≤Neurodevelopmental Outcomes Hirosuke Inoue, MD, PhD,​a,b​ Masayuki Ochiai, MD, PhD,​a,b​ Yasunari Sakai, MD, PhD,a,​ b​ Kazuaki Yasuoka, MD,a,​ b​ Koichiin Tanaka,Infants MD,​a,​b Masako Ichiyama, With MD,a,​ ​b Hiroaki Birth Kurata, MD,a,​ ​b WeightJunko Fujiyoshi, MD,a,​ ​b Yuki Matsushita, MD, PhD,a,​ ​b Satoshi Honjo, MD, PhD,c​ Kazuaki Nonaka, DDS, PhD,​b Tomoaki Taguchi, MD, PhD, FACS,​b Kiyoko Kato, MD, PhD,​b Shouichi500 Ohga, MD, g PhD, at​a,b​ on behalf3 ofYears the Neonatal Research of NetworkAge of Japan

OBJECTIVES: abstract ≤ To determine neurodevelopmental outcomes at 3 years of age in children born METHODS: with a birth weight (BW) of 500 g. ≤ Infants who were born with a BW of 500 g from 2003 to 2012 in the Neonatal Research Network of Japan and survived to discharge from the NICU were eligible in this study. The study population consisted of 460 children (56.7% of 811 surviving infants) who were evaluated at 36 to 42 months of age. Neurodevelopmental impairment (NDI) was defined as having cerebral palsy, visual impairment, hearing impairment, or a RESULTS: developmental quotient score of <70. – The overall proportion of NDI was 59.1% (95% confidence interval [CI]: 54.6% 63.5%). The trend revealed no significant change during the study period. – P In a multivariate modified Poisson regression analysis, NDI was associated with severe – P intraventricular hemorrhage (adjusted risk ratio [RR]: 1.42; 95% CI: 1.19 1.68; < .01), – P cystic periventricular leukomalacia (adjusted RR: 1.40; 95% CI: 1.13 1.73; < .01), severe – P necrotizing enterocolitis (adjusted RR: 1.31; 95% CI: 1.07 1.60; < .01), surgical ligation – P for patent ductus arteriosus (adjusted RR: 1.29; 95% CI: 1.09 1.54; < .01), and male sex CONCLUSIONS: (adjusted RR: 1.19; 95% CI: 1.01 2.40; = .04). ≤ This cohort showed that neurodevelopmental outcomes of infants with a BW of 500 g have not improved from 2003 to 2012. Multivariate analysis revealed that severe intracranial hemorrhage and cystic periventricular leukomalacia were the strongest ≤ risk factors for NDIs. Our data suggested that measures aimed at reducing neurologic morbidities will be important for improving outcomes of infants with a BW of 500 g.

WHAT’S KNOWN ON THIS SUBJECT: The survival of infants born with a birth weight (BW) of 500 aDepartment of Pediatrics, Graduate School of Medical Sciences and bComprehensive Maternity and Perinatal ≤ Care Center, Kyushu University, Fukuoka, Japan; and cDepartment of Pediatrics, National Hospital Organization g has improved considerably in Japan; however, Fukuoka National Hospital, Fukuoka, Japan few studies have revealed the neurodevelopmental outcomes of survivors born with a BW of ≤500 g. Dr Inoue conceptualized and designed the study, contributed to the analysis and interpretation of the data, and drafted the initial manuscript; Drs Ochiai, Sakai, and Ohga conceptualized and WHAT THIS STUDY ADDS: Neurodevelopmental designed the study, contributed to the data analysis, and critically reviewed and revised the outcomes in early childhood among surviving infants manuscript; Drs Yasuoka, Tanaka, Ichiyama, Kurata, Fujiyoshi, and Matsushita made substantial born with a BW of ≤500 g did not improve in a recent contributions to the analysis and interpretation of the data and reviewed and revised the decade. manuscript; Dr Honjo supervised and supported the statistical analyses for the completion of the study and reviewed and revised the manuscript; Drs Nonaka, Taguchi, and Kato supervised the study design, contributed to the interpretation of the data, and critically reviewed and revised the manuscript; and all authors approved the final manuscript as submitted. DOI: https://​doi.​org/​10.​1542/​peds.​2017-​4286 To cite: Inoue H, Ochiai M, Sakai Y, et al. Neurodevelopmental Accepted for publication Sep 13, 2018 Outcomes in Infants With Birth Weight ≤500 g at 3 Years of Age. Pediatrics. 2018;142(6):e20174286

