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172 doi: 10.1111/ppe.12035

Risk Factors for Acute Respiratory Morbidity in

Moderately Preterm Infants
Maria Altman,a Mireille Vanpée,b Sven Cnattingius,c Mikael Normana
a
Department of Clinical Science, Intervention and Technology
b
Department of Women’s and Children’s Health
c
Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden

Abstract
Background: Infants born preterm account for a substantial part of neonatal morbidity, with acute respiratory
disorders being a dominating clinical problem. Whereas focus in recent studies has been on extremely and very
preterm infants, less is known about contemporary rates and risk factors for acute respiratory morbidity in
moderately and late preterm infants. The objective of this population-based Swedish study was to establish rates
for different acute respiratory diseases in moderately preterm infants, and to identify maternal, obstetric and
neonatal risk factors for the two most common diagnoses, transient tachypnoea of the newborn (TTN) and respi-
ratory distress syndrome (RDS).
Methods: The study included 4679 moderately preterm [gestational age (GA): 30 to 34 weeks], 15 036 late preterm
infants (GA 35 to 36 weeks) and 451 479 term infants (GA: 37 to 41 weeks). All infants were born in 2004–2008.
Results: In moderately preterm infants, risk factors for TTN in multivariable analyses were multiparity, caesarean
section before and after onset of labour, male sex, Apgar score 4–6 at 5 min and lower GA. Risk factors for RDS
were multiparity, caesarean section before and after onset of labour, male sex, Apgar score <7 at 5 min and lower
GA. Preterm rupture of membranes, antenatal corticosteroid treatment and being small for gestational age reduced
the risk of RDS.
Conclusion: We conclude that acute respiratory morbidity in moderately preterm infants is common and predicted
by multiparity, caesarean section, low Apgar score and male sex.

Keywords: preterm, respiratory morbidity, neonatal, risk factors.

Recent advances in neonatal care have contributed to a
dramatically improved survival after preterm delivery.
Preterm delivery is therefore increasingly considered
a medically indicated intervention in the management
of both maternal and fetal pregnancy complications.
Among preterm births today, approximately 45%
result from a medical intervention and induced deliv-
ery.1 However, infants born preterm – and not only
those born very or extremely preterm – still face a
substantial risk of neonatal morbidity.2–4 Because of
the large numbers, contributions from moderately
preterm births to neonatal morbidity, later complica-
tions and resource utility are considerable.5–7
In a previous study, we found that almost one-third
of preterm infants born at 30–34 gestational weeks
Correspondence:
Maria Altman, Astrid Lindgren Children’s Hospital B 57,
Karolinska University Hospital Huddinge, 141 86 Stockholm,
Sweden.
E-mail: maria.altman@ki.se
exhibited either transient tachypnoea of the newborn
(TTN) and/or respiratory distress syndrome (RDS).2
Accordingly, these acute respiratory disorders are
common diagnoses after moderately preterm birth.
Compared with 30-year-old Swedish data, the inci-
dence rates of these diseases have not decreased
among preterm infants, if anything, the opposite
seems to be the case.8
Risk factors for respiratory morbidity have
recently been investigated in large studies of
extremely or very preterm infants9 and late pre-
term infants.3,4,10,11 However, the predictors of
acute respiratory morbidity in the large group in
between, i.e. in preterm infants born at 30–34
gestational weeks, have been poorly explored.12 To
address this gap in knowledge, we performed a large
population-based study of clinically important and
readily available maternal, obstetric and infant risk
factors for TTN and RDS in moderately preterm
infants.

