Lung (2013) 191:425–433

DOI 10.1007/s00408-013-9475-3

Characteristics of Respiratory Distress Syndrome in Infants

of Different Gestational Ages
Huiqing Sun • Falin Xu • Hong Xiong • Wenqing Kang • Qiongdan Bai •

Yinghui Zhang • Chongchen Zhou • Fangli Zhuang • Xiaoyang Wang •

Changlian Zhu

Received: 17 September 2012 / Accepted: 3 May 2013 / Published online: 31 May 2013
Ó Springer Science+Business Media New York 2013

Abstract Results There was an increasing trend in incidence of

Background The purpose of this study was to compare RDS among the NICU admissions annually. Caesarean
the risk factors, clinical characteristics, and complications section without labor was significantly associated with
of respiratory distress syndrome (RDS) in infants delivered RDS in term and late preterm infants (P \ 0.001). Rates of
very preterm, late preterm, and term in order to help requirements for ventilator and pulmonary surfactant were
optimize the management of RDS in neonates. similar in very preterm and term infants but significantly
Methods A retrospective study was conducted on neo- lower in late preterm infants (P \ 0.001). The oxygenation
nates admitted to the NICU between January 2006 and index value was not substantially lower in late preterm and
December 2010. The enrolled infants with RDS were cate- term infants compared to very preterm infants, and the
gorized as very preterm (\320/7 weeks gestation), moder- arterial oxygenation efficiency was improved slowly
ately preterm (320/7–336/7 weeks), late preterm (340/7–366/7 (P \ 0.001). Incidence of pneumonia and occurrence of
weeks), and term (370/7–420/7 weeks). The rates, potential pneumothorax were significantly higher in term infants
risk factors, clinical characteristics, and complications of (P \ 0.001).
RDS of these four groups were comparatively analyzed. Conclusions Term infants with RDS showed an associa-
tion of RDS with caesarean section without labor and lung
infection. These infants also showed slower improvement
H. Sun and F. Xu contributed equally to this work.
of oxygenation after surfactant administration and
H. Sun
F. Xu
Q. Bai
F. Zhuang
X. Wang
C. Zhu (&) mechanical ventilation, and they experienced a high rate of
Department of Pediatrics, The Third Affiliated Hospital of pneumothorax complication, which was also noticed in late
Zhengzhou University, Zhengzhou 450052, China preterm neonates.
e-mail: zhuc@zzu.edu.cn

H. Sun (&)
H. Xiong
W. Kang
Y. Zhang
C. Zhou Keywords Respiratory distress syndrome
Preterm
Department of Pediatrics, Zhengzhou Children’s Hospital, infants
Term infants
Caesarean section
Lung infection
Zhengzhou 450053, China
e-mail: s_huiqing@sina.com
Abbreviations
X. Wang
C. Zhu BPD Bronchopulmonary dysplasia
Henan Key Laboratory for Neonatal Brain Injury, CMV Conventional mechanical ventilation
Zhengzhou, China CPAP Continuous positive airway pressure
CRP C-reactive protein
X. Wang
Perinatal Center, Sahlgrenska Academy, University FIO2 Fraction of inspiration oxygen
of Gothenburg, Göteborg, Sweden INSURE Intubation-surfactant-extubation
IVH Intraventricular hemorrhage
C. Zhu
MAP Mean airway pressure
Center for Brain Repair and Rehabilitation, Institute of
Neuroscience and Physiology, University of Gothenburg, MOSF Multiple organ system failure
Göteborg, Sweden NEC Necrotizing enterocolitis

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NICU Neonatal intensive care unit (320/7–336/7 weeks of gestation), late preterm (340/7–366/7
OI Oxygenation index weeks of gestation), and term (370/7–420/7 weeks of ges-
PaO2 Partial arterial oxygen pressure tation) [5]. Infants were excluded from study enrollment if
PS Pulmonary surfactant they had incomplete medical records, were admitted to the
RDS Respiratory distress syndrome NICU at [72 h of age, or had a major congenital anomaly.
The study was approved by the hospitals’ ethical
committees.

