Original Paper
Neonatology 2017;112:258–266
DOI: 10.1159/000477293
Neurodevelopment at 3 Years in Neonates Born
by Vaginal Delivery versus Cesarean Section at
<26 Weeks of Gestation: Retrospective Analysis
of a Nationwide Registry in Japan
Takeshi Kimura Masato Takeuchi Takumi Imai Shiro Tanaka
Koji Kawakami Neonatal Research Network of Japan
Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University,
Kyoto, Japan
Keywords
Extreme prematurity · Neurodevelopment · Cesarean
section · Vaginal delivery
Abstract
Background: A high proportion of extremely preterm (EPT)
infants are born by cesarean section (CS). However, whether
the mode of delivery is related to long-term neurodevelop-
ment in these infants is unclear. Objectives: This study aimed
to determine whether the mode of delivery is associated
with mortality and long-term outcomes in EPT infants. Meth-
ods: We analyzed data of the Neonatal Research Network in
Japan (NRNJ), a population-based, nationwide registry. In-
clusion criteria were neonates who were born between 2003
and 2012 with a gestational age <26 weeks. The primary
composite outcome was death before 3 years or neurodevel-
opmental impairment (NDI) at 3 years. Confounder-adjusted
odds ratios (OR) were estimated by logistic generalized lin-
ear mixed models, which accounted for clustering within
hospitals. Results: 2,138 eligible infants (703 by vaginal de-
livery [VD] and 1,435 by CS) were identified for primary anal-
ysis. The composite outcome of death or NDI was not differ-
ent between both groups (66.7% by VD and 62.7% by CS,
© 2017 S. Karger AG, Basel
E-Mail karger@karger.com
www.karger.com/neo
Received: December 18, 2016
Accepted after revision: May 4, 2017
Published online: July 14, 2017
p = 0.075). After multivariate analysis adjusting for con-
founders, we found that CS did not improve the composite
outcome of death or NDI (OR = 0.839, 95% confidence inter-
val = 0.816–1.328, p = 0.742). For secondary outcomes, mor-
tality (OR = 0.824, p = 0.150), NDI (OR = 1.237, p = 0.165), and
other neurodevelopmental outcomes were not different be-
tween the groups. Conclusions: Among neonates born at
<26 weeks, CS does not improve mortality and neurodevel-
opmental outcomes at 3 years in the NRNJ cohort. However,
because of several potential biases such as high rates of in-
fants lost to follow-up, further evidence may be required.
© 2017 S. Karger AG, Basel
Introduction
Extremely preterm (EPT) infants, defined as neonates
born between 22 0/7 and 25 6/7 weeks of gestation, have
a high prevalence of perinatal death and future neurodis-
ability [1–3]. Short-term outcomes of EPT infants have
improved, but poor impaired neurodevelopment is still a
major long-term complication [4–6]. In Japan, the rate of
mortality during initial neonatal intensive care unit
(NICU) admission is 25.2%. The rate of impaired devel-
132.236.27.111 - 7/19/2017 3:45:22 PM
Koji Kawakami, MD, PhD
Department of Pharmacoepidemiology
Cornell University Library
Graduate School of Medicine and Public Health, Kyoto University
Yoshida Konoecho, Sakyoku, Kyoto 606-8501 (Japan)
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E-Mail kawakami.koji.4e @ kyoto-u.ac.jp
opment at 3 chronological years was 42.4% in a previous
study [2]. Therefore, it is important to improve the peri-
natal management of EPT infants.
The optimal mode of delivery for EPT infants is still
controversial. Several studies have reported that neonates
delivered by cesarean section (CS) have a lower mortality
than those with vaginal delivery (VD), but some studies
have reported no such association [7–9]. Despite unclear
benefits of CS in EPT infants, EPT infants are delivered
by CS more frequently than other more mature preterm
infants [10]. This could be due to concerns about labor,
which potentially affects EPT infants.
Only a few studies have reported the association be-
tween the mode of delivery and long-term neurodevelop-
mental outcome in EPT infants [11, 12]. These studies
concluded that the mode of delivery was unrelated. How-
ever, these studies included more mature preterm infants
than EPT infants. They did not have a sufficient number
of EPT infants to draw a definite conclusion. In EPT in-
fants, who are the most vulnerable infants, VD might in-
crease intraventricular hemorrhage and infection due to
head compression or skin injury. Both are known risk
factors of neurodevelopmental impairment (NDI) [13].
Therefore, VD may have unfavorable effects on neurode-
velopmental outcome only in EPT infants.
This study aimed to determine whether the mode of
delivery is associated with mortality and neurodevelop-
mental outcome at 3 years of chronological age in EPT
infants. To address this research aim, we used data from
a large-scale, population-based neonatal registry in Ja-
pan.
Methods
Selection of Subjects
We investigated anonymized and de-identified data, which
were obtained from a population-based cohort study that was
conducted by the Neonatal Research Network in Japan (NRNJ;
see Appendix for participating centers). The NRNJ is a national
database for clinical characteristics and morbidities of very-low-
birth-weight (VLBW) infants in Japan [14]. The data included
96% (72/75 as of 2008) of newborns from level 3 NICUs and from
7 level 2 NICUs [15]. Among the eligible EPT infants in this
study, 91.4% (4,932/5,394) were born in level 3 NICUs. Each cen-
ter registered all VLBW infants who were admitted to the NICU
within 28 days after birth. The database did not contain data on
stillbirth, and details on whether the fetus was alive at the start of
VD or CS but was then stillborn. During the study period, the
indication of CS was decided by obstetricians at each hospital.
Detailed information on the indication of each CS (i.e., fetal in-
dication or maternal indication) could not be obtained from the
database.
