- Email: [email protected]
Mortality and Neurodevelopmental Outcomes in the Heart Rate Characteristics Monitoring Randomized Controlled Trial
ORIGINAL ARTICLES Mortality and Neurodevelopmental Outcomes in the Heart Rate Characteristics Monitoring Randomized Controlled Trial Robert L. Schelonka, MD1, Waldemar A. Carlo, MD2, Charles R. Bauer, MD3, Myriam Peralta-Carcelen, MD2, Vivien Phillips, BSN2, Jennifer Helderman, MD4, Christina T. Navarrete, MD4, J. Randall Moorman, MD5, Douglas E. Lake, PhD5, John Kattwinkel, MD5, Karen D. Fairchild, MD5, and T. Michael O’Shea, MD6 Objective To test whether the composite outcome of death or neurodevelopmental impairment (NDI) at 18-22 months corrected age for infants £1000 g at birth is decreased by continuous monitoring of heart rate characteristics during neonatal intensive care. Study design We studied a subset of participants enrolled in a multicenter randomized trial of heart rate characteristics monitoring. Survivors were evaluated at 18-22 months corrected age with a standardized neurologic examination and the Bayley Scales of Infant Development-III (BSID-III). NDI was defined as Gross Motor Function Classification System of >2 (moderate or severe cerebral palsy), BSID-III language or cognitive scores of <70, severe bilateral hearing impairment, and/or bilateral blindness. Results The composite outcome, death or NDI, was obtained for 628 of 884 study infants (72%). The prevalence of this outcome was 44.4% (136/306) among controls (infants randomized to heart rate characteristics monitored but not displayed) and 38.9% (125/322) among infants randomized to heart rate characteristics monitoring displayed (relative risk, 0.87; 95% CI, 0.73-1.05; P = .17). Mortality was reduced from 32.0% (99/307) among controls to 24.8% (81/326) among monitoring displayed infants (relative risk, 0.75; 95% CI, 0.59 to 0.97; P = .028). The composite outcomes of death or severe CP and death or mildly low Bayley cognitive score occurred less frequently in the displayed group (P < .05). Conclusions We found no difference in the composite outcome of death or NDI for extremely preterm infants whose heart rate characteristics were and were not displayed during neonatal intensive care. Two outcomes that included mortality or a specific NDI were less frequent in the displayed group. (J Pediatr 2020;-:1-6).
A
dvances in neonatal intensive care have increased survival of extremely low birth weight infants (ELBW; weighing £1000 g at birth) but about one-third of survivors have moderate to severe neurodevelopmental impairment (NDI) when assessed at 18-22 months.1,2 By school age, approximately 50% of ELBW infants show cognitive deficits and 17% have cerebral palsy (CP).3,4 Systemic infections, a frequent complication among ELBW preterm infants, are associated with short-term sequelae and an increased risk of death.5,6 There is mounting evidence that nosocomial infections and the systemic inflammatory response damage cerebral white matter7,8 and contribute to long-term disability in ELBW infants.9-11 The diagnosis of sepsis in the newborn period is challenging. The clinical signs of nosocomial sepsis and/or meningitis in ELBW infants are often nonspecific. Blood and body fluid cultures are reported sterile in more than one-third of ELBW infants with a clinical sepsis syndrome.10 There are numerous adjunctive, nonspecific diagnostic and screening tests used to aid in the diagnosis of neonatal sepsis and/or meningitis. Although abnormalities of the complete blood count and neutrophil indices, acute phase reactants, and cytokines may suggest serious infection, few of these adjunctive tests have a high specificity and only rarely have a positive predictive value of >40% for proven neonatal sepsis.12 A recent advance in the diagnosis of neonatal sepsis is continuous heart rate characteristics monitoring to detect the presence of decreased variability and From the Department of Pediatrics, Division of Neonatology, Oregon Health and Science University, transient decelerations, which occur with increased frequency in the preclinical Portland, OR; Department of Pediatrics, University of phases of septicemia.13,14 The result is a monitoring system that has allowed diagAlabama at Birmingham, Birmingham, AL; Department of Pediatrics, University of Miami, Coral Gables, FL; nosis and treatment of bacterial sepsis in infants before showing overt signs of Department of Pediatrics, Wake Forest School of Medicine, Winston-Salem, NC; Department of illness. Heart rate characteristics monitoring underwent rigorous testing as Pediatrics and Medicine, University of Virginia, 1
2
3
4
5
Charlottesville, VA; and 6Department of Pediatrics, University of North Carolina, Chapel Hill, NC
BSID-III CP ELBW GMFCS NDI RR
Bayley Scales of Infant and Toddler Development, third edition Cerebral palsy Extremely low birth weight Gross Motor Function Classification System Neurodevelopmental impairment Relative risk
Supported by the National Institutes of Health grant (R01-HD48562 [to J.M.], R01 HD048562 [to T.O.]), and Florida-Children’s Medical Services (COQZH [to C.B.]). J.M. and D.L. have consulting agreements and equity shares in Medical Predictive Science Corporation, Charlottesville, VA. The other authors declare no conflicts of interest. 0022-3476/$ - see front matter. ª 2020 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jpeds.2019.12.066
1
THE JOURNAL OF PEDIATRICS
www.jpeds.com
part of a National Institute of Child Health and Human Development-funded multicenter, randomized, controlled trial of 3003 very low birth weight infants (<1500 g at birth), including 1513 ELBW infants.15 The current study was motivated by the need to assess the impact of heart rate characteristics technology on the prevention or amelioration of disability in survivors of extreme prematurity. We hypothesized that heart rate characteristics monitoring of ELBW infants leads to a reduction of moderate to severe NDI or death at 18-22 months for these infants.