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Advances in perinatal and neonatal of 1500 g admitted to the 204 treat bronchopulmonary dysplasia intensive care have improved participating NICUs, accounting for (BPD) or refractory hypotension. the survival rate of periviable, or 54.3% of 376 secondary and tertiary- Moderate to severe BPD was defined – ’ extremely preterm,1 3 infants near the level NICUs in Japan. The participants as the need for supplemental oxygen limit of viability. ‍‍ On the other in this study were born between or positive pressure15 at 36 weeks hand, researchers in recent4 studies January 1, 2003, and December 31, postmenstrual age. Treatment with have reported5 decreasing,​ 6,7​ 2012. Decisions regarding the pursuit indomethacin or surgical ligation unchanged,​ or increasing rates ‍ of active treatment versus comfort was conducted for closures of patent in neurodevelopmental disabilities care were made by neonatologists ductus arteriosus (PDA) diagnosed among periviable infants who on the basis of fetal information, the clinically and by echocardiography. survive compared with previous status of the infants at birth, and their Severe intraventricular hemorrhage16 decades. These variable data lead communications with the parents. (IVH) was defined as grade III or IV. to a concern that increased survival In general, attending neonatologists Cystic periventricular leukomalacia ≥ may come at the cost of later attempt to save the lives of neonates (cPVL) was diagnosed by cranial neurodevelopmental8 disabilities at a GA of 23 weeks, and this ultrasound or head MRI. Sepsis among survivors. Thus, providing principle has not changed during the was defined as culture-proven accurate data on both mortality study period. The perinatal data were13 septicemia or bacteremia during and long-term neurodevelopmental collected as previously described. the NICU stay. Severe necrotizing ≤ outcomes is important for families enterocolitis (NEC) was defined as Children who were born with a BW ≥ and professionals in neonatal care of 500 g and survived to discharge pneumoperitoneum17 or Bell stage in making appropriate 9decisions for from the NICU were included in 2. Retinopathy of prematurity these high-risk infants. this study. We excluded the infants (ROP) was coded if treatment was Gestational age (GA) and birth weight who had died in the operating or required with laser coagulation or cryocoagulation. This study was (BW), alone or combined, are the delivery room before admission to ’ the NICU, those transferred to other approved by the Internal Review critical factors– that affect the survival hospitals, those born at a GA of <22 Board of Tokyo Women s Medical rate of extremely9 11 preterm and small infants. ‍‍ Early ultrasound weeks, and those without available University. Written informed consent assessment provides an accurate records of mortality during the was obtained from the parents or estimation of GA in most cases, but NICU stay. Chorioamnionitis was guardiansOutcomes ofand all Neurodevelopmental infants in the NRNJ. ± diagnosed clinically. Antenatal use Assessments it is also known to12 cause an error as high as 15%. On the other of corticosteroids was defined as the hand, BW is a direct measurement of administration of corticosteroids the body size of offspring. We have to the mother at any time before Our primary objective in recently shown favorable results of delivery. In most cases, GA was this study was to determine ≤ calculated from the date of the neurodevelopmental impairment survival rates for infants with a BW of ≤ 500 g in Japan, whereas in-hospital last menstrual period and verified (NDI) in surviving children with by the fetal crown-rump length a BW of 500 g at 3 years of age. morbidity rates have13 remained high in the last decade. We extended on ultrasonography in the first NDI was defined as the following this study because the long-term trimester. However, their menstrual conditions: cerebral palsy (CP), ≤ outcomes of the infants with a BW of histories or ultrasonographic visual impairment, hearing 500 g were currently unavailable. findings were not recorded in the impairment, or cognitive impairment. In the current study, we investigate database. Small for gestational age Comprehensive neurodevelopmental neurodevelopmental outcomes at 3 (SGA) and severely SGA were defined and growth assessments were ≤ years of age for surviving children as a BW but not intrauterine fetal performed on the surviving children born with a BW of 500 g using the weight of less than the 10th and third14 at 36 to 42 months of chronological nationwide cohort database in Japan. percentiles for the GA, respectively. age at each participating institute. METHODS Major congenital abnormalities According to the protocol of the were defined as chromosomal Japanese Society for 18Follow-up Study Study Population and Data Collection abnormalities, congenital heart of High-Risk Infants,​ the postnatal defects, intestinal atresia, renal development and growth of the hypoplasia, skeletal dysplasia, and surviving children were assessed The Neonatal Research Network of inborn errors of metabolism. Nitric at 18 months of corrected age and Japan (NRNJ) database prospectively oxide inhalation was applied for at 3, 6, and 9 years