Health

Caesarean section adversely affects children’s immunity

الولادة القيصرية تؤثر سلبا على مناعة الأطفال

OBJECTIVES: Immune diseases such as asthma, allergy, inflammatory bowel disease, and type 1 diabetes have shown a parallel increase in prevalence during recent decades in westernized countries. The rate of cesarean delivery has also increased in this period and has been associated with the development of some of these diseases.

METHODS: Mature children born by cesarean delivery were analyzed for risk of hospital contact for chronic immune diseases recorded in the Danish national registries in the 35-year period 1977–2012. Two million term children participated in the primary analysis. We studied childhood diseases with a suspected relation to a deviant immune-maturation and a debut at young age. The effect of cesarean delivery on childhood disease incidences were estimated by means of confounder-adjusted incidence rate ratios with 95% confidence intervals obtained in Poisson regression analyses.

RESULTS: Children delivered by cesarean delivery had significantly increased risk of asthma, systemic connective tissue disorders, juvenile arthritis, inflammatory bowel disease, immune deficiencies, and leukemia. No associations were found between cesarean delivery and type 1 diabetes, psoriasis, or celiac disease.

CONCLUSIONS: Cesarean delivery exemplifies a shared environmental risk factor in early life associating with several chronic immune diseases. Understanding commonalities in the underlying mechanisms behind chronic diseases may give novel insight into their origin and allow prevention.

Chronic diseases such as asthma, allergy, inflammatory bowel disease, and type 1 diabetes have shown a parallel increase in prevalence during the last decades in westernized countries.1 Evidence suggests that early life events may be programming these diseases, as demonstrated by changes in disease prevalence in populations immigrating to westernized countries1 and by identification of perinatal risk factors.2 This suggests that the parallel increase in prevalence of immune diseases may be due to shared environmental risk factors and disease mechanisms in early life.

The rate of cesarean delivery has also increased in recent decades.3 Even though the World Health Organization recommends cesarean delivery as indicated choice of delivery mode in less than 15% of births,4 many developed countries have a much higher prevalence, pointing toward a less strict medical indication for the procedure.5,6 Cesarean delivery has been linked to the development of asthma and allergic rhinitis,7–10 as well as other immune disorders11–16 in the offspring.

We hypothesized cesarean delivery as an example of a shared environmental risk factor for immune-associated diseases. We analyzed children born by cesarean delivery for risk of hospital contact for diseases suspected to be related to a deviant immune maturation and with a debut at young age, including asthma, systemic connective tissue disorders, juvenile arthritis, inflammatory bowel disease, type 1 diabetes, immune deficiencies, psoriasis, celiac disease, and leukemia in the Danish national registries in the 35-year period 1977–2012.

Methods
The study was based on data from national registries and was approved by the Danish Data Protection Agency (J.no. 2012-41-0388). Subjects were not contacted as a part of the study; hence the ethics committee did not require written informed consent.

Study Cohort
The Danish Civil Registration System (CRS) has registered every person with a citizenship in Denmark since 1968. This provides a unique 10-digit number, encoding date of birth and gender, which is assigned at birth and is used as the identifying number in all Danish registries. Further, the register contains date of emigration.17

The Danish Medical Birth Registry has existed since 1973 and contains data on birth weight, parity, mode of delivery, and maternal smoking during pregnancy. The Danish Register of Causes of Death was computerized in 1970 and contains data on date of death.

The Danish National Patient Registry was established in 1977 and contains data on all primary and secondary diagnosis on all in-patient discharges since 1977, and on outpatient admissions since 1994. The diagnoses are based on the International Classification of Diseases, 8th Revision (ICD-8 until 1994; International Classification of Diseases, 10th Revision [ICD-10] thereafter).18

We identified a cohort of all live born children in Denmark in the period January 1, 1973, through January 1, 2012, and used their unique CRS number to link information on gender, parity, birth weight, mode of delivery, and maternal CRS from the Danish Medical Birth Registry; information on date of death from the National Death Registry, information on date of first hospital in- or outpatient admission for any of the predefined diseases (primary or secondary diagnosis) from the Danish National Patient Registry and information on date of migration from the Danish CRS.

Maternal Disease
We obtained information from the Danish National Patient Registry on mother’s hospital admission for the specified diseases to adjust the analyses for maternal disease. Only children whose mothers were born after 1952 were included in the analyses.

Exclusion Criteria
Premature children (defined as birth weight below 2500 g) and children missing information on birth weight were excluded from all analyses.