Methods The heart rate characteristics monitoring trial was a multicenter, randomized controlled trial in which 3003 very low birth weight infants (£1500 g) were enrolled at 9 hospitals (ClinicalTrials.gov: NCT00307333) The methods and results of the trial have been reported elsewhere.15,16 Briefly, in the heart rate characteristics trial, infants were randomly assigned to 1 of 2 groups after written, informed parental consent. One group of infants had the heart rate characteristics index displayed to the care team for the infants (display group). Providers used the heart rate characteristics index to aid in early detection and treatment of nosocomial infection in the display group. Infants in the control group had the heart rate characteristics index recorded by the data collection devices, but this information was not displayed locally to the team caring for the infants. Infants had blood, urine, and cerebrospinal fluid cultures obtained and antibiotics started based on clinical suspicion of infection. For infants in the control group, this management continued as usual practice. For the infants in the display group, the use of the heart rate characteristics index may have influenced the frequency and timing of obtaining cultures and starting antibiotics. When the heart rate characteristics index was considered abnormal by the clinician, then a complete blood count, blood culture, and other laboratory tests to assist with the assessment of the infant may have been obtained. In addition, the clinician may have obtained cultures and started antibiotics at his or her discretion if there was a clinical suspicion of infection, but the heart rate characteristics index had not reached a concerning level or was not displayed. Antibiotics were administered at the discretion of the attending neonatologist. Thus, infants were not denied antibiotics if the clinicians felt that antibiotics were indicated. Centers were selected for the follow-up component of the heart rate characteristics trial a priori based on the merits of their neurodevelopmental follow-up programs and consistency of the 18-22 months follow-up protocol. Investigators at the University of Alabama at Birmingham, Wake Forest University, and the University of Miami enrolled >50% of the patients in the heart rate characteristics trial. All ELBW infants (£1000 g) in the heart rate characteristics trial enrolled at these 3 sites were eligible to participate in the current study. Follow-up data were added to the heart rate characteristics trial in hospital database. Infant characteristics 2
Volume -
- 2020
during the first 120 days from randomization were collected for the heart rate characteristics trial. These included birth weight, gestational age, pregnancy, labor, delivery complications, and Apgar scores. The research ethics board at each of the clinical centers approved the protocol. Survivors underwent a comprehensive neurodevelopmental and neurologic assessment at 18-22 months of corrected age by examiners unaware of the treatment group. Cognitive function was assessed with the Bayley Scales of Infant and Toddler Development, third edition (BSID-III); scores are assessed relative to a standardized mean of 100 15 in the normative data, with higher scores indicating better performance.17 The modified Gross Motor Function Classification System (GMFCS) was used to classify gross motor performance, with levels ranging from 0 (normal) to 5 (most impaired).18 Moderate CP was defined as a GMFCS level of 2-3 and severe CP was defined as a GMFCS level of 4-5.19,20 Permanent hearing loss was defined as a requirement for bilateral hearing aids and blindness was defined as no functional vision in either eye. The prespecified primary composite outcome for this study was death before 18 to 22 months or NDI at 18-22 months of corrected age. NDI was defined as ³1 of the following: a cognitive or language composite score on the BSID-III of <70, GMFCS of ³2 (moderate or severe CP), hearing impairment, or bilateral visual impairment. The other prespecified secondary outcomes were individual components of the primary outcome, and mild NDI (GMFCS of 1 or BSID-III of 70-84). The sample size was based on the number of infants with a birth weight of <1000 g enrolled at the 3 study sites and was sufficient to detect a decrease in the proportion with death/ NDI of 10 percentage points (ie, 20% in the intervention group vs 30% for the control group) with 0.80 power and 2-sided significance level of .05, which would require 313 infants per group, for a total of 626. Data were entered on a database maintained at the University of Virginia. Baseline data and treatment group differences for infants who have known and unknown primary outcome (death or NDI) were compared by Student t tests for continuous data and c2 tests for categorical data. Fisher exact test was used for categorical outcomes with frequency counts of <6. Secondary outcomes include the components of NDI in survivors and death or moderate to severe CP, death or BSID-III Cognitive and Language scale of <70, death or hearing impairment, and death or blindness in all participants.
Results Death or NDI, the primary composite outcome, was known in 322 infants (73%) in the monitor display group and 306 infants (69%) in the control group. Of the 884 infants enrolled in the follow-up component of the original trial, 636 infants were available for follow-up at 18-22 months corrected age. A total of 458 infants was seen (248 in the display group, 210 in the control group), which was 74.7% and 69.2% of surviving infants, respectively (Figure). Schelonka et al
- 2020
ORIGINAL ARTICLES Enrollment
Assessed for eligibility (n= 3003)
Excluded (n=2119)
♦ Not meeting inclusion criteria (n=2119) ♦ Declined to participate (n=0) ♦ Other reasons (n=0) Randomized (n=884)
Allocation Allocated to Monitor Display (n=442) ♦ Received allocated intervention (n=442)
Allocated to Control Group (n=442)
♦ Received allocated intervention (n=442) ♦ Did not receive allocated intervention (n= 0)
♦ Did not receive allocated intervention (n=0)
Follow-Up Lost to follow-up (n=84)
Lost to follow-up (n=94)
Discontinued intervention (withdrew consent for follow up component) (n=31)
Discontinued intervention (withdrew consent for follow up component) (n= 39)
Analysis Analyzed (n=332) ♦ Excluded from analysis (incomplete data on follow up visit to classify presence/absence of NDI) (n=5 )
Analyzed (n=306)
♦ Excluded from analysis (incomplete data on follow up visit to classify presence/absence of NDI) (n=3 )
Figure. CONSORT diagram.
Baseline perinatal variables for the infants, including, gestational age, male sex, maternal chorioamnionitis, antenatal steroids, and an Apgar score of <7 at 5 minutes, did not differ between treatment groups. Infants in the monitor display group were on average 23 g heavier at birth than the control group (746 154 g vs 723 152 g; P = .05). The mean corrected age at the time of follow-up evaluation was 19.6 2.0 months for both the monitor display and control groups. Infants lost to follow-up were heavier at birth (794 g vs 735 g; P < .001); more mature (27 weeks vs 26 weeks); and less likely to have maternal antenatal steroids administered (71% vs 79%; P = .01) when compared with the infants whose primary outcome was known. There were no detectable differences in the loss to follow-up group with respect to sex, maternal chorioamnionitis, and Apgar scores of <7 at 5 minutes of age (Table I). Among the infants with known primary outcome, the proportion with death or NDI did not differ between groups (relative risk [RR], 0.89; 95% CI, 0.74-1.07). Death was decreased from 32.0% (99/309) for infants in the control group to 24.2% (79/327) in the monitor display group (RR, 0.75; 95% CI, 0.59-0.97; P = .028). Regarding death or
individual components of NDI, all RR estimates were <1 and the 95% CI crossed over 1 (Table II). Among survivors seen at follow-up, the proportion of infants who were blind and who had abnormal neurologic examination did not significantly differ. More infants in the display group than the control group were deaf: 11 in 248 (4.4%) vs 1 in 210 (0.5%; P = .008). To further delineate the impact of heart rate characteristics monitoring on specific neurodevelopmental outcomes, while controlling for death, we examined mild, moderate, and severe CP individually as well as intermediate Bayley III cognitive and language levels (70-84). Fewer infants in the display group than those in the control group had death or mild CP (114/325 [35.4%] vs 134/309 [43.4%]; P = .035), severe CP (85/325 [26.2%] vs 104/309 [33.7%]; P = .046), and Bayley cognitive scores of 70-84 (106/321 [33.0%] vs 125/306 [40.8%]; P = .047; Table III).