of chronological registered all of the clinical pulmonary hypertension. Systemic age. During these periods, parents information of infants with a BW postnatal corticosteroid was used to were advised to follow periodic Downloaded from www.aappublications.org/news by guest on September 28, 2021 2 INOUE et al check-ups for their children. CP was defined as a nonprogressive central nervous system disorder characterized by abnormal muscle tone in at least 1 extremity and abnormal19 control of movement and posture,​ and it was diagnosed by board-certified pediatricians who specialize in child neurology. Visual impairment included unilateral or bilateral blindness or severe myopia requiring corrective lenses diagnosed by ophthalmologists. Hearing impairment was diagnosed by otolaryngologists when serial test results indicated the loss of auditory functions. Cognitive impairment was defined as a developmental quotient (DQ) score of <70 with the Kyoto Scale of Psychological Development, a standard development-scoring20 system written in Japanese. The FIGURE 1 test was available at all participating Patient enrollment. Our study population consisted of all children with a BW of ≤500 g and GA of ≥22 institutes and was performed weeks who survived from the affiliated NICUs. VLBW, very low birth weight. by certified psychologists who were trained to assess childhood 25 development under blinding to 21,​22 perinatal histories at each institute. regression analysis. We included discharged from 113 NICUs were Interscorer reliability was not in the regression model all factors of considered eligible to participate examined. According to the protocol, neonatal characteristics, in-hospital in a follow-up evaluation at age 3 developmental function was interventions,P and neonatal years. These children were born at – – categorized as delayed (DQ <70), morbidities from univariate analysis a median GA of 24 6/7 (range: 22 ≥ – subnormal (DQ 70 84), and normal with a value of <.2. Adjusted risk 0/7 33 2/7) weeks and BW of 462 ≥ (DQ 85). No disability was defined ratios (with 95% confidence intervals (267 500) g. The study population as a DQ score of 85 with no CP or [CIs]) were calculated. finally consisted of 460 children visual or hearing impairment. Height, RESULTS (56.7%) in 78 NICUs who had weight, head circumference (HC), and recorded data of NDI at 3 years of BMI SD scores were calculated by Clinical Characteristics age (median 37 months; Fig 1). The NRNJ database includes information using Japanese23,24​ reference values for sex and age. ‍ concerning visual and hearing Statistical Analyses ≤ A total of 1613 live-born infants with impairments (presence or absence) for 442 (96.1%) and 393 (85.4%) a BW of 500 g were13 registered in the NRNJ database. Of these, the children, respectively. Drop-off Data were analyzed by using JMP following infants were excluded: children included 323 who were lost 11.0 (SAS Institute, Inc, Cary, NC) 44 infants who were not admitted during the follow-up period and 28 whose follow-up data were missing Pand Stata 14.2 (Stata Corp, College to the NICU, 71 infants who were Station, TX). Results with a 2-sided transferred to other hospitals, 3 at age 3 years. value of <.05 were considered infants born at a GA of <22 weeks, To determine if the study population significant. Continuous and and 22 infants without records of represented the whole eligible ≤ n categorical variables were compared mortality status. Of 1473 live-born population, baseline characteristics χ ≥ by2 using Wilcoxon rank sum tests and infants with a BW of 500 g at a GA from the study populationn ( = tests, respectively. The Cochran- of 22 weeks who were treated in 460) were compared with the Armitage test was used to assess the NICUs, 662 infants were excluded nonevaluated children ( = 351; temporal trends. Risks of NDI were because of death during the NICU ‍Table 1). There were significant but calculated with modified Poisson stay. Consequently, 811 children small differences in the proportions Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 142, number 6, December 2018 3 TABLE 1 Demographics for Surviving Infants With a BW of ≤500 g Study Population, Not Evaluated, N = 351 P N = 460 are shown in Supplemental TableP 7. NDI and no disability remained Maternal unchanged in their prevalence ( = Age ≥35 y 140 of 432 (32.4) 122 of 340 (35.9) .31 .70 and .78 for trend, respectively; Singleton 413 of 460 (89.8) 310 of 344 (90.1) .88 − Clinical chorioamnionitis 83 of 450 (18.4) 48 of 331 (14.5) .15 Fig 2). The proportions of children Antenatal corticosteroids 232 of 458 (50.7) 178 of 345 (51.6) .79 with < 2 SDs of weight, height, Cesarean delivery 359 of 459 (78.2) 268 of 345 (77.7) .86 HC, and BMI were 69.9%, 69.6%, Neonatal 40.6%, and 42.9%, respectively GA, wk 24 6/7, 22 0/7–32 2/7 24 6/7, 22 0/7–33 2/7 .79 BW, g 462, 276–500 462, 267–500 .96 (Table 2). There was no difference SGA 342 of 460 (74.3) 259 of 351 (73.8) .86 in anthropometric measurements Severely SGA 298 of 460 (64.8) 223 of 351 (63.5) .71 between the BW subgroups. Boy 187 of 460 (40.7) 158 of 351 (45.0) .21 Factors Associated With NDI Apgar score ≥4 at 5 min 385 of 447 (86.1) 282 of 334 (84.4) .51 Major congenital abnormalities 11 of 460 (2.4) 2 of 350 (0.6) .04 In-hospital interventions