Globally, the number of children born by cesarean delivery is constantly increasing. However, hormonal and physiological changes associated with labor and vaginal delivery are considered necessary for lung maturation.
We aimed to assess whether the mode of delivery is associated with changes in respiratory and atopic outcomes during infancy and at school age.
We included 578 children, born at ≥37 weeks of gestation, from a prospective birth cohort study. We compared weekly respiratory symptoms throughout the first year of life and infant lung function (tidal breathing and multiple-breath washout) at 5 weeks of age between children born by cesarean delivery (N=114) and those born by vaginal delivery (N=464) after term pregnancy in healthy women. At a follow-up visit conducted at 6 years of age (N=371, of which 65 were delivered by cesarean delivery), we assessed respiratory, atopic, and lung function outcomes (spirometry, body plethysmography, and multiple-breath washout). We performed adjusted regression analyses to examine the association between cesarean delivery and respiratory and atopic outcomes. To account for multiple testing, we used the Bonferroni correction, which led to an adapted significance level of P <.002.
During infancy, children born by cesarean delivery did not have more respiratory symptoms than those born by vaginal delivery (median, 4 weeks; interquartile range, 7 weeks vs median, 5 weeks; interquartile range, 7 weeks; adjusted incidence rate ratio, 0.8; 95% confidence interval, 0.6–1.0; P =.02). Infant lung function was similar between the groups. Children born by cesarean delivery did not have a higher incidence of “ever wheezing” (adjusted odds ratio, 0.9; 95% confidence interval, 0.5–1.8; P =.78) or current asthma (adjusted odds ratio, 0.4; 95% confidence interval, 0.0–3.5; P =.42) at school age than those born by vaginal delivery. There was no difference in the lung function parameters between the groups.
Cesarean delivery was not associated with respiratory symptoms in the first year of life, nor with different respiratory or atopic outcomes at school age, when compared with vaginal delivery. Our results indicate that there are no long-term consequences on the respiratory health of the child associated with cesarean delivery.
Globally, the number of children born by cesarean delivery (CD) has almost doubled over the last decades. CD rates vary from 4% in west and central Africa to 25% in Western Europe and 44% in Latin America and China. These differences show that indications for CD are influenced by socioeconomic factors and extend beyond medical reasons. There is an ongoing debate about the contribution of maternally requested CD on the increased rates worldwide. For women and obstetricians to make informed decisions regarding the mode of delivery, evidence about the consequences of CD is needed.
Although recently issued consensus statements on CD exist, there are limited data on the long-term consequences of CD on the child. There is emerging evidence that CD alters perinatal physiology with possible long-term effects. , Different mechanisms have been hypothesized, such as changes in the neonatal gut microbiota and a subsequently altered immune system. Different physical and hormonal stresses during CD might lead to suboptimal neonatal respiratory transition and impaired lung development. , Furthermore, perinatal stress experienced during vaginal delivery (VD) by activation of the hypothalamic-pituitary-adrenal axis is considered to be an important physiological trigger for epigenetic modifications.
Why was this study conducted?
There is good evidence for the association between cesarean delivery (CD) and postnatal morbidity (ie, respiratory distress syndrome). The long-term impact of CD on respiratory health in children is less conclusive.
CD was not associated with respiratory symptoms in infancy nor with asthma in school-aged children when compared with children born by vaginal delivery (VD). There was no difference in lung function during infancy or at school age between children born by CD and those born by VD.
What does this add to what is known?
Our results indicate that there are no long-term consequences related to respiratory health in infancy or at school age associated with CD. This adds essential evidence for women and obstetricians to make informed decisions about the mode of delivery.
Although there is evidence for the association of CD with postnatal respiratory morbidity, little is known about the long-term respiratory outcomes. There has been particular interest in the association of CD with asthma in children, but the results have been inconsistent. So far, no study has examined the important developmental period during infancy and combined that with follow-ups at school age.
A unique longitudinal dataset from a prospective birth cohort of term-born infants allowed us to examine short- and long-term respiratory outcomes in children born by CD. This study aimed to assess whether CD is associated with changes in respiratory symptoms and lung function in the first year of life and if CD is associated with respiratory, atopic, and lung function changes at 6 years of age when compared with children born by VD. We hypothesized that children born by CD would have more respiratory symptoms in infancy and show a higher risk for the development of asthma at school age than children born by VD.
Materials and Methods
Study design and participants
The prospective Bern Basel Infant Lung Development birth cohort comprises a group of unselected, healthy, term-born, White neonates recruited antenatally since 1999 in the region of Bern, Switzerland. The exclusion criteria were prematurity (birth at <37 weeks’ gestation), congenital malformation, substantial perinatal disease, severe maternal health problems, and maternal drug abuse excluding smoking. Pre- and perinatal information was collected by interviews using standardized questionnaires. Midwives reported data on the mode of delivery, which was categorized as VD, elective CD (ie, planned, primary CD without labor), or urgent CD (ie, unplanned, secondary CD, after attempted VD).
