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* Departments of Pediatrics
Medical Statistics, Leiden University Medical Center, Leiden, the Netherlands
Juliana Children’s Hospital, The Hague, the Netherlands
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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Design. Regional, prospective study; part of the Leiden Follow-Up Project on Prematurity.
Setting. Three health regions in The Netherlands.
Patients. A total of 266 live born infants (1996/1997) with GA <32 weeks; 46 infants were <27 weeks.
Main outcome measures. Neurologic examination (according to Hempel) and assessment of mental and psychomotor development using the Bayley Scales of Infant Development I, at the corrected age of 2 years.
Results. Mortality was 35% (16 of 46) <27 weeks, compared with 6% (14 of 220) in infants with GA 27 to 32 weeks; withdrawal of treatment in 60% and 43%, respectively. Below 27 weeks mortality was higher after extra-uterine transport and pregnancy induction. Neonatal morbidity was higher in infants <27 weeks compared with infants 27 to 32 weeks. Below 27 weeks postnatal use of dexamethasone and being hospitalized at term were associated with abnormal neurologic outcome; there was a higher incidence in (mild) mental developmental delay compared with the older infants. Adverse outcome (dead or abnormal neurologic, psychomotor, or mental development) in infants 23 to 24, 25, 26, and 27 to 32 weeks GA was, respectively, 92% (11 of 12), 64% (7 of 11), 35% (8 of 23), and 18% (40 of 220).
Conclusions. Mortality and neonatal morbidity were higher in infants with GA <27 weeks compared with infants born between 27 and 32 weeks. The high adverse outcome of infants <25 weeks suggests that one should carefully weigh whether or not to aggressively resuscitate and treat these extremely premature infants.
Key Words: extremely premature infants • mortality • neonatal morbidity • neurologic outcome • psychomotor and mental development • behavior
Abbreviations: GA, gestational age • BPD, bronchopulmonary dysplasia • BSID, Bayley Scales of Infant Development • DA, definitely abnormal • IVH, intraventricular hemorrhage • LFUPP, Leiden Follow-Up Project on Prematurity • MA, mildly abnormal • MDI, mental developmental index • NEC, necrotizing enterocolitis • NICU, neonatal intensive care unit • PDI, psychomotor developmental index • PVL, cystic periventricular leucomalacia • SES, socioeconomic status • OR, odds ratio • CI, confidence interval
In the 1990s, new techniques have been introduced to increase viability of very premature infants. The use of surfactant, antenatal steroids, and better ventilation strategies have resulted in an increased survival of infants of extremely low gestational age (GA) or low birth weight. Some studies report an increase in percentage of severe disabilities1 with this better survival, whereas others have reported that the handicap rate has remained the same.2–5 Finally, with a decreasing mortality and therefore more survivors, the absolute number of infants with handicap has increased.
Worldwide, there is a difference in opinion about the limit of viability: at what GA should one start to resuscitate? Studies from the United States report that resuscitation is indicated from 23 or 24 weeks of gestation, although the chances of intact survival are poor6–8; McElrath et al9 found no survivors, born at 23 weeks’ gestation, free from substantial morbidity. Studies from Japan report 18% survival in infants born at 22 to 23 weeks; these survivors, however, have high rates of neurologic sequelae.10 In Europe (Sweden,11 United Kingdom12–14), high mortality rates (>70%) at 23 and 24 weeks were found. Unfortunately, articles about GA and outcome are relatively scarce. In the past, Verloove et al15 showed that GA is a more important indicator of maturation than is birth weight.
The aim of this study, which is part of the Leiden Follow-Up Project on Prematurity (LFUPP), was to compare mortality, neonatal morbidity, and outcome (neurologic, psychomotor, mental, and behavioral) at the corrected age of 2 years, of infants born with a GA of <27 weeks to infants born between 27 and 32 weeks GA. In addition, we looked for intra-group differences among the infants <27 weeks GA. Furthermore, predictors of abnormal outcome at the corrected age of 2 years were explored.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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A total of 122 infants (46%) were born in the Leiden University Medical Center (LUMC), 45 (17%) were born in another university hospital with a neonatal intensive care unit (NICU), 64 (24%) in a regional hospital in The Hague and transported to the NICU of the Juliana Children’s Hospital; another 35 infants (13%) were born in another regional hospital. Infants admitted to one of the hospitals mentioned above but coming from another geographical area were not included in this study. The hospitals contributing to this study had the same clinical protocol for resuscitation, with the exception that other hospitals with a NICU did not resuscitate infants born <25 weeks, in contrast to the LUMC. Seventy percent of the infants were admitted to the LUMC or Juliana Children’s Hospital, 2 hospitals which have the same clinical neonatal care.
