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Infants born near the limit of viability are at high risk for death or adverse neurodevelopmental outcomes. It is unclear whether these outcomes have improved over the past 15 years.
Determine if death and neurodevelopmental impairment have declined over the past 15 years in infants born at 22 to 24 weeks’ gestation.
Retrospective cohort study
We identified infants born at 22 to 24 weeks’ gestation in our center in two epochs: 1998–2004 (Epoch 1) and 2005–2011 (Epoch 2).
The primary outcome, death or neurodevelopmental impairment, was evaluated at 17–25 months’ corrected gestational age with neurologic exams and Bayley Scales of Infant Development. Perinatal characteristics, major morbidities, and outcomes were compared between epochs.
Birth weight and gestational age were similar between 170 infants in Epoch 1 and 187 infants in Epoch 2. Mortality was significantly lower in Epoch 2, 55% vs. 42% (p=0.02). Among surviving infants, late-onset sepsis (p<0.01), bronchopulmonary dysplasia (p<0.01), and surgical necrotizing enterocolitis (p=0.04) were less common in Epoch 2. Neurodevelopmental impairment among surviving infants declined from 68% in Epoch 1 to 47% in Epoch 2, p=0.02. Odds of death or NDI were significantly lower in Epoch 2 vs. Epoch 1, OR=0.31 (95% confidence interval; 0.16, 0.58).
Risk of death or neurodevelopmental impairment decreased over time in infants born at 22 to 24 weeks’ gestation.
Infants born near the limit of viability are at high risk for death or adverse neurodevelopmental outcomes [1–5]. Recent evidence suggests that survival has improved in this population over the past 20 years [5, 6], but there is little evidence that neurodevelopmental outcomes of surviving infants have changed. Two multicenter studies by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network reported that neurodevelopmental outcomes did not improve over consecutive birth epochs in infants born 22–24 weeks’ gestation between 1993 and 2004 [1, 4]. The most recent of these studies reported death in 67.6% of these infants in 2002–2004, and neurodevelopmental impairment (NDI) in 58.7% of survivors . A recent study from Japan’s Neonatal Research Network described better than previously reported outcomes in this group, with death or NDI seen in 80.0% of infants born at 22 weeks’ gestation, 63.7% at 23 weeks’ gestation, and 38.9% at 24 weeks’ gestation . Current knowledge of outcomes for infants born at these early gestational ages is critical for clinicians and families when making early obstetrical and neonatal care decisions .
The objective of this study was to compare death and early childhood neurodevelopmental outcomes for infants born <25 weeks’ gestation in our center between two recent birth epochs.
We identified all infants born 22 0/7 – 24 6/7 weeks’ gestation that were admitted to the Neonatal Intensive Care Unit at Duke University Medical Center from January 1, 1998 to December 31, 2011. Infants admitted from an outside hospital at >48 hours of age were excluded. The study period was divided into two epochs. Epoch 1 included infants born from 1998 to 2004 and Epoch 2 included infants born from 2005 to 2011. Epoch 1 was chosen to overlap with the most recent NICHD Neonatal Research Network study showing no improvement in neurodevelopmental outcomes over time in this population, and Epoch 2 includes the years since this study . Our study was approved by the Duke Institutional Review Board.
Inpatient charts were reviewed to determine perinatal characteristics and neonatal morbidities. Antenatal steroid use was defined as any steroid exposure in the current pregnancy to accelerate fetal lung maturity. Severe intraventricular hemorrhage (IVH) was defined as unilateral or bilateral grade 3 or 4 hemorrhage . Severe retinopathy of prematurity (ROP) was defined as stage 3 or 4 disease requiring laser therapy. Sepsis was defined as ≥1 positive blood culture requiring antibiotic treatment. Sepsis was classified as early-onset if occurring in the first three days of life or late-onset sepsis if occurring after 72 postnatal hours. Necrotizing enterocolitis (NEC) was defined by modified Bell’s staging criteria, stage IIA or greater . Bronchopulmonary dysplasia (BPD) was defined by the need for supplemental oxygen at 36 weeks’ postmenstrual age. Receipt of postnatal dexamethasone for prevention or treatment of BPD was also noted.
