OBJECTIVES:

To determine neurodevelopmental outcomes at 3 years of age in children born with a birth weight (BW) of ≤500 g.

METHODS:

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 developmental quotient score of <70.

RESULTS:

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. In a multivariate modified Poisson regression analysis, NDI was associated with severe intraventricular hemorrhage (adjusted risk ratio [RR]: 1.42; 95% CI: 1.19–1.68; P < .01), cystic periventricular leukomalacia (adjusted RR: 1.40; 95% CI: 1.13–1.73; P < .01), severe necrotizing enterocolitis (adjusted RR: 1.31; 95% CI: 1.07–1.60; P < .01), surgical ligation for patent ductus arteriosus (adjusted RR: 1.29; 95% CI: 1.09–1.54; P < .01), and male sex (adjusted RR: 1.19; 95% CI: 1.01–2.40; P = .04).

CONCLUSIONS:

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 g has improved considerably in Japan; however, few studies have revealed the neurodevelopmental outcomes of survivors born with a BW of ≤500 g.

What This Study Adds:

Neurodevelopmental outcomes in early childhood among surviving infants born with a BW of ≤500 g did not improve in a recent decade.

Advances in perinatal and neonatal intensive care have improved the survival rate of periviable, or extremely preterm, infants near the limit of viability.1,3 On the other hand, researchers in recent studies have reported decreasing,4 unchanged,5 or increasing rates6,7 in neurodevelopmental disabilities among periviable infants who survive compared with previous decades. These variable data lead to a concern that increased survival may come at the cost of later neurodevelopmental disabilities among survivors.8 Thus, providing accurate data on both mortality and long-term neurodevelopmental outcomes is important for families and professionals in neonatal care in making appropriate decisions for these high-risk infants.9 

Gestational age (GA) and birth weight (BW), alone or combined, are the critical factors that affect the survival rate of extremely preterm and small infants.9,11 Early ultrasound assessment provides an accurate estimation of GA in most cases, but it is also known to cause an error as high as ±15%.12 On the other hand, BW is a direct measurement of the body size of offspring. We have recently shown favorable results of survival rates for infants with a BW of ≤500 g in Japan, whereas in-hospital morbidity rates have remained high in the last decade.13 We extended this study because the long-term outcomes of the infants with a BW of ≤500 g were currently unavailable. In the current study, we investigate neurodevelopmental outcomes at 3 years of age for surviving children born with a BW of ≤500 g using the nationwide cohort database in Japan.

The Neonatal Research Network of Japan (NRNJ) database prospectively registered all of the clinical information of infants with a BW of ≤1500 g admitted to the 204 participating NICUs, accounting for 54.3% of 376 secondary and tertiary-level NICUs in Japan. The participants in this study were born between January 1, 2003, and December 31, 2012. Decisions regarding the pursuit of active treatment versus comfort care were made by neonatologists on the basis of fetal information, the status of the infants at birth, and their communications with the parents. In general, attending neonatologists attempt to save the lives of neonates at a GA of ≥23 weeks, and this principle has not changed during the study period. The perinatal data were collected as previously described.13 Children who were born with a BW of ≤500 g and survived to discharge from the NICU were included in this study. We excluded the infants who had died in the operating or delivery room before admission to the NICU, those transferred to other hospitals, those born at a GA of <22 weeks, and those without available records of mortality during the NICU stay. Chorioamnionitis was diagnosed clinically. Antenatal use of corticosteroids was defined as the administration of corticosteroids to the mother at any time before delivery. In most cases, GA was calculated from the date of the last menstrual period and verified by the fetal crown-rump length on ultrasonography in the first trimester. However, their menstrual histories or ultrasonographic findings were not recorded in the database. Small for gestational age (SGA) and severely SGA were defined as a BW but not intrauterine fetal weight of less than the 10th and third percentiles for the GA, respectively.14 Major congenital abnormalities were defined as chromosomal abnormalities, congenital heart defects, intestinal atresia, renal hypoplasia, skeletal dysplasia, and inborn errors of metabolism. Nitric oxide inhalation was applied for pulmonary hypertension. Systemic postnatal corticosteroid was used to treat bronchopulmonary dysplasia (BPD) or refractory hypotension. Moderate to severe BPD was defined as the need for supplemental oxygen or positive pressure at 36 weeks’ postmenstrual age.15 Treatment with indomethacin or surgical ligation was conducted for closures of patent ductus arteriosus (PDA) diagnosed clinically and by echocardiography. Severe intraventricular hemorrhage (IVH) was defined as grade III or IV.16 Cystic periventricular leukomalacia (cPVL) was diagnosed by cranial ultrasound or head MRI. Sepsis was defined as culture-proven septicemia or bacteremia during the NICU stay. Severe necrotizing enterocolitis (NEC) was defined as pneumoperitoneum or Bell stage ≥2.17 Retinopathy of prematurity (ROP) was coded if treatment was required with laser coagulation or cryocoagulation. This study was approved by the Internal Review Board of Tokyo Women’s Medical University. Written informed consent was obtained from the parents or guardians of all infants in the NRNJ.

Our primary objective in this study was to determine neurodevelopmental impairment (NDI) in surviving children with a BW of ≤500 g at 3 years of age. NDI was defined as the following conditions: cerebral palsy (CP), visual impairment, hearing impairment, or cognitive impairment. Comprehensive neurodevelopmental and growth assessments were performed on the surviving children at 36 to 42 months of chronological age at each participating institute. According to the protocol of the Japanese Society for Follow-up Study of High-Risk Infants,18 the postnatal development and growth of the surviving children were assessed at 18 months of corrected age and at 3, 6, and 9 years of chronological age. During these periods, parents were advised to follow periodic 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 abnormal control of movement and posture,19 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-scoring system written in Japanese.20 The test was available at all participating institutes and was performed by certified psychologists who were trained to assess childhood development under blinding to perinatal histories at each institute.21,22 Interscorer reliability was not examined. According to the protocol, developmental function was categorized as delayed (DQ <70), subnormal (DQ 70–84), and normal (DQ ≥85). No disability was defined as a DQ score of ≥85 with no CP or visual or hearing impairment. Height, weight, head circumference (HC), and BMI SD scores were calculated by using Japanese reference values for sex and age.23,24 

Data were analyzed by using JMP 11.0 (SAS Institute, Inc, Cary, NC) and Stata 14.2 (Stata Corp, College Station, TX). Results with a 2-sided P value of <.05 were considered significant. Continuous and categorical variables were compared by using Wilcoxon rank sum tests and χ2 tests, respectively. The Cochran-Armitage test was used to assess temporal trends. Risks of NDI were calculated with modified Poisson regression analysis.25 We included in the regression model all factors of neonatal characteristics, in-hospital interventions, and neonatal morbidities from univariate analysis with a P value of <.2. Adjusted risk ratios (with 95% confidence intervals [CIs]) were calculated.

