Background. Advances in perinatal care have resulted in increased survival rates for extremely low birth weight children. We sought to examine the relative changes in rates of survival and neurodevelopmental impairment at 20 months of corrected age among 500- to 999-g birth weight infants born at our perinatal center during 2 periods, before and after the introduction of surfactant therapy in 1990.
Methods. Four hundred ninety-six infants with birth weights of 500 to 999 g were born at our perinatal center during period I (1982–1989) (mean body weight: 762 g; mean gestational age: 25.8 weeks) and 682 during period II (1990–1998) (mean body weight: 756 g; mean gestational age: 25.5 weeks). Rates of death and survival with and without neurodevelopmental impairment at 20 months of corrected age for the 2 periods were compared with logistic regression analyses, with adjustment for gestational age.
Results. Survival rates increased from 49% during period I to 67% during period II. Neonatal morbidity rates also increased during period II, including rates of sepsis (from 37% to 51%), periventricular leukomalacia (from 2% to 7%), and chronic lung disease, defined as oxygen dependence at 36 weeks of corrected age (from 32% to 43%). Rates of severe cranial ultrasound abnormalities were similar (22% vs 22%). Among children monitored, the rate of neurologic abnormalities, including cerebral palsy, increased from 16% during period I to 25% during period II and the rate of deafness increased from 3% to 7%. The overall rate of neurodevelopmental impairment (major neurosensory abnormality and/or Bayley Mental Developmental Index score of <70) increased from 26% to 36%. Compared with period I, in period II there were decreased rates of death (odds ratio [OR]: 0.3; 95% confidence interval [CI]: 0.2–0.4) and increased rates of survival with impairment (OR: 2.3; 95% CI: 1.7–3.3) but also increased rates of survival without impairment (OR: 1.7; 95% CI: 1.3–2.2). Compared with period I, for every 100 infants with birth weights of 500 to 999 g born in period II, 18 additional infants survived, of whom 7 were unimpaired and 11 were impaired.
Conclusions. The improved survival rates in the 1990s occurred with an increased risk of significant neurodevelopmental impairment. Prospective parents of extremely low birth weight infants should be advised of this substantial risk, to facilitate decision-making in the delivery room.
Technologic and therapeutic advances in perinatal care resulted in increased survival rates for extremely low birth weight infants born in the 1990s.1–3 The medical, ethical, and economic implications of providing care for such extremely low birth weight infants have been the subject of much debate.4–6 As infants of increasingly lower birth weight and gestational age have been resuscitated, questions have arisen regarding whether the improved survival rates have been accompanied by increased impairment rates, with a worsened quality of life, for the tiniest survivors.7–9 We sought to compare the rates of survival, neonatal morbidity, and neurodevelopmental impairment at 20 months of corrected age among children of 500- to 999-g birth weight who were born at our perinatal center during 2 periods, ie, 1982–1989 and 1990–1998; the latter period was associated with increased prenatal steroid therapy, cesarean section delivery, assisted ventilation in the delivery room, surfactant therapy, and postnatal steroid use. Extremely low birth weight infants were selected because they have been most affected by recent technologic improvements.10
The study population included 1178 live-born infants without major congenital malformations and with birth weights between 500 and 999 g who were delivered at our perinatal center, MacDonald Hospital for Women of the University Hospitals of Cleveland, during 2 periods, ie, January 1982 through December 1989 (period I) (n = 496) and January 1990 through December 1998 (period II) (n = 682). The mean birth weights and gestational ages for these 2 periods were 762 g and 756 g and 25.8 weeks and 25.5 weeks, respectively. Fifteen infants with major malformations were excluded from the population for period I, and 32 infants were excluded for period II. During period I, 216 infants had birth weights of 500 to 749 g and 280 had birth weights of 750 to 999 g; during period II, 327 infants had birth weights of 500 to 749 g and 355 had birth weights of 750 to 999 g.