Forty-six infants were born <27 weeks GA. Of these infants, 25 (55%) were born in the NICU of the LUMC, 8 (17%) in another NICU, and 13 (28%) in a regional hospital and immediately after birth transported to a NICU.
Although in the 3 mentioned health regions treatment (full resuscitation in the delivery room without restrictions) was started when an infant had a GA of at least 24+0 weeks, 2 infants with a GA of 23 weeks were included because the precise GA was uncertain at the time of birth. In general, the GA is very well known in the Netherlands because of good antenatal care and early ultrasound assessments. When a GA of 24 weeks is mentioned, a GA of 24+0 to 24+6 weeks is meant.
Data Collection
Antenatal and perinatal data were collected including health status and diseases of the mother, socioeconomic status (SES), pregnancy induction, reliability of GA, diseases and medication during pregnancy, GA, birth weight, APGAR score, and data about perinatal morbidity and medication. SES was determined by the level of education of each parent individually. A score of 1 was given if the parent’s education was low, a score of 2 for an average educational level, and a score of 3 for higher levels of education. SES scores of both parents were then combined and divided by 2 (range: 1–3). Dexamethasone was given in 1996/1997 in an initial dose of 0.5 mg/kg, tapered over 42 days to 0.1 mg/kg. Some infants who remained ventilator-dependent got a second course of dexamethasone, but this was not given in a standardized way. The condition at discharge from the hospital was noted and was considered to be normal when there was no neurologic disorder (on clinical examination); no pulmonary problems (need of oxygen and/or diuretics); no cardiac disorder; no feeding problems (tube feeding or regurgitation); and no visual, hearing, or psychosocial difficulties. The cause of death was noted and also whether they died naturally or after withdrawal of treatment.
The Medical Ethics Committee of the LUMC approved the study and informed consent of the parents was obtained.
Follow-Up
Children were assessed at 2 years of age (corrected for prematurity) by 4 neonatologists experienced in developmental assessment. The examination included a general examination and a neurologic examination according to Hempel,16 focused on major as well as minor neurologic dysfunctions. The children were considered definitely abnormal (DA) when muscle tone and reflexes were both abnormal (which meant the presence of a cerebral palsy), mildly abnormal (MA) when only part of the reflexes or muscle tone were abnormal, or normal.
Mental and psychomotor development were assessed by a developmental psychologist using the Dutch version of the Bayley-Scales of Infant Development (BSID) I.17,18 During the study period, the BSID II was not yet validated for the Dutch population. The BSID I have a mean value of 100 and a standard deviation of 16. A mental developmental index (MDI) or psychomotor developmental index (PDI) 
84 ( –1 SDS) was considered normal, MDI or PDI between 68 and 84 was considered as moderate delay, and <68 (< –2 SDS) as severe delay.
To attain a single outcome measure, neurologic outcome, PDI, and MDI were combined. When at least 1 of these 3 outcome measures was DA, children were considered DA, and when at least 1 outcome was MA, children were considered MA.
At 2 years of age, behavior was assessed using Achenbach’s Child Behavior Checklist19,20 for 2- to 3-year-old children, completed by the parents. According to this list, behavior could be assessed by using a total problem score: a score above the 90th percentile was defined as clinical (abnormal), a score from the 85th through 90th percentile as borderline clinical, below the 85th percentile as normal.
Statistical Analyses
SPSS10 for Windows was used for statistical analyses. The Fisher exact test was used to evaluate associations in a 2 x 2 table/
2 test. A test on linear association was used in a 2 x 3 table. Correction for confounding variables was done with binary logistic regression for mortality and the Hempel examination with GA and bronchopulmonary dysplasia (BPD) as confounders. Differences were considered significant with P values <.05.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Infants Born <27 Weeks GA
Seventy percent of the infants born <27 weeks had a birth weight <1000 g. Mortality was 50% when birth weight was <750 g. Mortality decreased with increasing birth weight.