A total of 1613 live-born infants with a BW of ≤500 g were registered in the NRNJ database.13 Of these, the following infants were excluded: 44 infants who were not admitted to the NICU, 71 infants who were transferred to other hospitals, 3 infants born at a GA of <22 weeks, and 22 infants without records of mortality status. Of 1473 live-born infants with a BW of ≤500 g at a GA of ≥22 weeks who were treated in the NICUs, 662 infants were excluded because of death during the NICU stay. Consequently, 811 children discharged from 113 NICUs were considered eligible to participate in a follow-up evaluation at age 3 years. These children were born at a median GA of 24 6/7 (range: 22 0/7–33 2/7) weeks and BW of 462 (267–500) g. The study population finally consisted of 460 children (56.7%) in 78 NICUs who had recorded data of NDI at 3 years of age (median 37 months; Fig 1). The NRNJ database includes information concerning visual and hearing impairments (presence or absence) for 442 (96.1%) and 393 (85.4%) children, respectively. Drop-off children included 323 who were lost during the follow-up period and 28 whose follow-up data were missing at age 3 years.

FIGURE 1

Patient enrollment. Our study population consisted of all children with a BW of ≤500 g and GA of ≥22 weeks who survived from the affiliated NICUs. VLBW, very low birth weight.

FIGURE 1

Patient enrollment. Our study population consisted of all children with a BW of ≤500 g and GA of ≥22 weeks who survived from the affiliated NICUs. VLBW, very low birth weight.

Close modal

To determine if the study population represented the whole eligible population, baseline characteristics from the study population (n = 460) were compared with the nonevaluated children (n = 351; Table 1). There were significant but small differences in the proportions of major congenital abnormalities, high-frequency ventilation, and antibiotics use.

TABLE 1

Demographics for Surviving Infants With a BW of ≤500 g

Study Population, N = 460Not Evaluated, N = 351P
Maternal    
 Age ≥35 y 140 of 432 (32.4) 122 of 340 (35.9) .31 
 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 
 Antenatal corticosteroids 232 of 458 (50.7) 178 of 345 (51.6) .79 
 Cesarean delivery 359 of 459 (78.2) 268 of 345 (77.7) .86 
Neonatal    
 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 
 SGA 342 of 460 (74.3) 259 of 351 (73.8) .86 
 Severely SGA 298 of 460 (64.8) 223 of 351 (63.5) .71 
 Boy 187 of 460 (40.7) 158 of 351 (45.0) .21 
 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 
 High-frequency ventilation 313 of 453 (69.1) 211 of 340 (62.1) .04 
 Inhaled nitric oxide 40 of 443 (9.0) 31 of 332 (9.3) .88 
 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 
 Antibiotics 384 of 452 (85.0) 306 of 341 (89.7) .047 
Neonatal morbidities    
 Any of the following morbidities 365 of 454 (80.4) 283 of 342 (82.7) .40 
 Moderate to severe BPD 255 of 450 (56.7) 197 of 335 (58.8) .55 
 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 
 cPVL 18 of 457 (3.9) 13 of 344 (3.8) .91 
 Sepsis 92 of 457 (20.1) 71 of 344 (20.6) .86 
 Severe NEC 35 of 460 (7.6) 30 of 351 (8.5) .63 
 Treatment of ROP 225 of 452 (49.8) 157 of 339 (46.3) .33 
Study Population, N = 460Not Evaluated, N = 351P
Maternal    
 Age ≥35 y 140 of 432 (32.4) 122 of 340 (35.9) .31 
 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 
 Antenatal corticosteroids 232 of 458 (50.7) 178 of 345 (51.6) .79 
 Cesarean delivery 359 of 459 (78.2) 268 of 345 (77.7) .86 
Neonatal    
 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 
 SGA 342 of 460 (74.3) 259 of 351 (73.8) .86 
 Severely SGA 298 of 460 (64.8) 223 of 351 (63.5) .71 
 Boy 187 of 460 (40.7) 158 of 351 (45.0) .21 
 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 
 High-frequency ventilation 313 of 453 (69.1) 211 of 340 (62.1) .04 
 Inhaled nitric oxide 40 of 443 (9.0) 31 of 332 (9.3) .88 
 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 
 Antibiotics 384 of 452 (85.0) 306 of 341 (89.7) .047 
Neonatal morbidities    
 Any of the following morbidities 365 of 454 (80.4) 283 of 342 (82.7) .40 
 Moderate to severe BPD 255 of 450 (56.7) 197 of 335 (58.8) .55 
 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 
 cPVL 18 of 457 (3.9) 13 of 344 (3.8) .91 
 Sepsis 92 of 457 (20.1) 71 of 344 (20.6) .86 
 Severe NEC 35 of 460 (7.6) 30 of 351 (8.5) .63 
 Treatment of ROP 225 of 452 (49.8) 157 of 339 (46.3) .33 

Data presented as the number, number with available information (percentage), or as the median and range. P values are obtained by using the Wilcoxon rank-sum test (continuous variables) and χ2 test (dichotomous variables).