© 2013 Blackwell Publishing Ltd

Paediatric and Perinatal Epidemiology, 2013, 27, 172–181

Methods
Data sources
The Swedish National Board of Health and Welfare,
and the Swedish Perinatal Quality Register (MedSci-
Net AB, Stockholm, Sweden) supported data from
two population-based registers. Record linkage of
individuals across these registers was made possible
through the unique National Registration Number
assigned to each Swedish resident at birth or immi-
gration. The Swedish Birth Registry started in 1973
and contains prospectively collected data on mother,
pregnancy, delivery and infant on 98% to 99% of all
births in Sweden. The Swedish Perinatal Quality Reg-
ister contains prospectively collected data on infants
admitted for any level of neonatal care in Sweden.
During the study period, 81% of Swedish neonatal
units reported data on all their admitted patients. The
study protocol was approved by the regional ethical
vetting board.
Study population
The study included infants born in Sweden at 30–34
completed weeks from 1 January 2004 through 30
June 2008, who were registered in the Perinatal
Quality Register. Three hundred and eighteen infants
were excluded because of lack of reliable identifica-
tion data, leaving 6362 moderately preterm infants
[defined as gestational age (GA) 300 to 346 weeks] in
the study group. In addition, we collected data from
the Birth Registry on 18 010 late preterm infants (GA
350 to 366 weeks) and 457 044 term infants (GA 370 to
416 weeks) born during the same time period. The
term infants were used as reference group. We
included single births only because neonatal morbid-
ity may differ between multiple and singleton born
infants, and because the reliability of identification of
same-sex twins was uncertain. After exclusion of all
multiple births, there were 4679 moderately preterm
infants in the study group in addition to 15 036 infants
born at 35–36 weeks and 451 479 infants born at 37–41
weeks in the term reference group.
Exposures
Based on a priori knowledge3,8,13 and availability in the
registers, the following exposure variables were
defined prior to analyses: self-reported smoking
habits (non-smoker, 1–9 cigarettes daily, 10 or more
© 2013 Blackwell Publishing Ltd
Paediatric and Perinatal Epidemiology, 2013, 27, 172–181
Preterm birth and respiratory morbidity 173
cigarettes daily) at the first antenatal visit, maternal
age and parity (primipara: no viable previous
pregnancies; multipara: at least one prior viable preg-
nancy), chronic diseases, assisted conception, preg-
nancy diagnoses and mode of delivery as well as the
infant’s year of birth, birthweight (BW), sex, GA and
diagnoses at discharge. Mothers’ body mass index
(BMI) was calculated as pre-pregnancy weight (kg)
divided by height squared (m). Diagnoses were coded
according to the 10th version of International Classifi-
cation of Diseases (ICD-10). GA was assessed by ultra-
sound at 16 to 18 postmenstrual weeks in 97% of the
pregnancies and by last menstrual period in remain-
ing pregnancies. BW was categorised into standard
deviations (SD) of expected BW for GA according to
the Swedish reference curve for normal fetal growth14
and small for gestational age (SGA) was defined as a
BW for GA of <2 SD below the mean.
The following variables were considered as possible
risk factors for TTN and RDS in the neonatal period:
maternal age (<24, 25–29, 30–34 and ⱖ35 years), parity
(primi- and multiparity), BMI in early pregnancy (<25,
25–29 and ⱖ30 kg/m2), chronic maternal diseases
[asthma n = 321 (7.3% of all mothers to moderately
preterm infants), renal disorders n = 31 (0.7%), diabe-
tes mellitus n = 83 (1.9%), ulcerative colitis n = 36
(1.0%), systemic lupus erythematosus n = 8 (0.2%) and
chronic hypertension n = 65 (1.5%)], assisted concep-
tion (hormonal stimulation of ovaries, surgical treat-
ment of infertility, intracytoplasmatic sperm injection
and/or other form of assisted conception), preec-
lampsia (including eclampsia), preterm rupture of
membranes before onset of labour (regardless of time
to delivery), mode of delivery [vaginal delivery, cae-
sarean section (CS) before onset of labour, CS after
onset of labour and unspecified CS], antenatal steroid
treatment, SGA, infant sex, Apgar score at 5 min age
(0–3, 4–6, 7–10) and GA in completed weeks.
Outcomes
To estimate morbidity rates at different GA, infant res-
piratory diagnoses were derived from the Swedish
Birth Registry. The following diseases were included
as outcomes: transient tachypnoea of the newborn
[(TTN) ICD-10 code P22.1], respiratory distress syn-
drome [(RDS) P22.0], pneumothorax and pulmonary
interstitial emphysema (P25.1 and P25.0), pneumonia