Our perinatal center is a tertiary referral center for mothers with high-risk pregnancies. Neonatal specialists attend all preterm deliveries. Decisions concerning active treatment of extremely preterm infants are made after consultation with the family, if possible, and/or according to the condition of the infant at birth. Despite some minor variations among individuals, there was general consensus during both periods regarding the criteria for not initiating active resuscitation in the delivery room. Prenatal steroid therapy to enhance fetal pulmonary maturity was initiated after 1990.11 Neonatal care was rendered according to established guidelines, with no significant changes in the clinical facility or care team in the 2 comparison eras.12,13 Maternal information included sociodemographic factors (maternal age, race, and marital status), duration of gestation, prenatal steroid therapy, and mode of delivery. Gestational age was determined from the date of the mother's last menstrual period and was confirmed with obstetric measures, including ultrasonographic findings in the majority of cases. Additional infant birth data included birth weight, multiple birth status, Apgar scores, and use of assisted ventilation in the delivery room. Neonatal morbidity included respiratory distress, defined as the need for oxygen therapy; chronic lung disease, defined as an oxygen dependence at 36 weeks of corrected age (postmenstrual plus postnatal age)14; patent ductus arteriosus, confirmed with echocardiography; episodes of sepsis, defined as clinical signs of infection with a positive blood culture; necrotizing enterocolitis, defined as described by Bell et al15; periventricular hemorrhage, defined as described by Papile et al16; and periventricular leukomalacia. Severe cerebral ultrasonographic abnormalities were categorized as the presence of grade III or IV periventricular hemorrhage, periventricular leukomalacia, or persistent ventricular dilation at the time of hospital discharge. Specific neonatal therapies included surfactant therapy, duration of oxygen and ventilator therapy, indomethacin treatment, and postnatal steroid therapy. Surfactant was used as “rescue therapy,” starting in 1990, for infants who required assisted ventilation and ≥30% ambient oxygen to maintain an arterial oxygen pressure of ≥50 mm Hg. Postnatal steroid therapy was prescribed, at the discretion of the individual attending neonatologist, for infants with chronic lung disease and prolonged ventilator dependence. Indomethacin therapy was used to treat symptomatic patent ductus arteriosus and was not used prophylactically.
Survival rates and neurodevelopmental status were measured to 20 months of corrected (postmenstrual plus postnatal) age. Measures of neurodevelopmental outcomes included neurosensory status and the Mental and Psychomotor Developmental Indices of the Bayley Scales of Infant Development (BSID).17 The children born after 1991 were tested with the revised BSID II, which has been reported to give lower scores than the original BSID used for children born in 1982 through 1991. We thus used a correction factor for scores obtained with the BSID II, to compare them with the BSID test scores.18 A neurologic examination of muscle tone was performed according to the method described by Amiel-Tison and Stewart.19 Major neurologic abnormalities included cerebral palsy, hypotonia, hypertonia, and shunt-dependent hydrocephalus without neurologic abnormalities. Cerebral palsy was defined as a persistent but not unchanging disorder of movement and posture appearing in early life and attributable to a nonprogressive disorder of the brain, the result of interference during its development.20 Neurodevelopmental impairment included any major neurologic abnormality, unilateral or bilateral blindness or deafness requiring a hearing aid, and/or a Mental Developmental Index (MDI) of <70 on the BSID. Eight neurologically impaired children (3 from period I and 5 from period II) were evaluated with a complete neurologic examination but were not testable with the BSID. They were therefore included among those with neurologic impairment but do not have BSID scores reported. Parents provided written informed consent for participation in the study, which was approved by the institutional review board.
Trends in delivery room care, survival rates, neonatal morbidity rates, and outcomes at 20 months of corrected age were compared between the 2 periods of study. These were also examined separately for the 2 birth weight subgroups, ie, 500 to 749 g and 750 to 999 g. Statistical comparisons were made with unpaired t tests for continuous variables and χ2 analyses for categorical variables. Because only gestational age differed between periods, logistic regression analysis was performed to examine the odds ratios (ORs) for death and survival with and without impairment, controlling for gestational age (Table 1). To compare the numbers of children who survived with or without neurodevelopmental impairment between the 2 periods, the individual numbers of normal and impaired children who survived in each period were divided by the total number of children born minus those lost to follow-up monitoring (Table 2). The follow-up rates were 88% and 90% for periods I and II, respectively.