Discussion For the ELBW infants enrolled in the 18- to 22-month follow-up component of the original heart rate
Mortality and Neurodevelopmental Outcomes in the Heart Rate Characteristics Monitoring Randomized Controlled Trial
3
THE JOURNAL OF PEDIATRICS
www.jpeds.com
Volume -
Table I. Characteristics of the infants with outcome known and not known according to monitoring assignment Outcome known
Variables Baseline Birth weight, g Gestational age, wk Male Maternal chorioamnionitis Antenatal steroids Neonatal outcomes* Apgar at 5 min of <7 Culture-proven sepsis
Outcome not known
Comparison
Display
Control
Display
Control
(n = 322)
(n = 306)
P value 1
(n = 120)
(n = 136)
P value 1
P value 2
746 154 26 2.1 172 (53.4) 37 (11.5) 256 (79.5)
723 152 26 1.9 153 (50.0) 37 (12.1) 239 (78.1)
.05 .3 .42 .9 .69
811 140 27 2.1 59 (49.2) 10 (8.3) 83 (69.2)
779 148 27 2.1 57 (41.9) 17 (12.5) 98 (72.1)
.07 .11 .26 .31 .68
.0001 .0001 .08 .64 .01
112/319 (37.1) 130/322 (40.4)
118/302 (37.0) 131/306 (42.8)
1.0 .57
38 (32.2) 42/120 (35.0)
46 (34.9) 49/136 (36.0)
.69 .89
.35 .11
Values are mean SD or number (%). *Total number refers to the number of infants assessed for the outcome if different from the number in that group.
characteristics trial, there was a significant decrease in mortality for those infants whose heart rate characteristics were displayed to the clinical care team. Although no specific evaluation or treatment for infection was dictated by the original study,15 for increases in the heart rate characteristics predicted infection risk score, providing the risk information resulted in significantly lower mortality. This decrease in mortality may have been due to earlier recognition and empirical treatment for nosocomial infection.16 We hypothesized that earlier recognition and treatment for infection would ameliorate disability in survivors of extreme prematurity. Contrary to our hypothesis, survivors in the heart rate characteristics displayed group did not have discernable decreases in the predetermined components of NDI, nor was there excess morbidity. Increased hearing loss noted among survivors in the heart rate characteristics display group was an unanticipated finding. Improved survival in the heart rate characteristics display group seems a likely explanation for this group’s
higher rate of deafness, because an intervention that improves the survival of infants most vulnerable to deafness could increase the rate of deafness among survivors. Consistent with this possibility is that infants with hearing loss in the heart rate characteristics follow-up study were smaller (695 129 g vs 776 137 g; P = .04) and more immature at birth (25 2 weeks vs 26 2 weeks; P = .01). A less likely explanation for the higher rate of hearing loss among survivors in the heart rate characteristics display group is ototoxicity owing to the 3-day increase in antibiotic exposure in the heart rate characteristics display group, as previously reported.16 However, treatment with ototoxic aminoglycoside antibiotics alone has not been definitively linked to excess hearing loss.21 The higher prevalence of increased deafness among survivors in the heart rate characteristics display group should be considered in light of the finding that death or deafness occurred less frequently in the heart rate characteristics display group, although the difference was not statistically significant, and other factors potentially associated with deafness.
Table II. Mortality and neurodevelopmental findings at 18-22 months according to treatment assignment Variables Primary outcome Death or NDI Death Death or the following specific components of NDI GMFCS level 2-5 (moderate/severe CP) Bilateral blindness Deafness Bayley cognitive <70 Bayley language <70 NDI and specific components of NDI, survivors only NDI GMFCS level 2-5 (moderate/severe CP) Bilateral blindness Deafness Bayley cognitive <70 Bayley language <70
Display
Control
RR (95% CI)
P value
127/321 (39.6) 79/327 (24.2)
136/306 (44.4) 99/309 (32.0)
0.89 (0.74-1.07) 0.75 (0.59-0.97)
.223 .028
127/321 (39.6) 83/326 (25.5) 90/327 (27.5) 102/322 (31.7) 115/320 (35.9)
136/306 (44.4) 99/309 (32.0) 100/309 (32.4) 113/306 (36.9) 127/305 (41.6)
0.89 (0.74-1.07) 0.79 (0.62-1.02) 0.85 (0.67-1.08) 0.86 (0.69-1.07) 0.86 (0.71-1.05)
.223 .079 .194 .179 .163
53/247 (21.5) 23/246 (9.4) 4/247 (1.6) 11/248 (4.4) 23/243 (9.5) 36/241 (14.9)
40/210 (19.1) 13/210 (6.2) 0/210 (0) 1/210 (0.5) 15/207 (7.3) 28/206 (13.6)
1.12 (0.78-1.63) 1.51 (0.78-2.9) 0 (0-0) 9.31 (1.21-71.55) 1.31 (0.70-2.43) 1.01 (0.69-1.74)
.561 .223 .128 .008 .497 .787
Values are number/total number (%). NDI is a GMFCS level of 2-5 (moderate/severe CP, blind, deaf, language or cognitive Bayley score <70). The RR is of the outcome in the display group as compared with the control group.
4
Schelonka et al
- 2020
ORIGINAL ARTICLES
Table III. Mortality and additional neurodevelopmental findings at 18-22 months according to treatment assignment Display
Control
RR (95% CI)
P value
114/325 (35.1) 96/325 (29.5) 85/325 (26.2) 106/321 (33.0) 148/320 (46.3)
134/309 (43.4) 107/309 (34.6) 104/309 (33.7) 125/306 (40.8) 164/306 (53.6)
0.81 (0.67-0.98) 0.85 (0.68-1.07) 0.78 (0.61-0.99) 0.81 (0.66-0.99) 0.86 (0.74-1.01)
.035 .174 .046 .047 .079
Death or the following neurodevelopmental outcomes GMFCS level 1 (mild CP) GMFCS level 2-3 (moderate CP) GMFCS level 4-5 (severe CP) Bayley cognitive 70 – 84 Bayley language 70 – 84
Values are number/total number (%). The RR is of the outcome in the display group as compared with the control group.