We analyzed neurodevelopmental and growth outcomes of the study population (n = 460) and compared these profiles between the subgroups with BWs of ≤400 g (n = 65) and 401 to 500 g (n = 395; Table 2). The GA did not differ between the BW ≤400 g (median: 25 0/7 weeks; range: 22 0/7–30 2/7 weeks) and 401 to 500 g (24 6/7 weeks, 22 0/7–32 2/7 weeks) groups (P = .09). The overall proportion of NDI was 59.1% (95% CI: 54.6%–63.5%), whereas this rate was not different between the 2 subgroups. We classified 113 NICUs into the following 4 categories according to the number of live-discharged infants (n = 811): <5 (n = 110 in 52 NICUs), 5 to 10 (267 in 36), 11 to 20 (219 in 16), and ≥21 (215 in 9). The proportions of NDI in the study population (n = 460) were not different among these 4 categories (69.6%, 52.4%, 62.6%, and 57.3%, respectively; P = .14). The DQ scores were missing in 20 (4.3%) of 460 eligible subjects. Children with a BW of 401 to 500 g had a lower proportion of cognitive impairment than those with a BW of ≤400 g, whereas other neurodevelopmental outcomes did not differ between them. Overall, 80 children (17.4%) of the 460 subjects had no disability. Among 375 children who had information on disabilities, 101 (26.9%), 57 (15.2%), 28 (7.5%), and 1 (0.3%) had a single, double, triple, and full disabilities, respectively (Supplemental Table 6). The profiles of 3 children with a BW of ≤300 g are shown in Supplemental Table 7. NDI and no disability remained unchanged in their prevalence (P = .70 and .78 for trend, respectively; Fig 2). The proportions of children with <−2 SDs of weight, height, HC, and BMI were 69.9%, 69.6%, 40.6%, and 42.9%, respectively (Table 2). There was no difference in anthropometric measurements between the BW subgroups.

TABLE 2

Outcomes of Survivors With a BW of ≤500 g at 3 Years of Age

OutcomesTotal, N = 460≤400 g, N = 65401–500 g, N = 395P
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 
OutcomesTotal, N = 460≤400 g, N = 65401–500 g, N = 395P
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.

FIGURE 2

Neurodevelopmental outcomes at 3 years of age in children with a BW of ≤500 g. Trends in the proportions of NDI (solid line) and no disability (dotted line) in children with BWs of ≤500 g during the 10 years of the study period (2003–2012) are represented by regression lines. The number of infants per year is shown below the graphic chart.

FIGURE 2

Neurodevelopmental outcomes at 3 years of age in children with a BW of ≤500 g. Trends in the proportions of NDI (solid line) and no disability (dotted line) in children with BWs of ≤500 g during the 10 years of the study period (2003–2012) are represented by regression lines. The number of infants per year is shown below the graphic chart.

Close modal

In Table 3, we present the perinatal and neonatal characteristics of children with NDI (n = 272) and non-NDI (n = 188). The median GA (24 4/7 weeks) of children with NDI was lower than that of children with non-NDI (25 2/7 weeks; P = .04). The children with NDI included significantly higher proportions of boys and all neonatal morbidities. Other characteristics such as BW, SGA, severe SGA, congenital abnormalities, and in-hospital interventions did not differ between them. Multivariate regression analysis revealed that NDI was significantly associated with severe IVH, cPVL, severe NEC, PDA ligation, and male sex (Table 4). We found the essentially same relations between the clinical variable and risk for developing multiple disabilities (Supplemental Table 8). Among 442 children without severe IVH or cPVL, 256 (57.9%) infants developed NDI. Anthropometric data revealed that 47.4% (82 of 173) of children with NDI had an HC of <−2 SDs, which was higher than that (29.5%, 31 of 105) of children with non-NDI (P < .01). Proportions of weight <−2 SDs (children with NDI: 72.3% [159 of 220] vs non-NDI: 66.2% [96 of 145]; P = .22), height <−2 SDs (72.8% [163 of 224] vs 64.9% [96 of 148]; P = .10), and BMI <−2 SDs (43.7% [83 of 190] vs 41.7% [50 of 120]; P = .73) did not differ between the 2 groups. Among 113 children with an HC of <−2 SDs, 12 (10.6%) and 10 (8.8%) had severe IVH and cPVL, respectively.

TABLE 3

Characteristics for NDI and Non-NDI Survivors With a BW of ≤500 g at 3 Years of Age

CharacteristicsNDI, N = 272Non-NDI, N = 188P
Maternal    
 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 
 Clinical chorioamnionitis 53 of 266 (19.9) 30 of 184 (16.3) .33 
 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 
Neonatal    
 GA, wk 24 4/7, 22 0/7–32 2/7 25 2/7, 22 0/7–29 3/7 .04 
 BW, g 456, 276–500 467, 286–500 .14 
 SGA 199 of 272 (73.2) 143 of 188 (76.1) .48 
 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 
 Apgar score ≥4 at 5 min 218 of 261 (83.5) 167 of 186 (89.8) .06 
 Major congenital abnormalities 6 of 272 (2.2) 5 of 188 (2.7) .75 
In-hospital interventions    
 Surfactant 222 of 272 (81.6) 149 of 185 (80.5) .77 
 High-frequency ventilation 189 of 269 (70.3) 124 of 184 (67.4) .52 
 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 
 Postnatal corticosteroids 155 of 236 (65.7) 92 of 156 (59.0) .18 
 Antibiotics 234 of 270 (86.7) 150 of 182 (82.4) .22 
Neonatal morbidities    
 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 
 PDA ligation 48 of 272 (17.6) 17 of 186 (9.1) .01 
 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 
 Sepsis 64 of 272 (23.5) 28 of 185 (15.1) .03 
 Severe NEC 28 of 272 (10.3) 7 of 188 (3.7) <.01 
 Treatment of ROP 150 of 270 (55.6) 75 of 182 (41.2) <.01 
CharacteristicsNDI, N = 272Non-NDI, N = 188P
Maternal    
 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 
 Clinical chorioamnionitis 53 of 266 (19.9) 30 of 184 (16.3) .33 
 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 
Neonatal    
 GA, wk 24 4/7, 22 0/7–32 2/7 25 2/7, 22 0/7–29 3/7 .04 
 BW, g 456, 276–500 467, 286–500 .14 
 SGA 199 of 272 (73.2) 143 of 188 (76.1) .48 
 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 
 Apgar score ≥4 at 5 min 218 of 261 (83.5) 167 of 186 (89.8) .06 
 Major congenital abnormalities 6 of 272 (2.2) 5 of 188 (2.7) .75 
In-hospital interventions    
 Surfactant 222 of 272 (81.6) 149 of 185 (80.5) .77 
 High-frequency ventilation 189 of 269 (70.3) 124 of 184 (67.4) .52 
 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 
 Postnatal corticosteroids 155 of 236 (65.7) 92 of 156 (59.0) .18 
 Antibiotics 234 of 270 (86.7) 150 of 182 (82.4) .22 
Neonatal morbidities    
 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 
 PDA ligation 48 of 272 (17.6) 17 of 186 (9.1) .01 
 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 
 Sepsis 64 of 272 (23.5) 28 of 185 (15.1) .03 
 Severe NEC 28 of 272 (10.3) 7 of 188 (3.7) <.01 
 Treatment of ROP 150 of 270 (55.6) 75 of 182 (41.2) <.01 