Characteristics of the Infants, Delivery Care, and Survival Rates
Table 1 presents a comparison of perinatal and birth data between periods I and II. Birth weights were similar during the 2 periods, although gestational age for the total group of 500- to 999-g infants was significantly less in period II. Infant race and gender did not differ between the 2 periods. Significantly more multiple births occurred during period I. This pertained specifically to the 500- to 749-g birth weight group, in which 27% vs 16% were multiple births, 25% vs 12% were twins, and 2% vs 3% were triplets. Prenatal steroid therapy was not used in period I, whereas 42% of mothers received this therapy in period II. Rates of cesarean section increased significantly in period II for both the 500- to 749-g birth weight and 750- to 999-g birth weight groups, as did the rates of assisted ventilation. Rates of birth depression, as evidenced by Apgar scores of <6 at 5 minutes, decreased significantly during period II. During period I, 64% of the 500- to 749-g birth weight infants received assisted ventilation, compared with 80% in period II (P < .001). Surfactant was administered as rescue therapy to only 1% of infants during period I, whereas 68% received this treatment during period II (P < .001).
Two hundred forty-two of the 496 infants (49%) survived to 20 months of corrected age during period I, compared with 460 of 682 (67%) during period II (P < .001). This increase in survival rates pertained to both the 500- to 749-g birth weight group, in which 27% (58 of 216 infants) vs 48% (158 of 327 infants) (P < .001) survived, and the 750- to 999-g birth weight group, in which 66% (184 of 280 infants) vs 85% (302 of 355 infants) (P < .001) survived. Compared with period I, survivors from period II were of significantly lower birth weight (826 g vs 802 g, P < .01) and gestational age (26.7 weeks vs 26.2 weeks, P < .001).
Causes of Death
The primary cause of death was determined on the basis of autopsy results in 77% and 65% of cases during periods I and II, respectively, and on the basis of clinical assessments in the rest of the cases. There were no significant differences in the primary cause of death between the 2 periods (Table 3). The most common cause of death was respiratory distress syndrome and/or its sequelae, accounting for 40% of all infants who died. Overall, 35% of infants who died during both periods were not offered assisted ventilation, ie, 56% vs 46% (P = .07) for those weighing <750 g and 1% vs 2% (P = 1.0) for those between 750 and 999 g, because they were not considered viable; therefore, the cause of death was defined as immaturity. During period I, 62% of infant deaths (158 of 254 deaths) occurred before 48 hours of age, compared with 53% (118 of 222 deaths) during period II (P = .057).
Neonatal Morbidity of the Survivors
Rates of respiratory distress requiring oxygen therapy did not change between the 2 periods (Table 4). The rate of chronic lung disease increased significantly in period II, however, mainly because of an increase among the 500- to 749-g birth weight subgroup. Postnatal steroid therapy, which was used rarely before 1990, increased significantly in period II for both birth weight subgroups. The rate of sepsis increased because of an increase in the 750- to 999-g birth weight group. There were no differences in the rates of periventricular hemorrhage, but the rate of periventricular leukomalacia increased significantly in period II, mainly because of an increase in the 750- to 999-g birth weight subgroup.
Neurodevelopmental Outcomes at 20 Months of Corrected Age
Complete information on neurodevelopmental status at 20 months of corrected age was available for 214 surviving children (88%) born during period I and 417 (90%) born during period II. The children who were monitored had similar birth weights and gestational ages, compared with those lost to follow-up monitoring. The educational level of the mothers was higher during period II, with 84% (609 of 682 subjects) having completed high school, compared with 77% (441 of 496 subjects) during period I (P < .03). Maternal race (65% vs 61% black) and marital status (57% vs 53% unmarried) did not differ between periods.
The overall rates of neurologic abnormalities were significantly higher during period II, mainly because of an increase in cerebral palsy in the 750- to 999-g birth weight group (Table 5). The rate of blindness tended to decrease, whereas the rate of deafness among the total 500- to 999-g group increased significantly during period II.
There were no significant differences in the mean MDI or in the rates of subnormal MDI scores (<70) during the 2 periods (Table 6). However, the mean Psychomotor Developmental Index decreased significantly during period II, because of a decrease in the 750- to 999-g birth weight group. This decline in Psychomotor Developmental Index scores is most likely attributable to the higher rate of cerebral palsy in this birth weight subgroup. The overall rates of neurodevelopmental impairment, including neurosensory abnormalities and/or subnormal MDI scores, increased significantly during period II (26% vs 36%, P < .02).