In an exploratory analysis, we questioned the influence of heart rate characteristics monitoring for ELBW infants who develop less severe cognitive impairment and varying severity of CP. In the heart rate characteristics display group, there was an 8.3% absolute decrease in the rates of death or mild CP, a 7.5% absolute decrease in the rates of death or severe CP, and a 7.8% absolute decrease in the rates of death or moderate cognitive impairment (Bayley III cognitive level 70-84) when compared with the control group (P = .035, .046, and .047, respectively). An intervention that decreases mortality and reduces moderate cognitive delays, without increasing severe disability, could have important implications for ELBW survivors. Early intervention tends to have a greater impact on long-term outcome for infants with moderate delays than for those with severe delays.22,23 However, such subgroup analyses should be interpreted with caution. There are limitations to our study. Although the rate of loss to follow-up was similar in the heart rate characteristics display and control groups (27.1% and 30.8%), this is a potential source of bias and loss of statistical power. Infants whose outcome could not be determined owing to loss to follow-up were on average 59 g heavier at birth and 1 week more mature (27 weeks vs 26 weeks). Because of the known influence of birth weight and gestational age on prevalence of neurodevelopmental disability, we might have overestimated the proportion of infants with the composite primary outcome and individual components of NDI. We identified NDIs at 18-22 months; often impairments observed at that age do not persist at school age.24 There are also strengths to our study. We prospectively followed a large cohort of ELBW infants who participated in a randomized controlled trial with a preplanned analysis and prespecified definitions for outcomes. Trained examiners used standardized neurologic assessments and psychometric evaluations. The patient population demographics and neurodevelopmental outcomes of patients in the heart rate characteristics trial are comparable with large observational studies of ELBW infants from the Eunice Kennedy Shriver National Institute of Child Health and Human Developmental Neonatal Research Network.6,10,11,25,26 n We thank M. Pamela Griffin, MD (Global Clinical Lead, BioPharmaceuticals AstraZeneca), and William E. King, MS, (Chief Executive Officer of Medical Predictive Science Corporation) for contributions in the clinical application of heart rate characteristics monitoring in neonates and data warehousing for the original clinical trial.
Submitted for publication Nov 13, 2019; last revision received Dec 27, 2019; accepted Dec 30, 2019. Reprint requests: Robert L. Schelonka, MD, Division of Neonatology, Oregon Health & Science University, Mail code: CDRCP, 707 S.W. Gaines St, Portland, OR 97239-2998. E-mail: [email protected]
References 1. Rysavy MA, Li L, Bell EF, Das A, Hintz SR, Stoll BJ, et al. Between-hospital variation in treatment and outcomes in extremely preterm infants. N Engl J Med 2015;372:1801-11. 2. Fanaroff AA, Stoll BJ, Wright LL, Carlo WA, Ehrenkranz RA, Stark AR, et al. Trends in neonatal morbidity and mortality for very low birthweight infants. Am J Obstet Gynecol 2007;196:147.e1-8. 3. Hirschberger RG, Kuban KCK, O’Shea TM, Joseph RM, Heeren T, Douglass LM, et al. Co-occurrence and severity of neurodevelopmental burden (cognitive impairment, cerebral palsy, autism spectrum disorder, and epilepsy) at age ten years in children born extremely preterm. Pediatr Neurol 2018;79:45-52. 4. Joseph RM, O’Shea TM, Allred EN, Heeren T, Hirtz D, Jara H, et al. Neurocognitive and academic outcomes at age 10 years of extremely preterm newborns. Pediatrics 2016;137:e20154343. 5. Stoll BJ, Hansen N. Infections in VLBW infants: studies from the NICHD Neonatal Research Network. Semin Perinatol 2003;27: 293-301. 6. Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA, Ehrenkranz RA, et al. Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Pediatrics 2002;110:285-91. 7. Dammann O, Kuban KC, Leviton A. Perinatal infection, fetal inflammatory response, white matter damage, and cognitive limitations in children born preterm. Ment Retard Dev Disabil Res Rev 2002;8:46-50. 8. Hagberg H, Mallard C. Effect of inflammation on central nervous system development and vulnerability. Curr Opin Neurol 2005;18:117-23. 9. O’Shea TM, Klinepeter KL, Meis PJ, Dillard RG. Intrauterine infection and the risk of cerebral palsy in very low-birthweight infants. Paediatr Perinat Epidemiol 1998;12:72-83. 10. Stoll BJ, Hansen NI, Adams-Chapman I, Fanaroff AA, Hintz SR, Vohr B, et al. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA 2004;292: 2357-65. 11. Pappas A, Kendrick DE, Shankaran S, Stoll BJ, Bell EF, Laptook AR, et al. Chorioamnionitis and early childhood outcomes among extremely lowgestational-age neonates. JAMA Pediatr 2014;168:137-47. 12. Polin RA. The “ins and outs” of neonatal sepsis. J Pediatr 2003;143:3-4. 13. Griffin MP, Lake DE, O’Shea TM, Moorman JR. Heart rate characteristics and clinical signs in neonatal sepsis. Pediatr Res 2007;61:222-7. 14. Griffin MP, Lake DE, Bissonette EA, Harrell FE Jr, O’Shea TM, Moorman JR. Heart rate characteristics: novel physiomarkers to predict neonatal infection and death. Pediatrics 2005;116:1070-4. 15. Moorman JR, Carlo WA, Kattwinkel J, Schelonka RL, Porcelli PJ, Navarrete CT, et al. Mortality reduction by heart rate characteristic monitoring in very low birth weight neonates: a randomized trial. J Pediatr 2011;159:900-6.e1.
Mortality and Neurodevelopmental Outcomes in the Heart Rate Characteristics Monitoring Randomized Controlled Trial
5
THE JOURNAL OF PEDIATRICS
www.jpeds.com
16. Fairchild KD, Schelonka RL, Kaufman DA, Carlo WA, Kattwinkel J, Porcelli PJ, et al. Septicemia mortality reduction in neonates in a heart rate characteristics monitoring trial. Pediatr Res 2013;74:570-5. 17. Bayley N, Bayley N, PsychCorp. Bayley scales of infant and toddler development, technical manual. 3rd ed. San Antonio, TX: Harcourt Assessment; 2006. 18. Palisano R, Rosenbaum P, Walter S, Russell D, Wood E, Galuppi B. Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol 1997;39:214-23. 19. Rosenbaum P, Paneth N, Leviton A, Goldstein M, Bax M, Damiano D, et al. A report: the definition and classification of cerebral palsy April 2006. Dev Med Child Neurol Suppl 2007;109:8-14. 20. Amiel-Tison C, Gosselin J. Neurological development from birth to six years: guide for examination and evaluation. Baltimore (MD): Johns Hopkins University Press; 2001. 21. Finitzo-Hieber T, McCracken GH Jr, Roeser RJ, Allen DA, Chrane DF, Morrow J. Ototoxicity in neonates treated with gentamicin and kanamycin: results of a four-year controlled follow-up study. Pediatrics 1979;63:443-50.
