetric department, whereas no infant was delivered by cesarean section at 23 weeks and only one fifth at 24 weeks, indicating that life-saving interventions were withheld commonly. Among the survivors, the risk of severe complications and illness decreased with increasing GA. However, apart from cryotherapy for ROP this association was moderate, and the risk was not increased significantly for 23 weeks. The reason for this rather unexpected good prognosis at 23 weeks may be that the threshold for discontinuing life support was lower at this extreme limit of viability if any complication occurred. The need for intensive medical treatment increased markedly for each week below 26 weeks, as judged from the duration of mechanical ventilation. Among the survivors, one third had severe chronic lung disease, defined as the need for assisted ventilation or oxygen supplementation at 36 weeks’ PCA, 17 and the proportion increased with decreasing GA. At 40 weeks’ PCA, however, the proportion had decreased to 9% and there was no significant difference according to GA.
Study Population
The strengths of this study were the large size, a prospective and population-based design, a very high participation rate, and information on outcomes of all births and not only live-born infants or infants admitted to a NICU. Because the study included all infants with a GA of <28 weeks and all with a BW of <1000 g, it allows for comparisons with most previous studies, which were based usually on only 1 of these 2 criteria. We consider, however, that GA is more important than BW in perinatal care, because decisions concerning active intervention during pregnancy and delivery and the decision to initiate life support in the delivery room need to be based on knowledge of prognoses related to GAs. In Norway, virtually all pregnant women have ultrasound determinations of GA by trained personnel at 17 to 18 weeks of gestation, which probably makes this dating the most reliable basis for studying prognoses related to GAs. Outcomes were nearly identical if GAs were calculated on the basis of LMP, although LMP data tended to give slightly greater GAs. In a different setting and with more infants, it is possible that these 2 ways of determining GA might result in somewhat different figures for outcomes at the lowest GAs.
Comparisons With Other Studies
For extremely premature infants, reported survival and morbidity rates vary considerably because of differences in criteria for selection (eg, whether stillbirths are accounted for adequately) and in measures of outcomes (for review, see ref 1). Even when such variations are accounted for, differences may be attributable to demographic characteristics 11 or organization of care and to attitudes toward resuscitation and life support at extreme prematurity. Low survival rates at early gestation may be the result of a self-fulfilling prophecy, in that obstetric intervention and neonatal resuscitation may be avoided and life support may be more readily discontinued in the event of neonatal complications. The results of the present study are in agreement with such a concept, particularly for 22 and 23 weeks’ GA, although the data suggest that pediatricians in Norway are more willing to provide treatment than are those in many other countries. 4, 18 Among the survivors, the rates of neurosensory and pulmonary morbidity did not increase substantially with decreasing GA. This finding is in agreement with some recent studies 4, 8, 18, 19 but in contrast to others. 20
Hack and Fanaroff 1 reviewed extensively studies on mortality and morbidity rates of extremely premature infants during the 1990s. In the present study, both mortality and morbidity rates were favorable whether analyses were based on GA or BW. Indeed, in that review, the lowest survival rates were generally noted among the regional studies like the present study. Compared with the EPICure study 18 (Table 11), which included infants with GA of <26 weeks but otherwise had a similar design and participation rate, the present cohort had a higher NICU admission rate, a higher survival rate for those admitted, and lower rates of oxygen dependency at 36 and 40 weeks’ PCA. The rates of ROP requiring treatment were identical, whereas the rate of pathologic cerebral ultrasound scans was higher in the present cohort. Pathologic scans were classified differently in the 2 studies, however; with reclassification of our findings as in the EPICure study, the rate of normal scans was probably higher in the present study (Table 11).