A total of 2 study visits were completed at 5 weeks and 6 years of age during which detailed lung function measurements were collected. In addition, study nurses phoned parents weekly throughout the first year of life to assess the respiratory health status of the child by standardized questionnaires. We included children born between April 1999 and May 2019 with follow-up visits at 6 years, if available, between August 2005 and October 2019. The ethics committee of the Canton of Bern approved the study, and written consent was obtained.
Respiratory outcomes in infancy
We assessed weekly respiratory rates (RRs) and respiratory symptoms (including coughing and wheezing) prospectively throughout the first year of life by weekly phone interviews with parents. At the 5-week study site visit, parents were instructed on how to perform RR measurements weekly at home for 60 seconds during regular quiet sleep. For the assessment of respiratory symptoms, we used a standardized score with high sensitivity for lower respiratory tract symptoms. Weeks with any respiratory symptoms were defined as a score of >0 and weeks with severe respiratory symptoms as a score of ≥3 ( Supplemental Table 1 , online supplement [OLS]). We included infants with at least 40 weeks of assessment.
Infant lung function assessments included 10 minutes of tidal breathing followed by multiple-breath washouts (MBWs) using the Exhalyzer D (Eco Medics AG, Duernten, Switzerland). Lung function measurements were performed during quiet natural sleep according to current standards. For tidal breathing measurements, we analyzed the mean values of 20 consecutive breaths for tidal volume per bodyweight, RR, minute ventilation, and the ratio of time to peak tidal expiratory flow and expiratory time. MBW was performed using 4% sulfur hexafluoride (OLS). The main outcomes were functional residual capacity (FRC MBW ) and lung clearance index (LCI), the latter representing a sensitive marker for ventilation inhomogeneity and small airway disease.
Respiratory and atopic outcomes at school age
At 6 years of age, we assessed respiratory and atopic outcomes through an interview with a clinician using a standardized questionnaire adapted from the International Study of Asthma and Allergies in Childhood. We defined respiratory (ever wheezing, current asthma) and atopic outcomes (allergic rhinoconjunctivitis, atopic dermatitis) as described in Supplemental Table 2 (OLS).
Spirometry and body plethysmography were performed using the MasterLab setup (Jaeger MasterScreen, CareFusion, Hochberg, Germany) according to the guidelines. , The following spirometry parameters were investigated: forced expiratory volume in 1 second (FEV 1 ), forced vital capacity (FVC), ratio of FEV 1 to FVC, and flow when 75% of FVC has been exhaled (FEF 75 ). Main outcomes of body plethysmography were FRC pleth , total lung capacity (TLC), and specific effective airway resistance (sReff). The combination of these outcomes allows the detection of obstructive and restrictive lung disease.
Nitrogen MBW (N 2 MBW) was performed according to consensus using the Exhalyzer D (OLS). The main outcomes were FRC MBW and LCI. ,
Fractional exhaled nitric oxide (FeNO) as a maker of eosinophilic airway inflammation was measured by the single-breath online method using 2 setups (the WBreath 3.28.0, ndd Medizintechnik AG, Zürich, Switzerland until September 2012, and the CLD88sp FeNO analyzer, Eco Medics AG, Duernten, Switzerland since September 2012).
We performed regression analyses to assess the differences in the outcomes between children born by CD and those born by VD. We used the analysis most appropriate for the distribution of outcome data, namely Poisson regression analysis for respiratory symptoms, linear regression analysis for lung function parameters and RR, and logistic regression analysis for respiratory and atopic outcomes. First, we performed univariable regressions. We applied multilevel linear regressions to account for multiple RR measurements in the same individual by adding a random effect term. Second, we adjusted the models for potential risk factors and included anthropometric factors distributed unequally among groups (age and body length at infant study visit) ( Table 1 ). , , We repeated all analyses comparing only the subgroups of elective or urgent CD with children born by VD. Finally, we performed additional analyses to rule out effect modification by birthweight, breastfeeding, transient signs of respiratory distress, and antepartum administration of antibiotics (OLS).