(P23 and J12-J18) and persistent pulmonary hyperten-
sion (P29.3B).
174 M. Altman et al.
For the risk factor analysis, we chose to study the
two most common outcomes, i.e. TTN and RDS,
separately. The risk factor analysis was restricted to
the group of moderately preterm infants (born at 300–
346 weeks of GA) who all (both those with and
without respiratory disorders) had been admitted for
neonatal care and for which data had been prospec-
tively collected in the Perinatal Quality Register. In
this register, TTN was predefined as an acute, non-
infectious respiratory disorder with abnormal chest
X-ray findings and decreasing need for supplemental
oxygen therapy during the first 24 h after birth. RDS
was defined as progressively increasing central cya-
nosis or increasing need for supplemental oxygen
to maintain PaO2 ⱖ 50 mmHg (ⱖ6.6 kPa) during the
first 24 h after birth, combined with a typical chest
X-ray.
Statistical analyses
Data are presented as means [standard deviations
(SD)] or proportions (numbers and percentages).
Group differences were tested by c2-test. Logistic
regression was used to obtain odds ratios (OR) and
95% confidence intervals (CI) in multivariable analy-
ses. The risk of respiratory disease in term infants was
used as reference (OR = 1.0) in comparisons of infants
born at different GAs.
Risk factors for TTN and RDS were divided into
maternal, obstetric and infant risk factors. GA was a
priori considered to be the strongest risk factor for
respiratory morbidity and was included in all multi-
variable models. Because maternal and/or obstetric
risk factors may confound associations between infant
characteristics and outcomes, the final multivariable
model included all risk factors. However, the infant
characteristics factors may appear in the causal
pathway from some of the maternal/obstetric factors
to the diagnosis of TTN or RDS. Accordingly, the
infant characteristics (except GA) are not included in
the final multivariable model of maternal/obstetric
characteristics. The analysis did not account for
correlations between births to the same mother, but
multiparity was included as a confounder in the
multivariable analysis.
SGA was a priori considered a possible effect modi-
fier on the association of GA and RDS. Effect modifi-
cation was tested by likelihood ratio interaction test
and stratification of variables with suspected interac-
tion, and a P-value <0.05 was considered significant.
All analyses were performed with Stata 9.2 software
(Stata-Corp, College Station, TX, USA).
Results
Between 2004 and 2008, mean maternal age at deliv-
ery was 30.3 years in Sweden, 22% of the mothers
were born outside the Nordic countries (i.e. not born
in Sweden, Denmark, Finland, Iceland or Norway),
25% were overweight (BMI ⱖ 25 kg/m2) in early
pregnancy and daily smoking in early pregnancy
decreased from 8.8% to 6.9%.15
Of the 4679 moderately preterm infants, mean GA
was 32.8 (1.3) weeks and mean BW was 2117 (484) g.
Fifty-six per cent of all infants were boys. Mean Apgar
score at 5 min was 9.1 (1.4), and 52 (1.1%) had an
Apgar score of 0 to 3 at 5 min. Of the 15 036 infants in
the late preterm population, mean GA was 36.1 (0.6)
weeks and mean BW was 2817 (454) g. Fifty-three per
cent of all late preterm infants were boys, mean Apgar
score at 5 min was 9.6 (1.0) and 61 late preterm infants
(0.4%) had an Apgar score of 0 to 3 at 5 min. Of the
451 479 infants in the term reference population, mean
GA was 39.9 (1.1) weeks and mean BW was 3535
(462) g. Forty-nine per cent of all reference infants
were boys, mean Apgar score at 5 min was 9.8 (0.6)
and 365 reference infants (0.04%) had an Apgar score
of 0 to 3 at 5 min. The proportions of maternal and
obstetric risk factors are described in Table S1. Risks
of TTN, RDS, pneumothorax/PIE, pneumonia and
PPHN among infants born at 30–32 weeks, 33–34
weeks and 35–36 weeks as compared with term
infants are presented in Table 1.
Respiratory morbidity in moderately
preterm infants
The most common respiratory disease in both moder-
ately preterm infants and the term reference popula-
tion was TTN (Table 1). Compared with the reference
group, moderately preterm infants had substantially
increased risks of all respiratory diseases. Of the total
population of moderately preterm infants, 28% had
TTN and/or RDS. The corresponding rates were 59%
among infants born at 30 and 17% among infants born
at 34 gestational weeks.
Risk factors for TTN
Within the population of moderately preterm infants,
14% (n = 663) had TTN, ranging from 11% at 34 weeks
© 2013 Blackwell Publishing Ltd
Paediatric and Perinatal Epidemiology, 2013, 27, 172–181
 Preterm birth and respiratory morbidity 175