|
The reasons for an overall better prognosis in the present study than in the EPICure study may be many. Our infants were born 4 to 5 years later. Differences may therefore be attributable partly to a more active attitude toward life support at this limit of viability and partly to a general improvement in management over time. Such assumptions may be supported by the observation that greater proportions of NICU infants received prenatal steroids and were born through cesarean section in the present study than in the EPICure study. For prenatal steroids, the figures were 82% and 81% vs 47% and 70% for 23 weeks and combined 24 and 25 weeks’ GA, respectively; for cesarean section, the figures were 21% and 38% vs 12% and 22% for 24 and 25 weeks’ GA. GA was calculated from ultrasound findings in the present study and from LMP in the EPICure study, but it is unlikely that maturity differed significantly between the 2 studies, because median BWs according to GA were similar (Table 11). Other significant factors may be differences in general knowledge in the population and organization of care. In the large Vermont Oxford Network Study, mortality and morbidity rates decreased during the first half of the 1990s but not since 1995, which suggests that principles of management have not changed significantly in recent years 6 and that the improved prognosis in the present study may be partly attributable to population characteristics and organization of care.
In a Swedish national cohort born in 1990–1992, the survival rates were 5% of all births and 13% of live births for 23 weeks, 22% and 36% for 24 weeks, 52% and 69% for 25 weeks, and 62% and 77% for 26 weeks. 21 GA was mainly based on ultrasound findings, as in the present study, and management options differed basically in that prenatal steroids were not used widely and only a few units provided surfactant therapy. The much higher survival rates in the present study may be attributable to improvements in management and partly to differences in attitude with respect to providing life support for infants with GA of 23 and 24 weeks. Among the survivors, early morbidity rates (eg, rates of PVH, PVL, ROP, and need of oxygen supplementation at 36 weeks’ PCA) were similar in the 2 studies, which suggests that increased survival rates were not associated with higher morbidity rates.
In a large multicenter study, the survival rate for live-born infants with BWs of 500 to 801 g was 57%, and the authors inferred that the survival rate would have been 65% if all infants had been offered mechanical ventilation. 22 In the present study, the survival rate was 70% for this weight category, and 90% of the infants underwent mechanical ventilation. Of the 18 infants (10%) who did not undergo ventilation, only 2 died during the first day because mechanical ventilation was not offered, which suggests that our survival rate for such low BW live-born infants is at the calculated maximal level, again reflecting an optimistic approach to life support for the smallest infants.
Organization of Care
Despite the low population density and long distances to hospitals with NICU facilities in many parts of Norway, 95% of the resuscitated infants were born in hospitals where they also received their initial intensive care treatment. Therefore, prenatal transfer to an appropriate perinatal center was obviously successful. The abilities of pregnant women, primary health care workers, and local hospitals to recognize pregnancy complications and imminent premature labor were also demonstrated by the high rate of prenatal steroid use and probably in part by the findings that preeclampsia was associated with a reduced risk of prenatal death and various pregnancy complications were associated with a reduced risk of postnatal death. It might be surprising that the provision of prenatal steroids was not protective against neonatal death, but any possible effect might be disguised because of the high rate of treatment and possibly confounded by indications for treatment. Furthermore, perinatal management might have been well organized generally, because as many as two thirds of the infants received surfactant in the delivery room and two thirds had an ISS of 0 or 1, which means that they were not acidotic and had low requirements for oxygen during early postnatal life. However, the infants were treated at relatively small NICUs, which is considered commonly to be less favorable. 21, 23, 24