Mode of Delivery and Neurodevelopment
in EPT Infants
Neonates who were born at 23 0/7 to 25 6/7 weeks of gesta-
tional age (GA) between 2003 and 2012 were included in the pres-
ent study. Neonates who were born at 22 weeks of GA were not
included because they frequently received palliative care.
We excluded multiple births, newborns who had any major
congenital malformations (serious congenital heart disease or ma-
jor genetic disorder), out-of-hospital birth, and those who had no
information on the mode of delivery.
Outcomes
The primary objective of this study was to determine whether
the mode of delivery is associated with the composite outcome of
death or NDI at 3 years of chronological age in EPT infants. We
defined the composite outcome of death or NDI as the co-primary
outcomes because CS is undesirable when it only slightly improves
the survival rate, but it is strongly associated with serious long-
term disabilities in survivors. Considering mortality and neurode-
velopmental outcomes is important. The single outcome of death
and neurodevelopmental outcome were assessed as secondary
endpoints.
Neurodevelopmental Assessment
NDI was defined as any of following: cerebral palsy (CP), hear-
ing impairment, visual impairment, or a developmental quotient
(DQ) score <70. The DQ was measured with the Kyoto Scale of
Psychological Development (KSPD) [16]. In Japan, the KSPD is a
widely used scale for evaluating motor and cognitive function of
children in early childhood who are born preterm. The KSPD was
evaluated by certified psychologists at each center. A DQ <70 was
defined as significant cognitive delay. The KSPD is well correlated
with the Bayley III, which is used globally [16]. Neuromotor assess-
ment was performed by a trained pediatrician. CP was defined as
a nonprogressive, nontransient central nervous system disorder
characterized by abnormal muscle tone in at least one extremity,
and abnormal control of movement and posture [17]. Hearing im-
pairment was defined as the need for amplification. Visual impair-
ment was defined as blindness with no functional vision in one or
both eyes. These neurodevelopmental assessments were per-
formed at each center.
Definitions
GA was determined in the following order: (1) an obstetric ex-
amination with ultrasonography during the first trimester, (2) ob-
stetric history taking into account the last menstrual period, and
(3) a postnatal physical examination of the neonate. Small for ges-
tational age (SGA) was defined as a birth weight being more than
2 SD below the mean based on Japanese standard neonatal anthro-
pometric charts [18]. Antenatal steroid use was defined as admin-
istration of any corticosteroid to accelerate fetal maturity with at
least 1 dose. Clinical chorioamnionitis, premature rupture of
membranes, and nonreassuring fetal heart rate were defined as
previously described [15].
Statistical Analysis
The data are summarized using proportions for categorical
variables and means and SD for continuous variables. Proportions
were compared by the Fisher exact test. Continuous variables were
compared by the Student t test or Wilcoxon rank sum test accord-
ing to their distribution. Confounder-adjusted odds ratios (ORs)
and 95% confidence intervals (CIs) were estimated by logistic gen-
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Neonatology 2017;112:258–266 259
DOI: 10.1159/000477293
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 Infants born <32 weeks GA or •1,500 g
(NRNJ database 2003–2012)
n = 40,806
Infants born 23–25 weeks GA
n = 7,346
Missing data on mode delivery
n = 44
Vaginal delivery
n = 2,361
Excluded (total n = 580)
‡ Out-of-hospital birth; n = 295
‡ Multiple births; n = 250
‡ Major malformation; n = 61
n = 1,781
Death before 3 years; n = 357
n = 1,424
Missing data on NDI; n = 1,078
Infants with full data on NDI; n = 346
Fig. 1. Flowchart of the study cohort. GA, gestational age; NRNJ, Neonatal Research Network in Japan; NDI,
neurodevelopmental impairment.
eralized linear mixed models, which accounted for clustering with-
in hospitals to investigate the effect of delivery mode on outcome.
Based on previous studies [19, 20], the following factors were in-
cluded in the models as confounders: GA, SGA, male sex, CS, an-
tenatal steroids, clinical chorioamnionitis, and nonreassuring fetal
heart rate. A two-sided p value <0.05 was considered statistically
significant. Data analysis was carried out using SAS 9.4 (SAS Insti-
tute, Cary, NC, USA).
Subgroup Analysis
To address potential confounders and missing data, we repeat-
ed analysis on mortality, NDI, and composite outcome of death or
NDI by stratified subgroup analyses. These were performed ac-
260 Neonatology 2017;112:258–266
DOI: 10.1159/000477293
Cesarean section
n = 4,941
Excluded (total n = 1,328)
‡ Out-of-hospital birth; n = 300
‡ Multiple births; n = 984
‡ Major malformation; n = 128
n = 3,613
Death before 3 years; n = 604
n = 3,009
Missing data on NDI; n = 2,178
Infants with full data on NDI; n = 831
cording to GA, fetal presentation, SGA, premature rupture of
membranes, antenatal steroids, and follow-up rate (restricted to
hospitals with a >50% follow-up rate).
Sensitivity Analysis
In the dataset used for primary analysis, neonates with missing
data on outcomes or covariates were excluded. For sensitivity anal-
ysis, we performed multiple imputation of the outcomes and co-
variates by fully conditional specification [21] to test the robust-
ness of the findings from the primary analysis. We then performed
analysis in which neonates were divided into groups of the first and
second 5 years of the study period. We also repeated the analysis
on infants, including those who had out-of-hospital birth.
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 Table 1. Demographic and perinatal characteristics of the study population

