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* 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
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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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.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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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.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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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).
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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.
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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).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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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).
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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.
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ACKNOWLEDGMENTS |
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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.
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FOOTNOTES |
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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.
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REFERENCES |
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