Case Definitions
Cases were identified by the ICD-8 and ICD-10 diagnoses. Nine groups of diseases were investigated. Asthma (ICD-10 J45.x; J46.x), systemic connective tissue disorders (ICD-10 M3x.x), juvenile arthritis (ICD-10 M05.x; M08.x; M09.x; M13.x), inflammatory bowel diseases (ICD-10 K50.x; K51.x), diabetes type 1 (ICD-10 E10.x; E13.x; E14.x), immune deficiencies (ICD-10 D80.x–D89.x), psoriasis (ICD-10 L40.x), celiac disease (ICD-10 K90.0), and leukemia (ICD-10 C91.x–C96.x). Negative control: fractured forearm or elbow (ICD-10 S52.x). A list of the corresponding ICD-8 diagnosis codes is provided in Supplemental Table 2.

Confounders
Confounders were chosen a priori as gender, parity (first child, second child, third child, or more), birth weight (≥2.5 to <3.0 kg; ≥3.0 to <3.5 kg; ≥3.5 to 4.0 kg; 4.0 kg or more), attained age (1-year groups), calendar time (3-year groups), season of birth (December to February; March to May; June to August; September to November), maternal age (≤25; 26–30; 31–35; ≥36 years), and maternal illness (maternal diagnosis of the disease in question, see above).

Statistical Methods
We investigated the effect of cesarean delivery versus vaginal birth in all children born 1973–2012. Children were followed for hospitalizations from January 1, 1977, where the registry started, or from date of birth if this occurred after January 1, 1977. Children were followed until January 1, 2012, or until age 16 years, migration, or death, whichever came first.

For each disease category, we accumulated person-time and -events (cases) stratified by cesarean delivery and chosen confounders.19 Thereby we calculated the specific incidence rates (cases per person years).

The overall effects of cesarean delivery on the number of cases in each separate disease category in the complete time period and across the entire age span were estimated with log-linear Poisson regression models offset by the log of person time (years of observation), where any underlying age and calendar time variations for the various disease groups can be taken into account by adjusting for the attained age and calendar year as confounders (3-year intervals were chosen). Further, we add the chosen confounders to obtain the fully adjusted estimates for the effect of cesarean delivery. All confounders were included as categorical variables. The incidence rate ratio (IRR) with 95% confidence interval was calculated to show the effect of cesarean delivery. The population attributable risk fraction (PARF) was calculated from the adjusted IRR (aIRR) estimates as follows: PAR = Pe (RRe−1)/[1 + Pe (RRe−1)], where Pe is the prevalence of the exposure and RRe is the relative risk of disease because of that exposure. Potential changes in the effect were investigated as interaction terms between cesarean delivery and blocks of calendar years (eg, for changes in registration practice).

A significance level of 0.05 is used in all analyses. The data processing was computed with SAS version 9.3 for Windows (SAS Institute, Inc, Cary, NC).

Results
Two and a half million children were born in Denmark in the period 1973–2012. Five percent had low birth weight (birth weight below 2500 g); 15% had missing data on birth weight or other confounders and were excluded from analysis, leaving 1.9 million (80%) children for the primary analysis. The study population was followed from 1977 to 2012 for a total of 23 million person years in the age range 0 to 15 years. Approximately 14% of the study population was delivered by cesarean delivery with a marked increase in the proportion of cesarean deliveries during the observation time (Fig 1). Disease prevalence is presented in Table 1.

The prevalence of several diseases among the mothers was significantly higher if they had ever delivered by cesarean delivery when compared with vaginal delivery. Especially mothers with type 1 diabetes (27%) had an increased risk of cesarean delivery compared with mothers without diabetes type 1 (14%; Supplemental Table 3).

Children delivered by cesarean section had significantly increased aIRR for asthma, systemic connective tissue disorders, juvenile arthritis, inflammatory bowel diseases, immune deficiencies, and leukemia (Table 1). Type 1 diabetes, psoriasis, and celiac disease were not associated with cesarean delivery. Arm fracture (included as “control condition”) was not associated with cesarean delivery.

Limiting the children with asthma to those older than 5 years at first contact did not change the conclusion: aIRR 1.16 (1.13–1.19); P < .0001.

The effects of cesarean delivery were not impacted by the registry changes in terms of disease classification systems and outpatient registrations (no significant effect modification considering the number of interaction test; data not shown).

The PARF ranges up to 6% (Table 1).

Discussion
Principal Findings of the Study
Cesarean delivery was a shared risk factor for several immune-related diseases including asthma, systemic connective tissue disorders, juvenile arthritis, inflammatory bowel diseases, immune deficiencies, and leukemia. There was no significant association with diabetes type 1, psoriasis, or celiac disease.