Definitions
Introduction
Neonates were diagnosed with RDS if they presented with
In China, the number of preterm infants with respiratory grunting, flaring, tachypnea, retractions, and/or supple-
distress syndrome (RDS) has risen steadily every year over mental oxygen requirement [6], and had imaging findings
the past decade. While the reason for the increase in pre- of homogeneous opaque infiltrates with air bronchograms,
term births is not well understood, possible contributing indicating contrast in airless lung tissue seen against air-
factors include the increased use of reproductive technol- filled bronchi or decreased lung volumes on chest radiog-
ogies [1–3] and of some newer obstetric practices such as raphy [7]. Perinatal variables included premature rupture of
caesarean section [1–4]. Preterm infants, born before membranes, defined as rupture of membranes before the
37 weeks of gestation (259 days from the first day of the first stage of labor; and maternal diabetes, defined as
mother’s last menstrual period) [1–3], are associated with a women who had preexisting diabetes mellitus, gestational
higher rate of respiratory morbidity. However, many of the diabetes, or an abnormal glucose-tolerance test result. The
obstetric management decisions use 34 weeks as an influ- chorioamnionitis was defined as either clinically diagnosed
ential marker for assessing the potential for developing chorioamnionitis [presence of maternal fever C38 °C,
newborn complications because by 34 weeks of gestation, elevated maternal C-reactive protein (CRP) [10 mg/L,
neonates have a lower risk for complications such as RDS fetal tachycardia, and prolonged ([24 h) rupture of mem-
[1–3]. The term ‘‘late preterm’’ was proposed to describe branes] or histologically diagnosed chorioamnionitis [8].
neonates born at 340/7–366/7 weeks of gestation [5]. Most of Primary emergency caesarean section was defined as cae-
the studies on morbidity and outcome of preterm infants to sarean section performed on an emergency basis for a
date have addressed either very preterm (\32 weeks of mother who had not had a previous caesarean section [9].
gestation) [1] or low-birth weight infants; very few studies Neonatal complications included bronchopulmonary dys-
have addressed problems in late preterm infants. Thus, the plasia (BPD), defined as the need for supplemental oxygen
differences in risk, clinical characteristics, and complica- on corrected age at 36 weeks of gestation [10, 11]; sepsis,
tions of RDS among the late preterm, moderately preterm, defined as neonatal laboratory data obtained in the setting
very preterm, and term infants remains unclear. of suspected early-onset sepsis, with or without associated
The purpose of this study was to compare the risks, antibiotic treatment, and which was detected by one of
clinical characteristics, and complications between very three clinical approaches: (a) blood culture and complete
preterm, moderately preterm, late preterm, and term infants blood count with differential count, (b) option (a) plus
with RDS. These data are expected to highlight areas antibiotic treatment for 48 h, or (c) option (a) plus antibi-
where further intervention is needed and to identify pre- otic therapy for at least 7 days [10, 11]; necrotizing
ventive aspects, thereby decreasing the incidence of RDS enterocolitis (NEC), defined according to the modified
and improving perinatal outcomes for all infants with RDS. Bell’s staging criteria [12] and for which NEC ‘‘watch’’
was carried out to evaluate NEC over a brief period
(48–72 h) without abdominal radiographs demonstrating
Materials and Methods the presence of pneumatosis; neonatal pneumonia [13],
defined as a neonate with respiratory distress (indicated by
Patient Population rapid, noisy, or difficult breathing, respiratory rate [60/
min, chest retractions, cough, or grunting) as well as a
Newborn infants admitted to the neonatal intensive care positive blood culture or any two or more of the following:
unit (NICU) at either Zhengzhou Children’s Hospital or the (1) predisposing factors: maternal fever (38 °C), foul
Third Affiliated Hospital of Zhengzhou University from smelling liquor, prolonged rupture of membranes ([24 h);
January 2006 to December 2010 were retrospectively (2) clinical features of sepsis: poor feeding, lethargy,
included in the study. The infants were categorized as very poor neonatal reflexes, hypothermia or hyperthermia,
preterm (\320/7 weeks of gestation), moderately preterm abdominal distension; (3) radiography findings suggestive

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of pneumonia that are not resolved within 48 h, i.e., nod- RDS), 1,851 moderately preterm infants (892 with RDS
ular or coarse patchy infiltrate, diffuse haziness or granu- and 959 without RDS), 5,060 late preterm infants (657 with
larity, air bronchogram, lobar or segmental consolidation; RDS and 4,403 without RDS), and 16,513 term infants
(4) sepsis screening positive results for leukocyte bands (276 with RDS and 16,237 without RDS) (Fig. 1).
[20 %, leukocyte count out of reference range (\4 9 109,
[12 9 109), elevated CRP ([10 mg/L), or elevated Demographic Characteristics of RDS
erythrocyte sedimentation rate ([10 mm/h).
NICU admissions showed an increasing annual trend. There
Data Collection was no significant difference in the mean birth weight for each
of the 5 years of the study period. The overall ratio of RDS
Each patient’s data were recorded on a standardized case among the NICU admissions increased yearly from 5.4 % in
report form. The data included demographic variables, 2006 to 21.1 % in 2010 (P \ 0.001). The incidence of RDS
perinatal history, maternal diseases, mode of delivery, over the 5-year period in the very preterm, moderately pre-
problems at birth, neonatal morbidity, and complications. term, late preterm, and term groups was 10, 9, 6.6, and 2.8 %,
The annual rates of RDS in very preterm, moderately respectively. The incidence of RDS increased annually for all
preterm, late preterm, and term infants were calculated and groups over the 5-year study period, with intergroup differ-
compared for the calendar years of 2006–2010. The dif- ences showing statistical significance (Table 1). Intriguingly,
ferences in demographic variables, risk factors, clinical the increase was highest in the very preterm group and lowest
outcomes, and complications between the groups of the in the term group. Moreover, the annual increases for the term
very preterm, moderately preterm, late preterm, and term group were significantly different from 2006 to 2009, and for
infants with RDS were analyzed. For infants who received late preterm infants in 2010 compared to 2009 (Table 1).
mechanical ventilation, the oxygenation index (OI = By birth weight category, the incidence of RDS over the
[mean arterial pressure (MAP) 9 fraction of inspiration 5-year period in the less than 1,500-g group was 22 %, and in
oxygen (FiO2) 9 100]/partial arterial oxygen pressure the 1,500–2,000-g, 2,001–2,500-g, and more than 2,500-g
(PaO2)) and the PaO2/FiO2 ratio were calculated. To ensure groups it was 21.8, 10.6, and 7.4 %, respectively. The increase
quality, data collection was supervised by NICU directors was highest in the less than 1,500-g group and lowest in the
of the respective hospitals. more than 2,500-g group. The annual increase in RDS inci-
dence for the less than 1,500-g group was significantly dif-
Statistical Analyses ferent in 2008 compared to 2007 and in 2010 compared to
2009; for the 1,500–2,000-g group in 2009 compared to 2008
Statistical analyses were performed using SPSS 17.0 soft- and in 2010 compared to 2009; for the 2,001–2,500-g group in
ware (SPSS, Inc., Chicago, IL, USA). Univariate analyses 2008 compared to 2007; or for the more than 2,500-g group in
on continuous variables were compared by one-way 2008 compared to 2007 and in 2009 compared to 2008.
ANOVA test, and categorical variables were compared by The ratio of males to females was 1,240/682 (64.5 %) in
v2 test or Fisher’s exact test as appropriate. Continuous the very preterm group, 584/308 (65.5 %) in the moderately
variables are expressed as mean ± SD or as median with preterm group, 445/212 (67.7 %) in the late preterm group,
range, and categorical variables are expressed as counts or and 234/42 (84.8 %) in the term group. Boys are more vul-
rates. The level of statistical significance was set at nerable to RDS than girls and it is even more pronounced in
P \ 0.05. the term infants (P \ 0.001). When age at admission and age
at need for mechanical ventilation were considered, term
infants were the oldest and late preterm infants were older
Results than very preterm infants. Prenatal steroid use was highest in
very preterm infants and lowest in term infants. Apgar score
A total of 26,634 infants less than 72 h of age were iden- at 5 min was highest in term infants and lowest in very pre-
tified for the study’s target period, which included 4,437 term infants. All of these characteristics were significantly
infants born in 2006; 4,288 infants born in 2007; 5,693 different between the very preterm, moderately preterm, late
infants born in 2008; 5,581 infants born in 2009; and 6,635 preterm, and term groups (P \ 0.001) (Table 2).
infants born in 2010. The annual admission rate increased
49.5 % over the 5-year study period. A total of 174 infants Risk Factors for RDS
(71 with incomplete medical records and 103 with a major
congenital anomaly) were excluded from analysis. The As shown in Table 3, maternal age [ 40 years, antenatal
remaining 26,460 infants used in analysis included 3,036 vaginal bleeding, oligohydramnios, premature rupture of
very preterm infants (1,922 with RDS and 1,114 without membranes, and fetal growth restriction were significantly