Variables Vaginal delivery Cesarean delivery p value

n = 703 n = 1,435

Mean gestational age (SD), weeks 24.3 (0.86) 24.6 (0.82) <0.001
Age at birth
23 weeks 294 (41.8) 343 (23.9)
24 weeks 231 (32.9) 523 (36.5)
25 weeks 178 (25.3) 569 (39.7)
Mean birth weight (SD), g 657 (124) 645 (140) 0.045
Birth weight
<500 g 65 (9.3) 212 (14.8)
500 – 749 g 478 (68.0) 901 (62.8)
750 – 999 g 157 (22.3) 314 (21.9)
≥1,000 g 3 (0.4) 8 (0.6)
SGA 27/673 (4.0) 175/1386 (12.6) <0.001
Male 376/703 (53.5) 765/1434 (53.4) 0.963
Breech presentation 194/701 (27.7) 631/1422 (44.4) <0.001
Antenatal steroids 292/702 (41.6) 712/1429 (49.8) <0.001
PROM 310/702 (44.2) 617/1432 (43.1) 0.033
Chorioamnionitis 265/697 (38.0) 485/1410 (34.4) 0.110
Nonreassuring FHR 150/695 (21.6) 380/1423 (26.7) 0.010
Median Apgar score at 1 min (25 – 75%tile) 3 (1 – 4) 3 (2 – 5) <0.001
Median Apgar score at 5 min (25 – 75%tile) 6 (4 – 7) 6 (5 – 8) <0.001

Values are n (%) or n/N (%) unless otherwise indicated. SGA, small for gestational age (birth weight <−2.0
SD); PROM, premature rupture of membranes; FHR, fetal heart rate.