“Risk/Benefit” Ratio: Survivors With Normal Versus Abnormal Neurodevelopment
Figure 1 illustrates the outcomes of all live-born infants. For the total population and for the 2 birth weight subgroups of infants, mortality rates decreased and rates of survival both with and without neurodevelopmental impairment increased significantly. Overall rates of death and/or impairment decreased from 66% to 58% (P < .01) for the total population, from 84% to 74% (P < .01) for the 500- to 749-g subgroup, and from 52% to 43% (P < .05) for the 750- to 999-g subgroup.
In a comparison of period II with period I, after adjustment for gestational age, the OR for death for all of the 500- to 999-g birth weight group was 0.3 (95% confidence interval [CI]: 0.2–0.4), that for survival with impairment was 2.3 (95% CI: 1.7–3.3), and that for survival without impairment was 1.7 (95% CI: 1.3–2.2). For the 500- to 749-g subgroup, the OR for death was 0.3 (95% CI: 0.16–0.40), that for survival with impairment was 3.0 (95% CI: 1.7–5.4), and that for survival without impairment was 2.3 (95% CI: 1.4–3.8). For the 750- to 999-g subgroup, the OR for death was 0.3 (95% CI: 0.21–0.46), that for survival with impairment was 2.1 (95% CI: 1.4–3.3), and for survival without impairment was 1.5 (95% CI: 1.1–2.1).
Calculation of the “risk” of improved survival in terms of an increase in neurodevelopmental impairment revealed that, for every 100 infants born during period II with birth weights of 500 to 999 g, there were 18 additional survivors, of whom 7 were considered unimpaired and 11 were considered impaired, 5 with cerebral palsy. In the 500- to 749-g and 750- to 999-g birth weight subgroups born during period II, there were 21 and 19 additional survivors for every 100 infants born, respectively, for whom the ratios of normal to neurodevelopmental impairment were similar (for the 500- to 749-g subgroup, 10 normal and 11 impaired for every 100 born; for the 750- to 999-g subgroup, 7 normal and 12 impaired for every 100 born) (Table 2).
The improved survival rates for extremely low birth weight infants that occurred as a result of the achievements of modern neonatal intensive care in the 1990s have generated concern regarding the potential for increased rates of neurodevelopmental impairment among surviving infants. Although <1% of infants weigh <1000 g at birth, these infants account for disproportionately large proportions of neonatal death, morbidity, and neurodevelopmental impairment.22 We sought to examine the benefits, in terms of intact survival, versus the increased risk of impairment resulting from therapeutic changes in the 1990s.
Our results indicated a significant increase in the survival rate for infants with birth weights of 500 to 999 g delivered at our perinatal center from 1990 through 1998, compared with the period from 1982 through 1989. In the later 1990s, during period II, there was a more active perinatal approach, including prenatal steroid therapy, increased use of cesarean section, ventilator assistance, and surfactant therapy, and increased postnatal steroid use. The decreased rate of multiple births (from 27% to 16%) for the 500- to 749-g class, although surprising, is likely related to maternal referral patterns by the various level I and level II community sites that transferred mothers to MacDonald Hospital. Compared with period I, survivors from period II were of significantly lower birth weight and younger gestational age. Infants who died tended to survive longer during period II. Neonatal morbidity increased during period II and included chronic lung disease, sepsis, and periventricular leukomalacia. Although less blindness occurred in the second period, likely because of laser therapy, the rate of deafness nearly doubled.23 With our definition of neurodevelopmental impairment, for every 100 infants born with birth weights of 500 to 999 g in the 1990s, there were 18 additional survivors, of whom 7 were considered normal and 11 impaired.
Improved survival rates similar to ours were reported universally for children with birth weights of <1000 g.24–27 For infants born in the early 1990s, some reported that, despite an increase in survival rates, the neonatal morbidity rates and 20-month neurodevelopmental outcomes were unchanged.25,27–32 Others reported increased rates of cerebral palsy, neurodevelopmental disabilities, and hearing loss.33–35 We speculate that the poorer neurodevelopmental outcomes in our study during period II are attributable to the increased survival rates for smaller, less mature infants, who have higher rates of sepsis, periventricular leukomalacia, chronic lung disease, and postnatal steroid use, all of which have been associated with poorer neurodevelopmental outcomes.36–39 However, our increased rate of periventricular leukomalacia might be related to improved cerebral ultrasonographic diagnostic techniques.
