Extreme Prematurity — The Continuing Dilemma
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《新英格兰医药杂志》
The tremendous advances in perinatal and neonatal care that were made beginning in the 1970s and through the 1990s have contributed to the survival of infants as immature as 22 to 25 weeks of gestational age.1,2,3,4 According to current guidelines developed by the American Academy of Pediatrics for the use of neonatologists when counseling parents,5 it is considered appropriate not to initiate resuscitation for infants younger than 23 weeks of gestational age or those whose birth weight is less than 400 g, given the dismal prognosis for these infants. The involvement of the family is considered critical to the decision-making process with regard to resuscitation. However, these guidelines continue to be controversial, and the families of infants born at 21 or 22 weeks of gestational age may pressure clinicians to resuscitate these infants.
This situation is becoming more common as a result of the increasing rate of premature births,6 advanced maternal age,6 the increased use of assisted reproductive technology,7 and the publicity about "miracle babies" in the media. Data on outcomes from large studies are therefore critically needed to guide decision making. One of the challenges, however, in assessing long-term outcomes is that the practices in antenatal and neonatal care are continually evolving — the outcomes for infants born in 2005 will reflect practices in neonatal intensive care units that differ from the standard practices of previous years.
In this issue of the Journal,8 Marlow et al. report outcomes at 6 years of age among children born at 25 or fewer completed weeks of gestation who were enrolled at birth in the EPICure study. This report is important, because great efforts were made to collect data prospectively on all the infants born at these gestational ages in the United Kingdom and Ireland in 1995, and not just on infants referred to a tertiary care center over a number of years. This approach results not only in an improved ability to generalize from these data, but also in numbers that are large enough to use to evaluate the range of outcomes among the most immature survivors. The report by Marlow et al. includes the results of comprehensive assessments of the status of neuromotor skills, cognitive ability, vision, and hearing. It is the largest study of infants born at 22 to 25 weeks of gestation with follow-up to school age, it achieved a high (78 percent) rate of follow-up among survivors, and it included a control group of classmates born at full term.
Among these extremely preterm infants, neonatal survival to discharge was low: 1 percent among those born at 22 weeks of gestation, 11 percent at 23 weeks, 26 percent at 24 weeks, and 44 percent at 25 weeks. The rates of survival with no disability at 6 years of age were even more troubling: none among infants born at 22 weeks of gestation, 1 percent at 23 weeks, 3 percent at 24 weeks, and 8 percent at 25 weeks. These data are all the more compelling because they are the most up-to-date data available and are relevant to current practices of obstetrical and neonatal intensive care. (More than 60 percent of these extremely premature infants received antenatal steroids, and 84 percent received surfactant.) This study shows our limitations not only in saving such infants but also in supporting the neurologic and cognitive development of those born at the lower border of viability.
Most studies report scores for children with cognitive impairment that are significantly lower than the mean scores on standardized tests. Recognizing that test scores have increased over time, the authors used classmates of the extremely preterm children for comparison and identified impairment as a score more than 2 standard deviations below the mean score for these controls. With the use of this reference group, the rate of serious impairment according to overall cognitive scores among the extremely preterm children was 41 percent. Only 20 percent of these children had no neuromotor or cognitive disability. Many children who had no appreciable disability at 30 months had evidence of disability at 6 years of age. This outcome probably reflects the increasing complexity of cognitive demands during childhood. The significantly lower scores for processing skills among the extremely preterm children at six years of age, as compared with the scores of their peers, arouse concern about challenges that require higher executive-functioning skills and about how these children will function in middle school and high school and as adults. These findings are important, because they indicate that such children will require comprehensive educational support. We must step back and ask why these children have such a high risk of neurodevelopmental sequelae.