Ethics Demographic and Perinatal Characteristics

The NRNJ study was approved by the Ethics Committee of To-
kyo Women’s Medical University, and the present study was ap-
proved by the Ethics Committee of Kyoto University School of
Medicine. Informed consent was obtained from parents when EPT
infants were admitted.
Results
Overview of the Patients
During the study period, 7,346 neonates who were
born at 23 0/7 to 25 6/7 weeks of GA were registered in the
NRNJ. Of these 7,346 EPT infants, 1,952 were excluded
because of missing data for delivery (n = 44), out-of-hos-
pital birth (n = 595), multiple births (n = 1,234), and major
malformations (n = 189) (Fig. 1). Of the remaining 5,394
EPT infants, 1,177 had data for neurodevelopmental out-
comes, and 961 died before neurodevelopmental assess-
ment. Finally, 2,138 EPT infants with a full set of data con-
stituted our study population, with 703 in the VD group
and 1,435 in the CS group. The proportion of excluded
patients was not different between the VD and CS groups
(60.5% [1,078/1,781] vs. 60.3% [2,178/3,613], p = 0.882).
Demographic and perinatal characteristics of the EPT
infants included in the study are shown in Table 1. GA
(mean, 24.3 vs. 24.6 weeks), birth weight (657 vs. 645 g),
the proportions of SGA (4.0 vs. 12.6%), antenatal steroids
(41.6 vs. 49.8%), premature rupture of membranes (44.2
vs. 43.1%), and nonreassuring fetal heart rate (21.6 vs.
26.7%), Apgar score at 1 min (median [25–75th percen-
tile], 3 [1–4] vs. 3 [2–5]), and Apgar score at 5 min (me-
dian [25–75th percentile], 6 [4–7] vs. 6 [5–8]) were sig-
nificantly different between the VD and CS groups.
We compared demographic and perinatal characteris-
tics of EPT infants who had data on NDI with those who
were lost to follow-up. This comparison aimed to deter-
mine whether infants with available data represented the
whole study population (online suppl. Table 1; see www.
karger.com/doi/10.1159/000477293 for all online suppl.
material). Almost all characteristics between EPT infants
with data on NDI and those who were lost to follow-up
were similar. However, there were significant, but small,
differences in the Apgar score, antenatal steroids, and
nonreassuring fetal heart rate between both groups of
EPT infants.
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 Table 2. Mortality, morbidity, and neurodevelopmental outcomes with univariate analysis

Outcomes Vaginal delivery Cesarean delivery p value

Death or NDI 469/703 (66.7) 900/1,435 (62.7) 0.075

NDI 112/346 (32.4) 296/831 (35.6) 0.313
Death before 3 years 357/703 (50.8) 604/1,435 (42.1) <0.001
Death at delivery room 11/1,781 (0.62) 15/3,613 (0.42) 0.304
Death before discharge 344/1,781 (19.3) 586/3,613 (16.2) 0.005
Death after discharge up to 3 years 13/720 (1.81) 18/1,648 (1.09) 0.171
Mean KSPD DQ (SD) 78.1 (18) 78.2 (18) 0.913
KSPD DQ <70 88/346 (25.4) 244/831 (29.4) 0.177
CP 36/346 (10.4) 77/831 (9.27) 0.587
Hearing impairment 5/346 (1.5) 10/831 (1.2) 0.777
Visual impairment 26/346 (7.5) 58/831 (6.9) 0.803
Chronic lung disease at 36 weeks 681/1,720 (39.6) 1,572/3,432 (45.8) <0.001
PDA ligation 259/1,774 (14.6) 546/3,574 (15.3) 0.542
Necrotizing enterocolitis 67/1,774 (3.8) 153/3,571 (4.3) 0.421
Severe intraventricular hemorrhage 229/1,757 (13.0) 413/3,561 (11.6) 0.139
Cystic PVL 73/1,770 (4.1) 139/3,573 (3.9) 0.709
ROP that required treatment 619/1,708 (36.2) 1,316/3,415 (38.5) 0.112
Sepsis 344/1,774 (19.4) 639/3,570 (17.9) 0.189