Surfactant 371 of 457 (81.2) 266 of 341 (78.0) .27 In Table 3, we presentn the perinatal High-frequency ventilation 313 of 453 (69.1) 211 of 340 (62.1) .04 and neonatal characteristics of Inhaled nitric oxide 40 of 443 (9.0) 31 of 332 (9.3) .88 n children with NDI ( = 272) and Indomethacin 319 of 458 (69.7) 243 of 344 (70.6) .76 Postnatal corticosteroids 247 of 392 (63.0) 182 of 300 (60.7) .53 non-NDI ( = 188). The median Antibiotics 384 of 452 (85.0) 306 of 341 (89.7) .047 GA (24 4/7 weeks) of children Neonatal morbidities with NDIP was lower than that of Any of the following morbidities 365 of 454 (80.4) 283 of 342 (82.7) .40 children with non-NDI (25 2/7 Moderate to severe BPD 255 of 450 (56.7) 197 of 335 (58.8) .55 weeks; = .04). The children with PDA ligation 65 of 458 (14.2) 39 of 343 (11.4) .24 Severe IVH 30 of 456 (6.6) 31 of 341 (9.1) .19 NDI included significantly higher cPVL 18 of 457 (3.9) 13 of 344 (3.8) .91 proportions of boys and all neonatal Sepsis 92 of 457 (20.1) 71 of 344 (20.6) .86 morbidities. Other characteristics Severe NEC 35 of 460 (7.6) 30 of 351 (8.5) .63 such as BW, SGA, severe SGA, Treatment of ROP 225 of 452 (49.8) 157 of 339 (46.3) .33 congenital abnormalities, and Data presented as the number, number with available information (percentage), or as the median and range. P values are in-hospital interventions did not obtained by using the Wilcoxon rank-sum test (continuous variables) and χ2 test (dichotomous variables). differ between them. Multivariate regression analysis revealed that n NDI was significantly associated with ≥ of major congenital abnormalities, ( = 110 in 52 NICUs), 5 to 10 (267 in severe IVH, cPVL, severe NEC, PDA high-frequency ventilation, and 36), 11 to 20 (219 in 16), and 21 ligation, and male sex (Table 4). We n found the essentially same relations Outcomesantibiotics use. (215 in 9). The proportions of NDI in the study population ( = 460) between the clinical variable and risk were not different among these 4 for developing multiple disabilities P (Supplemental Table 8). Among 442 categories (69.6%, 52.4%, 62.6%, We analyzed neurodevelopmental children without severe IVH or cPVL, n and 57.3%, respectively; = .14). The and growth outcomes of the study 256 (57.9%) infants developed NDI. DQ scores were missing in 20 (4.3%) population ( = 460) and compared Anthropometric data revealed that ≤ n of 460 eligible subjects. Children with − these profiles between the subgroups 47.4% (82 of 173) of children with n a BW of 401 to 500 g had a lower with BWs of 400 g ( = 65) and 401 ≤ NDI had an HC of < 2 SDs, which ≤ proportion of cognitive impairment P to 500 g ( = 395; Table 2). The GA was higher than that (29.5%, 31 of − did not differ between the BW 400 g than those with a BW of 400 g, 105) of children with non-NDI ( < – (median: 25 0/7 weeks; range: whereas other neurodevelopmental .01). Proportions of weight < 2 SDs – outcomes did not differ between 22 0/7 30 2/7 weeks)P and 401 to P(children with NDI: 72.3% [159 of them. Overall, 80 children (17.4%) − 500 g (24 6/7 weeks, 22 0/7 32 220] vs non-NDI: 66.2% [96 ofP 145]; 2/7 weeks) groups ( = .09). The of the 460 subjects had no disability. = .22), height < 2 SDs (72.8% [163 – Among 375 children who had − overall proportion of NDI was 59.1% of 224] vs 64.9% [96 ofP 148]; = .10), (95% CI: 54.6% 63.5%), whereas information on disabilities, 101 and BMI < 2 SDs (43.7% [83 of 190] this rate was not different between (26.9%), 57 (15.2%), 28 (7.5%), and vs 41.7% [50 of 120]; = .73) did not − the 2 subgroups. We classified 113 1 (0.3%) had a single, double, triple, differ between the 2 groups. Among and full disabilities, respectively 113 children with an HC of < 2 SDs, NICUs into the followingn 4 categories ≤ according to the number of live- (Supplemental Table 6). The profiles 12 (10.6%) and 10 (8.8%) had severe discharged infants ( = 811): <5 of 3 children with a BW of 300 g IVH and cPVL, respectively. Downloaded from www.aappublications.org/news by guest on September 28, 2021 4 INOUE et al TABLE 2 Outcomes of Survivors With a BW of ≤500 g at 3 Years of Age Outcomes Total, N = 460 ≤400 g, N = 65 401–500 g, N = 395 P na % (95% CI) na % na % NDI 272 of 460 59.1 (54.6–63.5) 44 of 65 67.7 228 of 395 57.7 .13 CP 100 of 451 22.2 (18.6–26.2) 18 of 62 29.0 82 of 389 21.1 .16 Visual impairment 94 of 442 21.3 (17.7–25.3) 16 of 62 25.8 78 of 380 20.5 .35 Hearing impairment 17 of 393 4.3 (2.7–6.8) 3 of 52 5.8 14 of 341 4.1 .58 Cognitive impairment 212 of 440 48.2 (43.5–52.8) 37 of 61 60.7 175 of 379 46.2 .04 No disability 80 of 460 17.4 (14.2–21.1) 8 of 65 12.3 72 of 395 18.2 .24 Anthropometric measurements Body wt <−2 SDs 255 of 365 69.9 (65.0–74.3) 42 of 56 75.0 213 of 309 68.9 .36 Body length <−2 SDs 259 of 372 69.6 (64.8–74.1) 44 of 57 77.2 215 of 315 68.3 .18 HC <−2 SDs 113 of 278 40.6 (35.0–46.5) 18 of 38 47.4 95 of 240 39.6 .36 BMI <−2 SDs 133 of 310 42.9 (37.5–48.5) 26 of 48 54.2 107 of 262 40.8 .09 NDI is defined as any of the following: CP, visual impairment, hearing impairment, or cognitive impairment. Cognitive impairment is defined as a DQ score of <70. No disability is defined as a DQ score of ≥85 with no CP or visual or hearing impairment. P values are obtained by using the χ2 test. a Number or number with available information.