After discharge, infants were followed in the Duke Special Infant Care Clinic. Neurodevelopmental outcomes were assessed at 17–25 months’ corrected gestational age (GA) with neurologic examinations performed by a physician trained in neurodevelopmental assessments and Bayley Scales of Infant Development performed by a licensed clinical psychologist. The Bayley II was used from 1998 to 2007 and the Bayley III was used from 2008 to 2011 [11, 12]. Data for infants who received follow-up care at outside clinics or outside of the 17–25 months’ corrected GA window were not included in the analysis. Death included in-hospital deaths as well as deaths that occurred from the time of discharge to the follow-up period. Neurodevelopmental impairment (NDI) was defined as any of the following: moderate or severe cerebral palsy (CP), significant cognitive impairment [Mental Developmental Index <70 (Bayley II) or cognitive composite score <85 (Bayley III)], significant motor impairment [Psychomotor Developmental Index <70 (Bayley II) or motor composite score <70 (Bayley III)], or bilateral blindness. We used the higher cognitive composite cut-off score of <85 on the Bayley III for comparison with the Bayley II Mental Developmental Index of <70 to improve consistency based on previous studies showing that the Bayley III overestimates cognitive performance relative to the Bayley II [13–16]. CP was defined as a static neurologic disorder characterized by abnormal muscle tone affecting at least one extremity and interfering with motor function. Those with moderate or severe CP required assistive device(s) for ambulation or were non-ambulatory at the time of follow-up.
Our primary outcome was death or NDI, as defined above. Secondary outcomes included death alone and each component of NDI alone in surviving infants who were seen in follow-up. Outcomes, including in-hospital outcomes such as severe IVH and severe ROP, were compared between groups using Fisher’s exact test for categorical variables and Wilcoxon ranksum test for continuous data. We also compared outcomes across epochs for subgroups of infants born at 23 weeks and 24 weeks of gestation. We did not include the 22 week infants as a separate subgroup given the low number of survivors at this gestational age. Risk of death or NDI by epoch was compared using logistic regression to control for GA at birth.
For all tests, significance was defined as P<0.05. Statistical analysis was performed using Stata version 12 (College Station, TX).
During the study period, a total of 357 infants were born at 22–24 weeks’ gestation. Of these infants, 170 (48%) were born in Epoch 1 and 187 (52%) were born in Epoch 2. Epoch 1 and 2 infants did not differ significantly in birth weight, GA, inborn status, gender, multiple gestations, or receipt of antenatal steroids (Table 1). The proportion of infants born by Cesarean delivery was higher in Epoch 2. Among surviving infants, incidence of severe IVH, periventricular leukomalacia, post-hemorrhagic hydrocephalus requiring ventricular shunt, severe ROP, medical NEC, early-onset sepsis, and PDA requiring surgical ligation was similar between Epochs. Incidence of BPD and use of postnatal dexamethasone were significantly lower in Epoch 2. Surgical NEC and late-onset sepsis were also less common among infants born in Epoch 2.
Data on the primary outcome was available for 140/170 (82%) of infants in Epoch 1 and 166/187 (89%) of infants in Epoch 2, p=0.10. Post-discharge follow-up among surviving infants was 75% across the entire study period. Follow-up was significantly higher in Epoch 2, with 49 infants (64% of survivors) in Epoch 1 and 91 infants (83% of survivors) in Epoch 2 having follow-up at 17–25 months’ corrected GA, p<0.01. Infants with and without follow-up had similar median (range) birth weight [647.5 (410–916) g versus 640 (450–900) g, p=0.60] and birth GA [24 (22–24) versus 24 (22–24) weeks, p=0.15]. The proportion of infants with severe IVH was greater among infants with follow-up than those lost to follow-up [35/140 (25%) versus 3/46 (7%), p<0.01]. Incidence of other major morbidities was similar between infants with and without follow-up, including periventricular leukomalacia, posthemorrhagic hydrocephalus requiring ventricular shunt, severe ROP, PDA ligation, NEC, sepsis, and BPD (data not shown). Of the infants with follow-up data, corrected GA at the time of follow-up was higher in Epoch 1, with a median (range) of 20 (17–25) months in Epoch 1 versus 19 (17–25) months in Epoch 2, p=0.03.
Overall, death occurred in 171 of 357 infants (48%). Mortality was significantly lower in Epoch 2 compared to Epoch 1 (Table 2). The primary outcome, the composite of death or NDI, was also lower in Epoch 2. NDI among surviving infants decreased in Epoch 2. Odds of death or NDI, adjusted for birth GA, were significantly lower in Epoch 2, OR=0.31 (95%CI; 0.16, 0.58). Incidence of the components of NDI, moderate or severe CP, significant cognitive impairment, significant motor impairment, and blindness, was similar between Epochs. When divided by birth GA, risk of death or NDI was lower in Epoch 2 among infants born at 24 weeks’ gestation, but did not change significantly in infants born at 23 weeks’ gestation (Table 2). For infants born at 23 weeks’ gestation, neither death alone nor NDI among survivors changed significantly. Among the 24 week infants, risk of death alone did not change significantly, but NDI among survivors decreased. Blindness decreased among the 24 week infants, while there was no significant change in other individual components of NDI.