Values are n/N (%) unless otherwise indicated. CP, cerebral palsy; KSPD, Kyoto Scale of Psychological Devel-
opment; DQ, developmental quotient; NDI, neurodevelopmental impairment (defined as any of the following:
CP, hearing impairment, visual impairment, and a DQ score <70); PDA, patent ductus arteriosus; ROP, reti-
nopathy of prematurity; PVL, periventricular leukomalacia. Chronic lung disease at 36 weeks was defined when
an infant required oxygen supplementation or positive pressure ventilation. Intraventricular hemorrhage was
defined according to the classification of Papile et al. [25]. Treatment of ROP was laser coagulation, cryocoagula-
tion, or both. Sepsis was defined as culture-proven bacteremia at any time during the NICU stay. Cystic PVL was
diagnosed by trained pediatricians using ultrasonography or magnetic resonance imaging.

Outcomes ing for covariates (Tables 2, 3). Other comorbidities, in-

The composite outcome of death or NDI was not dif-
ferent between both study groups (66.7 vs. 62.7%, p =
0.075; Table 2). In multivariate analysis adjusting for po-
tential confounders, CS did not have a significant positive
effect on the composite outcome of death or NDI (OR =
0.839, 95% CI = 0.816–1.328, p = 0.742; Table 3).
The proportion of death before 3 years was significant-
ly lower in the CS group than in the VD group (357/703
[50.8%] vs. 604/1,435 [42.1%]) by univariate analysis.
However, after adjustment for covariates, CS did not im-
prove mortality (OR = 0.824, 95% CI = 0.632–1.074, p =
0.150).
In univariate and multivariate analyses, NDI, the
KSPD score, CP, hearing impairment, and visual impair-
ment were not significantly different between the groups
(Table 3).
Chronic lung disease at 36 weeks and retinopathy of
prematurity that required treatment were significantly
higher in the CS group than in the VD group after adjust-
cluding patent ductus arteriosus ligation, necrotizing
enterocolitis, severe intraventricular hemorrhage, and
cystic periventricular leukomalacia, were not different
between both groups.
Subgroup analysis (online suppl. Tables 2–4) showed
that when limited to a breech presentation, CS was asso-
ciated with improvement in the composite outcome of
death or NDI (OR = 0.598, 95% CI = 0.373–0.959, p =
0.033).
In sensitivity analysis, when analyzing the full cohort
(n = 5,394) with multiple imputation for missing data, CS
did not have a significant positive effect on the composite
outcome of death or NDI (OR = 0.964, 95% CI = 0.783–
1.188, p = 0.734), death (OR = 0.899, 95% CI = 0.761–
1.061, p = 0.210), and NDI (OR = 0.788, 95% CI = 0.602–
1.033, p = 0.083). Similarly, we did not find any significant
differences between CS and VD in other types of sensitiv-
ity analyses, such as dividing by study period or including
out-of-hospital birth.
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262 Neonatology 2017;112:258–266 Kimura et al.

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 Table 3. Odds ratios for associations of cesarean section with adverse outcomes compared with vaginal delivery

Outcomes Odds ratio p

crude 95% CI adjusted 95% CI value

Death or NDI 0.839 0.694– 1.015 1.041 0.816 – 1.328 0.742

NDI 1.156 0.886 – 1.509 1.237 0.913 – 1.676 0.165
Death before 3 years 0.704 0.588 – 0.844 0.824 0.632 – 1.074 0.150
Death at the delivery room 0.671 0.307 – 1.464 0.739 0.294 – 1.861 0.518
Death before discharge 0.809 0.698 – 0.937 0.904 0.758 – 1.079 0.261
Death after discharge up to 3 years 0.601 0.293 – 1.232 0.673 0.285 – 1.589 0.361
KSPD DQ of <70 1.219 0.917 – 1.619 1.340 0.970 – 1.852 0.074
CP 0.879 0.579 – 1.335 0.859 0.537 – 1.373 0.516
Hearing impairment 0.831 0.282 – 2.448 0.920 0.289 – 2.925 0.885
Visual impairment 0.923 0.571 – 1.493 0.927 0.534 – 1.61 0.783
Chronic lung disease at 36 weeks 1.289 1.146 – 1.450 1.283 1.113 – 1.479 <0.001
PDA ligation 1.055 0.899 – 1.238 1.153 0.955 – 1.392 0.138
Necrotizing enterocolitis 1.140 0.851 – 1.529 1.197 0.866 – 1.654 0.274
Severe intraventricular hemorrhage 0.875 0.737 – 1.040 1.030 0.846 – 1.254 0.764
Cystic PVL 0.941 0.705 – 1.257 0.944 0.688 – 1.294 0.717
ROP requiring treatment 1.103 0.978 – 1.244 1.212 1.050 – 1.399 0.009
Sepsis 0.906 0.784 – 1.048 0.984 0.829 – 1.167 0.848