of >1 SD. Cognitive impairment

was assessed with the Stanford-26 Binet Intelligence Scale,​ Bayley28 Scales of Infant Development-II,​

Kaufmann29 Assessment Battery for30 Children,​ or an unknown scale. This heterogeneity has limited the direct comparison of data on neurodevelopmental outcomes across studies. The variability may also be related to population coverage (single institute versus nationwide cohort), health insurance system (universal versus private), and socioeconomic conditions. A universal health care system, which FIGURE 2 is available in Japan and Canada Neurodevelopmental outcomes at 3 years of age in children with a BW of ≤500 g. Trends in the but not in the United States, may proportions of NDI (solid line) and no disability (dotted line) in children with BWs of ≤500 g during provide equal access to medical the 10 years of the study period (2003–2012) are represented by regression lines. The number of care for all the eligible newborns infants per year is shown below the graphic chart. irrespective of socioeconomic status. Different ethnicity and homogeneous DISCUSSION (Japan and Germany) or diverse We reviewed the studies on the long- ethnic backgrounds (United States ≤ and Canada) might be also critical term outcomes of surviving infants– for their neurodevelopmental In our nationwide cohort, the overall born with a BW of 500 g using the 9,28,​ 31,​ 32​ 26 30 outcomes. ‍ ‍ However, proportion of NDI at age 3 years PubMed database (Table 5). ‍ ‍ The ≤ neurodevelopmental outcomes for surviving children with a BW prevalence of neurodevelopmental ≤ among infants with a BW of of 500 g born from 2003 to 2012 outcomes varied considerably in – 500 g seem not to improve over was estimated to be 59.1% (95% these reports. One of the reasons the 3 decades. CI: 54.6% 63.5%). The proportions for the variable results is that each of children with NDI as well as no study used its own respective Brain injury is a risk for 31,33​ disability remained unchanged over scale for neurologic assessments.28 neurodevelopmental sequelae. ‍ the 10 years of the study period. For example, Vohr et al defined We confirmed that severe IVH Multivariate analysis revealed that normal neurologic examination as and cPVL had great impact on

NDI was significantly associated with no abnormalities in the physical30 neurodevelopmental outcomes severe IVH, cPVL, severe NEC, PDA assessments, and Keir et al defined among selected variables.13 As we ligation, and male sex. no or minimal disability as a DQ previously reported,​ unchanged Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 142, number 6, December 2018 5 TABLE 3 Characteristics for NDI and Non-NDI Survivors With a BW of ≤500 g at 3 Years of Age Characteristics NDI, N = 272 Non-NDI, N = 188 P targets to control in perinatal Maternal medicine.− Age ≥35 y 78 of 258 (30.2) 62 of 174 (35.6) .24 Singleton 242 of 272 (89.0) 171 of 188 (91.0) .49 HCs of < 2 SDs at age 3 years Clinical chorioamnionitis 53 of 266 (19.9) 30 of 184 (16.3) .33 were significantly associated with Antenatal corticosteroids 138 of 271 (50.9) 94 of 187 (50.3) .89 Cesarean section 207 of 272 (76.1) 152 of 187 (81.3) .19 NDI in this34 study, as previously Neonatal reported. HC can be considered35 a GA, wk 24 4/7, 22 0/7–32 2/7 25 2/7, 22 0/7–29 3/7 .04 proxy for brain volume,​ and head BW, g 456, 276–500 467, 286–500 .14 growth is affected by nutritional SGA 199 of 272 (73.2) 143 of 188 (76.1) .48 34 and nonnutritional factors. Diffuse Severely SGA 170 of 272 (62.5) 128 of 188 (68.1) .22 Boy 124 of 272 (45.6) 63 of 188 (33.5) <.01 periventricular leukomalacia is Apgar score ≥4 at 5 min 218 of 261 (83.5) 167 of 186 (89.8) .06 associated with volumetric deficits Major congenital abnormalities 6 of 272 (2.2) 5 of 188 (2.7) .75 of the cerebral cortex and thalamus33 In-hospital interventions and delayed cortical maturation. Surfactant 222 of 272 (81.6) 149 of 185 (80.5) .77 These findings support the High-frequency ventilation 189 of 269 (70.3) 124 of 184 (67.4) .52 ongoing need for more extensive Inhaled nitric oxide 25 of 265 (9.4) 15 of 178 (8.4) .72 ’ Indomethacin 191 of 272 (70.2) 128 of 186 (68.8) .75 investigations into whether the Postnatal corticosteroids 155 of 236 (65.7) 92 of 156 (59.0) .18 children s postnatal nutrition Antibiotics 234 of 270 (86.7) 150 of 182 (82.4) .22 and/or environmental distress, Neonatal morbidities besides perinatal brain injury, are Any of the following morbidities 233 of 270 (86.3) 132 of 184 (71.7) <.01 Moderate to severe BPD 165 of 268 (61.6) 90 of 182 (49.5) .01 associated with their small HC. PDA ligation 48 of 272 (17.6) 17 of 186 (9.1) .01 We have recently reported that the Severe IVH 28 of 271 (10.3) 2 of 185 (1.1) <.01 ≤ cPVL 16 of 271 (5.9) 2 of 186 (1.1) <.01 survival rate of infants with a BW Sepsis 64 of 272 (23.5) 28 of 185 (15.1) .03 of 500 g has greatly improved13 Severe NEC 28 of 272 (10.3) 7 of 188 (3.7) <.01 from 2003 to 2012 in Japan. Treatment of ROP 150 of 270 (55.6) 75 of 182 (41.2) <.01 Their survival was associated with Data presented as the number, number with available information (percentage), or as the median and range. P values are several factors, including higher obtained by using the Wilcoxon rank-sum test (continuous variables) and 2 test (dichotomous variables). χ GA and BW, and the increasing rate of antenatal steroids and cesarean TABLE 4 Factors Related to NDI in Infants With a BW of ≤500 g at 3 Years of Age delivery contributed13 to improving Crude RR (95% CI) P Adjusted RR (95% CI) P their survival rate. Notably, these advantageous factors were not Severe IVH 1.64 (1.44–1.86) <.01 1.42 (1.19–1.68) <.01 ≤ cPVL 1.53 (1.28–1.84) <.01 1.40 (1.13–1.73) <.01 shown to reduce the risk of NDI for Severe NEC 1.39 (1.16–1.68) <.01 1.31 (1.07–1.60) <.01 survivors with BWs of 500 g. The PDA ligation 1.30 (1.09–1.53) <.01 1.29 (1.09–1.54) <.01 combined outcomes of mortality Boy 1.22 (1.05 1.42) <.01 1.19 (1.01 1.40) .04 – – or morbidity can be determined Moderate to severe BPD 1.23 (1.04–1.44) .01 1.20 (0.99–1.45) .06 – Apgar score ≤3 at 5 min 1.22 (1.02–1.48) .03 1.10 (0.88–1.37) .40 for all births or live births and9 11 are Treatment of ROP 1.26 (1.08–1.47) <.01 1.09 (0.93–1.29) .29 associated with GA and BW. ‍ Postnatal corticosteroids 1.12 (0.94–1.34) .19 1.08 (0.91–1.29) .38 However, neurologic outcomes can Sepsis 1.22 (1.04–1.44) .02 1.05 (0.88–1.26) .58 only be determined for survivors to GA (per wk) 0.97 (0.93 1.01) .09 1.01 (0.97 1.06) .63 – – the age of the follow-up assessment. BW (per 100 g) 0.86 (0.74–1.00) .06 0.92 (0.78–1.07) .27 Thus, analysis of NDI might mask Risk ratios and P values are obtained from univariate and multivariate modified Poisson regression analyses. Multivariate 32 analyses include 372 subjects for whom clinical variables are completely available, and adjusted risk ratios are obtained the effects of GA or BW. The after adjusting for all covariates listed here. RR, risk ratio. dissociated results are inevitable because severely affected infants are at high risk for death before discharge. Moreover, attrition in this ≤ morbidities of brain injury among portion of very preterm infants. study might reduce the power to infants with a BW of 500 g By contrast, noncystic or diffuse detect effects of GA or BW. Because might underlie the unimproved periventricular leukomalacia is a we selected surviving infants as neurodevelopmental outcomes predominant form of brain lesion eligible subjects, we were able to add during the 10 years of our study and is not readily33 detected by variables of in-hospital interventions period. cPVL, a severe form of neuroimaging. Therefore, early and neonatal complications in cerebral white matter injury, detection and prevention of white the current study. Consequently, has been observed in a small matter injuries will be the next severe IVH and cPVL were identified Downloaded from www.aappublications.org/news by guest on September 28, 2021 6 INOUE et al ≤ nd among the survivors with BWs of