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Fig. 1 Overview of the studied 26634 neonatal infants over 5 years (2006-2010)
neonates

4437 infants in 2006 4288 infants in 2007 5693infants in 2008 5581infants in 2009 6635infants in 2010

174 infants ineligible

3036 very preterm infants 1851 moderate preterm infants 5060 late preterm infants 16513 term infants

1922 with RDS 1114 no RDS 892 with RDS 959 no RDS 657 with RDS 4403 no RDS 276 with RDS 16237 no RDS

Table 1 RDS incidence in very preterm, moderately preterm, late preterm, and term infants over the 5-year study period
2006 2007 2008 2009 2010 P value

Neonates with RDS 240/4,437 (5.4) 404/4,288 (9.4)* 707/5,693 (12.4)** 997/5,581(17.9)*** 1,399/6,635 (21.1)**** \0.001
[n/N (%)]
Gestational age
Very preterm [n/N (%)] 141/235 (60.0) 216/337 (64.1) 392/622 (63.0) 498/753 (66.1) 675/961 (70.2) 0.006
Moderately preterm 66/218 (30.3) 94/311 (30.2) 153/493 (31.0) 228/645 (35.3) 351/897 (39.1) 0.004
[n/N (%)]
Late preterm [n/N (%)] 24/126 (19.0) 74/334 (22.2) 113/566 (20.0) 187/890 (21.0) 259/1,010 (25.6)**** 0.043
Term [n/N (%)] 9/3,858 (0.2) 20/3,306 (0.6)* 49/4,012 (1.2)** 84/3,293 (2.6)*** 114/3,767 (3.0) \0.001
Birth weight
\1,500 g [n/N (%)] 86/157 (54.9) 181/317 (57.2) 271/401 (67.6)** 333/484 (69.0) 525/683 (77.0)**** \0.001
*2,000 g [n/N (%)] 66/392 (17.0) 101/453 (22.3) 152/593 (25.6) 195/594 (32.8)*** 292/753 (38.8)**** \0.001
*2,500 g [n/N (%)] 59/440 (13.4) 97/634 (15.3) 148/711 (20.8) ** 182/791 (23.0) 235/982 (24.0) \0.001
[2,500 g [n/N (%)] 29/3,448 (0.8) 25/2,884 (0.9) 136/3,281 (4.1)** 287/3,712 (7.7)*** 347/4,217 (8.2) \0.001
* 2006 vs. 2007, P \ 0.05; ** 2007 vs. 2008, P \ 0.05; *** 2008 vs. 2009, P \ 0.05; **** 2009 vs. 2010, P \ 0.05

Table 2 Demographic data for very preterm, moderate preterm, late preterm, and term infants
Very preterm Moderately preterm Late preterm Term (n = 276) P values
(n = 1,922) (n = 892) (n = 657)

Overall RDS rate [n/total (%)] 1922/3,036 (63.3) 892/1,851 (48.2) 657/5,060 (13.0) 276/16,513 (1.7) \0.001
Male/female 1240/682 584/308 445/212 234/276 \0.001
Age at admission (h) (mean ± SD) 2.70 ± 4.18* 5.21 ± 4.71** 9.50 ± 6.80*** 11.01 ± 9.82**** \0.001
Prenatal steroid [n (%)] 947(49.3) 411(46.1) 235(35.8) 23(8.3) \0.001
Apgar score at 5 min (mean ± SD) 7.29 ± 2.21 7.31 ± 2.18 8.07 ± 2.09 8.95 ± 1.67 \0.001
Mechanical ventilation age 8.12 ± 9.35 12.23 ± 9.86 26.90 ± 19.71 29.13 ± 18.90 \0.0001
(h) (mean ± SD)
Maternal age in yearsa (mean ± SD) 30.31 ± 6.25 30.10 ± 5.97 29.34 ± 6.16 29.24 ± 4.90 \0.001
* range: 25, median: 2.70; **range: 28, median: 5.21; ***range: 40, median: 9.50; ****range: 59, median: 11.13
range: 13, median: 7.29; range: 13, median: 7.31; range: 12, median: 8.07; range: 10, median: 8.95
a
Maternal age in years (mean ± SD): F = 5.76, P \ 0.001

associated with RDS in preterm infants and especially in the very preterm, moderately preterm, and term groups but
very preterm infants. Maternal hypertension, diabetes, significantly lower in the late preterm group. Caesarean
chorioamnionitis, and reduced fetal movements were sig- section without labor was significantly associated with
nificantly higher in the late preterm group and significantly RDS in the term and late preterm groups. Maternal
lower in the term group. Asphyxia risk was similar among age [ 40 years, maternal hypertension, anemia, antenatal