Infants born at between 22 to 25 weeks of gestation are fragile and vulnerable, with immature organ systems. Their skin is gelatinous, and they breathe through terminal bronchioles because the alveoli have not yet formed. They are at high risk for brain injury from hypoxia and ischemia and undernutrition, as well as for sepsis, which starts the cascade of events that increase the risk of brain hemorrhage, white-matter injury (periventricular leukomalacia and ventriculomegaly), and poor brain growth, and for subsequent neurodevelopmental impairment. Active brain development occurs during the second and third trimesters, with neurogenesis, neuronal migration, maturation, apoptosis, and synaptogenesis.9,10 The immaturity of the brain at 22 to 25 weeks of gestation makes these extremely preterm infants particularly vulnerable.
Recent magnetic resonance imaging studies have shown decreased cerebral tissue volume, regional abnormalities of the brain, and decreased complexity in the cortical and surface area in preterm children studied at eight years of age,11 with associated alterations in semantic processing and visuospatial processing.12,13,14 Specifically, decreased sensorimotor and midtemporal cortical volumes were associated with low scores on full-scale, performance, and verbal IQ testing. These findings suggest that some of the neurodevelopmental impairments identified in extremely preterm children may be difficult to prevent because of the level of brain maturation at birth.
On the positive side, there is some evidence of improvement in test scores over time, in that children who were born prematurely have higher scores on cognitive evaluations than on tests performed when they were infants.15 It is unclear whether this improvement represents resistance to injury or resilience. The proportion of children with no disability in the current report (20 percent) suggests the possibility of identifying biologic, environmental, and genetic factors that provide protection to these vulnerable infants; more research is warranted to understand such factors better.
Pending further advances that could improve neurologic outcomes after extremely preterm birth, carefully conducted follow-up studies such as this one by Marlow et al. provide critical information that is needed for decision making by neonatologists and parents.
Source Information
From Women and Infants Hospital, Providence, R.I. (B.R.V.); and Johns Hopkins Hospital, Baltimore (M.A.).
References
Hack M, Fanaroff AA. Outcomes of extremely-low-birth-weight infants between 1982 and 1988. N Engl J Med 1989;321:1642-1647.
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.
El-Metwally D, Vohr B, Tucker R. Survival and neonatal morbidity at the limits of viability in the mid 1990s: 22 to 25 weeks. J Pediatr 2000;137:616-622.
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.
Special considerations. In: Braner D, Kattwinkel J, Denson S, Zaichkin J, eds. Textbook of neonatal resuscitations. 4th ed. Elk Grove Village, Ill.: American Academy of Pediatrics, 2000:7-19.
Arias E, MacDorman MF, Strobino DM, Guyer B. Annual summary of vital statistics -- 2002. Pediatrics 2003;112:1215-1230. [Abstract/Full Text]
Balen AH, MacDougall J, Tan SL. The influence of the number of embryos transferred in 1060 in-vitro fertilization pregnancies on miscarriage rates and pregnancy outcome. Hum Reprod 1993;8:1324-1328.
Marlow N, Wolke D, Bracewell MA, Samara M. Neurologic and developmental disability at six years of age after extremely preterm birth. N Engl J Med 2005;352:9-19.
Huttenlocher PR. Morphometric study of human cerebral cortex development. Neuropsychologia 1990;28:517-527.
Huttenlocher PR, Dabholkar AS. Regional differences in synaptogenesis in human cerebral cortex. J Comp Neurol 1997;387:167-178.
Peterson BS, Vohr B, Staib LH, et al. Regional brain volume abnormalities and long-term cognitive outcome in preterm infants. JAMA 2000;284:1939-1947.
Isaacs EB, Edmonds CJ, Chong WK, Lucas A, Gadian DG. Cortical anomalies associated with visuospatial processing deficits. Ann Neurol 2003;53:768-773.
Peterson BS, Vohr B, Kane MJ, et al. A functional magnetic resonance imaging study of language processing and its cognitive correlates in prematurely born children. Pediatrics 2002;110:1153-1162.