No Disability 500 g as the highest risk factors for NDI but not GA, BW, or obstetric

intervention. Given13 the improving

nd survival rates and the unchanged 61.5 30.8 35.7 57.1 41.233.3 26.3 11.1 48.2 17.4

Cognitive neurodevelopmental outcomes, Impairment the number of both survivors with NDI and those without apparent disabilities were likely to increase 7.7 7.1 4.3 22.7 10.5 11.1 b in Japan. Nonetheless, these data Hearing

Impairment provide useful information to guide the treatment of extremely small infants and social consensus, which is a goal of future research. Impairment This study has several limitations. First, the follow-up rate was 56.7%. Neurodevelopmental Outcomes Because of the low follow-up rate, we failed to count the number of infants who died after discharge. –

NDI CP Visual In fact, the rates in drop-off were

commonly high (30% 36%)21,22​ in previous NRNJ studies. ‍ One of

32 69.2 nd 46.2 15.9 15.3 9.1 the reasons might be that not all

Age at infants were followed-up at the Evaluation, y same hospitals from which they f f e were discharged. Therefore, their

SGA follow-up data were not recovered to a level comparable to those in former

d reports from other countries. Three

Rate perinatal parameters (congenital Follow-up abnormalities, high-frequency

c ventilation, and antibiotics use) 9 64.3 88.9 3 88.9 33.3 22.2 n 13 72.2 94.4 14 77.8 73.3 1.5 nd 28.6 21.4 44 72.1 90.2 460 56.7 74.3 3 59.1 22.2 21.3 revealed significant differences

a between the study population and

≤ 500 g the nonevaluated survivors (Table 1). 48 26 nd 212 113 1473 <501 g 19 65.5 94.7 5 52.6 36.8 26.3 ≤ 500 g ≤ 500 g ≤ 500 g ≤ 500 g Two of these differences suggest

Population n the study population is sicker than the population without follow-up; therefore, the rate of NDI may be overestimated for the former. Second, 1983 – 1994 1993 – 1994 401 – 500 g 1989 – 2009 2005 – 2010 2003 – 2012 1998 – 2001

Year of Birth there is no information on receiving the mode of active treatment. Therefore, neurodevelopmental outcomes in this study might be better than those for all births or live births. The third limitation is the lack of comparison with term- born infants, which may introduce Canada (Single center) Unites States (Regional cohort) (Multicenter) Unites States Australia (3 centers) (Single center) Germany (Nationwide cohort) expectation bias. However, the NDI  Neurodevelopmental Outcomes of Infants With a BW rate at age 3 years in this study was – higher than those of children with – 25 ‍ ‍ 27 Ref. No. Location (Type of Study) ‍ ‍ 26 29 This study Japan ‍ 28 Neurodevelopmental outcomes data are expressed as the percentage of evaluated infants. Note that the definitions of each outcome are different in study. Neurodevelopmental outcomes data are expressed as the percentage of evaluated infants. Note from NICUs. Follow-up rates are expressed as percentages and calculated by dividing the number of surviving and evaluated infants by the total number of survivals to discharge Number of live-born infants who are admitted to NICUs. Data are expressed as percentages of surviving and evaluated infants. Number of surviving and evaluated infants. Data are expressed as percentages of all surviving infants. nd, not described. a b c d e f TABLE 5 a BW of >500 g (501 750 g, 36.3%;