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vaginal bleeding, oligohydramnios, chorioamnionitis, pre- preterm group; the term infants were the oldest
mature rupture of membranes, caesarean section without (P \ 0.001). In addition, the association of pneumonia
labor, perinatal asphyxia, reduced fetal movements, and with RDS was significantly higher in the term group
fetal growth restriction were all significantly associated (P \ 0.001) and otherwise similar among the other three
with RDS in the very preterm group (P \ 0.05) (Table 4). groups. More term infants received continuous positive
In the moderately preterm group, the occurrence of mul- airway pressure (CPAP) than very preterm infants, and the
tiple birth (twins and triplets) in addition to above-men- use of CPAP was lowest in the late preterm group. The use
tioned factors were also significantly associated with RDS of mechanical ventilation and administration of surfactant
(P \ 0.05). In the late preterm group, the occurrence of were similar in the very preterm group and the term group
multiple birth (twins and triplets), maternal age [ 40 and were lowest in the late preterm group (all P \ 0.001)
years, maternal hypertension, diabetes, anemia, vaginal (Table 6).
bleeding, oligohydramnios, chorioamnionitis, premature None of the groups showed significant differences in OI,
rupture of membranes, caesarean section without labor, and PaO2/FiO2 ratio, and PaCO2 measured before mechanical
perinatal asphyxia were significantly associated with RDS ventilation and after ventilation with surfactant use. The OI
(P \ 0.05) (data not shown). In the term group, occurrence value was substantially lower in the very preterm and
of multiple birth (twins and triplets), maternal age [ 40 moderately preterm groups than in the late preterm and
years, maternal hypertension, diabetes, oligohydramnios, term groups, which accompanied improvements in the
chorioamnionitis, premature rupture of membranes, cae- PaO2/FiO2 ratio. Significant difference in this ratio was
sarean section without labor, and perinatal asphyxia were observed 4 h after ventilation (P \ 0.05) (Table 7).
significantly associated with RDS (P \ 0.05) (Table 5).
Complications in Infants with RDS
Comparison of Respiratory Morbidity
The occurrence of pneumothorax was 9/1,922 (0.5 %) in
When age at NICU admission and age at surfactant the very preterm group, 5/892 (0.6 %) in the moderately
administration were evaluated, both the term group and the preterm group, 11/657 (1.7 %) in the late preterm group,
late preterm group were significantly older than the very and 19/276 (6.9 %) in the term group; it was highest in the

Table 3 Risk factors for RDS in very preterm, moderately preterm, late preterm, and term infants
Very preterm Moderately preterm Late preterm Term infants P value
(n = 1,922) (n = 892) (n = 657) (n = 276)

Singletons [n (%)] 1,392 (72.4) 585 (65.6) 399 (60.7) 272 (98.6) \0.001
Twins and triplets [n (%)] 530 (27.6) 307 (34.4) 258 (39.3) 4 (1.4) \0.001
Maternal age [n (%)]
18–40 years 1,480 (77.0) 702 (78.7) 526 (80.1) 232 (84.2) 0.04
[40 years 442 (23.0) 190 (21.3) 131 (19.9) 44 (15.8) 0.04
Maternal hypertension [n (%)] 559 (29.0) 269 (30.2) 207 (31.5) 22 (8.0) \0.001
Diabetes [n (%)] 13 (0.7) 13 (1.5) 97 (14.8) 29 (10.5) \0.001
Anemia [n (%)] 67 (3.5) 28 (3.1) 10 (1.5) 6 (2.2) 0.06
Vaginal bleeding [n (%)] 521 (27.1) 198 (22.2) 135 (20.5) 15 (5.4) \0.001
Oligohydramnios [n (%)] 401 (20.9) 170 (19.1) 101 (15.4) 17 (6.2) \0.001
Chorioamnionitis [n (%)] 288 (15.0) 127 (14.2) 131 (19.9) 52 (18.8) 0.005
PROM [n (%)] 596 (31.0) 251 (28.1) 139 (21.1) 15 (5.8) \0.001
Delivery type [n (%)]
Caesarean section 793 (41.3) 364 (40.8) 537 (81.7) 241 (87.3) \0.001
Caesarean section 220 (11.0) 99 (11.1) 101 (15.4) 136 (49.3) \0.001
without labor
Perinatal asphyxia [n (%)] 323 (16.8) 136 (15.3) 73 (11.1) 45 (16.3) 0.006
Reduced fetal 462 (24.0) 218 (24.4) 199 (30.3) 53 (19.2) \0.001
movements [n (%)]
Fetal growth restriction [n (%)] 365 (19.0) 162 (18.2) 73 (11.1) 4 (1.4) \0.001
PROM premature rupture of membrane

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Table 4 Association of risk factors for RDS in very preterm infants

Very preterm with Very preterm without OR [95 % CI] P value
RDS (n = 1922) RDS (n = 1,114)