Table 1. Risk of acute respiratory morbidity in preterm infants (categorised according to gestational age) as compared with term infants
(gestational age 37–41 weeks)

Gestational age (weeks)

Respiratory Total number
morbidity of cases 30–32 (n = 1683) 33–34 (n = 2996) 35–36 (n = 15 036) 37–41 (n = 451 479)

TTN 2833
Rate (%) 17.9 11.5 3.5 0.4
OR [95% CI] 57.4 [50.2, 65.7] 34.3 [30.2, 39.0] 9.5 [8.6, 10.5] 1.0 [Reference]
RDS 969
Rate (%) 23.2 6.3 1.4 0.04
OR [95% CI] 806 [668, 973] 201 [163, 248] 38.7 [31.6, 47.3] 1.0 [Reference]
Pneumothorax/PIE 773
Rate (%) 3.7 1.6 0.7 0.1
OR [95% CI] 32.3 [24.8, 42.1] 15.4 [11.5, 20.7] 5.8 [4.7, 7.2] 1.0 [Reference]
Pneumonia 674
Rate (%) 0.7 1.0 0.4 0.1
OR [95% CI] 5.7 [3.2, 10.1] 9.0 [6.2, 13.0] 3.0 [2.3, 4.0] 1.0 [Reference]
PPHN 253
Rate (%) 1.2 0.6 0.3 0.04
OR [95% CI] 33.5 [21.3, 52.9] 18.9 [11.8, 30.4] 7.0 [5.0, 9.9] 1.0 [Reference]

Live singleton births in Sweden 2004–2008.

TTN, transient tachypnoea of the newborn; OR, odds ratio; CI, confidence interval; RDS, respiratory distress syndrome; PIE, pulmonary
interstitial emphysema; PPHN, persistent pulmonary hypertension.

to 21% at 30 weeks of GA. In the unadjusted analyses
of maternal and obstetric risk factors and TTN, high
(ⱖ35 years) maternal age, multiparity, preeclampsia
and CS were associated with increased risks of TTN,
whereas preterm rupture of membranes decreased
the risk of TTN (Table 2). After adjusting for
maternal/obstetric factors and GA, multiparity
increased the risk by 30% and CS after and before
onset of labour increased the risk of TTN by 30% and
60%, respectively. Overweight in the mother (BMI
25.0–29.9) was associated with a 20% decreased risk.
Adding infant characteristics to the model did not
change the results except for multiparity, which was
no longer significant (OR 1.23 [1.00, 1.51], data not
shown).
In the unadjusted analysis of infant risk factors and
TTN, use of antenatal steroids, male sex, low Apgar
scores (4–6) at 5 min and low GA were associated
with increased risks (Table 3). In the adjusted analy-
ses, there was no association between antenatal
corticosteroid use and risk of TTN, while other asso-
ciations remained essentially unchanged.
Risk factors for RDS
Within the population of moderately preterm infants,
13% (n = 630) had RDS, ranging from 6% at 34 weeks
to 38% at 30 weeks of GA. In the unadjusted analyses
of maternal and obstetric risk factors and RDS, multi-
parity, obesity (BMI ⱖ 30.0), chronic disease, preec-
lampsia and CS were associated with increased risks
and preterm rupture of membranes was associated
with a decreased risk (Table 4). After adjusting for
maternal/obstetric factors and GA, multiparity
increased risk of RDS by almost 50% and CS before
and after onset of labour more than doubled the risk.
Preterm rupture of membranes decreased the risk of
RDS. Adding infant characteristics to the multivari-
able model did not change the results (data not
shown).
In the unadjusted analysis of infant characteristics
and RDS, use of antenatal steroids, male sex, low
Apgar scores (0–3 and 4–6) at 5 min and low GA were
associated with increased risks (Table 5). However, in
the full model – adjusting for both maternal and
infant factors – use of antenatal steroids and SGA
status were associated with a reduced risk, which in
both cases was due to adjustment for gestational age.
Adjusting for infant characteristics only did not
change the results compared with the full model in
Table 5, except for moderately low Apgar scores
which remained a significant risk factor when
adjusted for infant characteristics only (OR 1.83 [1.29,
2.60]). The loss of moderately low Apgar scores as a

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Paediatric and Perinatal Epidemiology, 2013, 27, 172–181
176 M. Altman et al.

Table 2. Multivariable analysis of maternal and obstetric risk factors for transient tachypnoea of the newborn among 4679 moderately
preterm infants

Transient tachypnoea of the newborn (n = 663)

Maternal/obstetric risk factors Total (n) TTN (n) TTN (%) Unadjusted OR [95% CI] Adjusteda OR [95% CI]