751 1000 g,21 20.1%) in a previous NRNJ study. Lastly, other Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 142, number 6, December 2018 7 prognostic factors for Hospital, Tsukuba University, Hospital, Niigata University, Niigata ’ neurodevelopmental disability Tsuchiura Kyodo Hospital, Ibaraki Prefectural Central Hospital, Niigata such as parental education level, Children s Hospital, Dokkyo Medical Municipal Hospital, Nagaoka Red erythropoietin treatment, aggressive University, Jichi Medical University, Cross Hospital, Koseiren Takaoka ’ nutritional support, and specific Ashikaga Red Cross Hospital, Gunma Hospital, Toyama Prefectural strategies of ventilation32 and steroids Children s Medical Center, Kiryu Central Hospital, Toyama University, administration were not analyzed. Kosei General Hospital, Fuji Heavy Ishikawa Medical Center for Maternal Identifying the key environmental Industries Health Insurance Society and Child Health, Kanazawa Medical ’ factors among these variables will Ota Memorial Hospital, Gunma University, Kanazawa Medical further unveil the potential targets University, Saitama Children s Center, Fukui Prefectural Hospital, of intervention for extremely small Medical Center, Nishisaitama-chuo Fukui University, Gifu Prefectural infants. National Hospital, Saitama Medical General Medical Center, National CONCLUSIONS University Saitama Medical Center, Hospital Organization Nagara Kawaguchi Municipal Medical Center, Medical Center, Takayama Red Cross Hospital, Seirei Hamamatsu Jichi Medical University Saitama ’ Medical Center, Asahi General Hospital, Shizuoka Saiseikai Hospital, Neurodevelopmental outcomes in ≤ Hospital, Chiba Kaihin Municipal Shizuoka Children s Hospital, early childhood among surviving ’ Hospital, Kameda Medical Center, Hamamatsu Medical University, infants with a BW of 500 g did Tokyo Women s Medical University Numazu Municipal Hospital, Yaizu not improve in a recent decade. Yachiyo Medical Center, Juntendo City Hospital, Fujieda Municipal In this large-population study, we ’ University Urayasu Hospital, Tokyo General Hospital, Nagoya Red Cross verified that perinatal brain injury ’ Metropolitan Children s Medical Daini Hospital, Nagoya University, was an unfavorable risk factor for Center, Tokyo Women s Medical Nagoya Red Cross Daiichi Hospital, NDI. Changes in medical management University, Aiiku Hospital, Nihon Toyohashi Municipal Hospital, that are able to ameliorate brain University Itabashi Hospital, National Nagoya City West Medical Center, injury would be expected to reduce Center for Global Health and Anjo kosei Hospital, Tosei General adverse neurodevelopmental Medicine, Tokyo Medical University, Hospital, Komaki Municipal Hospital, burdens for extremely small Teikyo University, Showa University, TOYOTA Memorial Hospital, Okazaki infants. Japan Red Cross Medical Center, Municipal Hospital, Konan Kosei ACKNOWLEDGMENTS National Center for Child Health and Hospital, National Mie Central Development, Tokyo Metropolitan Medical Center, Ise Red Cross Otsuka Hospital, Toho University, Hospital, Yokkaichi Municipal Institutions enrolled in the study of Tokyo Metropolitan Bokuto Hospital, Hospital, Otsu Red Cross Hospital, Tokyo Jikei Medical University, Shiga University of Medical Science the NRNJ were as follows: Sapporo ’ City General Hospital, Asahikawa Tokyo Medical and Dental University, Hospital, Nagahama Red Cross Kosei General Hospital, Engaru- Saint Luke s International Hospital, Hospital, Uji Tokushukai Hospital, Kosei General Hospital, Kushiro Juntendo University, Sanikukai The Japan Baptist Hospital, Kyoto Red Cross Hospital, Obihiro-Kosei Hospital, Katsushika Red Cross University, Kyoto Red Cross Daiichi General Hospital, Tenshi Hospital, Hospital, Yokohama Rosai Hospital, Hospital, National Maizuru Medical NTT Higashinihon Sapporo Hospital, Yokohama City University Medical Center, Fukuchiyama City Hospital, Center, St. Marianna University Kyoto Prefectural University of Nikko Memorial Hospital, Nayoro City ’ General Hospital, Sapporo Medical School of Medicine Hospital, Medicine Hospital, Kyoto City University, Asahikawa Medical Kanagawa Children s Medical Center, Hospital, Mitsubishi Kyoto Hospital, University, Aomori Prefectural Tokai University, Kitazato University, Yodogawa Christian Hospital, Central Hospital, Iwate Medical Odawara Municipal Hospital, Nippon Osaka Medical Center and Research University, Iwate Prefectural Ofunato Medical School Musashi Kosugi Institute for Maternal and Child Hospital, Iwate Prefectural Kuji Hospital, Saiseikai Yokohamashi Health, Osaka University, Takatsuki Hospital, Iwate Prefectural Ninohe Tobu Hospital, National Hospital General Hospital, Kansai Medical Organization Yokohama Medical University, Osaka City General Hospital, Sendai Red Cross Hospital, ’ Akita Red Cross Hospital, Tsuruoka Center, Yamanashi Prefectural Hospital, Osaka City Sumiyoshi Municipal Shonai Hospital, Yamagata Central Hospital, Nagano Children s Hospital, Aizenbashi Hospital, University, Yamagata Prefectural Hospital, Shinshu University, Toyonaka Municipal Hospital, Central Hospital, Fukushima Iida Municipal Hospital, National National Cerebral and Cardiovascular Medical University, Takeda General Hospital Organization Shinshu Center, Kitano Hospital, Saiseikai Hospital, Fukushima National Ueda Medical Center, Saku General Suita Hospital, Chifune Hospital, Downloaded from www.aappublications.org/news by guest on September 28, 2021 8 INOUE et al ’

