American Journal of Obstetrics and Gynecology (2005) 193, 1061–4
www.ajog.org
Cesarean delivery and respiratory distress syndrome:
Does labor make a difference?
Kim A. Gerten, MD,a Dean V. Coonrod, MD, MPH,a R. Curtis Bay, PhD,b
Linda R. Chambliss, MD, MPHa
Department of Obstetrics, Gynecology & Women’s Health,a Research,b Maricopa Integrated Health System,
MedPro,a,b Phoenix Integrated Residency in Obstetrics and Gynecologya; University of Arizonaa
Phoeniz, AZ
Received for publication March 1, 2005; revised May 3, 2005; accepted May 9, 2005
KEY WORDS
Respiratory distress
syndrome
Cesarean section
Labor
Mode of delivery
Objective: The purpose of this study was to determine if cesarean delivery is a risk factor for
respiratory distress syndrome (RDS) and if this risk is modified by labor before cesarean.
Study design: This population-based case-control study compared 4778 cases of RDS to 5 times
as many controls.
Results: Unadjusted, cesarean delivery was associated with RDS, odds ratio (OR) 3.5 (95% CI
3.2–3.8). After controlling for potential confounding variables, cesarean remained an independent
risk factor, OR 2.3 (95% CI 2.1–2.6). Labor modified this risk significantly (P =.02)dwith labor,
cesarean delivery had an OR of 1.9 (95% CI 2.2–2.9), without labor, the OR was 2.6 (95% CI
1.3–2.8).
Conclusion: Cesarean delivery was an independent risk factor for RDS. The risk was reduced
with labor before cesarean, but still elevated. This supports the importance of being certain of
fetal lung maturity before cesarean delivery, particularly when done before labor.
Ó 2005 Mosby, Inc. All rights reserved.
Cesarean delivery has become more common.1 Increases in the rate of cesarean delivery are associated
with more liberal obstetric indications, as well as an
increase in the demand for elective cesarean deliveries.2
A concern with elective cesarean in particular is that of
iatrogenic prematurity and complications associated
with it, such as respiratory distress syndrome (RDS).3
Presented at the Twenty-fifth Annual Society of Maternal-Fetal
Medicine Meeting, Reno, Nev, February 7-12, 2005.
Funded in part by CMS Award #25-P-90947/9-02.
Reprints not available from the authors.
0002-9378/$ - see front matter Ó 2005 Mosby, Inc. All rights reserved.
doi:10.1016/j.ajog.2005.05.038
Previous studies have shown a positive association
between cesarean delivery and RDS. However, many of
these studies have been limited by small sample sizes
and most were hospital-based.3-8 In addition, few studies
have addressed the affect of labor before cesarean
delivery, and were limited once again by a small sample
size9-11; none of these studies validated this hypothesis
formally with an interaction test.
This study aims to ascertain whether cesarean section
is an independent risk factor in the development of
neonatal RDS and whether labor before cesarean delivery is protective, using a population-based neonatal care
registry that allows for the consideration of multiple
1062
confounding variables and testing for interaction (effect
modification).
Material and methods
This was a population-based case-control study comparing neonates diagnosed with RDS to a control group
without RDS. The risk factor (or variable) of interest
was cesarean delivery. Furthermore, the presence of
labor before cesarean delivery was analyzed as a potential effect modifier on RDS development. The cases of
interest were neonates enrolled in a Neonatal Intensive
Care Program (the Program). This program, administered by the Arizona Department of Health Services,
assures care for the sickest neonates. Membership in the
Program is not income-based but contingent on markers
of severe morbidity, such as a prolonged stay in the
neonatal intensive care unit (O72 hoursd95% of Program infants had at least this length of stay), readmission within 96 hours of birth, transport to a NICU, or a
neonatologist’s recommendation. Data on the 19,617
infants enrolled in the NICP were merged with 372,276
Arizona birth certificates from 1994 to 1998, with a 98%
match rate yielding 19,300 NICP patients successfully
matched. This merged data set served as the source of
cases and controls. Excluded from this data set were
infants with congenital malformations and pregnancies
complicated by placenta previa, breech presentation,
twins, or higher order multiples. For this study, RDS
was defined as having RDS marked on the Program
data form. Neonatal medical personnel completed this
discharge summary form for Program use. As this was
completed following the nursery stay of at least 72 hours
and was a clinical database, it was felt to be a reliable
measure of the presence of the condition. Using these
criteria, 4778 infants with RDS were identified as cases.