Data presented as the number, number with available information (percentage), or as the median and range. P values are obtained by using the Wilcoxon rank-sum test (continuous variables) and χ2 test (dichotomous variables).

TABLE 4

Factors Related to NDI in Infants With a BW of ≤500 g at 3 Years of Age

Crude RR (95% CI)PAdjusted RR (95% CI)P
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 
Severe NEC 1.39 (1.16–1.68) <.01 1.31 (1.07–1.60) <.01 
PDA ligation 1.30 (1.09–1.53) <.01 1.29 (1.09–1.54) <.01 
Boy 1.22 (1.05–1.42) <.01 1.19 (1.01–1.40) .04 
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 
Treatment of ROP 1.26 (1.08–1.47) <.01 1.09 (0.93–1.29) .29 
Postnatal corticosteroids 1.12 (0.94–1.34) .19 1.08 (0.91–1.29) .38 
Sepsis 1.22 (1.04–1.44) .02 1.05 (0.88–1.26) .58 
GA (per wk) 0.97 (0.93–1.01) .09 1.01 (0.97–1.06) .63 
BW (per 100 g) 0.86 (0.74–1.00) .06 0.92 (0.78–1.07) .27 
Crude RR (95% CI)PAdjusted RR (95% CI)P
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 
Severe NEC 1.39 (1.16–1.68) <.01 1.31 (1.07–1.60) <.01 
PDA ligation 1.30 (1.09–1.53) <.01 1.29 (1.09–1.54) <.01 
Boy 1.22 (1.05–1.42) <.01 1.19 (1.01–1.40) .04 
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 
Treatment of ROP 1.26 (1.08–1.47) <.01 1.09 (0.93–1.29) .29 
Postnatal corticosteroids 1.12 (0.94–1.34) .19 1.08 (0.91–1.29) .38 
Sepsis 1.22 (1.04–1.44) .02 1.05 (0.88–1.26) .58 
GA (per wk) 0.97 (0.93–1.01) .09 1.01 (0.97–1.06) .63 
BW (per 100 g) 0.86 (0.74–1.00) .06 0.92 (0.78–1.07) .27 

Risk ratios and P values are obtained from univariate and multivariate modified Poisson regression analyses. Multivariate analyses include 372 subjects for whom clinical variables are completely available, and adjusted risk ratios are obtained after adjusting for all covariates listed here. RR, risk ratio.

In our nationwide cohort, the overall proportion of NDI at age 3 years for surviving children with a BW of ≤500 g born from 2003 to 2012 was estimated to be 59.1% (95% CI: 54.6%–63.5%). The proportions of children with NDI as well as no disability remained unchanged over the 10 years of the study period. Multivariate analysis revealed that NDI was significantly associated with severe IVH, cPVL, severe NEC, PDA ligation, and male sex.

We reviewed the studies on the long-term outcomes of surviving infants born with a BW of ≤500 g using the PubMed database (Table 5).26,30 The prevalence of neurodevelopmental outcomes varied considerably in these reports. One of the reasons for the variable results is that each study used its own respective scale for neurologic assessments. For example, Vohr et al28 defined normal neurologic examination as no abnormalities in the physical assessments, and Keir et al30 defined no or minimal disability as a DQ of >1 SD. Cognitive impairment was assessed with the Stanford-Binet Intelligence Scale,26 Bayley Scales of Infant Development-II,28 Kaufmann Assessment Battery for Children,29 or an unknown scale.30 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 is available in Japan and Canada but not in the United States, may provide equal access to medical care for all the eligible newborns irrespective of socioeconomic status. Different ethnicity and homogeneous (Japan and Germany) or diverse ethnic backgrounds (United States and Canada) might be also critical for their neurodevelopmental outcomes.9,28,31,32 However, neurodevelopmental outcomes among infants with a BW of ≤500 g seem not to improve over the 3 decades.