Twins and triplets [n (%)] 530 (27.6) 245 (22.0) 0.98 [0.83–1.16] 0.83
Maternal age [ 40 years [n (%)] 442 (23.0) 119 (10.7) 2.45 [2.01–3.11] \0.001
Maternal hypertension [n (%)] 559 (29.0) 215 (19.3) 1.72 [1.44–2.05] \0.001
Diabetes [n (%)] 13 (0.7) 14 (1.3) 0.54 [0.25–1.14] 0.11
Anemia [n (%)] 67 (3.5) 89 (8.0) 0.42 [0.3–0.58] \0.001
Vaginal bleeding [n (%)] 521 (27.1) 257 (23.1) 1.24 [1.04–1.47] 0.01
Oligohydramnios [n (%)] 401 (20.9) 187 (16.8) 1.31 [1.08–1.58] 0.01
Chorioamnionitis [n (%)] 288 (15.0) 85 (7.6) 2.13 [1.66–2.75] \0.001
PROM [n (%)] 596 (31.0) 183 (16.4) 2.29 [1.90–2.75] \0.001
Caesarean section without labor [n (%)] 220 (11.4) 89 (8.0) 1.49 [1.15–1.93] 0.002
Perinatal asphyxia [n (%)] 323 (16.8) 20 (1.8) 11.05 [6.99–17.47] \0.001
Reduced fetal movements [n (%)] 462 (24.0) 223 (20.0) 1.26 [1.06–1.51] 0.01
Fetal growth restriction [n (%)] 365 (19.0) 135 (12.1) 1.70 [1.37–2.10] \0.001
PROM premature rupture of membrane

Table 5 Associations of risk factors for RDS in term infants

Term infants with Term infants without OR [95 % CI] P value
RDS (n = 276) RDS (n = 16,237)

Twins and triplets [n (%)] 4 (1.4) 32 (0.2) 7.42 [2.61–21.13] 0.003

Maternal age [ 40 years [n (%)] 44 (15.8) 160 (1.0) 19.06 [13.32–27.26] \0.001
Maternal hypertension [n (%)] 22 (8.0) 747 (4.6) 1.80 [1.16–2.79] 0.01
Diabetes [n (%)] 29 (10.5) 97 (0.6) 19.54 [12.67–30.14] \0.001
Anemia [n (%)] 6 (2.2) 162 (1.0) 2.21 [0.97–5.03] 0.06
Vaginal bleeding [n (%)] 15 (5.4) 1120 (6.9) 0.78 [0.46–1.31] 0.40
Oligohydramnios [n (%)] 17 (6.2) 373 (2.3) 2.89 [1.75–4.28] \0.001
Chorioamnionitis [n (%)] 52 (18.8) 97 (0.6) 38.63 [26.90–55.46] \0.001
PROM [n (%)] 15 (5.8) 161 (1.0) 5.74 [3.33–9.88] \0.001
Caesarean section without labor [n (%)] 136 (49.3) 860 (5.3) 17.37.20 [13.59–22.21] \0.001
Perinatal asphyxia [n (%)] 45 (16.3) 146 (0.9) 21.44 [14.98–30.69] \0.001
Reduced fetal movements [n (%)] 53 (19.2) 3258 (20.1) 0.95 [0.70–1.28] 0.76
Fetal growth restriction [n (%)] 4 (1.4) 325 (2.0) 0.72 [0.27–1.94] 0.67
PROM premature rupture of membrane

term group and lowest in the very preterm group 0.001 and P \ 0.001, respectively). There was no signifi-
(P \ 0.001). The occurrence of pulmonary hemorrhage cant difference in the occurrence of sepsis among the dif-
was 142/1,922 (7.4 %) in the very preterm group, 61/892 ferent gestation age groups (Table 8).
(6.8 %) in the moderately preterm group, 20/657 (3.0 %) in The incidence of NEC was 39/1,922 (2.0 %) in the very
the late preterm group, and 15/276 (5.4 %) in the term preterm group, and 33 of those infants had medical NEC
group; it was highest in the very preterm group, followed (10 with stage I, 11 with stage IIa, 7 with stage IIb, and 5
by the moderately preterm group (P \ 0.001). The occur- with stage IIIa) and 6 had surgical NEC. In the moderately
rence of intracranial hemorrhage was 135/1,922 (7.0 %) in preterm group, 11/892 (1.2 %) had NEC, including 9 with
the very preterm group, 47/892 (5.3 %) in the moderately medical NEC (4 with stage I, 3 with stage IIa, 1 with stage
preterm group, 13/657 (2.0 %) in the late preterm group, IIb, and 1 with stage IIIa) and 2 had surgical NEC. In the
and 2/276 (0.7 %) in the term group. The very preterm late preterm group, 5/657 (0.8 %) had NEC and all of them
group also had the highest occurrences of intracranial were medical (2 with stage I, 2 with stage IIa, and 1 with
hemorrhage [ grade II and BPD, while the rates of these stage IIb). In the term infants, only 1/276 (0.3 %) had NEC
two complications were lowest in the term group (P \ and the case was medical NEC (stage IIa). No cases of

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Table 6 Age at admission, incidence of pneumonia, and respiratory support for RDS in the neonatal groups
Very preterm Moderately preterm Late preterm Term P value
(n = 1,922) (n = 892) (n = 657) (n = 276)