Bellland General Hospital, Rinku Yamaguchi University, Yamaguchi and Children s Medical Center, General Medical Center, Osaka Grand Medical Center, Tokushima Okinawa Prefectural Chubu Hospital, Red Cross Hospital, Yao Municipal University, Tokushima Municipal Naha City Hospital, Okinawa Red Hospital, Osaka General Medical Hospital, Kagawa University, National Cross Hospital. ’ ’ Center, Osaka City University, Hyogo Hospital Organization Kagawa Prefectural Kobe Children s Hospital, Children s Hospital, Matsuyama Red ABBREVIATIONS Kobe University, Kakogawa West Cross Hospital, Ehime Prefectural ’ City Hospital, Saiseikai Hyogoken Central Hospital, Kochi Health Hospital, Kobe City Medical Center Science Center, St. Mary s Hospital, BPD: bronchopulmonary General Hospital, Hyogo College of National Kyushu Medical Center, dysplasia Medicine Hospital, Himeji Red Cross Kurume University, Kitakyushu BW: birth weight Hospital, Toyooka Public Hospital, Municipal Medical Center, University CI: confidence interval Hyogo Prefectural Awaji Medical of Occupational and Environmental CP: cerebral palsy Center, Nara Medical University, Health, Fukuoka University, Kyushu cPVL: cystic periventricular Wakayama Medical University, University, Iizuka Hospital, National leukomalacia Tottori Prefectural Central Hospital, Hospital Organization Kokura DQ: developmental quotient Tottori University, Shimane Medical Center, National Hospital GA: gestational age Prefectural Central Hospital, Matsue Organization Saga Hospital, National HC: head circumference Red Cross Hospital, Kurashiki Central Hospital Organization Nagasaki IVH: intraventricular Hospital, Tsuyama Central Hospital, Medical Center, Kumamoto City hemorrhage Kawasaki Medical School Hospital, Hospital, Kumamoto University, NDI: neurodevelopmental National Hospital Organization Oita Prefectural Hospital, Almeida impairment Okayama Medical Center, Okayama Memorial Hospital, Nakatsu NEC: necrotizing enterocolitis Red Cross Hospital, Hiroshima Municipal Hospital, Miyazaki NRNJ: Neonatal Research City Hiroshima Citizens Hospital, University, National Hospital Network of Japan Hiroshima Prefectural Hospital, Organization Miyakonojo Medical PDA: patent ductus arteriosus Hiroshima University, Tsuchiya Center, Kagoshima City Hospital, ROP: retinopathy of prematurity General Hospital, National Hospital Imakiire General Hospital, Okinawa SGA: small for gestational age Organization Kure Medical Center, Prefectural Nanbu Medical Center Address correspondence to Hirosuke Inoue, MD, PhD, Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi- ku, Fukuoka 812-8582, Japan. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2018 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: Funded in part by JSPS KAKENHI grant JP17K16300 (Dr Inoue), JP15K09717 (Dr Ochiai), and JP16K19688 (Dr Fujiyoshi). POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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Downloaded from www.aappublications.org/news by guest on September 28, 2021 10 INOUE et al Neurodevelopmental Outcomes in Infants With Birth Weight ≤500 g at 3 Years of Age Hirosuke Inoue, Masayuki Ochiai, Yasunari Sakai, Kazuaki Yasuoka, Koichi Tanaka, Masako Ichiyama, Hiroaki Kurata, Junko Fujiyoshi, Yuki Matsushita, Satoshi Honjo, Kazuaki Nonaka, Tomoaki Taguchi, Kiyoko Kato, Shouichi Ohga and on behalf of the Neonatal Research Network of Japan Pediatrics 2018;142; DOI: 10.1542/peds.2017-4286 originally published online November 16, 2018;

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Downloaded from www.aappublications.org/news by guest on September 28, 2021 Neurodevelopmental Outcomes in Infants With Birth Weight ≤500 g at 3 Years of Age Hirosuke Inoue, Masayuki Ochiai, Yasunari Sakai, Kazuaki Yasuoka, Koichi Tanaka, Masako Ichiyama, Hiroaki Kurata, Junko Fujiyoshi, Yuki Matsushita, Satoshi Honjo, Kazuaki Nonaka, Tomoaki Taguchi, Kiyoko Kato, Shouichi Ohga and on behalf of the Neonatal Research Network of Japan Pediatrics 2018;142; DOI: 10.1542/peds.2017-4286 originally published online November 16, 2018;

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