6
Volume -
22. Guralnick MJ. The next decade of research on the effectiveness of early intervention. Except Child 1991;58:174-83. 23. McCormick MC, Brooks-Gunn J, Buka SL, Goldman J, Yu J, Salganik M, et al. Early intervention in low birth weight premature infants: results at 18 years of age for the Infant Health and Development Program. Pediatrics 2006;117:771-80. 24. Hack M, Taylor HG, Drotar D, Schluchter M, Cartar L, WilsonCostello D, et al. Poor predictive validity of the Bayley Scales of Infant Development for cognitive function of extremely low birth weight children at school age. Pediatrics 2005;116:333-41. 25. Boghossian NS, McDonald SA, Bell EF, Carlo WA, Brumbaugh JE, Stoll BJ, et al. Association of antenatal corticosteroids with mortality, morbidity, and neurodevelopmental outcomes in extremely preterm multiple gestation infants. JAMA Pediatr 2016;170: 593-601. 26. Vohr BR, Stephens BE, Higgins RD, Bann CM, Hintz SR, Das A, et al. Are outcomes of extremely preterm infants improving? Impact of Bayley assessment on outcomes. J Pediatr 2012;161:222-8.e3.
Schelonka et al
A
dvances in neonatal intensive care have increased survival of extremely low birth weight infants (ELBW; weighing £1000 g at birth) but about one-third of survivors have moderate to severe neurodevelopmental impairment (NDI) when assessed at 18-22 months.1,2 By school age, approximately 50% of ELBW infants show cognitive deficits and 17% have cerebral palsy (CP).3,4 Systemic infections, a frequent complication among ELBW preterm infants, are associated with short-term sequelae and an increased risk of death.5,6 There is mounting evidence that nosocomial infections and the systemic inflammatory response damage cerebral white matter7,8 and contribute to long-term disability in ELBW infants.9-11 The diagnosis of sepsis in the newborn period is challenging. The clinical signs of nosocomial sepsis and/or meningitis in ELBW infants are often nonspecific. Blood and body fluid cultures are reported sterile in more than one-third of ELBW infants with a clinical sepsis syndrome.10 There are numerous adjunctive, nonspecific diagnostic and screening tests used to aid in the diagnosis of neonatal sepsis and/or meningitis. Although abnormalities of the complete blood count and neutrophil indices, acute phase reactants, and cytokines may suggest serious infection, few of these adjunctive tests have a high specificity and only rarely have a positive predictive value of >40% for proven neonatal sepsis.12 A recent advance in the diagnosis of neonatal sepsis is continuous heart rate characteristics monitoring to detect the presence of decreased variability and From the Department of Pediatrics, Division of Neonatology, Oregon Health and Science University, transient decelerations, which occur with increased frequency in the preclinical Portland, OR; Department of Pediatrics, University of phases of septicemia.13,14 The result is a monitoring system that has allowed diagAlabama at Birmingham, Birmingham, AL; Department of Pediatrics, University of Miami, Coral Gables, FL; nosis and treatment of bacterial sepsis in infants before showing overt signs of Department of Pediatrics, Wake Forest School of Medicine, Winston-Salem, NC; Department of illness. Heart rate characteristics monitoring underwent rigorous testing as Pediatrics and Medicine, University of Virginia, 1
2
3
4
5
Charlottesville, VA; and 6Department of Pediatrics, University of North Carolina, Chapel Hill, NC
BSID-III CP ELBW GMFCS NDI RR
Bayley Scales of Infant and Toddler Development, third edition Cerebral palsy Extremely low birth weight Gross Motor Function Classification System Neurodevelopmental impairment Relative risk
Supported by the National Institutes of Health grant (R01-HD48562 [to J.M.], R01 HD048562 [to T.O.]), and Florida-Children’s Medical Services (COQZH [to C.B.]). J.M. and D.L. have consulting agreements and equity shares in Medical Predictive Science Corporation, Charlottesville, VA. The other authors declare no conflicts of interest. 0022-3476/$ - see front matter. ª 2020 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jpeds.2019.12.066
1
THE JOURNAL OF PEDIATRICS
www.jpeds.com
part of a National Institute of Child Health and Human Development-funded multicenter, randomized, controlled trial of 3003 very low birth weight infants (<1500 g at birth), including 1513 ELBW infants.15 The current study was motivated by the need to assess the impact of heart rate characteristics technology on the prevention or amelioration of disability in survivors of extreme prematurity. We hypothesized that heart rate characteristics monitoring of ELBW infants leads to a reduction of moderate to severe NDI or death at 18-22 months for these infants.
Methods The heart rate characteristics monitoring trial was a multicenter, randomized controlled trial in which 3003 very low birth weight infants (£1500 g) were enrolled at 9 hospitals (ClinicalTrials.gov: NCT00307333) The methods and results of the trial have been reported elsewhere.15,16 Briefly, in the heart rate characteristics trial, infants were randomly assigned to 1 of 2 groups after written, informed parental consent. One group of infants had the heart rate characteristics index displayed to the care team for the infants (display group). Providers used the heart rate characteristics index to aid in early detection and treatment of nosocomial infection in the display group. Infants in the control group had the heart rate characteristics index recorded by the data collection devices, but this information was not displayed locally to the team caring for the infants. Infants had blood, urine, and cerebrospinal fluid cultures obtained and antibiotics started based on clinical suspicion of infection. For infants in the control group, this management continued as usual practice. For the infants in the display group, the use of the heart rate characteristics index may have influenced the frequency and timing of obtaining cultures and starting antibiotics. When the heart rate characteristics index was considered abnormal by the clinician, then a complete blood count, blood culture, and other laboratory tests to assist with the assessment of the infant may have been obtained. In addition, the clinician may have obtained cultures and started antibiotics at his or her discretion if there was a clinical suspicion of infection, but the heart rate characteristics index had not reached a concerning level or was not displayed. Antibiotics were administered at the discretion of the attending neonatologist. Thus, infants were not denied antibiotics if the clinicians felt that antibiotics were indicated. Centers were selected for the follow-up component of the heart rate characteristics trial a priori based on the merits of their neurodevelopmental follow-up programs and consistency of the 18-22 months follow-up protocol. Investigators at the University of Alabama at Birmingham, Wake Forest University, and the University of Miami enrolled >50% of the patients in the heart rate characteristics trial. All ELBW infants (£1000 g) in the heart rate characteristics trial enrolled at these 3 sites were eligible to participate in the current study. Follow-up data were added to the heart rate characteristics trial in hospital database. Infant characteristics 2
Volume -
- 2020