Neonatal mortality was higher in infants born in peripheral hospitals and then immediately afterward transported to an NICU, compared with infants born in a hospital with an NICU: 10 of 13 (77%) versus 6 of 33 (18%); odds ratio (OR) 15 (95% confidence interval [CI]: 3.1–71.7), P < .001. After correction for GA, the OR remained about the same: 13.4 (95% CI: 2.4–75.1; P = .003). Mortality was higher when pregnancy was induced: 5 of 7 (71%) in in vitro fertilization4/intra-cytoplasmatic sperm injection1 compared with 11 of 39 (28%) in spontaneous pregnancies (OR: 6.4, 95% CI: 1.1–37.8; P = .04). After correction for GA, the OR remained at the same level of 6.1 (95% CI: 0.8–45.0; P = .08), hence little confounding in the data. Although multiple births occurred more often in case of pregnancy induction (P = .001), multiple birth itself was not associated with higher mortality: 25% in multiple pregnancy compared with 37% in singleton pregnancy; this was not statistically significant.
Withdrawal of treatment (when further treatment was considered futile) occurred in 60% of cases (n = 9). Two infants died the first day; 8 infants (53%) died in the first week, mainly because of pulmonary or intracerebral problems; withdrawal of treatment occurred in 63% of them. Another 7 infants died before the fourth week because of various problems. One infant died at the age of 6 months secondary to BPD.21 In the 14 infants born between 27 and 32 weeks gestation that died, treatment was withdrawn in 43%.
For a more detailed study of the extremely premature infants, we divided the group into infants with a GA of 23 to 25 weeks (n = 23) and of 26 weeks (n = 23). In the first group, 12 infants died (52%), in the second group 4 infants (17%) OR: 5.1, 95% CI: 1.3–20.1, P = .03.
Perinatal Morbidity
Comparison of Infants <27 Weeks GA to Infants of 27 to 32 Weeks GA
The mean GA in the group <27 weeks GA was 25.7 weeks, compared with 30.0 weeks in the group 27 to 32 weeks GA; mean birth weight was 843 g and 1335 g, respectively. The incidence of perinatal problems in infants with a GA <27 weeks was compared with the incidence in infants born between 27 and 32 weeks. The incidence of pregnancy-induction, male gender, percentage of twin or triplet, use of antenatal steroids, and the number of infants with intrauterine growth failure did not vary between the 2 groups; the percentage of delivery by Cesarian section was higher (P < .001) in the infants born between 27 and 32 weeks of gestation (Table 1). Neonatal morbidity was much higher in the more premature group (Table 2).
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Neurologic Outcome at 2 Years
At 2 years, 23 of the 30 survivors (87%) with GA <27 weeks were examined according to Hempel; 1 child was examined by another pediatrician and considered normal; 2 children were considered completely normal according to another pediatrician at the age of 18 months corrected age, and they were not followed any further because they were doing so well. The results of these 26 children are shown in Fig 1.
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Although 27% of the infants born between 23 and 25 weeks GA had a normal neurologic examination at 2 years, compared with 53% of the infants born at 26 weeks GA, this difference did not reach significance (P = .4).
Bayley Scales at 2 Years
The developmental psychologist tested two thirds of the survivors born <27 weeks: in 21 children an MDI was measured, in 22 children a PDI. Children were lost because of different reasons: in 1 case removal to another country, 1 child was blind, 1 was in the hospital for a long time for pulmonary problems, 2 were seen by another pediatrician, 1 couple of parents did not want any contact with the hospital anymore, and 2 children were tested by the Stutsman Intelligence Test instead of the BSID I. The lost group did not differ from the tested group in GA, gender, neonatal morbidity, or SES.
In the immature group (<27 weeks), more (mild) mental delay occurred compared with the older premature infants (27 to 32 weeks; P = .048); psychomotor delay occurred also more frequently (45% compared with 30%), but this difference did not reach significance (Fig 2). No association was found between any of the perinatal factors (SES, RDS, hypotension, patent ductus arteriosus, NEC, PVL, IVH, etc, as summarized in Table 2) and the developmental delay.
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Combining Neurologic Development, MDI, and PDI at 2 Years in a Total Outcome Score
Twenty-six of the 30 survivors were neurologically examined. Of the 4 children without a neurologic examination, in 2 cases an intelligence test according to Stutsman was done: one child had a normal IQ, the other a MA IQ. For the total score (neurologic, psychomotor, and mental development), these 2 children were included. Finally, the loss in the immature group was 2 of 30 (7%) for this total outcome score.
Thirty-six percent (10 of 28) of the assessed survivors born <27 weeks had a DA outcome compared with 16% (26 of 167) of the assessed survivors born between 27 and 32 weeks GA (OR: 3.0, 95% CI: 1.3–7.3, P = .02). Infants born at 23 to 25 weeks were classified as DA in 55% (6 of 11), infants born at 26 weeks GA in 21% (4 of 17); this difference did not reach significance.