Kesler SR, Ment LR, Vohr B, et al. Volumetric analysis of regional cerebral development in preterm children. Pediatr Neurol 2004;31:318-325.
Vohr BR, Allan WC, Westerveld M, et al. School-age outcomes of very low birth weight infants in the indomethacin intraventricular hemorrhage prevention trial. Pediatrics 2003;111:e340-e346.(Betty R. Vohr, M.D., and )
This situation is becoming more common as a result of the increasing rate of premature births,6 advanced maternal age,6 the increased use of assisted reproductive technology,7 and the publicity about "miracle babies" in the media. Data on outcomes from large studies are therefore critically needed to guide decision making. One of the challenges, however, in assessing long-term outcomes is that the practices in antenatal and neonatal care are continually evolving — the outcomes for infants born in 2005 will reflect practices in neonatal intensive care units that differ from the standard practices of previous years.
In this issue of the Journal,8 Marlow et al. report outcomes at 6 years of age among children born at 25 or fewer completed weeks of gestation who were enrolled at birth in the EPICure study. This report is important, because great efforts were made to collect data prospectively on all the infants born at these gestational ages in the United Kingdom and Ireland in 1995, and not just on infants referred to a tertiary care center over a number of years. This approach results not only in an improved ability to generalize from these data, but also in numbers that are large enough to use to evaluate the range of outcomes among the most immature survivors. The report by Marlow et al. includes the results of comprehensive assessments of the status of neuromotor skills, cognitive ability, vision, and hearing. It is the largest study of infants born at 22 to 25 weeks of gestation with follow-up to school age, it achieved a high (78 percent) rate of follow-up among survivors, and it included a control group of classmates born at full term.
Among these extremely preterm infants, neonatal survival to discharge was low: 1 percent among those born at 22 weeks of gestation, 11 percent at 23 weeks, 26 percent at 24 weeks, and 44 percent at 25 weeks. The rates of survival with no disability at 6 years of age were even more troubling: none among infants born at 22 weeks of gestation, 1 percent at 23 weeks, 3 percent at 24 weeks, and 8 percent at 25 weeks. These data are all the more compelling because they are the most up-to-date data available and are relevant to current practices of obstetrical and neonatal intensive care. (More than 60 percent of these extremely premature infants received antenatal steroids, and 84 percent received surfactant.) This study shows our limitations not only in saving such infants but also in supporting the neurologic and cognitive development of those born at the lower border of viability.
Most studies report scores for children with cognitive impairment that are significantly lower than the mean scores on standardized tests. Recognizing that test scores have increased over time, the authors used classmates of the extremely preterm children for comparison and identified impairment as a score more than 2 standard deviations below the mean score for these controls. With the use of this reference group, the rate of serious impairment according to overall cognitive scores among the extremely preterm children was 41 percent. Only 20 percent of these children had no neuromotor or cognitive disability. Many children who had no appreciable disability at 30 months had evidence of disability at 6 years of age. This outcome probably reflects the increasing complexity of cognitive demands during childhood. The significantly lower scores for processing skills among the extremely preterm children at six years of age, as compared with the scores of their peers, arouse concern about challenges that require higher executive-functioning skills and about how these children will function in middle school and high school and as adults. These findings are important, because they indicate that such children will require comprehensive educational support. We must step back and ask why these children have such a high risk of neurodevelopmental sequelae.
Infants born at between 22 to 25 weeks of gestation are fragile and vulnerable, with immature organ systems. Their skin is gelatinous, and they breathe through terminal bronchioles because the alveoli have not yet formed. They are at high risk for brain injury from hypoxia and ischemia and undernutrition, as well as for sepsis, which starts the cascade of events that increase the risk of brain hemorrhage, white-matter injury (periventricular leukomalacia and ventriculomegaly), and poor brain growth, and for subsequent neurodevelopmental impairment. Active brain development occurs during the second and third trimesters, with neurogenesis, neuronal migration, maturation, apoptosis, and synaptogenesis.9,10 The immaturity of the brain at 22 to 25 weeks of gestation makes these extremely preterm infants particularly vulnerable.