Resources and Long-Term Outcomes
Although the outcome in terms of survival without major neurosensory complications may be considered favorable at 23 and 24 weeks’ GA, treatment was demanding, as reflected by a long duration of mechanical ventilation and a large proportion of patients who required oxygen or assisted ventilation at 36 and 40 weeks’ PCA. The significance of this finding with respect to future pulmonary function remains to be seen, but it is disturbing that deRegnier et al 25 and Vohr et al 2 reported a 32% incidence of severe neurodevelopmental or sensory deficits at 1 year of age if the infants still required oxygen at 36 weeks. Furthermore, Short et al 26 reported recently an adverse effect of long-term oxygen requirement on cognitive and academic achievement at 8 years. However, the association between prolonged oxygen requirement and developmental deficits may be at least partly attributable to postnatal steroid treatment. 26 In a study from the era before postnatal steroid treatment, infants with severe prolonged pulmonary problems showed marked developmental catch-up when pulmonary function improved. 27
In previous studies of children born in 1986–1988 without early major handicaps, we did not find differences in long-term neurodevelopmental outcomes at 5 and 11 years between those with BWs of <1000 g and 1000 to 2000 g, and socioeconomic status was a much stronger predictor of outcome than BW. 28, 29 However, few infants had a GA of <26 weeks, and the results may not be representative of extremely premature infants born today. In a more recent Dutch regional study, outcomes at 2 years were extremely poor for infants born at 23 and 24 weeks’ GA, compared with those born at 25 and 26 weeks, although the difference in morbidity rates at discharge was similar to that in the present study. 8 Others found that late neurodevelopmental outcomes were related mainly to early cerebral ultrasound findings and not to GA 30 or BW. 31 In the large National Institute of Child Health and Human Development study, the rate of abnormal neurodevelopmental outcomes at 18 months of corrected age increased with decreasing BW but, with adjustment for various complicating factors such as early cerebral ultrasound findings, chronic lung disease, and postnatal steroid administration, BW had no significant impact on major neurologic deficits. 2 Interpretation of these various studies, particularly the National Institute of Child Health and Human Development study, suggests that extremely premature infants may have a long functional catch-up phase and follow-up assessments at 1 to 2 years may be too early to give reliable estimates of long-term outcomes.
In the past few years, principles of early neonatal management have not changed dramatically. On the basis of findings of only modest increases in possibly handicapping early morbidity with decreasing GA, it may be difficult to withhold treatment on the basis of GA alone and reported follow-up results at 1 to 2 years of age. These uncertainties call for long-term follow-up studies to describe more accurately perinatal and neonatal predictors of long-term outcomes. For the present study population, long-term followup monitoring is underway.
|
ACKNOWLEDGMENTS |
|---|
The study was funded by the Norwegian Foundation for Health and Rehabilitation and the Research Council of Norway.
Other members of the Norwegian Extreme Prematurity Study were as follows: Pediatrics: Inger E. Silberg, Østfold Central Hospital, Fredrikstad; Theresa Farstad, Akershus Central Hospital, Lørenskog; Jørgen Hurum, Oppland Central Hospital, Lillehammer; Rugmini Palat, Hedmark Central Hospital, Elverum; Per A. Tølløfsrud, Buskerud Central Hospital, Drammen; Alf Meberg, Vestfold Central Hospital, Tønsberg; Sveinung Slinde, Telemark Central Hospital, Skien; Marianne Skreden, Aust-Agder Central Hospital, Arendal; Kaare Danielsen, Vest-Agder Central Hospital, Kristiansand; Lars Stjernberg, Haugesund County Hospital, Haugesund; Jens Terum, Sogn and Fjordane Central