during the first 120 days from randomization were collected for the heart rate characteristics trial. These included birth weight, gestational age, pregnancy, labor, delivery complications, and Apgar scores. The research ethics board at each of the clinical centers approved the protocol. Survivors underwent a comprehensive neurodevelopmental and neurologic assessment at 18-22 months of corrected age by examiners unaware of the treatment group. Cognitive function was assessed with the Bayley Scales of Infant and Toddler Development, third edition (BSID-III); scores are assessed relative to a standardized mean of 100 15 in the normative data, with higher scores indicating better performance.17 The modified Gross Motor Function Classification System (GMFCS) was used to classify gross motor performance, with levels ranging from 0 (normal) to 5 (most impaired).18 Moderate CP was defined as a GMFCS level of 2-3 and severe CP was defined as a GMFCS level of 4-5.19,20 Permanent hearing loss was defined as a requirement for bilateral hearing aids and blindness was defined as no functional vision in either eye. The prespecified primary composite outcome for this study was death before 18 to 22 months or NDI at 18-22 months of corrected age. NDI was defined as ³1 of the following: a cognitive or language composite score on the BSID-III of <70, GMFCS of ³2 (moderate or severe CP), hearing impairment, or bilateral visual impairment. The other prespecified secondary outcomes were individual components of the primary outcome, and mild NDI (GMFCS of 1 or BSID-III of 70-84). The sample size was based on the number of infants with a birth weight of <1000 g enrolled at the 3 study sites and was sufficient to detect a decrease in the proportion with death/ NDI of 10 percentage points (ie, 20% in the intervention group vs 30% for the control group) with 0.80 power and 2-sided significance level of .05, which would require 313 infants per group, for a total of 626. Data were entered on a database maintained at the University of Virginia. Baseline data and treatment group differences for infants who have known and unknown primary outcome (death or NDI) were compared by Student t tests for continuous data and c2 tests for categorical data. Fisher exact test was used for categorical outcomes with frequency counts of <6. Secondary outcomes include the components of NDI in survivors and death or moderate to severe CP, death or BSID-III Cognitive and Language scale of <70, death or hearing impairment, and death or blindness in all participants.
Results Death or NDI, the primary composite outcome, was known in 322 infants (73%) in the monitor display group and 306 infants (69%) in the control group. Of the 884 infants enrolled in the follow-up component of the original trial, 636 infants were available for follow-up at 18-22 months corrected age. A total of 458 infants was seen (248 in the display group, 210 in the control group), which was 74.7% and 69.2% of surviving infants, respectively (Figure). Schelonka et al
- 2020
ORIGINAL ARTICLES Enrollment
Assessed for eligibility (n= 3003)
Excluded (n=2119)
♦ Not meeting inclusion criteria (n=2119) ♦ Declined to participate (n=0) ♦ Other reasons (n=0) Randomized (n=884)
Allocation Allocated to Monitor Display (n=442) ♦ Received allocated intervention (n=442)
Allocated to Control Group (n=442)
♦ Received allocated intervention (n=442) ♦ Did not receive allocated intervention (n= 0)
♦ Did not receive allocated intervention (n=0)
Follow-Up Lost to follow-up (n=84)
Lost to follow-up (n=94)
Discontinued intervention (withdrew consent for follow up component) (n=31)
Discontinued intervention (withdrew consent for follow up component) (n= 39)
Analysis Analyzed (n=332) ♦ Excluded from analysis (incomplete data on follow up visit to classify presence/absence of NDI) (n=5 )
Analyzed (n=306)
♦ Excluded from analysis (incomplete data on follow up visit to classify presence/absence of NDI) (n=3 )
Figure. CONSORT diagram.
Baseline perinatal variables for the infants, including, gestational age, male sex, maternal chorioamnionitis, antenatal steroids, and an Apgar score of <7 at 5 minutes, did not differ between treatment groups. Infants in the monitor display group were on average 23 g heavier at birth than the control group (746 154 g vs 723 152 g; P = .05). The mean corrected age at the time of follow-up evaluation was 19.6 2.0 months for both the monitor display and control groups. Infants lost to follow-up were heavier at birth (794 g vs 735 g; P < .001); more mature (27 weeks vs 26 weeks); and less likely to have maternal antenatal steroids administered (71% vs 79%; P = .01) when compared with the infants whose primary outcome was known. There were no detectable differences in the loss to follow-up group with respect to sex, maternal chorioamnionitis, and Apgar scores of <7 at 5 minutes of age (Table I). Among the infants with known primary outcome, the proportion with death or NDI did not differ between groups (relative risk [RR], 0.89; 95% CI, 0.74-1.07). Death was decreased from 32.0% (99/309) for infants in the control group to 24.2% (79/327) in the monitor display group (RR, 0.75; 95% CI, 0.59-0.97; P = .028). Regarding death or
individual components of NDI, all RR estimates were <1 and the 95% CI crossed over 1 (Table II). Among survivors seen at follow-up, the proportion of infants who were blind and who had abnormal neurologic examination did not significantly differ. More infants in the display group than the control group were deaf: 11 in 248 (4.4%) vs 1 in 210 (0.5%; P = .008). To further delineate the impact of heart rate characteristics monitoring on specific neurodevelopmental outcomes, while controlling for death, we examined mild, moderate, and severe CP individually as well as intermediate Bayley III cognitive and language levels (70-84). Fewer infants in the display group than those in the control group had death or mild CP (114/325 [35.4%] vs 134/309 [43.4%]; P = .035), severe CP (85/325 [26.2%] vs 104/309 [33.7%]; P = .046), and Bayley cognitive scores of 70-84 (106/321 [33.0%] vs 125/306 [40.8%]; P = .047; Table III).
Discussion For the ELBW infants enrolled in the 18- to 22-month follow-up component of the original heart rate
Mortality and Neurodevelopmental Outcomes in the Heart Rate Characteristics Monitoring Randomized Controlled Trial
3
THE JOURNAL OF PEDIATRICS
www.jpeds.com
Volume -
Table I. Characteristics of the infants with outcome known and not known according to monitoring assignment Outcome known
Variables Baseline Birth weight, g Gestational age, wk Male Maternal chorioamnionitis Antenatal steroids Neonatal outcomes* Apgar at 5 min of <7 Culture-proven sepsis
Outcome not known
Comparison
Display
Control
Display
Control
(n = 322)
(n = 306)
P value 1
(n = 120)
(n = 136)
P value 1
P value 2
746 154 26 2.1 172 (53.4) 37 (11.5) 256 (79.5)
723 152 26 1.9 153 (50.0) 37 (12.1) 239 (78.1)
.05 .3 .42 .9 .69
811 140 27 2.1 59 (49.2) 10 (8.3) 83 (69.2)
779 148 27 2.1 57 (41.9) 17 (12.5) 98 (72.1)
.07 .11 .26 .31 .68
.0001 .0001 .08 .64 .01
112/319 (37.1) 130/322 (40.4)
118/302 (37.0) 131/306 (42.8)
1.0 .57
38 (32.2) 42/120 (35.0)
46 (34.9) 49/136 (36.0)
.69 .89
.35 .11
Values are mean SD or number (%). *Total number refers to the number of infants assessed for the outcome if different from the number in that group.