Five times as many neonates free of RDS were frequency matched by year of birth to form the control
group (n = 23,890). To be assured that controls were
free of the diagnosis of RDS, besides being marked as
not having RDS on the Program discharge form, they
could not have been admitted to the NICU and not have
RDS, both as ascertained from birth certificate data.
The power was calculated to be 80% with an alpha of
0.05 and rates of cesarean delivery of 15%, and OR of 2.5,
both assumed from the literature. This could be achieved
with a control group of twice the size of the controls.
However, 5 times more controls than cases were chosen
because the sample sizes to ascertain effect modification
are considerably larger,12 and this was the only way to
increase study power because all potential cases were
included in the case group. Variables considered as
potential confounders included: maternal age, race/ethnicity, education, marital status, insurance, parity, prenatal care, smoking, diabetes, preeclampsia/eclampsia,
Gerten et al
chronic hypertension, maternal lung, cardiac or renal
disease, gestational age, birth weight, small for gestational age, 5-minute Apgar, infant sex, fever in labor,
abruption, meconium passage, prolonged rupture of
membranes, and fetal distress. These were tested using
univariate statistics. To be included in the next analysis
phase, an association with both cesarean delivery and
with RDS had to be demonstrated. These were further
considered using logistic regression. The following variables were forced into the initial model: maternal age,
parity, prenatal care, infant sex, and birth weight. Then,
groups of variables (corresponding to socioeconomic
status, maternal medical conditions, and those possibly
related to fetal distress) were added to determine if any
variables in the groups remained as independent predictors. A model was created incorporating these predictors
to determine if cesarean delivery remained an independent predictor. Finally, to determine if the risk was
modified by labor, a variable indicating labor was
constructed with any positive of the following considered
as indicating that labor had occurred: precipitous labor,
prolonged labor, induction of labor, stimulated labor,
dysfunctional labor, and cephalo-pelvic disproportion.
This was entered as a confounder and interaction term.
ORs and 95% CIs were considered our risk measures;
these were calculated using SAS (Cary, NC).
The Institutional Review Boards of Arizona State
University and the Arizona Department of Health
Services approved the study.
Results
Unadjusted, cesarean delivery was associated with an
increased risk of RDS, OR 3.5 (95% CI 3.2–3.8). After
controlling for maternal age and race/ethnicity, diabetes, parity, prenatal care, birth weight, infant sex, and
variables associated with fetal distress, cesarean delivery
remained an independent risk factor, OR 2.3 (95% CI
2.1–2.6). When we tested for effect modification, there
was evidence that labor modified this risk significantly
(P =.02). With labor, cesarean delivery had an OR of
1.9 (95% CI 2.2–2.9) and without labor the OR was 2.6
(95% CI 1.3–2.8). When these analyses were repeated
substituting gestational age for birth weight, no important differences were noted.
Comment
In this study, we found that the risk of RDS in infants
delivered by cesarean was elevated and affected by the
presence or absence of labor. Respiratory distress syndrome is characterized by tachypnea, grunting, intercostal and accessory muscle use, nasal flaring, and
cyanosis that develop rapidly after the birth of the
neonate. Apnea and irregular respirations soon develop
Gerten et al
followed by fatigue and finally respiratory failure.13
RDS is the second leading cause of neonatal mortality in
the US.13 RDS can be differentiated from transient
tachypnea of the newborn (TTN), described as wet lung
disease, by the rapid spontaneous resolution of symptoms, often within 24 hours of birth.14
RDS is thought to be caused by high lung alveolar
surface tension, causing atelectesis and hyaline membrane
formation secondary to a lack of pulmonary surfactant.
Surfactant is a combination of lecithin, phosphatidylglycerol, cholesterol, and surfactant apoproteins. The production of surfactant by the fetal lung begins by week 20, but
does not reach the surface of the fetal lung until much later.