Adjusted odds ratios derived from logistic generalized linear mixed models are reported. Hospitals were de-
fined as a random effect. Gestational age, birth weight <−2.0 SD, sex, antenatal glucocorticoid exposure, nonre-
assuring fetal heart status, and chorioamnionitis were defined as fixed effects. See Table 2 for abbreviations.

Discussion are more likely to be affected by CS than appropriate-for-

This study investigated the associations between the
mode of delivery and mortality and neurodevelopmental
outcomes at 3 years in EPT infants, using a nationwide,
large database in Japan. In the present study, the mode of
delivery was not associated with mortality and neurode-
velopmental outcomes, including the DQ score, CP, hear-
ing impairment, and visual impairment. We performed
several sensitivity and subgroup analyses to account for
potential biases (e.g., high missing data), and found that
the results were stable after these analyses.
In our study, the GA of the study population was
shorter and the sample size was larger than those in pre-
vious studies [11, 12]. However, CS was not related to
improvement in mortality and neurodevelopmental out-
comes, which is in line with previous studies. Although
there have been numerous retrospective studies that as-
sessed the relationship between the mode of delivery and
mortality in EPT or VLBW infants, they reported con-
flicting results [7, 11, 22]. In our study, CS had no rela-
tionship with mortality after adjusting for covariates,
which may be because our study group had a low propor-
tion of SGA. Some studies have shown that SGA infants
gestational-age infants. Furthermore, differences in the
mortality of EPT infants among countries could explain
the discrepancy in results among studies [2].
There are limited data regarding the association be-
tween the mode of delivery and long-term neurodevelop-
ment in EPT infants. A retrospective cohort study includ-
ing VLBW infants (n = 710) reported that the mode of
delivery made no detectable difference in Bayley II scores
at 2 years [11]. A secondary analysis of another random-
ized, controlled trial including neonates delivered be-
tween 23 4/7 and 25 6/7 weeks of GA (n = 158) did not
show improvement by CS in Bayley II scores at 2 years
[12]. In our study, there was a significant difference in
NDI at 3 years between the CS and VD cohorts, consistent
with the 2 previous studies [11, 12]. Because some chil-
dren without signs of NDI at 2–3 years of age will have
deficits that manifest at school age, future research with a
longer follow-up may be required.
Despite the absence of a standard indication for CS in
EPT infants, the proportion of EPT infants delivered by
CS is high (57–60%) [2, 10]. This finding may be due to
physicians’ concern about the vulnerability of EPT in-
fants. Theoretically, EPT infants are more susceptible to
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traumatic birth because of a more prolonged labor than
more mature preterm infants [23]. However, there is no
strong evidence supporting routine CS for EPT infants.
Subgroup analysis of breech presentation of the fetus
showed that CS was associated with a reduction in mortal-
ity and the composite outcome of death or NDI. This result
is in line with a previous study [20]. In the clinical setting,
a fetus in the breech position can be born by VD because
labor of EPT infants occasionally progresses rapidly be-
yond expectations. Fetuses <26 weeks GA with breech pre-
sentation require close observation during labor.
There are several limitations to our study. First, many
EPT infants did not have information on NDI at 3 years.
The reasons for a high attrition are multifactorial. After
discharge, a subset of patients was followed up at an insti-
tution different from the NRNJ hospitals where they were
admitted during the neonatal period. In such cases, fol-
low-up data could have easily been lost because data entry
of follow-up data were not required at institutions outside
the NRNJ. Another possible reason for missing data was
the workload of medical staff. In the NRNJ, data entry was
web based, and in most NRNJ institutions, data entry was
performed by pediatricians/neonatologists without addi-