Recent magnetic resonance imaging studies have shown decreased cerebral tissue volume, regional abnormalities of the brain, and decreased complexity in the cortical and surface area in preterm children studied at eight years of age,11 with associated alterations in semantic processing and visuospatial processing.12,13,14 Specifically, decreased sensorimotor and midtemporal cortical volumes were associated with low scores on full-scale, performance, and verbal IQ testing. These findings suggest that some of the neurodevelopmental impairments identified in extremely preterm children may be difficult to prevent because of the level of brain maturation at birth.
On the positive side, there is some evidence of improvement in test scores over time, in that children who were born prematurely have higher scores on cognitive evaluations than on tests performed when they were infants.15 It is unclear whether this improvement represents resistance to injury or resilience. The proportion of children with no disability in the current report (20 percent) suggests the possibility of identifying biologic, environmental, and genetic factors that provide protection to these vulnerable infants; more research is warranted to understand such factors better.
Pending further advances that could improve neurologic outcomes after extremely preterm birth, carefully conducted follow-up studies such as this one by Marlow et al. provide critical information that is needed for decision making by neonatologists and parents.
Source Information
From Women and Infants Hospital, Providence, R.I. (B.R.V.); and Johns Hopkins Hospital, Baltimore (M.A.).
References
Hack M, Fanaroff AA. Outcomes of extremely-low-birth-weight infants between 1982 and 1988. N Engl J Med 1989;321:1642-1647.
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.
El-Metwally D, Vohr B, Tucker R. Survival and neonatal morbidity at the limits of viability in the mid 1990s: 22 to 25 weeks. J Pediatr 2000;137:616-622.
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.
Special considerations. In: Braner D, Kattwinkel J, Denson S, Zaichkin J, eds. Textbook of neonatal resuscitations. 4th ed. Elk Grove Village, Ill.: American Academy of Pediatrics, 2000:7-19.
Arias E, MacDorman MF, Strobino DM, Guyer B. Annual summary of vital statistics -- 2002. Pediatrics 2003;112:1215-1230. [Abstract/Full Text]
Balen AH, MacDougall J, Tan SL. The influence of the number of embryos transferred in 1060 in-vitro fertilization pregnancies on miscarriage rates and pregnancy outcome. Hum Reprod 1993;8:1324-1328.
Marlow N, Wolke D, Bracewell MA, Samara M. Neurologic and developmental disability at six years of age after extremely preterm birth. N Engl J Med 2005;352:9-19.
Huttenlocher PR. Morphometric study of human cerebral cortex development. Neuropsychologia 1990;28:517-527.
Huttenlocher PR, Dabholkar AS. Regional differences in synaptogenesis in human cerebral cortex. J Comp Neurol 1997;387:167-178.
Peterson BS, Vohr B, Staib LH, et al. Regional brain volume abnormalities and long-term cognitive outcome in preterm infants. JAMA 2000;284:1939-1947.
Isaacs EB, Edmonds CJ, Chong WK, Lucas A, Gadian DG. Cortical anomalies associated with visuospatial processing deficits. Ann Neurol 2003;53:768-773.
Peterson BS, Vohr B, Kane MJ, et al. A functional magnetic resonance imaging study of language processing and its cognitive correlates in prematurely born children. Pediatrics 2002;110:1153-1162.
Kesler SR, Ment LR, Vohr B, et al. Volumetric analysis of regional cerebral development in preterm children. Pediatr Neurol 2004;31:318-325.
Vohr BR, Allan WC, Westerveld M, et al. School-age outcomes of very low birth weight infants in the indomethacin intraventricular hemorrhage prevention trial. Pediatrics 2003;111:e340-e346.(Betty R. Vohr, M.D., and )