Age at NICU admission 3.41 ± 3.74 5.12 ± 4.27 10.65 ± 6.32 16.78 ± 8.39 \0.001
(h) (mean ± SD)*
Infants with pneumonia [n (%)]** 766 (39.9) 348 (39.0) 263 (40.0) 182 (65.9) \0.001
Respiratory support [n (%)]**
CPAP 1209 (62.9) 536 (60.1) 383 (58.3) 199 (72.1) \0.001
Ventilator 749 (39.0) 331 (37.1) 171 (26.0) 110 (39.9) \0.001
Surfactant administration 1459 (75.9) 561 (62.9) 380 (57.8) 193 (70.0) \0.001
Age at surfactant administration 4.72 ± 4.53 5.38 ± 4.91 11.89 ± 11.73 17.73 ± 14.23 \0.001
(h) (mean ± SD)
* P values by one-way ANOVA test; ** P values by v2 test or Fisher’s exact test, as appropriate
CPAP continuous positive airway pressure

Table 7 Respiratory outcomes for infants with RDS

CMV CMV ? PS
Very preterm Moderately Late preterm F value P value Very preterm Moderately Late preterm F value P value
(n = 181) preterm and term (n = 568) preterm and term
(n = 134) (n = 106) (n = 197) (n = 175)

OI
0h 24.2 ± 4.6 24.4 ± 4.8 24.6 ± 5.1 0.24 0.78 28.3 ± 5.2 28.2 ± 5.2 28.1 ± 4.9 0.09 0.91
4h 20.2 ± 4.1 20.4 ± 4.1 21.8 ± 4.3 5.39 \0.001 21.4 ± 4.9 21.9 ± 5.0 23.5 ± 5.6 11.95 \0.001
8h 18.1 ± 5.7 18.9 ± 4.9 21.0 ± 4.7 10.46 \0.001 16.5 ± 3.7 17.4 ± 4.0 24.9 ± 4.2 325.03 \0.001
12 h 15.9 ± 4.3 16.1 ± 4.2 20.2 ± 3.9 39.89 \0.001 13.1 ± 4.8 15.0 ± 4.4 23.1 ± 4.7 303.08 \0.001
24 h 13.6 ± 4.1 13.8 ± 4.2 19.8 ± 4.0 87.27 \0.001 9.9 ± 3.7 10.1 ± 4.0 20.1 ± 4.5 471.67 \0.001
PaO2/FiO2
0h 109.4 ± 62.1 104.6 ± 59.1 103.1 ± 40.5 0.50 0.61 93.7 ± 30.3 94.1 ± 30.2 94.9 ± 29.6 0.10 0.91
4h 110.3 ± 13.2 111.3 ± 15.1 100.9 ± 30.3 10.17 \0.001 129.2 ± 30.2 129.0 ± 29.7 110.2 ± 28.4 28.81 \0.001
8h 118.2 ± 17.3 116.5 ± 18.1 107.6 ± 25.7 9.97 \0.001 139.1 ± 26.3 138.4 ± 6.0 112.7 ± 25.3 71.90 \0.001
12 h 129.3 ± 13.2 128.3 ± 14.4 116.2 ± 29.8 17.48 \0.001 151.2 ± 27.1 149.7 ± 25.5 111.5 ± 24.8 158.45 \0.001
24 h 150.3 ± 14.7 149.9 ± 15.4 139.3 ± 20.1 17.16 \0.001 193.3 ± 31.3 190.3 ± 30.2 141.3 ± 25.2 208.30 \0.001
CMV conventional mechanical ventilation, PS pulmonary surfactant

Table 8 Complications among infants with RDS

Very preterm Moderately preterm Late preterm Term P value
(n = 1,922) (n = 892) (n = 657) (n = 276)

Pneumothorax [n (%)] 9 (0.5) 5 (0.6) 11 (1.7) 19 (6.9) \0.001

Pulmonary hemorrhage [n (%)] 142 (7.4) 61 (6.8) 20 (3.0) 15 (5.4) \0.001
Intracranial hemorrhage [ grade II 135 (7.0) 47 (5.3) 13 (2.0) 2 (0.7) \0.001
[n (%)]
BPD [n (%)] 154 (8.0) 46 (5.2) 18 (2.7) 3 (1.1) \0.001
NEC [n (%)] 39 (2.0) 11 (1.2) 5 (0.8) 1 (0.3) \0.001
Sepsis [n (%)] 51 (2.7) 17 (1.9) 12 (1.8) 4 (1.4) 0.35
Mortality [n (%)] 97 (5.0) 25 (2.8) 13 (2.0) 3 (1.1) \0.001

surgical NEC occurred in the late preterm and term groups. 2 % (13/657) for late preterm infants, and 1.1 % (3/276)
The mortality rate was 5.0 % (97/1,922) for very preterm for term infants. Mortality decreased with increase in
infants, 2.8 % (25/892) for moderately preterm infants, gestational age (P \ 0.001) (Table 8).