When we add behavior to this total outcome score, 46% (13 of 28) of the assessed survivors born <27 weeks had a DA outcome (compared with 21% of the infants born between 27 and 32 weeks, P < .001).
One of the infants born <27 weeks was blind, and 2 infants were deaf at the age of 2 years (all 3 neurologically abnormal).
Neurologic examination as well as both the Bayley tests and the Child Behavior Checklist were available from 21 of the 30 survivors born <27 weeks gestation; of these 21 children, only 3 had a normal outcome at all tests (2 born at 25 weeks, 1 born at 26 weeks).
Adverse Outcome
Overall, adverse outcome (defined as dead or at least 1 conclusion DA in neurologic, mental, or psychomotor development) was 57% in infants born <27 weeks gestation compared with 18% in infants born between 27 and 32 weeks. Adverse outcome in infants born at 23 to 24, 25, and 26 weeks gestation was, respectively, 92%, 64%, and 35% (Fig 3).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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In the health regions in the Netherlands, where this study was performed, treatment was started at 24+0 weeks. In-hospital survival in infants with a GA of 24 weeks was 40%, at the age of 2 years survival was 30%, which is comparable with studies from the United Kingdom,12,13,26 Sweden,11 and Canada.27,28 Most studies from the United States found higher survival rates: survival at discharge and in the first year was 48% to 62%.6–8,24,26–28 Survival in the infants born at 25 weeks GA was 64% in our study, comparable to various results from Sweden11 and Canada,27,28 somewhat higher than in the United Kingdom12–14,29 but lower than in the United States.3,4,7,8,26,30–32 Survival in infants of 26 weeks GA was 83%, rather high compared with the literature.8,13,28,31,32 Jacobs et al33 found exactly the same mortality rate (35%) as we did in infants born between 23 and 26 weeks, born between 1990 and 1994. Because mortality was higher in the group infants transported postnatally compared with infants born in a center with a NICU (77% vs 18%, independent of GA), we expect that mortality would be lower when all infants would have been born in a neonatal center. It is also concerning that mortality was higher in infants born after pregnancy induction, irrespective of multiple pregnancy.
Neonatal Morbidity
With respect to literature, we found a comparable incidence of grade III/IV IVH (18%) and cystic PVL (11%) in infants <27 weeks GA. Gibson34 reported incidences of 25% to 32% for the combination of serious IVH and PVL; Hack and Fanaroff24 in a recent review found a range of 10% to 83% for infants born at 23 to 24 weeks GA and of 10% to 22% for infants born at 25 weeks GA for severe cranial ultrasound abnormalities. The incidence of NEC (15%) was comparable with literature, the incidence of severe retinopathy of prematurity (2%) somewhat lower. Gibson34 reports that the need of oxygen at the age of 28 days is almost universal, like in this study (97%). We found a rather high percentage of infants with BPD (50%) compared with, for example, Kilpatrick (15%),7 but Hack and Fanaroff24 report a wide range in BPD: 57% to 70%, 23% to 89%, and 16% to 71% for infants born at respectively, 23, 24, and 25 weeks of gestation. The reason could be a difference in oxygen saturation monitoring practices with varying criteria for the administration and weaning of oxygen.24
Outcome at 2 Years
Perhaps even more important than survival itself is intact survival. Hack and Fanaroff24 report that there is a wide variety in outcome among survivors of extremely premature infants: they found severe disabilities in 30%, 17% to 45%, and 12% to 35% for infants of 23, 24, and 25 weeks of GA, respectively. There are many explanations for these wide ranges, but the most important ones are differences in definition of disabilities and handicaps and in the length of follow-up. For example, Holtrop35 found a good short-term outcome in 90% of the survivors of 23 to 25 weeks GA, this just being defined as the absence of PVL or IVH, whereas Piecuch36 demonstrated that in extremely premature infants, PVL and IVH do not account for all of the neurologic abnormalities. However, in our study, an IVH grade III or IV or cystic PVL were not associated with abnormal neurologic outcome at the age of 2 years, maybe because of small numbers. In general, Cooke29 found in a 10-year cohort of premature infants with a GA <26 weeks 74% free of serious handicaps; Tin14 also reported 75% of the survivors with a GA <26 weeks free from a severe disability. In our study, 55% of the survivors born <26 weeks had a normal or MA outcome at the age of 2 years.