characteristics trial, there was a significant decrease in mortality for those infants whose heart rate characteristics were displayed to the clinical care team. Although no specific evaluation or treatment for infection was dictated by the original study,15 for increases in the heart rate characteristics predicted infection risk score, providing the risk information resulted in significantly lower mortality. This decrease in mortality may have been due to earlier recognition and empirical treatment for nosocomial infection.16 We hypothesized that earlier recognition and treatment for infection would ameliorate disability in survivors of extreme prematurity. Contrary to our hypothesis, survivors in the heart rate characteristics displayed group did not have discernable decreases in the predetermined components of NDI, nor was there excess morbidity. Increased hearing loss noted among survivors in the heart rate characteristics display group was an unanticipated finding. Improved survival in the heart rate characteristics display group seems a likely explanation for this group’s
higher rate of deafness, because an intervention that improves the survival of infants most vulnerable to deafness could increase the rate of deafness among survivors. Consistent with this possibility is that infants with hearing loss in the heart rate characteristics follow-up study were smaller (695 129 g vs 776 137 g; P = .04) and more immature at birth (25 2 weeks vs 26 2 weeks; P = .01). A less likely explanation for the higher rate of hearing loss among survivors in the heart rate characteristics display group is ototoxicity owing to the 3-day increase in antibiotic exposure in the heart rate characteristics display group, as previously reported.16 However, treatment with ototoxic aminoglycoside antibiotics alone has not been definitively linked to excess hearing loss.21 The higher prevalence of increased deafness among survivors in the heart rate characteristics display group should be considered in light of the finding that death or deafness occurred less frequently in the heart rate characteristics display group, although the difference was not statistically significant, and other factors potentially associated with deafness.
Table II. Mortality and neurodevelopmental findings at 18-22 months according to treatment assignment Variables Primary outcome Death or NDI Death Death or the following specific components of NDI GMFCS level 2-5 (moderate/severe CP) Bilateral blindness Deafness Bayley cognitive <70 Bayley language <70 NDI and specific components of NDI, survivors only NDI GMFCS level 2-5 (moderate/severe CP) Bilateral blindness Deafness Bayley cognitive <70 Bayley language <70
Display
Control
RR (95% CI)
P value
127/321 (39.6) 79/327 (24.2)
136/306 (44.4) 99/309 (32.0)
0.89 (0.74-1.07) 0.75 (0.59-0.97)
.223 .028
127/321 (39.6) 83/326 (25.5) 90/327 (27.5) 102/322 (31.7) 115/320 (35.9)
136/306 (44.4) 99/309 (32.0) 100/309 (32.4) 113/306 (36.9) 127/305 (41.6)
0.89 (0.74-1.07) 0.79 (0.62-1.02) 0.85 (0.67-1.08) 0.86 (0.69-1.07) 0.86 (0.71-1.05)
.223 .079 .194 .179 .163
53/247 (21.5) 23/246 (9.4) 4/247 (1.6) 11/248 (4.4) 23/243 (9.5) 36/241 (14.9)
40/210 (19.1) 13/210 (6.2) 0/210 (0) 1/210 (0.5) 15/207 (7.3) 28/206 (13.6)
1.12 (0.78-1.63) 1.51 (0.78-2.9) 0 (0-0) 9.31 (1.21-71.55) 1.31 (0.70-2.43) 1.01 (0.69-1.74)
.561 .223 .128 .008 .497 .787
Values are number/total number (%). NDI is a GMFCS level of 2-5 (moderate/severe CP, blind, deaf, language or cognitive Bayley score <70). The RR is of the outcome in the display group as compared with the control group.
4
Schelonka et al
- 2020
ORIGINAL ARTICLES
Table III. Mortality and additional neurodevelopmental findings at 18-22 months according to treatment assignment Display
Control
RR (95% CI)
P value
114/325 (35.1) 96/325 (29.5) 85/325 (26.2) 106/321 (33.0) 148/320 (46.3)
134/309 (43.4) 107/309 (34.6) 104/309 (33.7) 125/306 (40.8) 164/306 (53.6)
0.81 (0.67-0.98) 0.85 (0.68-1.07) 0.78 (0.61-0.99) 0.81 (0.66-0.99) 0.86 (0.74-1.01)
.035 .174 .046 .047 .079
Death or the following neurodevelopmental outcomes GMFCS level 1 (mild CP) GMFCS level 2-3 (moderate CP) GMFCS level 4-5 (severe CP) Bayley cognitive 70 – 84 Bayley language 70 – 84
Values are number/total number (%). The RR is of the outcome in the display group as compared with the control group.
In an exploratory analysis, we questioned the influence of heart rate characteristics monitoring for ELBW infants who develop less severe cognitive impairment and varying severity of CP. In the heart rate characteristics display group, there was an 8.3% absolute decrease in the rates of death or mild CP, a 7.5% absolute decrease in the rates of death or severe CP, and a 7.8% absolute decrease in the rates of death or moderate cognitive impairment (Bayley III cognitive level 70-84) when compared with the control group (P = .035, .046, and .047, respectively). An intervention that decreases mortality and reduces moderate cognitive delays, without increasing severe disability, could have important implications for ELBW survivors. Early intervention tends to have a greater impact on long-term outcome for infants with moderate delays than for those with severe delays.22,23 However, such subgroup analyses should be interpreted with caution. There are limitations to our study. Although the rate of loss to follow-up was similar in the heart rate characteristics display and control groups (27.1% and 30.8%), this is a potential source of bias and loss of statistical power. Infants whose outcome could not be determined owing to loss to follow-up were on average 59 g heavier at birth and 1 week more mature (27 weeks vs 26 weeks). Because of the known influence of birth weight and gestational age on prevalence of neurodevelopmental disability, we might have overestimated the proportion of infants with the composite primary outcome and individual components of NDI. We identified NDIs at 18-22 months; often impairments observed at that age do not persist at school age.24 There are also strengths to our study. We prospectively followed a large cohort of ELBW infants who participated in a randomized controlled trial with a preplanned analysis and prespecified definitions for outcomes. Trained examiners used standardized neurologic assessments and psychometric evaluations. The patient population demographics and neurodevelopmental outcomes of patients in the heart rate characteristics trial are comparable with large observational studies of ELBW infants from the Eunice Kennedy Shriver National Institute of Child Health and Human Developmental Neonatal Research Network.6,10,11,25,26 n We thank M. Pamela Griffin, MD (Global Clinical Lead, BioPharmaceuticals AstraZeneca), and William E. King, MS, (Chief Executive Officer of Medical Predictive Science Corporation) for contributions in the clinical application of heart rate characteristics monitoring in neonates and data warehousing for the original clinical trial.