Maternal age
<24 678 88 13.0 1.00 [Reference] 1.00 [Reference]
25–29 1329 149 11.2 0.85 [0.64, 1.12] 0.82 [0.60, 1.12]
30–34 1552 237 15.3 1.21 [0.93, 1.57] 1.09 [0.81, 1.47]
ⱖ35 1120 189 16.9 1.36 [1.04, 1.79] 1.02 [0.74, 1.41]
Parity
Primiparous 2639 328 12.4 1.00 [Reference] 1.00 [Reference]
Multiparous 2040 335 16.4 1.38 [1.17, 1.63] 1.28 [1.05, 1.56]
BMI
ⱕ24.9 2395 339 14.2 1.00 [Reference] 1.00 [Reference]
25.0–29.9 943 117 12.4 0.86 [0.69, 1.07] 0.79 [0.62, 0.99]
ⱖ30.0 527 78 14.8 1.05 [0.81, 1.38] 0.92 [0.69, 1.21]
Daily smoking in early pregnancy
No 3661 505 13.8 1.00 [Reference] 1.00 [Reference]
Yes 409 62 15.2 1.12 [0.84, 1.49] 1.15 [0.85, 1.56]
Chronic disease
No 4133 582 14.1 1.00 [Reference] 1.00 [Reference]
Yes 546 81 14.8 1.06 [0.83, 1.37] 1.05 [0.80, 1.38]
Assisted conception
No 4422 623 14.1 1.00 [Reference] 1.00 [Reference]
Yes 257 40 15.6 1.12 [0.79, 1.59] 1.24 [0.86, 1.79]
Preeclampsia
No 3866 523 13.5 1.00 [Reference] 1.00 [Reference]
Yes 813 140 17.2 1.33 [1.08, 1.63] 0.99 [0.76, 1.28]
Preterm rupture of membranes
No 3298 498 15.1 1.00 [Reference] 1.00 [Reference]
Yes 1381 165 11.9 0.76 [0.63, 0.92] 0.81 [0.65, 1.02]
Mode of delivery
Vaginal delivery 2326 266 11.4 1.00 [Reference] 1.00 [Reference]
CS after onset of labour 1878 304 16.2 1.50 [1.25, 1.79] 1.27 [1.02, 1.58]
CS before onset of labour 292 60 20.5 2.00 [1.47, 2.73] 1.59 [1.10, 2.30]
Unspecified CS 183 33 18.0 1.70 [1.14, 2.54] 1.50 [0.96, 2.33]

a
Adjusted for maternal age, parity, BMI, daily smoking in early pregnancy, chronic disease, assisted conception, preeclampsia, preterm
rupture of membranes, mode of delivery and infant’s gestational age.
TTN, transient tachypnoea of the newborn; OR, odds ratio; CI, confidence interval; BMI, body mass index; CS, caesarean section.

risk factor for RDS when adjusting for maternal/
obstetric factors was mainly due to BMI and smoking
status – when we only added these variables to the
model of infant characteristics, the corresponding OR
for moderately low Apgar scores was 1.31 [0.87, 1.98].
There was no interaction between SGA and GA on
risk of RDS.
Comment
In this nation-wide Swedish study, we found that risks
of TTN and RDS among infants born at 30–32 weeks
were increased by 57 and 806 times, respectively,
when compared with infants born at term. And risks
of TTN and RDS among infants born at 33–34 weeks
were increased by 12 and 201 times, respectively,
when compared with infants born at term. Risk factor
analysis within the group of moderately preterm
infants revealed three important findings: first,
increased risks of both TTN and RDS were associated
with low GA, low Apgar scores, delivery by caesarean
section and male sex. Secondly, vaginal delivery,
preterm rupture of membranes, antenatal corticoster-
oid therapy and SGA status were associated with a

© 2013 Blackwell Publishing Ltd

Paediatric and Perinatal Epidemiology, 2013, 27, 172–181
 Preterm birth and respiratory morbidity 177

Table 3. Multivariable analysis of infant characteristics and risk factors for transient tachypnoea of the newborn among 4679 moderately
preterm infants

Transient tachypnoea of the newborn (n = 663)

Infant characteristics Total (n) TTN (n) TTN (%) Unadjusted OR [95% CI] Adjusteda OR [95% CI]