At 2 years, the percentage of children with a completely normal neurologic examination remained about the same as at term age (48% at term—data not shown—and 42% at 2 years), but the percentage of children with an MA examination decreased (from 33% to 19%) at the cost of an increase in the number of children with a DA neurologic examination (16% to 39%). We know that a lot of problems concerning speech and language development, concentration, and behavior appear later and are not noticed yet at the age of 2 years.37 It is alarming that 36% (10 of 28) of the assessed survivors born <27 weeks’ gestation had a DA total outcome score at this age; 46% (13 of 28) when behavior was added to this score.
Starting Active Treatment
Worldwide, people do not agree about the limit of viability: Kramer8 from the United States suggests an active approach from 24 completed weeks; Kilpatrick7 advises not to resuscitate infants born at 23 and 24 weeks GA (only if the parents insist) and to resuscitate infants from 25 weeks GA only when birth weight is >600 g; Sanders38 (United States) and Battin5 (Canada) agree that 22 weeks is not acceptable, 23 to 24 weeks a sort of limit with high morbidity, and they suggest starting at 25 weeks. Piecuch36 remarks that in infants born at 24 and 25 weeks, the high rate of cognitive problems is concerning. Recently, Wood39 from the EPICure Study Group showed that severe disability is common among children born <26 weeks GA (half of the infants had any disability; 23% a severe disability) and remains a major challenge in this group of infants. The question remains if one should start to resuscitate these infants when there is a 25%, 50%, or 75% chance on intact survival? There will always be differences in opinion on what is ethical. Maybe one can start resuscitation (at 24 or 25 weeks), but after having started one should not be negative toward withdrawal of treatment in cases of very poor prognosis. However, not starting treatment always seems easier than withdrawing treatment.40 Recently, Lorenz et al41 reported about the differences in management strategies for extreme prematurity in the United States and some countries in Europe like the Netherlands. They explain that in the United States (offering intensive care to all infants), there will be more survivors at the cost of a higher percentage of disabling cerebral palsy, whereas in the Netherlands (more selective treatment) some infants will die who might have survived without disability. This is a moral dilemma without a definitive answer, depending on the personal view of parents and doctors.
It would be helpful if there were some risk factors associated with adverse outcome. In this study, the postnatal use of dexamethasone and still being admitted at term seem to be associated with an abnormal neurologic outcome. Both factors could be taken into consideration in the communication with the parents. An explanation for the lack of association between other perinatal factors and outcome could be the small numbers in this study.
The set up of our study was prospective and regional. Not only was a standardized neurologic examination performed, but also mental and psychomotor development and behavior were assessed. In the Netherlands, the GA is in general precisely known in pregnant women, so this makes it possible to associate outcome with GA instead of birth weight. The endpoint was the corrected age of 2 years, which is not so frequently described in cohort infants born in the 1990s. The flaws of this study are the small numbers and the rather high loss (
30%) in the BSID, but the parameters of the lost group and the assessed group did not differ and the conclusions point in the same direction as found in literature: higher mortality and morbidity with decreasing GA. We also found higher mortality in extremely premature infants born after pregnancy induction (P = .04) and when transported extra-uterinely (P < .001); the association between abnormal neurologic outcome and the postnatal use of dexamethasone is compatible with literature. The high percentage (74%) of adverse outcome in infants born <26 weeks gestation is reason for concern and needs to be kept in mind when counseling the parents. The even higher percentage of adverse outcome in infants <25 weeks (92%) suggests that one should carefully weigh whether or not to aggressively resuscitate and treat these extremely premature infants.
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ACKNOWLEDGMENTS |
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Other participants of the LFUPP include the pediatric staff of Lange Land Hospital, Zoetermeer, the Netherlands (Irene Hofmeier; Harriet C. J. Roggeveen), Rijnland Hospital, Leiderdorp, the Netherlands (Nel E. C. Mourad-Baars), Diaconessen Hospital, Leiden, the Netherlands (Adèle C. Engelberts), Reinier de Graaf Hospital, Delft, the Netherlands (Piet J. C. van der Straaten), and Antoniushove Hospital, Leidschendam, the Netherlands (Theo A. Nijenhuis).
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FOOTNOTES |
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Reprint requests to (M.R.) Neonatology, J6-S, Leiden University Medical Center, Box 9600, 2300 RC Leiden, the Netherlands. E-mail: m.rijken{at}lumc.nl
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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