TABLE 5

Neurodevelopmental Outcomes of Infants With a BW of ≤500 g

Ref. No.Location (Type of Study)Year of BirthPopulation naNeurodevelopmental Outcomesb
ncFollow-up RatedSGAeAge at Evaluation, yNDICPVisual ImpairmentHearing ImpairmentCognitive ImpairmentNo Disability
25  Canada 1983–1994 ≤500 g 13 72.2 94.4f 69.2 46.2 15.3 7.7 61.5 30.8 
 (Regional cohort)  113           
26  Unites States 1989–2009 ≤500 g 44 72.1 90.2f nd 15.9 9.1 22.7 nd nd 
 (Single center)  212           
27  Unites States 1993–1994 401–500 g 14 77.8 73.3 1.5 nd 28.6 21.4 7.1 35.7 57.1 
 (Multicenter)  nd           
28  Germany 1998–2001 <501 g 19 65.5 94.7 52.6 36.8 26.3 10.5 41.2 26.3 
 (3 centers)  48           
29  Australia 2005–2010 ≤500 g 64.3 88.9 88.9 33.3 22.2 11.1 33.3 11.1 
 (Single center)  26           
This study Japan 2003–2012 ≤500 g 460 56.7 74.3 59.1 22.2 21.3 4.3 48.2 17.4 
 (Nationwide cohort)  1473           
Ref. No.Location (Type of Study)Year of BirthPopulation naNeurodevelopmental Outcomesb
ncFollow-up RatedSGAeAge at Evaluation, yNDICPVisual ImpairmentHearing ImpairmentCognitive ImpairmentNo Disability
25  Canada 1983–1994 ≤500 g 13 72.2 94.4f 69.2 46.2 15.3 7.7 61.5 30.8 
 (Regional cohort)  113           
26  Unites States 1989–2009 ≤500 g 44 72.1 90.2f nd 15.9 9.1 22.7 nd nd 
 (Single center)  212           
27  Unites States 1993–1994 401–500 g 14 77.8 73.3 1.5 nd 28.6 21.4 7.1 35.7 57.1 
 (Multicenter)  nd           
28  Germany 1998–2001 <501 g 19 65.5 94.7 52.6 36.8 26.3 10.5 41.2 26.3 
 (3 centers)  48           
29  Australia 2005–2010 ≤500 g 64.3 88.9 88.9 33.3 22.2 11.1 33.3 11.1 
 (Single center)  26           
This study Japan 2003–2012 ≤500 g 460 56.7 74.3 59.1 22.2 21.3 4.3 48.2 17.4 
 (Nationwide cohort)  1473           

nd, not described.

a

Number of live-born infants who are admitted to NICUs.

b

Neurodevelopmental outcomes data are expressed as the percentage of evaluated infants. Note that the definitions of each outcome are different in each study.

c

Number of surviving and evaluated infants.

d

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 from NICUs.

e

Data are expressed as percentages of surviving and evaluated infants.

f

Data are expressed as percentages of all surviving infants.

Brain injury is a risk for neurodevelopmental sequelae.31,33 We confirmed that severe IVH and cPVL had great impact on neurodevelopmental outcomes among selected variables. As we previously reported,13 unchanged morbidities of brain injury among infants with a BW of ≤500 g might underlie the unimproved neurodevelopmental outcomes during the 10 years of our study period. cPVL, a severe form of cerebral white matter injury, has been observed in a small portion of very preterm infants. By contrast, noncystic or diffuse periventricular leukomalacia is a predominant form of brain lesion and is not readily detected by neuroimaging.33 Therefore, early detection and prevention of white matter injuries will be the next targets to control in perinatal medicine.

HCs of <−2 SDs at age 3 years were significantly associated with NDI in this study, as previously reported.34 HC can be considered a proxy for brain volume,35 and head growth is affected by nutritional and nonnutritional factors.34 Diffuse periventricular leukomalacia is associated with volumetric deficits of the cerebral cortex and thalamus and delayed cortical maturation.33 These findings support the ongoing need for more extensive investigations into whether the children’s postnatal nutrition and/or environmental distress, besides perinatal brain injury, are associated with their small HC.

We have recently reported that the survival rate of infants with a BW of ≤500 g has greatly improved from 2003 to 2012 in Japan.13 Their survival was associated with several factors, including higher GA and BW, and the increasing rate of antenatal steroids and cesarean delivery contributed to improving their survival rate.13 Notably, these advantageous factors were not shown to reduce the risk of NDI for survivors with BWs of ≤500 g. The combined outcomes of mortality or morbidity can be determined for all births or live births and are associated with GA and BW.9,11 However, neurologic outcomes can only be determined for survivors to the age of the follow-up assessment. Thus, analysis of NDI might mask the effects of GA or BW.32 The dissociated results are inevitable because severely affected infants are at high risk for death before discharge. Moreover, attrition in this study might reduce the power to detect effects of GA or BW. Because we selected surviving infants as eligible subjects, we were able to add variables of in-hospital interventions and neonatal complications in the current study. Consequently, severe IVH and cPVL were identified among the survivors with BWs of ≤500 g as the highest risk factors for NDI but not GA, BW, or obstetric intervention. Given the improving survival rates13 and the unchanged neurodevelopmental outcomes, the number of both survivors with NDI and those without apparent disabilities were likely to increase in Japan. Nonetheless, these data provide useful information to guide the treatment of extremely small infants and social consensus, which is a goal of future research.

This study has several limitations. First, the follow-up rate was 56.7%. Because of the low follow-up rate, we failed to count the number of infants who died after discharge. In fact, the rates in drop-off were commonly high (30%–36%) in previous NRNJ studies.21,22 One of the reasons might be that not all infants were followed-up at the same hospitals from which they were discharged. Therefore, their follow-up data were not recovered to a level comparable to those in former reports from other countries. Three perinatal parameters (congenital abnormalities, high-frequency ventilation, and antibiotics use) revealed significant differences between the study population and the nonevaluated survivors (Table 1). Two of these differences suggest the study population is sicker than the population without follow-up; therefore, the rate of NDI may be overestimated for the former. Second, 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 expectation bias. However, the NDI rate at age 3 years in this study was higher than those of children with a BW of >500 g (501–750 g, 36.3%; 751–1000 g, 20.1%) in a previous NRNJ study.21 Lastly, other prognostic factors for neurodevelopmental disability such as parental education level, erythropoietin treatment, aggressive nutritional support, and specific strategies of ventilation and steroids administration32 were not analyzed. Identifying the key environmental factors among these variables will further unveil the potential targets of intervention for extremely small infants.

Neurodevelopmental outcomes in early childhood among surviving infants with a BW of ≤500 g did not improve in a recent decade. In this large-population study, we verified that perinatal brain injury was an unfavorable risk factor for NDI. Changes in medical management that are able to ameliorate brain injury would be expected to reduce adverse neurodevelopmental burdens for extremely small infants.