Antenatal corticosteroid therapy

No 3001 384 12.8 1.00 [Reference] 1.00 [Reference]
Yes 1678 279 16.6 1.36 [1.15, 1.61] 1.08 [0.86, 1.34]
SGA status
No 4062 570 14.0 1.00 [Reference] 1.00 [Reference]
Yes 589 87 14.8 1.07 [0.83, 1.36] 0.79 [0.59, 1.07]
Sex
Female 2051 255 12.4 1.00 [Reference] 1.00 [Reference]
Male 2628 408 15.5 1.29 [1.09, 1.53] 1.25 [1.03, 1.52]
Apgar score at 5 min
0–3 52 9 17.3 1.32 [0.64, 2.72] 0.93 [0.38, 2.27]
4–6 213 46 21.6 1.74 [1.24, 2.44] 1.65 [1.13, 2.41]
7–10 4292 586 13.7 1.00 [Reference] 1.00 [Reference]
Gestational age (weeks)
30 384 81 21.1 2.25 [1.69, 3.00] 2.06 [1.44, 3.00]
31 562 109 19.3 2.03 [1.57, 2.62] 1.99 [1.44, 2.73]
32 737 131 17.7 1.82 [1.43, 2.31] 1.53 [1.13, 2.06]
33 1102 141 12.8 1.23 [0.98, 1.55] 1.18 [0.90, 1.56]
34 1894 201 10.6 1.00 [Reference] 1.00 [Reference]

a
Adjusted for maternal age, parity, BMI, daily smoking in early pregnancy, chronic disease, assisted conception, preeclampsia, preterm
rupture of membranes, mode of delivery, antenatal corticosteroid therapy, SGA status, sex, Apgar score at 5 min and gestational age.
TTN, transient tachypnoea of the newborn; OR, odds ratio; CI, confidence interval; SGA, small for gestational age; BMI, body mass
index.

reduced risk of RDS. Finally, maternal age, obesity,
assisted reproduction, smoking in pregnancy, chronic
disease or preeclampsia did not affect the risk of TTN
or RDS in moderately preterm infants.
The epidemiology of neonatal respiratory diseases
in Sweden has previously been reported.8 In a
population-based multicentre study from 1975,
approximately 35% of all preterm infants born at
30–34 weeks of GA were found to suffer from TTN or
RDS.8 In a hospital-based, longitudinal study of mor-
bidity in moderately preterm infants,16 we found no
significant change in RDS incidence between 1983 and
2002. Adding present findings, there is no evidence
that TTN or RDS morbidity in moderately preterm
infants has declined in Sweden over the past 30 years.
In a recent US multicentre study of 850 infants born
at 30–34 gestational weeks, the outcome was defined
as need for surfactant therapy which was used as a
proxy for RDS. In this US study, the risk difference
between 30-week and 34-week infants was substan-
tially larger than in our study but the CI was wider
because of the smaller study population.13 In addition,
four main factors were associated with reduction of
RDS incidence: non-White race (OR 0.5), longer gesta-
tional duration (30 vs. 34 weeks, OR 22.1), female sex
(OR 0.7) and use of antenatal corticosteroids (OR 0.6).
The effects of sex and antenatal corticosteroids of the
US study were comparable to our results, both in
direction and magnitude.
The strengths of the present study include the
population-based and contemporary design. The
number of observations was large, which provides
high precision in estimates. The cohort was defined
and stratified according to GA, estimated by ultra-
sound in 97% of all pregnancies. The fact that we
limited our study to singleton births means that
results can only be extrapolated to singletons,
accounting for 74% of all moderate preterm births in
the original cohort. Another limitation is the use of
register-derived data. Information and diagnoses were
prospectively collected and transferred to the registers
at the time of discharge of every infant. Although the
Perinatal Quality Register contains pre-made defini-
tions of all diagnoses, there may still be discrepancies

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Paediatric and Perinatal Epidemiology, 2013, 27, 172–181
178 M. Altman et al.

Table 4. Multivariable analysis of maternal and obstetric risk factors for respiratory distress syndrome among 4679 moderately
preterm infants

Respiratory distress syndrome (n = 630)

Maternal/obstetric risk factors RDS (n) RDS (%) Unadjusted OR [95% CI] Adjusteda OR [95% CI]