|CD total |
|CD urgent |
|CD elective |
|P value a|
|VD vs total CD||VD vs elective CD|
|Male, n (%)||243 (52)||64 (56)||39 (64)||23 (49)||.47||.65|
|Gestational age (wk), mean (SD)||39.8 (1.1)||39.5 (1.3)||40.2 (1.2)||38.6 (0.8)||.006||<.001|
|Birthweight (Z-score), mean (SD)||0.2 (0.9)||0.0 (1.0)||0.3 (0.9)||−0.3 (1.0)||.04||<.001|
|Birth length (Z-score), mean (SD)||0.1 (1.0)||−0.1 (1.2)||0.4 (1.1)||−0.6 (1.0)||.26||<.001|
|Season of birth b (autumn), n (%)||126 (27)||30 (26)||15 (25)||12 (26)||.93||.96|
|Maternal age (y), mean (SD)||33 (4)||34 (4)||34 (4)||36 (4)||.003||<.001|
|Transient signs of respiratory distress at birth (yes), n (%)||70 (15)||14 (12)||7 (12)||7 (15)||.45||.60|
|Older siblings (yes), n (%)||268 (58)||59 (52)||25 (41)||31 (66)||.35||.16|
|Childcare (yes), n (%)||108 (23)||37 (33)||25 (41)||10 (21)||.03||.78|
|Exclusive breastfeeding (wk), mean (SD)||21 (13)||19 (14)||19 (14)||20 (14)||.16||.59|
|Maternal smoking during pregnancy c (yes), n (%)||79 (17)||17 (15)||9 (15)||6 (13)||.64||.49|
|Parental smoking (yes), n (%)||58 (13)||16 (14)||10 (16)||5 (11)||.87||.67|
|Educational status mother d (low), n (%)||112 (24)||18 (16)||9 (15)||7 (15)||.15||.32|
|Educational status father d (low), n (%)||64 (14)||12 (11)||4 (7)||5 (11)||.05||.06|
|Atopy mother e (yes), n (%)||143 (31)||36 (32)||23 (38)||12 (26)||.76||.55|
|Atopy father e (yes), n (%)||174 (38)||41 (36)||23 (38)||15 (32)||.88||.56|
|Age (d), mean (SD)||36 (5)||37 (6)||36 (6)||38 (5)||.25||.02|
|Bodyweight (Z-score), mean (SD)||−0.2 (0.9)||−0.5 (0.9)||−0.2 (0.8)||−0.8 (1.0)||.009||<.001|
|Body height (Z-score), mean (SD)||−0.1 (1.1)||−0.3 (1.1)||0.1 (0.9)||−0.8 (1.1)||.09||<.001|
b Winter was defined as the period from December 21 to March 20, spring was defined as the period from March 21 to June 20, summer was from June 21 to September 20, and autumn was from September 21 to December 20
We aimed to detect at least a difference of 3.0 breaths per minute in the RR and a difference in FEV1 of 0.5 Z-scores between children born by CD and those born by VD. With our sample size of 578 infants, we could have detected a difference of 2.1 breaths per minute in the RR in the first quarter with a power of 80% and a significance level of P <.002. For the follow-up at 6 years of age with a sample size of 371, we could have detected a difference of 0.4 FEV 1 in the Z-scores.
To assess differences in the anthropometric and risk factors among groups, the significance level was defined at a P value of <.05 for 2-sided tests. As we investigated multiple outcome variables, we used a Bonferroni correction to account for multiple testing. The Bonferroni correction led to an adjusted significance level for outcome variables at a P value of <.002 for 2-sided tests. All analyses were performed in Stata 16.0 (StataCorp LLC, College Station, TX). Reporting fulfills the Strengthening the Reporting of Observational Studies in Epidemiology guidelines.
We included 578 children of whom 114 (20%) were born by CD. Of all children born by CD, 47 (41%) were classified as being born by elective CD, 61 (54%) were classified as being born by urgent CD, and further classification was missing for 6 (5%) ( Figure 1 ). Table 1 shows the anthropometric data and potential risk factors (missing data is provided in Supplemental Table 3 , OLS). At birth, children born by CD had substantially lower gestational ages and birthweights and substantially older mothers, with the differences being more pronounced in the subgroup of elective CD. In addition, children born by CD showed substantially higher attendance of childcare, and at the first study visit, infants born by CD and elective CD were substantially lighter and shorter, although the infants in the elective CD subgroup were older at this first study visit. Follow-up data at 6 years of age were available for 371 children with 65 (18%) of them being born by CD and 24 (37%) of them being born by elective CD ( Figure 1 ). The dropout rate for follow-up visits was 14%. There was no clinically relevant difference between the children included in the follow-ups and those who dropped out ( Supplemental Table 4 , OLS).
Respiratory outcomes in infancy
Children born by CD did not have more respiratory symptoms in the first year of life than children born by VD. Of all the children, 526 (93%) suffered from any respiratory symptoms during the first year of life, 99 (19%) of whom were born by CD. Of the 526 children with respiratory symptoms, 220 (42%) showed severe respiratory symptoms at least once, 36 (16%) of whom were born by CD. The median (range) number of weeks with any respiratory symptoms was 4 weeks (0–22 weeks) in the CD group and 5 weeks (0–34 weeks) in the VD group with no relevant differences between day- and nighttime symptoms ( Figure 2 ). The median (range) number of weeks with severe respiratory symptoms was 0 weeks (0–8 weeks in the CD group and 0–11 weeks in the VD group) in both groups. The adjusted incidence rate ratio (IRR) was 0.8 (95% confidence interval [CI], 0.6–1.0; P =.02) among children born by CD overall and was similar in the subgroup of children born by elective CD (IRR, 0.8; 95% CI, 0.6–1.1; P =.10) and those born by urgent CD (IRR, 0.8; 95% CI, 0.6–1.1; P =.13) ( Table 2 ). Considering the adjusted significance level of P <.002 after Bonferroni correction, the IRR for respiratory symptoms did not differ substantially between children born by CD and those born by VD. Older siblings and childcare were the only risk factors associated with substantially more respiratory symptoms in our final regression model (OLS).