     
  • BPD

    bronchopulmonary dysplasia

  •  
  • BW

    birth weight

  •  
  • CI

    confidence interval

  •  
  • CP

    cerebral palsy

  •  
  • cPVL

    cystic periventricular leukomalacia

  •  
  • DQ

    developmental quotient

  •  
  • GA

    gestational age

  •  
  • HC

    head circumference

  •  
  • IVH

    intraventricular hemorrhage

  •  
  • NDI

    neurodevelopmental impairment

  •  
  • NEC

    necrotizing enterocolitis

  •  
  • NRNJ

    Neonatal Research Network of Japan

  •  
  • PDA

    patent ductus arteriosus

  •  
  • ROP

    retinopathy of prematurity

  •  
  • SGA

    small for gestational age

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 designed the study, contributed to the data analysis, and critically reviewed and revised the manuscript; Drs Yasuoka, Tanaka, Ichiyama, Kurata, Fujiyoshi, and Matsushita made substantial contributions to the analysis and interpretation of the data and reviewed and revised the 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.

FUNDING: Funded in part by JSPS KAKENHI grant JP17K16300 (Dr Inoue), JP15K09717 (Dr Ochiai), and JP16K19688 (Dr Fujiyoshi).

Institutions enrolled in the study of the NRNJ were as follows: Sapporo City General Hospital, Asahikawa Kosei General Hospital, Engaru-Kosei General Hospital, Kushiro Red Cross Hospital, Obihiro-Kosei General Hospital, Tenshi Hospital, NTT Higashinihon Sapporo Hospital, Nikko Memorial Hospital, Nayoro City General Hospital, Sapporo Medical University, Asahikawa Medical University, Aomori Prefectural Central Hospital, Iwate Medical University, Iwate Prefectural Ofunato Hospital, Iwate Prefectural Kuji Hospital, Iwate Prefectural Ninohe Hospital, Sendai Red Cross Hospital, Akita Red Cross Hospital, Tsuruoka Municipal Shonai Hospital, Yamagata University, Yamagata Prefectural Central Hospital, Fukushima Medical University, Takeda General Hospital, Fukushima National Hospital, Tsukuba University, Tsuchiura Kyodo Hospital, Ibaraki Children’s Hospital, Dokkyo Medical University, Jichi Medical University, Ashikaga Red Cross Hospital, Gunma Children’s Medical Center, Kiryu Kosei General Hospital, Fuji Heavy Industries Health Insurance Society Ota Memorial Hospital, Gunma University, Saitama Children’s Medical Center, Nishisaitama-chuo National Hospital, Saitama Medical University Saitama Medical Center, Kawaguchi Municipal Medical Center, Jichi Medical University Saitama Medical Center, Asahi General Hospital, Chiba Kaihin Municipal Hospital, Kameda Medical Center, Tokyo Women’s Medical University Yachiyo Medical Center, Juntendo University Urayasu Hospital, Tokyo Metropolitan Children’s Medical Center, Tokyo Women’s Medical University, Aiiku Hospital, Nihon University Itabashi Hospital, National Center for Global Health and Medicine, Tokyo Medical University, Teikyo University, Showa University, Japan Red Cross Medical Center, National Center for Child Health and Development, Tokyo Metropolitan Otsuka Hospital, Toho University, Tokyo Metropolitan Bokuto Hospital, Tokyo Jikei Medical University, Tokyo Medical and Dental University, Saint Luke’s International Hospital, Juntendo University, Sanikukai Hospital, Katsushika Red Cross Hospital, Yokohama Rosai Hospital, Yokohama City University Medical Center, St. Marianna University School of Medicine Hospital, Kanagawa Children’s Medical Center, Tokai University, Kitazato University, Odawara Municipal Hospital, Nippon Medical School Musashi Kosugi Hospital, Saiseikai Yokohamashi Tobu Hospital, National Hospital Organization Yokohama Medical Center, Yamanashi Prefectural Central Hospital, Nagano Children’s Hospital, Shinshu University, Iida Municipal Hospital, National Hospital Organization Shinshu Ueda Medical Center, Saku General Hospital, Niigata University, Niigata Prefectural Central Hospital, Niigata Municipal Hospital, Nagaoka Red Cross Hospital, Koseiren Takaoka Hospital, Toyama Prefectural Central Hospital, Toyama University, Ishikawa Medical Center for Maternal and Child Health, Kanazawa Medical University, Kanazawa Medical Center, Fukui Prefectural Hospital, Fukui University, Gifu Prefectural General Medical Center, National Hospital Organization Nagara Medical Center, Takayama Red Cross Hospital, Seirei Hamamatsu Hospital, Shizuoka Saiseikai Hospital, Shizuoka Children’s Hospital, Hamamatsu Medical University, Numazu Municipal Hospital, Yaizu City Hospital, Fujieda Municipal General Hospital, Nagoya Red Cross Daini Hospital, Nagoya University, Nagoya Red Cross Daiichi Hospital, Toyohashi Municipal Hospital, Nagoya City West Medical Center, Anjo kosei Hospital, Tosei General Hospital, Komaki Municipal Hospital, TOYOTA Memorial Hospital, Okazaki Municipal Hospital, Konan Kosei Hospital, National Mie Central Medical Center, Ise Red Cross Hospital, Yokkaichi Municipal Hospital, Otsu Red Cross Hospital, Shiga University of Medical Science Hospital, Nagahama Red Cross Hospital, Uji Tokushukai Hospital, The Japan Baptist Hospital, Kyoto University, Kyoto Red Cross Daiichi Hospital, National Maizuru Medical Center, Fukuchiyama City Hospital, Kyoto Prefectural University of Medicine Hospital, Kyoto City Hospital, Mitsubishi Kyoto Hospital, Yodogawa Christian Hospital, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka University, Takatsuki General Hospital, Kansai Medical University, Osaka City General Hospital, Osaka City Sumiyoshi Hospital, Aizenbashi Hospital, Toyonaka Municipal Hospital, National Cerebral and Cardiovascular Center, Kitano Hospital, Saiseikai Suita Hospital, Chifune Hospital, Bellland General Hospital, Rinku General Medical Center, Osaka Red Cross Hospital, Yao Municipal Hospital, Osaka General Medical Center, Osaka City University, Hyogo Prefectural Kobe Children’s Hospital, Kobe University, Kakogawa West City Hospital, Saiseikai Hyogoken Hospital, Kobe City Medical Center General Hospital, Hyogo College of Medicine Hospital, Himeji Red Cross Hospital, Toyooka Public Hospital, Hyogo Prefectural Awaji Medical Center, Nara Medical University, Wakayama Medical University, Tottori Prefectural Central Hospital, Tottori University, Shimane Prefectural Central Hospital, Matsue Red Cross Hospital, Kurashiki Central Hospital, Tsuyama Central Hospital, Kawasaki Medical School Hospital, National Hospital Organization Okayama Medical Center, Okayama Red Cross Hospital, Hiroshima City Hiroshima Citizens Hospital, Hiroshima Prefectural Hospital, Hiroshima University, Tsuchiya General Hospital, National Hospital Organization Kure Medical Center, Yamaguchi University, Yamaguchi Grand Medical Center, Tokushima University, Tokushima Municipal Hospital, Kagawa University, National Hospital Organization Kagawa Children’s Hospital, Matsuyama Red Cross Hospital, Ehime Prefectural Central Hospital, Kochi Health Science Center, St. Mary’s Hospital, National Kyushu Medical Center, Kurume University, Kitakyushu Municipal Medical Center, University of Occupational and Environmental Health, Fukuoka University, Kyushu University, Iizuka Hospital, National Hospital Organization Kokura Medical Center, National Hospital Organization Saga Hospital, National Hospital Organization Nagasaki Medical Center, Kumamoto City Hospital, Kumamoto University, Oita Prefectural Hospital, Almeida Memorial Hospital, Nakatsu Municipal Hospital, Miyazaki University, National Hospital Organization Miyakonojo Medical Center, Kagoshima City Hospital, Imakiire General Hospital, Okinawa Prefectural Nanbu Medical Center and Children’s Medical Center, Okinawa Prefectural Chubu Hospital, Naha City Hospital, Okinawa Red Cross Hospital.