The results of our comparison of outcomes in 2 time periods are similar to those reported by Lorenz et al,40 who compared the survival rates and 5-year neurodevelopmental outcomes of infants born in the middle 1980s and treated aggressively in New Jersey or treated conservatively in the Netherlands. The aggressive perinatal approach in the United States, including higher rates of cesarean section and nearly universal initiation of neonatal intensive care, resulted in increased rates of survival both with and without neurodevelopmental disabilities, with 24 additional survivors and 7 cases of disabling cerebral palsy per 100 live births and greater resource expenditure for infants born in New Jersey, compared with those born in the Netherlands.40
Potential limitations of our study include the relatively short-term nature of the follow-up monitoring. Children reported as having cerebral palsy in early childhood may “outgrow” the diagnosis in later years, and multiple educational and therapeutic interventions may later improve outcomes for children born to mothers of low sociodemographic and educational status.41–43 Although we used a correction factor to adjust scores obtained with the second edition of the BSID after 1991, any test bias would favor improved outcomes in the earlier period. Furthermore, recent data suggested poor long-term predictive validity of the BSID II, demonstrating improved cognitive function of extremely low birth weight children tested with the Kaufman KABC at 8 years.44 Prenatal steroid therapy was prescribed uniformly after the National Institutes of Health Consensus Conference in 1994.11 Although increasing from 9% in 1990 to 79% by 1998, the overall rate of prenatal steroid use in the second period was low, compared with current standards. Finally, because fetal deaths were not included in this study, the reported survival rates may underestimate the overall rates of perinatal death.
Concern has been expressed that aggressive resuscitative efforts should be withheld from extremely low birth weight infants, on the grounds that they either prolong ultimate death at extraordinary financial and emotional expense or result in severe impairment among the survivors.4–6,45 The ethical debate pertains mainly to the resuscitation of infants with birth weights of <750 g; however, in our experience, the worsened neurodevelopmental outcomes associated with the increased survival rates in the 1990s were attributable mainly to the survival of infants with birth weights of 750 to 999 g. Although we cannot fully explain this finding, we speculate that, although active resuscitation was used nearly universally for the larger infants, selective resuscitation and support were offered only to the most vigorous infants who were <750 g, who thus represented a select group. Our data suggest that all prospective parents of extremely low birth weight infants should be advised of the substantial risk for neurodevelopmental problems and should consider the risks and benefits of various approaches to their care.46 Because parental wishes overwhelmingly drive decision-making in the delivery room, efforts to enhance prenatal consultations and family education are essential.47
Despite the increase in neurodevelopmental impairment rates for extremely low birth weight infants born in the 1990s, our results should not minimize the significant success of modern neonatal intensive care. Given a decrease in the rate of death and/or impairment from 66% in period I to 58% in period II, there was an overall improvement in outcomes, with an absolute increase in the numbers of developmentally normal survivors. These results present an ethical dilemma concerning the best approach to the treatment of infants born at the lower limits of viability. Although an aggressive obstetric and neonatal approach would likely increase survival rates, the “cost” might include significant resource utilization and increased rates of disabilities among the survivors. A more conservative approach might utilize fewer resources and minimize long-term morbidity but might result in the death of potentially normal children. Future attempts to improve neonatal outcomes will require either preventing preterm births or reducing neonatal morbidity and associated neurodevelopmental impairment among survivors. Because the goal of decreasing premature birth rates has not been achieved, research needs to focus on better understanding the pathophysiologic features of neonatal morbidity and designing interventions to prevent injury.48
This work was supported by grant MO1RR00080 from the General Clinical Research Center and partially supported by grant HD21364 from the National Institute of Child Health and Human Development Neonatal Network.
We are extremely grateful to Mark Schluchter, PhD, for statistical advice and to Angelia Williams, Bonnie Siner, RN, and Nancy Newman, RN, for their help in conducting this research.
- Accepted August 23, 2004.
- Address correspondence to Deanne Wilson-Costello, MD, Division of Neonatology, Rainbow Babies and Children's Hospital, University Hospitals of Cleveland, 11100 Euclid Ave, Cleveland, OH 44106-6010. E-mail:
No conflict of interest declared.
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