In our center, survival of infants born 22–24 weeks’ GA has improved over the past 15 years. In fact, we observed decreased mortality as well as decreased NDI among survivors. When the cohort was divided by birth GA, we saw a decrease in NDI in infants born at 24 weeks’ gestation, but no improvement in outcomes among the infants born at 23 weeks’ gestation. While these results are limited by the small number of surviving infants born at 23 weeks’ gestation in our cohort, it suggests that the trend in improved outcomes seen in the 24 week infants did not extend to the less mature infants.
The factors underlying the improved outcomes in our study are unclear, but there are a number of possible contributing factors. The increased proportion of Cesarean deliveries in Epoch 2 suggests a more proactive perinatal care approach, which has been associated with better outcomes at these early gestational ages . Lower proportions of infants in Epoch 2 had late-onset sepsis, surgical NEC, receipt of dexamethasone, and BPD, each of which has been associated with adverse neurologic outcomes [19–24]. There were a number of quality improvement efforts and practice changes in our unit over the study period that may have contributed to the improved outcomes. In 2001, we introduced an educational campaign to prevent lung injury and established written guidelines to promote a consistent approach to caring for extremely premature infants. In 2007, we initiated an infection control program that resulted in a significant reduction in bloodstream infections . In 2008, we began using donor breast milk in place of preterm formula when mother’s milk was unavailable. In 2010, we introduced the use of early oropharyngeal colostrum in extremely low birth weight infants .
Our study did not include data on the number of infants in each epoch in whom delivery room resuscitation was not attempted. While our results may be reflective of changes in these practices over time, our general approach to delivery room resuscitation at the limits of viability did not change over the study period. We do not routinely attempt resuscitation in the delivery room for infants born <23 0/7ths weeks’ gestation. The majority of infants born 23–24 weeks’ gestation are resuscitated, except when a decision has been made in conjunction with the infant’s family to not attempt resuscitation or when other poor prognostic factors are present, such as congenital anomalies or extremely small size (<400 g birth weight). Resuscitation is often limited for infants who do not respond to intubation and positive pressure ventilation. This practice has also not changed over the study period.
Our results are contrary to previous multicenter studies of extremely premature infants showing no improvement in neurodevelopmental outcomes over time [1, 4]. One potential explanation for this divergence is the single-center nature of our study. Previous studies have shown that regional and center differences are significant determinants of outcome [27–29]. Center differences in outcomes are most pronounced in the least mature infants [28, 30]. In multicenter studies, improving outcomes in certain centers may be offset by other centers that have stable or worsening outcomes. Exploration of factors associated with improving outcomes at individual centers, including demographic factors, perinatal and neonatal care practices, and approach to extremely premature infants is critical.
One limitation of our study was the number of infants lost to follow-up, with a greater number and percentage of infants receiving follow-up care in Epoch 2. Previous studies have shown that infants who are seen in follow-up may have different outcomes than those who are lost to follow-up [17, 31]. In our study, infants with and without follow-up were similar in terms of baseline characteristics and major morbidities, with the exception that severe IVH was more common among infants with follow-up. Nonetheless, we found that neurodevelopmental outcomes improved as follow-up rates improved in Epoch 2, supporting our conclusion of improved outcomes over time.
Another limitation of our study was the use of different versions of the Bayley over the study period. Previous studies have shown that compared with the Bayley II, the Bayley III overestimates cognitive performance, raising caution about making direct comparisons between the two versions of the test [13–16, 32]. An MDI<70, which is two standard deviations below the mean on the Bayley II, correlates more closely with a cognitive composite score of 80–85 on the Bayley III, or one standard deviation below the mean [13–15]. To address this limitation, we raised the cut-off for significant cognitive impairment to the more conservative cut-off cognitive composite score of <85 on the Bayley III.
In our center, the incidence of death or NDI decreased over time in infants born 22–24 weeks’ gestation. In particular, NDI significantly decreased in infants born at 24 weeks’ gestation. While these results are encouraging, the rates of death or NDI remain very high and clinicians should continue to counsel parents of the significant risks at these early gestational ages. Further research is needed to identify and implement practices associated with improving outcomes in this vulnerable population.
Dr. Younge received support from National Institutes of Health (5T32HD043728-10). Dr. Smith received support from the National Institutes of Health and the National Center for Advancing Translational Sciences (HHSN267200700051C, HHSN275201000003I and UL1TR001117); he also receives research support from industry for neonatal and pediatric drug development (www.dcri.duke.edu/research/coi.jsp). Dr. Cotten received support from National Institutes of Health (5U10 HD040492-10).
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Conflicts of interest:
The authors have no relevant conflicts of interest to disclose.