1
Stoll
BJ
,
Hansen
NI
,
Bell
EF
, et al;
Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network
.
Trends in care practices, morbidity, and mortality of extremely preterm neonates, 1993-2012.
JAMA
.
2015
;
314
(
10
):
1039
1051
[PubMed]
2
Patel
RM
,
Kandefer
S
,
Walsh
MC
, et al;
Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network
.
Causes and timing of death in extremely premature infants from 2000 through 2011.
N Engl J Med
.
2015
;
372
(
4
):
331
340
[PubMed]
3
Younge
N
,
Goldstein
RF
,
Bann
CM
, et al;
Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network
.
Survival and neurodevelopmental outcomes among periviable infants.
N Engl J Med
.
2017
;
376
(
7
):
617
628
[PubMed]
4
Younge
N
,
Smith
PB
,
Gustafson
KE
, et al
.
Improved survival and neurodevelopmental outcomes among extremely premature infants born near the limit of viability.
Early Hum Dev
.
2016
;
95
:
5
8
[PubMed]
5
Tommiska
V
,
Heinonen
K
,
Lehtonen
L
, et al
.
No improvement in outcome of nationwide extremely low birth weight infant populations between 1996-1997 and 1999-2000.
Pediatrics
.
2007
;
119
(
1
):
29
36
[PubMed]
6
Hintz
SR
,
Kendrick
DE
,
Vohr
BR
,
Poole
WK
,
Higgins
RD
;
National Institute of Child Health and Human Development Neonatal Research Network
.
Changes in neurodevelopmental outcomes at 18 to 22 months’ corrected age among infants of less than 25 weeks’ gestational age born in 1993-1999.
Pediatrics
.
2005
;
115
(
6
):
1645
1651
[PubMed]
7
Hintz
SR
,
Kendrick
DE
,
Wilson-Costello
DE
, et al;
NICHD Neonatal Research Network
.
Early-childhood neurodevelopmental outcomes are not improving for infants born at <25 weeks’ gestational age.
Pediatrics
.
2011
;
127
(
1
):
62
70
[PubMed]
8
Wilson-Costello
D
,
Friedman
H
,
Minich
N
,
Fanaroff
AA
,
Hack
M
.
Improved survival rates with increased neurodevelopmental disability for extremely low birth weight infants in the 1990s.
Pediatrics
.
2005
;
115
(
4
):
997
1003
[PubMed]
9
Ecker
JL
,
Kaimal
A
,
Mercer
BM
, et al;
American College of Obstetricians and Gynecologists and the Society for Maternal–Fetal Medicine
.
Periviable birth: interim update.
Am J Obstet Gynecol
.
2016
;
215
(
2
):
B2
B12.e1
[PubMed]
10
Salihu
HM
,
Salinas-Miranda
AA
,
Hill
L
,
Chandler
K
.
Survival of pre-viable preterm infants in the United States: a systematic review and meta-analysis.
Semin Perinatol
.
2013
;
37
(
6
):
389
400
[PubMed]
11
Tyson
JE
,
Parikh
NA
,
Langer
J
,
Green
C
,
Higgins
RD
;
National Institute of Child Health and Human Development Neonatal Research Network
.
Intensive care for extreme prematurity–moving beyond gestational age.
N Engl J Med
.
2008
;
358
(
16
):
1672
1681
[PubMed]
12
American College of Obstetricians and Gynecologists
.
ACOG practice bulletin no. 101: ultrasonography in pregnancy.
Obstet Gynecol
.
2009
;
113
(
2, pt 1
):
451
461
[PubMed]
13
Inoue
H
,
Ochiai
M
,
Yasuoka
K
, et al;
Neonatal Research Network of Japan (NRNJ)
.
Early mortality and morbidity in infants with birth weight of 500 grams or less in Japan.
J Pediatr
.
2017
;
190
(
11
):
112
117.e3
[PubMed]
14
Itabashi
K
,
Miura
F
,
Uehara
R
,
Nakamura
Y
.
New Japanese neonatal anthropometric charts for gestational age at birth.
Pediatr Int
.
2014
;
56
(
5
):
702
708
[PubMed]
15
Ehrenkranz
RA
,
Walsh
MC
,
Vohr
BR
, et al;
National Institutes of Child Health and Human Development Neonatal Research Network
.
Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia.
Pediatrics
.
2005
;
116
(
6
):
1353
1360
[PubMed]
16
Papile
LA
,
Burstein
J
,
Burstein
R
,
Koffler
H
.
Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm.
J Pediatr
.
1978
;
92
(
4
):
529
534
[PubMed]
17
Bell
MJ
,
Ternberg
JL
,
Feigin
RD
, et al
.
Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging.