Hospital, Førde; Steinar Spangen, Møre and Romsdal Central Hospital, Aalesund; Bjørn Myklebust, Innherred Hospital, Levanger; Ingebjørg Fagerli, Nordland Central Hospital, Bodø; Pal Ivan, Hammerfest Hospital, Hammerfest; Obstetrics: Lillian N. Berge, Ulleval University Hospital, Oslo; Per E. Børdahl, Rikshospitalet University Hospital, Oslo; Bjørg Lorentzen, Aker Hospital, Oslo; Ditlev Fossen, Østfold Central Hospital, Fredrikstad; Aasle-Marit Ullern, Akershus Central Hospital, Lørenskog; Jacob Nakling, Oppland Central Hospital, Lillehammer; Harry Aronsen, Oppland Central Hospital, Gjøvik; Turid Skjaeret Pedersen, Hedmark Central Hospital, Elverum; Erik Hovland, Kongsvinger Hospital, Kongsvinger; Liv Ellingsen, Buskerud Central Hospital, Drammen; Ulf Jan Andersen, Ringerike Hospital, Hønefoss; Halfdan Sundt, Vestfold Central Hospital, Tønsberg; Arne Christensen, Telemark Central Hospital, Skien; Arild Kloster Jensen, Aust-Agder Central Hospital, Arendal; Eli Smedvig, Rogaland Central Hospital, Stavanger; Torunn Eikeland, Haugesund County Hospital, Haugesund; Odd Harald Rognerud Jensen and Ingrid Borthen, Haukeland University Hospital, Bergen; Peer E. Bjørgo, Voss County Hospital, Voss; Bjørg Ladehaug, Sogn and Fjordane Central Hospital, Førde; Paal Wølner-Hanssen, Laerdal Hospital, Laerdal; Arna Jaernbart, Nordfjordeid County Hospital, Nordfjordeid; Jørg Kessler, Møre and Romsdal Central Hospital, Aalesund; Ottar Rekkedal, Volda County Hospital, Volda; Runa Heimstad, St Olav's University Hospital, Trondheim; Oddbjørn J. Bolaas, Innherred Hospital, Levanger; Helge Brobak, Namdal Hospital, Namsos; Bjørn Holdø, Nordland Central Hospital, Bodø; Odd Andersen, Vefsn Hospital, Mosjøen; Margit Steinholt, Sandnessjöen Hospital, Sandnessjøen; Einar D. Johansen, Harstad Hospital, Harstad; Ingar N. Vold, Lofoten Hospital, Gravdal; Kristen Olav Lind, Stokmarknes Hospital, Stokmarknes; Ingard Nilsen, University Hospital of Northern Norway, Tromsø.
|
FOOTNOTES |
|---|
Accepted Sep 7, 2004.
Reprint requests to (T.M.) Department of Pediatrics, Sykehuset Innlandet HF, Gjovik, 2819 Norway. E-mail: trond.markestad{at}sykehuset-innlandet.no
No conflict of interest declared.
|
REFERENCES |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
- Hack M, Fanaroff AA. Outcomes of children of extremely low birthweight and gestational age. Early Hum Dev. 1999;53 :193 –218[CrossRef][Web of Science][Medline]
- Vohr BR, Wright LL, Dusick AM, et al. Neurodevelopmental and functional outcomes of extremely low birth weight infants in the National Institute of Child Health and Human Development Neonatal Research Network, 1993–1994.
Pediatrics. 2000;105
:1216
–1226
[Abstract/Free Full Text] - Wood NS, Costeloe K, Gibson AT, et al. The EPICure study: growth and associated problems in children born at 25 weeks of gestational age or less.
Arch Dis Child Fetal Neonatal Ed. 2003;88
:F492
–F500
[Abstract/Free Full Text] - Tin W, Wariyar U, Hey E, Northern Neonatal Network. Changing prognosis for babies of less than 28 weeks' gestation in the north of England between 1983 and 1994.
BMJ. 1997;314
:107
–111
[Abstract/Free Full Text] - Hack M, Friedman H, Fanaroff AA. Outcomes of extremely low birth weight infants.
Pediatrics. 1996;98
:931
–937
[Abstract/Free Full Text] - Horbar JD, Badger GJ, Carpenter JH, et al. Trends in mortality and morbidity for very low birth weight infants 1991–1999.
Pediatrics. 2002;110
:143
–151
[Abstract/Free Full Text] - MacDonald H, American Academy of Pediatrics, Committee on Fetus and Newborn. Perinatal care at the threshold of viability.
Pediatrics. 2002;110
:1024
–1027
[Abstract/Free Full Text] - Rijken M, Stoelhorst GM, Martens SE, et al. Mortality and neurologic, mental, and psychomotor development at 2 years in infants born less than 27 weeks' gestation: the Leiden follow-up project on prematurity.
Pediatrics. 2003;112
:351
–358
[Abstract/Free Full Text] - Sheldon T. Dutch doctors change policy on treating preterm babies.
BMJ. 2001;322
:1383
[Free Full Text] - Norwegian Research Council. Limits of Treatment for Extremely Preterm Infants. Oslo, Norway: Norwegian Research Council; 1999
- Field D, Petersen S, Clarke M, Draper ES. Extreme prematurity in the UK and Denmark: population differences in viability.