tional payment. The burden of data entry on the medical
staff may have led to high attrition of follow-up data on
EPT infants. Moreover, the number of certified psycholo-
gists who evaluated the KSPD was limited, even at levels
2–3 NICUs in Japan. All of these issues are related to a
high rate of missing follow-up data, which was common-
ly observed in previous research using NRNJ registry data
[2, 24]. We assumed that the reasons for missing data were
not related to events or outcomes (i.e., mode of delivery or
neurodevelopment), and we analyzed data of patients
with a complete set of data (i.e., complete case analysis).
However, our assumption could not be validated. There-
fore, we performed sensitivity analyses using multiple im-
putation, which can address missing data, regardless of
the reasons for missing data. Sensitivity analyses also
showed that the outcomes were not different between the
CS and VD groups. Additionally, sensitivity analyses
showed no clinically important differences in perinatal
characteristics between EPT infants who had data avail-
able for NDI and survivors who were lost to follow-up.
Therefore, we assumed that a high attrition of outcome
data was unlikely to have led to biased estimates, but
whether this assumption holds true is uncertain. Second,
as in all observational studies, uncontrolled confounding,
particularly indication bias, is a limitation of our study. To
confirm the robustness of main analysis, we repeated var-
ious sensitivity and subgroup analyses, ensuring that the
264 Neonatology 2017;112:258–266
DOI: 10.1159/000477293
results did not largely differ from the main analysis, How-
ever, even after adjustment by multivariate analysis, we
could not be sure whether confounding and bias were
eliminated. Third, we did not use the Bayley Scales of In-
fant Development III, which is used worldwide, but used
the KSPD instead, which is only used in Japan. However,
a previous study showed that the KSPD is well correlated
with the Bayley III [16]. Fourth, the NRNJ database does
not include information on stillbirth. Fetuses for whom
physicians attempted VD or CS, but who eventually died
in utero, were not registered in this database. There could
have been bias in both directions.
Our study shows that there is no relationship between
the mode of delivery and neurodevelopment in EPT in-
fants with respect to death, the DQ score, and sensory
impairment at 3 years, which is consistent with limited
data in previous studies. However, in some EPT infants
(e.g., breech presentation at birth), CS is probably associ-
ated with a favorable outcome. Our analysis was compli-
cated because of several potential confounding factors,
such as a high attrition rate and baseline imbalances. Fur-
ther evidence from randomized controlled trials or well-
designed, prospective, observational studies is required.
Until this high-quality evidence is available, our research
could help in decision making for those involved in the
care of neonates born before 26 weeks of gestation.
Appendix
Institutions that were enrolled in the study of the NRNJ were
as follows: Sapporo City General Hospital, Asahikawa Kosei Gen-
eral Hospital, Engaru-Kosei General Hospital, Kushiro Red Cross
Hospital, Obihiro-Kosei General Hospital, Tenshi Hospital, NTT
Higashinihon Sapporo Hospital, Nikko Memorial Hospital, Nay-
oro City General Hospital, Sapporo Medical University, Asahika-
wa Medical University, Aomori Prefectural Central Hospital,
Iwate Medical University, Iwate Prefectural Ofunato Hospital,
Iwate Prefectural Kuji Hospital, Iwate Prefectural Ninohe Hospi-
tal, Sendai Red Cross Hospital, Akita Red Cross Hospital, Tsu-
ruoka Municipal Shonai Hospital, Yamagata University, Yamaga-
ta Prefectural Central Hospital, Fukushima Medical University,
Takeda General Hospital, Fukushima National Hospital, Tsukuba
University, Tsuchiura Kyodo Hospital, Ibaraki Children’s Hospi-
tal, Dokkyo Medical University, Jichi Medical University, Ashika-
ga Red Cross Hospital, Gunma Children’s Medical Center, Kiryu
Kosei General Hospital, Fuji Heavy Industries Health Insurance
Society Ota Memorial Hospital, Gunma University, Saitama Chil-
dren’s Medical Center, Nishisaitama-chuo National Hospital,