Ann Surg
.
1978
;
187
(
1
):
1
7
[PubMed]
18
Kono
Y
,
Mishina
J
,
Sato
N
,
Watanabe
T
,
Honma
Y
.
Developmental characteristics of very low-birthweight infants at 18 months’ corrected age according to birthweight.
Pediatr Int
.
2008
;
50
(
1
):
23
28
[PubMed]
19
Bax
MC
.
Terminology and classification of cerebral palsy.
Dev Med Child Neurol
.
1964
;
6
:
295
297
[PubMed]
20
Kono
Y
,
Yonemoto
N
,
Kusuda
S
, et al
.
Developmental assessment of VLBW infants at 18 months of age: a comparison study between KSPD and Bayley III.
Brain Dev
.
2016
;
38
(
4
):
377
385
[PubMed]
21
Kono
Y
,
Mishina
J
,
Yonemoto
N
,
Kusuda
S
,
Fujimura
M
.
Outcomes of very-low-birthweight infants at 3 years of age born in 2003-2004 in Japan.
Pediatr Int
.
2011
;
53
(
6
):
1051
1058
[PubMed]
22
Ishii
N
,
Kono
Y
,
Yonemoto
N
,
Kusuda
S
,
Fujimura
M
;
Neonatal Research Network, Japan
.
Outcomes of infants born at 22 and 23 weeks’ gestation.
Pediatrics
.
2013
;
132
(
1
):
62
71
[PubMed]
23
Suwa
S
,
Tachibana
K
.
Standard growth charts for height and weight of Japanese children from birth to 17 years based on a cross-sectional survey of national data.
Clin Pediatr Endocrinol
.
1993
;
2
(
2
):
87
97
24
Kato
N
,
Takimoto
H
,
Sudo
N
.
The cubic functions for spline smoothed L, S and M values for BMI reference data of Japanese children.
Clin Pediatr Endocrinol
.
2011
;
20
(
2
):
47
49
[PubMed]
25
Zou
GY
,
Donner
A
.
Extension of the modified Poisson regression model to prospective studies with correlated binary data.
Stat Methods Med Res
.
2013
;
22
(
6
):
661
670
[PubMed]
26
Sauve
RS
,
Robertson
C
,
Etches
P
,
Byrne
PJ
,
Dayer-Zamora
V
.
Before viability: a geographically based outcome study of infants weighing 500 grams or less at birth.
Pediatrics
.
1998
;
101
(
3, pt 1
):
438
445
[PubMed]
27
Upadhyay
K
,
Pourcyrous
M
,
Dhanireddy
R
,
Talati
AJ
.
Outcomes of neonates with birth weight⩽500 g: a 20-year experience.
J Perinatol
.
2015
;
35
(
9
):
768
772
[PubMed]
28
Vohr
BR
,
Wright
LL
,
Dusick
AM
, et al
.
Neurodevelopmental and functional outcomes of extremely low birth weight infants in the National Institute of Child Health and Human Development Neonatal Research Network, 1993-1994.
Pediatrics
.
2000
;
105
(
6
):
1216
1226
[PubMed]
29
Rieger-Fackeldey
E
,
Blank
C
,
Dinger
J
,
Steinmacher
J
,
Bode
H
,
Schulze
A
.
Growth, neurological and cognitive development in infants with a birthweight <501 g at age 5 years.
Acta Paediatr
.
2010
;
99
(
9
):
1350
1355
[PubMed]
30
Keir
A
,
McPhee
A
,
Wilkinson
D
.
Beyond the borderline: outcomes for inborn infants born at ≤500 grams.
J Paediatr Child Health
.
2014
;
50
(
2
):
146
152
[PubMed]
31
Jarjour
IT
.
Neurodevelopmental outcome after extreme prematurity: a review of the literature.
Pediatr Neurol
.
2015
;
52
(
2
):
143
152
[PubMed]
32
Linsell
L
,
Malouf
R
,
Morris
J
,
Kurinczuk
JJ
,
Marlow
N
.
Prognostic factors for poor cognitive development in children born very preterm or with very low birth weight: a systematic review.
JAMA Pediatr
.
2015
;
169
(
12
):
1162
1172
[PubMed]
33
Volpe
JJ
.
Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances.
Lancet Neurol
.
2009
;
8
(
1
):
110
124
[PubMed]
34
Raghuram
K
,
Yang
J
,
Church
PT
, et al;
Canadian Neonatal Network
;
Canadian Neonatal Follow-Up Network Investigators
.
Head growth trajectory and neurodevelopmental outcomes in preterm neonates.
Pediatrics
.
2017
;
140
(
1
):
e20170216
[PubMed]
35
Cheong
JL
,
Hunt
RW
,
Anderson
PJ
, et al
.
Head growth in preterm infants: correlation with magnetic resonance imaging and neurodevelopmental outcome.
Pediatrics
.
2008
;
121
(
6
). Available at: www.pediatrics.org/cgi/content/full/121/6/e1534
[PubMed]

Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

Supplementary data