Maternal age
<24 84 12.4 1.00 [Reference] 1.00 [Reference]
25–29 166 12.5 1.01 [0.76, 1.33] 0.99 [0.71, 1.37]
30–34 212 13.7 1.11 [0.85, 1.47] 0.91 [0.65, 1.26]
ⱖ35 168 15.0 1.25 [0.94, 1.65] 0.84 [0.60, 1.20]
Parity
Primiparous 309 11.7 1.00 [Reference] 1.00 [Reference]
Multiparous 321 15.7 1.41 [1.19, 1.67] 1.46 [1.18, 1.81]
BMI
ⱕ24.9 303 12.7 1.00 [Reference] 1.00 [Reference]
25.0–29.9 119 12.6 1.00 [0.79, 1.25] 0.95 [0.75, 1.22]
ⱖ30.0 89 16.9 1.40 [1.09, 1.81] 1.10 [0.82, 1.46]
Daily smoking in early pregnancy
No 479 13.1 1.00 [Reference] 1.00 [Reference]
Yes 56 13.7 1.05 [0.78, 1.42] 0.82 [0.59, 1.16]
Chronic disease
No 537 13.0 1.00 [Reference] 1.00 [Reference]
Yes 93 17.0 1.37 [1.08, 1.75] 1.31 [1.00, 1.73]
Assisted conception
No 600 13.6 1.00 [Reference] 1.00 [Reference]
Yes 30 11.7 0.84 [0.57, 1.24] 0.81 [0.52, 1.25]
Preeclampsia
No 478 12.4 1.00 [Reference] 1.00 [Reference]
Yes 152 18.7 1.63 [1.33, 1.99] 0.84 [0.64, 1.09]
Preterm rupture of membranes
No 528 16.0 1.00 [Reference] 1.00 [Reference]
Yes 102 7.4 0.42 [0.34, 0.52] 0.50 [0.38, 0.66]
Mode of delivery
Vaginal delivery 184 7.9 1.00 [Reference] 1.00 [Reference]
CS after onset of labour 358 19.1 2.74 [2.27, 3.31] 2.13 [1.67, 2.72]
CS before onset of labour 66 22.6 3.40 [2.49, 4.65] 2.57 [1.75, 3.77]
Unspecified CS 22 12.0 1.59 [0.99, 2.54] 1.26 [0.74, 2.15]

a
Adjusted for maternal age, parity, BMI, daily smoking in early pregnancy, chronic disease, assisted conception, preeclampsia, preterm
rupture of membranes, mode of delivery and infant’s gestational age.
RDS, respiratory distress syndrome; OR, odds ratio; CI, confidence interval; BMI, body mass index; CS, caesarean section.

between regions, centres or individual physicians in
definitions of certain diseases.
The risk of neonatal respiratory morbidity is con-
tinuously decreasing as gestational age increases. We
chose to study infants of 30–34 gestational weeks
because they are routinely admitted for neonatal care
and because population-based studies on their neona-
tal outcome are rare. Late preterm infants have higher
risks than full-term infants.3,4,10,11 By including late
preterm infants, we compared the respiratory morbid-
ity rates of moderately preterm infants not only with
those at the lowest risk (term infants), but also with
the outcome they would possibly have, had it been
possible to prolong pregnancy a few weeks more.
The risk of neonatal respiratory disease after
preterm rupture of membranes is modified by many
factors, such as GA, SGA status, latency period to
delivery,10 presence of histological chorioamnionitis17
and use of antibiotic therapy.18 Prenatal exposure to
cytokines and inflammatory mediators during sub-
clinical or clinical chorioamnionitis after prelabour
preterm rupture of membranes has been thought to
accelerate fetal lung maturation and decrease the inci-
dence of RDS.19 However, clinical observations have

© 2013 Blackwell Publishing Ltd

Paediatric and Perinatal Epidemiology, 2013, 27, 172–181
 Preterm birth and respiratory morbidity 179

Table 5. Multivariable analysis of infant characteristics and risk factors for respiratory distress syndrome among 4679 moderately
preterm infants

Respiratory distress syndrome (n = 630)

Infant characteristics RDS (n) RDS (%) Unadjusted OR [95% CI] Adjusteda OR [95% CI]

Antenatal corticosteroid therapy

No 348 11.2 1.00 [Reference] 1.00 [Reference]
Yes 282 16.8 1.54 [1.30, 1.83] 0.68 [0.54, 0.86]
SGA status
No 541 13.3 1.00 [Reference] 1.00 [Reference]
Yes 84 14.2 1.08 [0.84, 1.38] 0.52 [0.38, 0.72]
Sex
Female 232 11.3 1.00 [Reference] 1.00 [Reference]
Male 398 15.1 1.40 [1.18, 1.66] 1.58 [1.28, 1.96]
Apgar score at 5 min
0–3 17 32.7 3.42 [1.90, 6.14] 2.62 [1.29, 5.32]
4–6 52 24.4 2.27 [1.64, 3.14] 1.09 [0.71, 1.66]
7–10 534 12.4 1.00 [Reference] 1.00 [Reference]
Gestational age (weeks)
30 146 38.0 9.40 [7.11, 12.43] 12.00 [8.28, 17.39]
31 146 26.0 5.38 [4.12, 7.02] 7.36 [5.19, 10.43]
32 121 16.4 3.01 [2.30, 3.95] 3.94 [2.81, 5.53]
33 101 9.2 1.55 [1.17, 2.04] 1.82 [1.30, 2.54]
34 116 6.1 1.00 [Reference] 1.00 [Reference]

a
Adjusted for maternal age, parity, BMI, daily smoking in early pregnancy, chronic disease, assisted conception, preeclampsia, preterm
rupture of membranes, mode of delivery, antenatal corticosteroid therapy, SGA status, sex, Apgar score at 5 min and gestational age.
RDS, respiratory distress syndrome; OR, odds ratio; CI, confidence interval; SGA, small for gestational age; BMI, body mass index.