Saitama Medical University Saitama Medical Center, Kawaguchi
Municipal Medical Center, Jichi Medical University Saitama Med-
ical Center, Asahi General Hospital, Chiba Kaihin Municipal Hos-
pital, Kameda Medical Center, Tokyo Women’s Medical Univer-
sity Yachiyo Medical Center, Juntendo University Urayasu Hospi-
132.236.27.111 - 7/19/2017 3:45:22 PM
Kimura et al.
Cornell University Library
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tal, Tokyo Metropolitan Children’s Medical Center, Tokyo
Women’s Medical University, Aiiku Hospital, Nihon University
Itabashi Hospital, National Center for Global Health and Medi-
cine, Tokyo Medical University, Teikyo University, Showa Uni-
versity, Japan Red Cross Medical Center, National Center for
Child Health and Development, Tokyo Metropolitan Otsuka Hos-
pital, Toho University, Tokyo Metropolitan Bokuto Hospital, To-
kyo Jikei Medical University, Tokyo Medical and Dental Univer-
sity, Saint Luku’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, Shin-
shu University, Iida Municipal Hospital, National Hospital Orga-
nization Shinshu Ueda Medical Center, Saku General Hospital,
Niigata University, Niigata Prefectural Central Hospital, Niigata
Municipal Hospital, Nagaoka Red Cross Hospital, Koseiren Taka-
oka Hospital, Toyama Prefectural Central Hospital, Toyama Uni-
versity, 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 Hospi-
tal, 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 Hospi-
tal, Komaki Municipal Hospital, Toyota Memorial Hospital, Oka-
zaki Municipal Hospital, Konan Kosei Hospital, National Mie
Central Medical Center, Ise Red Cross Hospital, Yokkaichi Mu-
nicipal Hospital, Otsu Red Cross Hospital, Shiga University of
Medical Science Hospital, Nagahama Red Cross Hospital, Uji
Tokushukai Hospital, The Japan Baptist Hospital, Kyoto Univer-
sity, Kyoto Red Cross Daiichi Hospital, National Maizuru Medical
Center, Fukuchiyama City Hospital, Kyoto Prefectural University
of Medicine Hospital, Kyoto City Hospital, Mitsubishi Kyoto Hos-
pital, Yodogawa Christian Hospital, Osaka Medical Center and
Research Institute for Maternal and Child Health, Osaka Univer-
sity, Takatsuki General Hospital, Kansai Medical University, Osa-
ka City General Hospital, Osaka City Sumiyoshi Hospital, Aizen-
bashi Hospital, Toyonaka Municipal Hospital, National Cerebral
and Cardiovascular Center, Kitano Hospital, Saiseikai Suita Hos-
pital, Chifune Hospital, Bell Land General Hospital, Rinku Gen-
eral 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 Univer-
sity, Wakayama Medical University, Tottori Prefectural Central
Hospital, Tottori University, Shimane Prefectural Central Hospi-
tal, Matsue Red Cross Hospital, Kurashiki Central Hospital,
Tsuyama Central Hospital, Kawasaki Medical School Hospital,
National Hospital Organization Okayama Medical Center, Okaya-
ma Red Cross Hospital, Hiroshima City Hiroshima Citizens Hos-
pital, Hiroshima Prefectural Hospital, Hiroshima University,
Tsuchiya General Hospital, National Hospital Organization Kure
Medical Center, Yamaguchi University, Yamaguchi Grand Medi-
cal Center, Tokushima University, Tokushima Municipal Hospi-
tal, Kagawa University, National Hospital Organization Kagawa
Children’s Hospital, Matsuyama Red Cross Hospital, Ehime Pre-
fectural Central Hospital, Kochi Health Science Center, St. Mary’s
Hospital, National Kyushu Medical Center, Kurume University,
Kitakyushu Municipal Medical Center, University of Occupation-
al and Environmental Health, Fukuoka University, Kyushu Uni-
versity, Iizuka Hospital, National Hospital Organization Kokura
Medical Center, National Hospital Organization Saga Hospital,
National Hospital Organization Nagasaki Medical Center, Kuma-
moto City Hospital, Kumamoto University, Oita Prefectural Hos-
pital, Almeida Memorial Hospital, Nakatsu Municipal Hospital,
Miyazaki University, National Hospital Organization Miyakonojo
Medical Center, Kagoshima City Hospital, Imakiire General Hos-
pital, Okinawa Prefectural Nanbu Medical Center & Children’s
Medical Center, Okinawa Prefectural Chubu Hospital, Naha City
Hospital, and Okinawa Red Cross Hospital.
Disclosure Statement
The authors declare no conflicts of interest.

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