Arch Dis Child Fetal Neonatal Ed. 2002;87
:F172
–F175
[Abstract/Free Full Text] - Irgens LM. The Medical Birth Registry of Norway: epidemiological research and surveillance throughout 30 years. Acta Obstet Gynecol Scand. 2000;79 :435 –439[CrossRef][Web of Science][Medline]
- Baumer JH, Wright D, Mill T. Illness severity measured by CRIB score: a product of changes in perinatal care? Arch Dis Child Fetal Neonatal Ed. 1997;77 :F211—F215
- International Neonatal Network. The CRIB (Clinical Risk Index for Babies) score: a tool for assessing initial neonatal risk and comparing the performances of neonatal intensive care units. Lancet. 1993;342 :193 –198[CrossRef][Web of Science][Medline]
- Papile LA, Burstein J, Burstein R. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birthweights less than 1,500 g. J Pediatr. 1978;92 :529 –534[CrossRef][Web of Science][Medline]
- Committee for the Classification of Retinopathy of Prematurity. An international classification of retinopathy of prematurity.
Arch Ophthalmol. 1984;102
:1130
–1134
[Abstract/Free Full Text] - Jobe AH, Bancalari E. Bronchopulmonary dysplasia.
Am J Respir Crit Care Med. 2001;163
:1723
–1729
[Free Full Text] - Costeloe K, Hennessy E, Gibson AT, Marlow N, Wilkinson AR. The EPICure study: outcomes to discharge from hospital for infants born at the threshold of viability.
Pediatrics. 2000;106
:659
–671
[Abstract/Free Full Text] - Lefebvre F, Glorieux J, St-Laurent-Gagnon T. Neonatal survival and disability rate at 18 months for infants born between 23 and 28 weeks gestation. Am J Obstet Gynecol. 1996;174 :833 –838[CrossRef][Web of Science][Medline]
- Allen MC, Donohue PK, Dusman AE. The limit of viability: neonatal outcome of infants born at 22 to 25 weeks' gestation.
N Engl J Med. 1993;329
:1597
–1601
[Abstract/Free Full Text] - Finnstrom O, Olaussen PO, Sedin G, et al. The Swedish national prospective study on extremely low birthweight (ELBW) infants: incidence, mortality, morbidity and survival in relation to level of care. Acta Paediatr. 1997;86 :503 –511[Web of Science][Medline]
- Tyson JE, Younes N, Verter J, Wright LL. Viability, morbidity and resource use among newborns of 501–800 g birth weight.
JAMA. 1996;276
:1645
–1651
[Abstract/Free Full Text] - Cifuentes J, Bronstein J, Phibbs CS, Phibbs RH, Schmitt SK, Carlo WA. Mortality in low birth weight infants according to level of neonatal care at hospital of birth.
Pediatrics. 2002;109
:745
–751
[Abstract/Free Full Text] - Johansson S, Montgomery SM, Ekbom A, et al. Preterm delivery, level of care, and infant death in Sweden: a population-based study.
Pediatrics. 2004;113
:1230
–1235
[Abstract/Free Full Text] - deRegnier RA, Roberts D, Ramsey D, Weaver RG Jr, O'Shea TM. Association between the severity of chronic lung disease and first-year outcomes of very low birth weight infants. J Perinatol. 1997;17 :375 –382[Medline]
- Short EJ, Klein NK, Lewis BA, et al. Cognitive and academic consequences of bronchopulmonary dysplasia and very low birth weight: 8-year-old outcomes. Pediatrics. 2003;112(5) . Available at: www.pediatrics.org/cgi/content/full/112/5/e359
- Markestad T, Fitzhardinge P. Growth and development in children recovering from bronchopulmonary dysplasia. J Pediatr. 1981;98 :597 –602[CrossRef][Web of Science][Medline]
- Sommerfelt K, Ellertsen B, Markestad T. Parental factors in cognitive outcome of non-handicapped low birthweight infants. Arch Dis Child. 1995;73 :F135 –F142[Web of Science]
- Elgen I, Sommerfelt K. Low birthweight children: coping in school? Acta Paediatr. 2002;91 :939 –945[CrossRef][Web of Science][Medline]
- Vollmer B, Roth S, Baudin J, Stewart AL, Neville BG, Wyatt JS. Predictors of long-term outcome in very preterm infants: gestational age versus neonatal cranial ultrasound.