Other identified risk factors for the development of RDS
include premature birth, maternal diabetes, multifetal
pregnancy, precipitous delivery, asphyxia, cold stress,
fetal sex, and a history of previous affected infants.13
Previous smaller studies have shown a positive association between cesarean delivery and RDS. In a Norwegian population-based cohort study of 1235 cases of
RDS, Reed et al. found cesarean delivery to be a major
risk factor associated with the development of RDS.6 A
hospital-based case-control study of 78 cases of RDS in
Beirut showed that after controlling for other factors,
RDS was twice as likely in infants delivered by cesarean
delivery.4 Parilla et al examined all elective cesarean
deliveries without preceding labor in women greater
than 37 weeks’ gestation and O2500 g and found an
incidence of RDS of 1 in every 241 elective deliveries.3
The magnitude of the risk estimate in these studies was
comparable to ours.
Published studies have demonstrated the protective
nature of labor before cesarean delivery in lowering the
incidence of RDS. Curet et al found cesarean delivery
to be a significant risk factor for the development of
RDS in 47 patients studied with the diagnosis of RDS.
Patients delivered vaginally had an 11.8% incidence of
RDS, whereas those delivered via cesarean delivery with
preceding labor had an RDS incidence of 12.7%, and
those delivered via cesarean delivery with no preceding
labor had an RDS incidence of 41%.9 In a cohort study
of infants delivered preterm before 36 weeks, White et al
found cesarean delivery to be associated with a much
higher incidence of RDS (47%), followed by cesarean
delivery preceded by labor 35.4%, and finally vaginal
delivery 27.6%.11 Goldberg et al performed a retrospective study of 236 infants between 1000 and 2500 g
delivered by cesarean delivery. A trend towards decreased RDS in patients who labored before cesarean
delivery was observed.10 None of these studies, however,
tested formally for effect modification, unlike our study.
Some authors have suggested that the mechanism for
decreased RDS in labored patients is associated with
endogenous prostaglandin production stimulated by
uterine activity.15-17 Some have suggested labor results
in the release of lung surfactant into the airways. Other
1063
theories to explain RDS in cesarean delivery–delivered
infants include persistent fetal circulation, as well as
increased retention of pulmonary fluid in neonates
delivered by cesarean section.18 Others have suggested
that a beta-adrenergic surge during labor may be
responsible for the ultimate fetal lung expulsion of
surfactant in preparation for birth.19
Analysis of our data confirms previously published
studies showing a positive association between RDS
and cesarean delivery. This positive association persisted
after controlling for several variables including gestational age. The data also showed the protective nature of
labor before cesarean delivery in preventing RDS. The
strength of our study was the large case sample size
(4778) in comparison to previous studies with just a
fraction of the number of cases.
Limitations in our study include an imprecise definition of RDS. RDS was identified by physician assignment
without stringent prespecified criteria. We did use a case
definition that was completed by neonatal personnel at
discharge, which is likely more precise than its ascertainment on the birth certificate that is typically completed
early in the neonate’s hospital course. However, in the
case set the neonate was admitted to the NICU for greater
than 72 hours and, thus, this would eliminate most cases
of transient tachypnea of the newborn,14 leaving the
majority to have RDS caused by hyaline membrane
disease. Furthermore, our case definition of having a
72-hour NICU stay implies significant morbidity in its
own right. We also had an imprecise definition of labor
and no information on the length of labor. The program
does not have strict diagnostic criteria for RDS; however,
variation would be an example of nonsystematic error,
which would bias our results toward the null hypotheses.
However, a strength of our study was the very large
number of infants who were enrolled, and the ability to
access an entire state’s delivery records. Because the study
involved the entire state we were able to evaluate the risk
in several types of hospitals, ranging from small rural
facilities to tertiary urban referral centers.
Implications for clinical care suggest the importance
of being certain of fetal lung maturity, such as American
College of Obstetrics and Gynecology dating criteria
before elective cesarean delivery.20 Furthermore, our data
suggest that awaiting the onset of labor before cesarean
delivery decreases the chances of subsequent RDS regardless of gestational age; this information may be used when
counseling patients requiring cesearean section.