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432 Lung (2013) 191:425–433

Discussion born by caesarean section after the onset of labor. The

concentration of surfactant protein-Ain cord blood has also
NICU admissions have continued to increase in China, as has been shown to be significantly lower in neonates who were
the incidence rate of RDS in neonates. In the past, RDS delivered by elective caesarean section close to term than
has been studied mainly in very preterm infants and less so in those delivered after onset of labor [23].
in late preterm and term infants [14]. In China, however, late The gestational age-related decline in both the incidence
preterm and term infants account for many of the NICU of RDS and the need for mechanical ventilation observed
admissions for respiratory failure, including cases of RDS. in the present study agrees with the results of a previous
The present study found that the incidence of RDS in late epidemiological study [24]. In addition, the term infants
preterm infants was one-third of that in very preterm infants, with RDS showed a higher pneumonia rate than the pre-
and that the incidence in term infants was one-fifth of that in term infants. The term infants with RDS improved with
very preterm infants. Males accounted for 84.8 % of the CPAP more often than the very preterm infants or the late
term, 67.7 % of the late preterm, and 64.5 % of the very preterm infants, both of whom required more intubations.
preterm infants with RDS. Preterm males have a greater risk The need for ventilator and surfactant administration was
of RDS than their female counterparts [15], and this differ- similar among term infants and very preterm infants with
ence was more significant for term infants. When the age at RDS but was lower in late preterm infants.
admission and age at mechanical ventilation were analyzed, In the present study, OI and PaO2/FiO2 ratio did not
the term infants and late preterm infants were found to be change dramatically after ventilation or surfactant admin-
older than the moderately preterm and very preterm infants. istration in term or late preterm infants with RDS compared
This fact indicates that the clinical signs of RDS in late to very preterm infants. This finding may indicate a dif-
preterm infants and term infants appear later than in the ferent pathogenesis of RDS in late preterm and term infants
moderately and very preterm infants. [23]. It is likely that the high rates of chorioamnionitis and
Advanced age of the mother [16] and twin gestation [17] pneumonia in late preterm infants and term infants may
have been previously reported as associated with increased have contributed, at least partly, to the RDS. Infection can
risk of preterm delivery, and the results from the current result in direct injury to the type II alveolar cells of the
study agree with those findings. Hypertension and fetal lung, decreasing synthesis, release, and processing of sur-
growth restriction are the other major predisposing condi- factant. Increased permeability of the alveolar capillary
tions for elective preterm delivery, but neither was inves- membrane to both fluid and solutes is known to result in
tigated in the present study. Finally, the strong association entry of plasma proteins into the alveolar hypophase, fur-
of vaginal bleeding, oligohydramnios, and premature rup- ther inhibiting the surface properties of surfactant [25]. In
ture of membranes in pregnancy with both spontaneous and term neonates, early RDS development manifests as a more
elective preterm deliveries in the present study also agreed severe form of the condition and its pathogenesis evolves
with a previous report [18]. more rapidly; thus, it is more likely to lead to the devel-
Caesarean section without labor was found to be opment of persistent pulmonary hypertension of the new-
strongly associated with RDS in late preterm and term born and multiple organ system failure (MOSF), especially
neonates in the present study. In recent decades, the rate of involving myocardial injury and acute renal failure [5].
caesarean section in China has increased and may be Most neonates with this condition require prolonged
related to the concomitant increase in RDS incidence in mechanical ventilation, ranging from 10 to 14 days, while
late preterm and/or term infants. Caesarean section without a minority requires mechanical ventilation for only 7 days
labor has already been reported as increasing the risk of [6]. Regardless, the mortality rate remains relatively high
respiratory morbidity in neonates [19, 20] due to delayed for these infants, and mortality is most often related to
clearance of lung fluid [21]. Transient tachypnea of the severe infection complicated by MOSF [26]. Cheong et al.
newborn is one such morbid condition [22] and usually [27] identified adenosine triphosphate-binding cassette
lasts for 2–5 days [7]. Neonates born by caesarean section protein, member A3 in term neonates with fatal RDS of
have a larger residual volume of lung fluid and secrete less unknown etiology.
surfactant to the alveolar surface; thus, they are at higher The use of ventilation and CPAP was much higher in term
risk of developing RDS. The process of labor is considered infants than in late preterm infants [110/276 (39.9 %) vs.
beneficial to the maturation of the surfactant system, by 171/657 (26.0 %)]; correspondingly, there was a higher
which the surfactant protein’s maturation and secretion are incidence of pneumothorax in term infants than in late pre-
triggered by b-adrenergic agents and prostaglandins. The term infants. Management strategies for very preterm infants
lungs of neonates born by caesarean section prior to the and moderately preterm infants with RDS include early
onset of labor are significantly more immature (as evi- surfactant administration, the intubation-surfactant-extuba-
denced by the lecithin–sphingomyelin ratio) than those tion sequence (known as INSURE) [28], and noninvasive