been contradictory and both beneficial and detrimen-
tal effects of inflammation on the fetal lung have been
reported.20–22
The association of caesarean section and increased
risks of TTN and RDS are in line with previous
studies of term infants.23,24 There are several proposed
explanations, including lack of mechanical squeezing
of lung fluid during the passage through the birth
canal, absence of molecular promotion of alveolar
fluid drainage by activation of sodium channels25 and
deficiency of the physiological surge of stress hor-
mones26 seen in the fetus during labour and vaginal
delivery. Since RDS is common with overall rates
varying from 40% at 30 weeks of GA to 5% at 34
weeks of GA,2 the added risk after caesarean section
carries a significant contribution to neonatal respira-
tory morbidity in absolute numbers. In this paper,
caesarean section before onset of labour was a
stronger risk factor for TTN and RDS than caesarean
section after onset of delivery, indicating either that
the fetus was less prepared for delivery, or that
mothers with severe complications were more fre-
quently delivered by caesarean section before onset of
labour (confounding by indication), or both. Adjust-
ing for pregnancy complications in the analyses may
have reduced the effect of confounding by indication.
Although there is well-established evidence that
antenatal steroid treatment is effective for RDS pre-
vention in preterm infants,18 corticosteroids were only
administered to one-third of the mothers. We have
previously found that 39% of Swedish pregnant
women at 33 weeks and 12% at 34 weeks of GA were
treated with antenatal corticosteroids.2 There are prob-
ably variations in practice which may affect generalis-
ability to other populations. In a recent US study, the
conclusion was that treatment with antenatal steroids
may be beneficial also in moderately preterm infants.27
Given the fact that RDS incidence has not declined as
expected,8 the high number of infants and an RDS
incidence of 5–9% at 33–34 gestational weeks,2 as well
as the short- and long-term safety of one-course ante-
natal corticosteroid treatment,18,28 current practice and
recommendations in Sweden should be discussed and
possibly be extended to include 34 weeks.
Intrauterine growth restriction (IUGR) has previ-
ously been regarded as a protective factor for RDS,

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Paediatric and Perinatal Epidemiology, 2013, 27, 172–181
180 M. Altman et al.
according to similar lung maturation hypotheses as
with inflammation.29 Recently, the opinion seems to
have changed towards a more cautious interpretation
of the effect of IUGR on RDS. Studies have shown
both increased and decreased RDS incidence in SGA
infants, and that the effect of IUGR may vary by GA.30
Animal models have shown that IUGR in fact does not
accelerate lung maturation but delays it.31
The male disadvantage in neonatal respiratory mor-
bidity is well known from previous studies. RDS and
other respiratory diseases are more common in boys
than in girls.32 Preterm boys need more respiratory
support than girls.33 The cause of this sex difference is
so far largely unknown, but infant sex-specific hormo-
nal influences on fetal lung development have been
proposed.34
We found that 28% of infants born at 30–34 gesta-
tional weeks (59% at 30 weeks and 17% at 34 weeks of
GA) were affected by TTN and/or RDS. These find-
ings can be used as a contemporary benchmark for
the magnitude of respiratory problems in moderately
preterm infants born in a society with a generally
healthy population and with an almost universal
access to an evidence-based system for antenatal and
neonatal care.
Among risk factors (besides GA) independently
associated with TTN and RDS, caesarean section
before labour was found to be the largest, associated
with a doubling of the risks of TTN and RDS. Male
sex and low Apgar scores at 5 min were found to
increase the risk of RDS, whereas SGA and antenatal
steroids decreased the risk. These results provide a
basis for risk assessments regarding timing and mode
of delivery and support us with further knowledge to
discriminate those moderately preterm infants that
face an increased risk of developing acute respiratory
morbidity.
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Supporting information
Additional supporting information may be found in
the online version of this article.
Table S1. Numbers and proportions of transient tach-
ypnoea of the newborn and respiratory distress syn-
drome in relation to different characteristics among
4679 moderately preterm singleton infants.