References
1. Rietberg CC, Elferink-Stinkens PM, Visser GH. The effect of the
Term Breech Trial on medical intervention behaviour and neonatal
outcome in The Netherlands: an analysis of 35,453 term breech
infants. BJOG 2005;112:205-9.
2. Joseph KS, Young DC, Dodds L, O’Connell CM, Allen VM,
Chandra S, et al. Changes in maternal characteristics and obstetric
1064
3.
4.
5.
6.
7.
8.
9.
10.
practice and recent increases in primary cesarean delivery. Obstet
Gynecol 2003;102:791-800.
Parilla BV, Dooley SL, Jansen RD, Socol ML. Iatrogenic respiratory distress syndrome following elective repeat cesarean delivery. Obstet Gynecol 1993;81:392-5.
Beydoun H, Yunis KA, Khogali M, Usta I, Tamim H. Caesarean
route of delivery and hyaline membrane disease: a hospital-based
case-control study in Greater Beirut. Paediatr Perinat Epidemiol
2003;17:363-8.
Nielsen TF, Hokegard KH. The incidence of acute neonatal
respiratory disorders in relation to mode of delivery. Acta Obstet
Gynecol Scand 1984;63:109-14.
Reed DM, Bakketeig LS, Nugent RP. The epidemiology of
respiratory distress syndrome in Norway. Am J Epidemiol
1978;107:299-310.
Usher RH, Allen AC, McLean FH. Risk of respiratory distress
syndrome related to gestational age, route of delivery, and maternal
diabetes. Am J Obstet Gynecol 1971;111:826-32.
Dani C, Reali MF, Bertini G, Wiechmann L, Spagnolo A, Tangucci
M, et al. Risk factors for the development of respiratory distress
syndrome and transient tachypnoea in newborn infants. Italian
Group of Neonatal Pneumology. Eur Respir J 1999;14:155-9.
Curet LB, Zachman RD, Rao AV, Poole WK, Morrison J, Burkett
G. Effect of mode of delivery on incidence of respiratory distress
syndrome. Int J Gynaecol Obstet 1988;27:165-70.
Goldberg JD, Cohen WR, Friedman EA. Cesarean section indication and the risk of respiratory distress syndrome. Obstet
Gynecol 1981;57:30-2.
Gerten et al
11. White E, Shy KK, Daling JR. An investigation of the
relationship between cesarean section birth and respiratory
distress syndrome of the newborn. Am J Epidemiol 1985;121:
651-63.
12. Breslow NE, Day NE. The design and analysis of cohort studies. .
Statistical methods in cancer research (Vol. II). Lyon: IARC
Scientific Publications; 1987.
13. Behrman RE, Kliegman RM, Jenson HB. Nelson textbook of
pediatrics. In: Behrman RE, Kliegman RM, Jenson HB, editors.
Philadelphia: WB Saunders Company; 2000.
14. Rawlings JS, Smith FR. Transient tachypnea of the newborn. An
analysis of neonatal and obstetric risk factors. Am J Dis Child
1984;138:869-71.
15. Flack JD, Jessup R, Ramwell PW. Prostaglandin stimulation of
rat corticosteroidogenesis. Science 1969;163:691-2.
16. de Fencl M, Tulchinsky D. Total cortisol in amniotic fluid and
fetal lung maturation. N Engl J Med 1975;292:133-6.
17. Farrell PM, Avery ME. Hyaline membrane disease. Am Rev
Respir Dis 1975;111:657-88.
18. Schreiner RL, Stevens DC, Smith WL, Lemons JA, Golichowski
AM, Padilla LM. Respiratory distress following elective repeat
cesarean section. Am J Obstet Gynecol 1982;143:689-92.
19. Odom MJ, Snyder JM, Mendelson CR. Adenosine 30 ,50 -monophosphate analogs and beta-adrenergic agonists induce the synthesis of the major surfactant apoprotein in human fetal lung in
vitro. Endocrinology 1987;121:1155-63.
20. American College of Obstetricians and Gynecologists. Practice
Bulletin #10. Induction of labor. Washington, DC: ACOG; 1999.