Submitted for publication Nov 13, 2019; last revision received Dec 27, 2019; accepted Dec 30, 2019. Reprint requests: Robert L. Schelonka, MD, Division of Neonatology, Oregon Health & Science University, Mail code: CDRCP, 707 S.W. Gaines St, Portland, OR 97239-2998. E-mail: [email protected]
References 1. Rysavy MA, Li L, Bell EF, Das A, Hintz SR, Stoll BJ, et al. Between-hospital variation in treatment and outcomes in extremely preterm infants. N Engl J Med 2015;372:1801-11. 2. Fanaroff AA, Stoll BJ, Wright LL, Carlo WA, Ehrenkranz RA, Stark AR, et al. Trends in neonatal morbidity and mortality for very low birthweight infants. Am J Obstet Gynecol 2007;196:147.e1-8. 3. Hirschberger RG, Kuban KCK, O’Shea TM, Joseph RM, Heeren T, Douglass LM, et al. Co-occurrence and severity of neurodevelopmental burden (cognitive impairment, cerebral palsy, autism spectrum disorder, and epilepsy) at age ten years in children born extremely preterm. Pediatr Neurol 2018;79:45-52. 4. Joseph RM, O’Shea TM, Allred EN, Heeren T, Hirtz D, Jara H, et al. Neurocognitive and academic outcomes at age 10 years of extremely preterm newborns. Pediatrics 2016;137:e20154343. 5. Stoll BJ, Hansen N. Infections in VLBW infants: studies from the NICHD Neonatal Research Network. Semin Perinatol 2003;27: 293-301. 6. Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA, Ehrenkranz RA, et al. Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Pediatrics 2002;110:285-91. 7. Dammann O, Kuban KC, Leviton A. Perinatal infection, fetal inflammatory response, white matter damage, and cognitive limitations in children born preterm. Ment Retard Dev Disabil Res Rev 2002;8:46-50. 8. Hagberg H, Mallard C. Effect of inflammation on central nervous system development and vulnerability. Curr Opin Neurol 2005;18:117-23. 9. O’Shea TM, Klinepeter KL, Meis PJ, Dillard RG. Intrauterine infection and the risk of cerebral palsy in very low-birthweight infants. Paediatr Perinat Epidemiol 1998;12:72-83. 10. Stoll BJ, Hansen NI, Adams-Chapman I, Fanaroff AA, Hintz SR, Vohr B, et al. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA 2004;292: 2357-65. 11. Pappas A, Kendrick DE, Shankaran S, Stoll BJ, Bell EF, Laptook AR, et al. Chorioamnionitis and early childhood outcomes among extremely lowgestational-age neonates. JAMA Pediatr 2014;168:137-47. 12. Polin RA. The “ins and outs” of neonatal sepsis. J Pediatr 2003;143:3-4. 13. Griffin MP, Lake DE, O’Shea TM, Moorman JR. Heart rate characteristics and clinical signs in neonatal sepsis. Pediatr Res 2007;61:222-7. 14. Griffin MP, Lake DE, Bissonette EA, Harrell FE Jr, O’Shea TM, Moorman JR. Heart rate characteristics: novel physiomarkers to predict neonatal infection and death. Pediatrics 2005;116:1070-4. 15. Moorman JR, Carlo WA, Kattwinkel J, Schelonka RL, Porcelli PJ, Navarrete CT, et al. Mortality reduction by heart rate characteristic monitoring in very low birth weight neonates: a randomized trial. J Pediatr 2011;159:900-6.e1.
Mortality and Neurodevelopmental Outcomes in the Heart Rate Characteristics Monitoring Randomized Controlled Trial
5
THE JOURNAL OF PEDIATRICS
www.jpeds.com
16. Fairchild KD, Schelonka RL, Kaufman DA, Carlo WA, Kattwinkel J, Porcelli PJ, et al. Septicemia mortality reduction in neonates in a heart rate characteristics monitoring trial. Pediatr Res 2013;74:570-5. 17. Bayley N, Bayley N, PsychCorp. Bayley scales of infant and toddler development, technical manual. 3rd ed. San Antonio, TX: Harcourt Assessment; 2006. 18. Palisano R, Rosenbaum P, Walter S, Russell D, Wood E, Galuppi B. Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol 1997;39:214-23. 19. Rosenbaum P, Paneth N, Leviton A, Goldstein M, Bax M, Damiano D, et al. A report: the definition and classification of cerebral palsy April 2006. Dev Med Child Neurol Suppl 2007;109:8-14. 20. Amiel-Tison C, Gosselin J. Neurological development from birth to six years: guide for examination and evaluation. Baltimore (MD): Johns Hopkins University Press; 2001. 21. Finitzo-Hieber T, McCracken GH Jr, Roeser RJ, Allen DA, Chrane DF, Morrow J. Ototoxicity in neonates treated with gentamicin and kanamycin: results of a four-year controlled follow-up study. Pediatrics 1979;63:443-50.
6
Volume -
22. Guralnick MJ. The next decade of research on the effectiveness of early intervention. Except Child 1991;58:174-83. 23. McCormick MC, Brooks-Gunn J, Buka SL, Goldman J, Yu J, Salganik M, et al. Early intervention in low birth weight premature infants: results at 18 years of age for the Infant Health and Development Program. Pediatrics 2006;117:771-80. 24. Hack M, Taylor HG, Drotar D, Schluchter M, Cartar L, WilsonCostello D, et al. Poor predictive validity of the Bayley Scales of Infant Development for cognitive function of extremely low birth weight children at school age. Pediatrics 2005;116:333-41. 25. Boghossian NS, McDonald SA, Bell EF, Carlo WA, Brumbaugh JE, Stoll BJ, et al. Association of antenatal corticosteroids with mortality, morbidity, and neurodevelopmental outcomes in extremely preterm multiple gestation infants. JAMA Pediatr 2016;170: 593-601. 26. Vohr BR, Stephens BE, Higgins RD, Bann CM, Hintz SR, Das A, et al. Are outcomes of extremely preterm infants improving? Impact of Bayley assessment on outcomes. J Pediatr 2012;161:222-8.e3.
Schelonka et al