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ventilation [29]. However, the management strategies for bronchopulmonary dysplasia group. Pediatrics 117(3 Pt 2):
late preterm infants and term infants with RDS are more com- S52–S56
11. Kim GB (2010) Pulmonary hypertension in infants with bron-
plex. Perinatally acquired infection usually causes RDS in chopulmonary dysplasia. Korean J Pediatr 53(6):688–693
term neonates and broad spectrum antibiotics need to be 12. Berman L, Moss RL (2011) Necrotizing enterocolitis: an update.
administered as soon as possible, in addition to surfactant Semin Fetal Neonatal Med 16(3):145–150
therapy and ventilation support. Meanwhile, attention should 13. Duke T (2005) Neonatal pneumonia in developing countries.
Arch Dis Child Fetal Neonatal Ed 90(3):F211–F219
be given to identify and treat any cases of myocardial injury. 14. Raju TN, Higgins RD, Stark AR, Leveno KJ (2006) Optimizing
In summary, the rates of preterm births and of RDS are care and outcome for late-preterm (near-term) infants: a summary
steadily on the rise in China. Surfactant deficiency is the of the workshop sponsored by the National Institute of Child
most frequent etiology of RDS in very preterm and mod- Health and Human Development. Pediatrics 118(3):1207–1214
15. Roberge S, Lacasse Y, Tapp S, Tremblay Y, Kari A, Liu J, Fekih
erately preterm infants, while caesarean section and lung M, Qublan HS, Amorim MM, Bujold E (2011) Role of fetal sex
infection play major roles in RDS development in late in the outcome of antenatal glucocorticoid treatment to prevent
preterm and term infants. Term infants with RDS need respiratory distress syndrome: systematic review and meta-anal-
more respiratory support and have a higher incidence of ysis. J Obstet Gynaecol Can 33(3):216–226
16. Schempf AH, Branum AM, Lukacs SL, Schoendorf KC (2007)
pneumothorax. The different etiologies of neonatal RDS at Maternal age and parity-associated risks of preterm birth: differ-
different gestational ages necessitate tailored preventive ences by race/ethnicity. Paediatr Perinat Epidemiol 21(1):34–43
and treatment strategies. 17. Obiechina N, Okolie V, Eleje G, Okechukwu Z, Anemeje O
(2011) Twin versus singleton pregnancies: the incidence, preg-
Acknowledgments This work was supported by Innovation Scien- nancy complications, and obstetric outcomes in a Nigerian ter-
tists and Technicians Troop Construction Projects of Henan Province, tiary hospital. Int J Womens Health 3:227–230
the joint project of the Chinese Health Ministry and the Health 18. Yuan W, Duffner AM, Chen L, Hunt LP, Sellers SM, Bernal AL
Department of Henan Province, China. (2010) Analysis of preterm deliveries below 35 weeks’ gestation
in a tertiary referral hospital in the UK. A case-control survey.
Conflict of interest The authors have no conflicts of interest or BMC Res Notes 3:119
financial ties to disclose. 19. Hansen AK, Wisborg K, Uldbjerg N, Henriksen TB (2008) Risk
of respiratory morbidity in term infants delivered by elective
caesarean section: cohort study. BMJ 336(7635):85–87
20. Wu XJ, Zhang XD, Shi LP (2009) Retrospective analysis of
elective caesarean section and respiratory distress syndrome in
References the term neonates. Zhonghua Er Ke Za Zhi 47(9):658–661
21. Ramachandrappa A, Jain L (2008) Elective cesarean section: its
1. Hankins GD, Longo M (2006) The role of stillbirth prevention impact on neonatal respiratory outcome. Clin Perinatol 35(2):
and late preterm (near-term) births. Semin Perinatol 30(1):20–23 373-393, vii
2. Masoura S, Kalogiannidis I, Margioula-Siarkou C, Diamanti E, 22. Yurdakok M, Ozek E (2012) Transient tachypnea of the newborn:
Papouli M, Drossou-Agakidou V, Prapas N, Agorastos T (2012) the treatment strategies. Curr Pharm Des 18(21):3046–3049
Neonatal outcomes of late preterm deliveries with pre-eclampsia. 23. Roth-Kleiner M, Wagner BP, Bachmann D, Pfenninger J (2003)
Minerva Ginecol 64(2):109–115 Respiratory distress syndrome in near-term babies after caesarean
3. Moutquin JM (2003) Classification and heterogeneity of preterm section. Swiss Med Wkly 133(19–20):283–288
birth. BJOG 110(Suppl 20):30–33 24. Gouyon JB, Ribakovsky C, Ferdynus C, Quantin C, Sagot P,
4. Linhart Y, Bashiri A, Maymon E, Shoham-Vardi I, Furman B, Gouyon B (2008) Severe respiratory disorders in term neonates.
Vardi H, Mazor M (2000) Congenital anomalies are an inde- Paediatr Perinat Epidemiol 22(1):22–30
pendent risk factor for neonatal morbidity and perinatal mortality 25. Speer CP (2011) Neonatal respiratory distress syndrome: an
in preterm birth. Eur J Obstet Gynecol Reprod Biol 90(1):43–49 inflammatory disease? Neonatology 99(4):316–319
5. Bérard A, Le Tiec M, De Vera MA (2012) Study of the costs and 26. Liu J, Shi Y, Dong JY, Zheng T, Li JY, Lu LL, Liu JJ, Liang J,
morbidities of late-preterm birth. Arch Dis Child Fetal Neonatal Zhang H, Feng ZC (2010) Clinical characteristics, diagnosis and
Ed 97(5):F329–F334 management of respiratory distress syndrome in full-term neo-
6. Wang ML, Dorer DJ, Fleming MP, Catlin EA (2004) Clinical nates. Chin Med J (Engl) 123(19):2640–2644
outcomes of near-term infants. Pediatrics 114(2):372–376 27. Cheong N, Madesh M, Gonzales LW, Zhao M, Yu K, Ballard PL,
7. Hermansen CL, Lorah KN (2007) Respiratory distress in the Shuman H (2006) Functional and trafficking defects in ATP
newborn. Am Fam Physician 76(7):987–994 binding cassette A3 mutants associated with respiratory distress
8. Schlapbach LJ, Frey S, Bigler S, Manh-Nhi C, Aebi C, Nelle M, syndrome. J Biol Chem 281(14):9791–9800
Nuoffer JM (2011) Copeptin concentration in cord blood in 28. Pfister RH, Soll RF (2012) Initial respiratory support of preterm
infants with early-onset sepsis, chorioamnionitis and perinatal infants: the role of CPAP, the INSURE method, and noninvasive
asphyxia. BMC Pediatr 11:38 ventilation. Clin Perinatol 39(3):459–481
9. Wylie BJ, Gilbert S, Landon MB, Spong CY, Rouse DJ, Leveno 29. Gizzi C, Papoff P, Giordano I, Massenzi L, Barbara CS, Campelli
KJ, Varner MW, Caritis SN, Meis PJ, Wapner RJ et al (2010) M, Panetta V, Agostino R, Moretti C (2012) Flow-synchronized
Comparison of transverse and vertical skin incision for emer- nasal intermittent positive pressure ventilation for infants
gency cesarean delivery. Obstet Gynecol 115(6):1134–1140 \ 32 weeks’ gestation with respiratory distress syndrome. Crit
10. Walsh MC, Szefler S, Davis J, Allen M, Van Marter L, Abman S, Care Res Pract 2012:301818
Blackmon L, Jobe A (2006) Summary proceedings from the

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