Pediatrics. 2003;112
:1108
–1114
[Abstract/Free Full Text] - Piecuch RE, Leonard CH, Cooper BA, Sehring SA. Outcome of extremely low birth weight infants (500 to 999 grams) over a 12-year period.
Pediatrics. 1997;100
:633
–639
[Abstract/Free Full Text]
PEDIATRICS (ISSN 1098-4275). ©2005 by the American Academy of Pediatrics
CiteULike 
Connotea 
Del.icio.us 
Digg 
Facebook 
Reddit 
Technorati 
Twitter What's this?
This article has been cited by other articles:
|
|
 |
|
  N Fischer, M A Steurer, M Adams, T M Berger, and for the Swiss Neonatal Network Survival rates of extremely preterm infants (gestational age <26 weeks) in Switzerland: impact of the Swiss guidelines for the care of infants born at the limit of viability Arch. Dis. Child. Fetal Neonatal Ed., November 1, 2009; 94(6): F407 - F413. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Austeng, K. B. M. Kallen, U. W. Ewald, P. G. Jakobsson, and G. E. Holmstrom Incidence of Retinopathy of Prematurity in Infants Born Before 27 Weeks' Gestation in Sweden Arch Ophthalmol, October 1, 2009; 127(10): 1315 - 1319. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Vento, M. Moro, R. Escrig, L. Arruza, G. Villar, I. Izquierdo, L. J. Roberts II, A. Arduini, J. J. Escobar, J. Sastre, et al. Preterm Resuscitation With Low Oxygen Causes Less Oxidative Stress, Inflammation, and Chronic Lung Disease Pediatrics, September 1, 2009; 124(3): e439 - e449. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S H W. Wold, K Sommerfelt, H Reigstad, A Ronnestad, S Medbo, T Farstad, P I Kaaresen, R Stoen, K T Leversen, L M Irgens, et al. Neonatal mortality and morbidity in extremely preterm small for gestational age infants: a population based study Arch. Dis. Child. Fetal Neonatal Ed., September 1, 2009; 94(5): F363 - F367. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. G. Berry, D. A. Graham, R. J. Graham, J. Zhou, H. L. Putney, J. E. O'Brien, D. W. Roberson, and D. A. Goldmann Predictors of Clinical Outcomes and Hospital Resource Use of Children After Tracheotomy Pediatrics, August 1, 2009; 124(2): 563 - 572. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Klingenberg, P. I. Kaaresen, and L. B. Dahl International Perspectives: Neonatology Above the Arctic Circle NeoReviews, July 1, 2009; 10(7): e323 - e329. [Full Text] [PDF]
|
|
|
|
|
|
D. G. Batton and Committee on Fetus and Newborn Antenatal Counseling Regarding Resuscitation at an Extremely Low Gestational Age Pediatrics, July 1, 2009; 124(1): 422 - 427. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. K Yeaney, E. M Murdoch, and C. C Lees The extremely premature neonate: anticipating and managing care BMJ, June 22, 2009; 338(jun22_2): b2325 - b2325. [Full Text]
|
|
|
|
 |
|
 The EXPRESS Group One-Year Survival of Extremely Preterm Infants After Active Perinatal Care in Sweden JAMA, June 3, 2009; 301(21): 2225 - 2233. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S M Aukland, K Rosendahl, C M Owens, K R Fosse, G E Eide, and T Halvorsen Neonatal bronchopulmonary dysplasia predicts abnormal pulmonary HRCT scans in long-term survivors of extreme preterm birth Thorax, May 1, 2009; 64(5): 405 - 410. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Itabashi, T. Horiuchi, S. Kusuda, K. Kabe, Y. Itani, T. Nakamura, M. Fujimura, and M. Matsuo Mortality Rates for Extremely Low Birth Weight Infants Born in Japan in 2005 Pediatrics, February 1, 2009; 123(2): 445 - 450. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Bodeau-Livinec, N. Marlow, P.-Y. Ancel, J. J. Kurinczuk, K. Costeloe, and M. Kaminski Impact of Intensive Care Practices on Short-Term and Long-term Outcomes for Extremely Preterm Infants: Comparison Between the British Isles and France Pediatrics, November 1, 2008; 122(5): e1014 - e1021. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S Pignotti Extremely preterm births: recommendations for treatment in European countries Arch. Dis. Child. Fetal Neonatal Ed., November 1, 2008; 93(6): F403 - F406. [Full Text] [PDF]
|
|
|
|
 |
|
 C. S. Morgen, C. Bjork, P. K. Andersen, L. H. Mortensen, and A.-M. Nybo Andersen Socioeconomic position and the risk of preterm birth--a study within the Danish National Birth Cohort Int. J. Epidemiol., October 1, 2008; 37(5): 1109 - 1120. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-C. Fauchere, C. Dame, R. Vonthein, B. Koller, S. Arri, M. Wolf, and H. U. Bucher An Approach to Using Recombinant Erythropoietin for Neuroprotection in Very Preterm Infants Pediatrics, August 1, 2008; 122(2): 375 - 382. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Moster, R. T. Lie, and T. Markestad Long-Term Medical and Social Consequences of Preterm Birth N. Engl. J. Med., July 17, 2008; 359(3): 262 - 273. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J Field, J. S Dorling, B. N Manktelow, and E. S Draper Survival of extremely premature babies in a geographically defined population: prospective cohort study of 1994-9 compared with 2000-5 BMJ, May 31, 2008; 336(7655): 1221 - 1223. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Qian, C. Liu, W. Zhuang, Y. Guo, J. Yu, H. Chen, S. Wang, Z. Lin, S. Xia, L. Ni, et al. Neonatal Respiratory Failure: A 12-Month Clinical Epidemiologic Study From 2004 to 2005 in China Pediatrics, May 1, 2008; 121(5): e1115 - e1124. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. Pignotti and G. Donzelli Perinatal Care at the Threshold of Viability: An International Comparison of Practical Guidelines for the Treatment of Extremely Preterm Births Pediatrics, January 1, 2008; 121(1): e193 - e198. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Limperopoulos, H. Bassan, K. Gauvreau, R. L. Robertson Jr, N. R. Sullivan, C. B. Benson, L. Avery, J. Stewart, J. S. S. MD, S. A. Ringer, et al. Does Cerebellar Injury in Premature Infants Contribute to the High Prevalence of Long-term Cognitive, Learning, and Behavioral Disability in Survivors? Pediatrics, September 1, 2007; 120(3): 584 - 593. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Tommiska, K. Heinonen, L. Lehtonen, M. Renlund, T. Saarela, O. Tammela, M. Virtanen, and V. Fellman No Improvement in Outcome of Nationwide Extremely Low Birth Weight Infant Populations Between 1996-1997 and 1999-2000 Pediatrics, January 1, 2007; 119(1): 29 - 36. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ikeda, S. Hayashida, I. Hokuto, S. Kusuda, H. Nishida, and on behalf of the Japan Neonatologist Association International Perspectives: Recent Short-term Outcomes of Ultrapreterm and Extremely Low-birthweight Infants in Japan NeoReviews, October 1, 2006; 7(10): e511 - e516. [Full Text] [PDF]
|
|
|
|
|
|
J L Watts and S Saigal Outcome of extreme prematurity: as information increases so do the dilemmas. Arch. Dis. Child. Fetal Neonatal Ed., May 1, 2006; 91(3): F221 - F225. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