Strength and Weaknesses of the Study
Our study was hypothesis driven, searching for a shared risk factor between immune diseases with a debut in children. We did not search all other diagnoses systematically for similar associations because our aim was to exemplify such communality rather than explain individual disorders.

The study base covers 35 years of diagnoses from national registries. The registry on hospitalization covers all admissions and outpatient hospital contacts nationwide.

A priori children with a birth weight below 2500 g were excluded, and all analyses were adjusted for age, calendar year, gender, parity, birth weight, and maternal heredity. By analyzing only children above 2500 g, we hope to get a more comparable group of children, with only the delivery method to differ between them and not an underlying pathology leading to preterm birth.

Particularly, we adjusted for maternal disease of these immune-related diseases, some of which are associated with cesarean delivery (Supplemental Table 3) and could thereby confound an association. After adjustment, the results for type 1 diabetes was no longer statistically significant, but otherwise maternal disease did not materially alter the results.

We included a “negative control” in terms of an analysis of association between cesarean delivery and hospital contact for arm fracture. This demonstrates that the associations seen for other diseases are not caused by a methodological problem of “overregistration” of disease in the children delivered by cesarean delivery.

It may be a limitation to our study that we excluded mild diseases managed in the primary health care sector only. Yet this ascertainment bias is unlikely to influence the conclusion of a common risk factor for the severe chronic diseases.

Diagnostic classification was changed in 1994 from ICD-8 to ICD-10, and registration of outpatient hospitalizations was initiated. The categories used across these different classifications may not be completely congruent. However, the analyses are adjusted for calendar year as a categorical variable, which corrects the main association from time changing effects, and sensitivity analyses did not suggest any effect of this on the results.

Diagnosing asthma in a young child may be inaccurate. We therefore did a sensitivity test of children with a first hospital contact after age 5, where the diagnosis is more robust. The association remained significant.

Interpretation of the Study
Cesarean delivery was a shared risk factor for different immune-related diseases including asthma, systemic connective tissue disorders, juvenile arthritis, inflammatory bowel diseases, immune deficiencies, and leukemia. This suggests that critical events around time of birth initiate a disease trajectory. Such early events may cause an immune aberration leading to a variety of chronic immune diseases presenting later in life. By identifying commonalities between diseases, we may understand mechanisms of the shared “epidemic” seen for these diseases.

Previous studies have revealed individual disorders generally showing associations between cesarean delivery and asthma and allergy,7–10 inflammatory bowel disease,11 celiac disease,12,13 type 1 diabetes,14 and cancers15,16 in the offspring. Another register-based study has associated cesarean delivery with a wide range of diagnoses.20 Our study is the first to reveal cesarean delivery as a common risk factor across several specific immune-related disease categories in the same study and in a nationwide database of children. This reduces the risk of publication bias.

There is increasing evidence that immune-related diseases are programmed in early life as a result of complex gene environment interactions. The prevalence of immune-related diseases is higher in westernized countries,21 and immigrant studies reveal that the children of immigrants moving to more westernized countries will acquire the disease risk of westernized countries,22 indicating the importance of early risk factors associated with western life style. Hygiene, in terms of disturbed early microbial exposure, is hypothesized to be responsible for the increasing prevalence of allergy-related diseases in westernized countries.23 A similar etiology is suspected behind the increasing prevalence of childhood leukemia,24 and a recent study revealed an association between allergy and later development of leukemia supporting a potential shared etiology in early life.25 Reduced cytokine levels at birth have been associated with later development of allergy26 and atopic predisposition,27 and children who later developed childhood leukemia also had markedly reduced interleukin-10 levels at birth.28

The birth setting around cesarean delivery is different from vaginal birth with respect to several factors including anesthetic agents and antibiotics during birth, physiologic effects on the newborn, and the hospital environment after birth.29 It may be speculated that the effect from cesarean delivery is mediated by changes in the microbiome of the newborn. The normal delivery canal exposes the child to a composite microbiome different from the one encountered during a cesarean delivery in an operation theater resulting in differences in microbiome of the newborn.30,31 Furthermore, it has become standard procedure to give prophylactic antibiotics to all women delivering by cesarean delivery to reduce postpartum infections in the mother,32 which is also likely to affect the microbiome of the newborn child. There are several indications that the diversity and composition of the human microbiome is associated with a variety of diseases such as asthma,33 allergy,34 inflammatory bowel diseases,35 and type 1 diabetes36 and type 2.37 However, cesarean delivery entails several other components, which may potentially affect the early environment of the newborn. Biomarkers in the blood in children born by cesarean delivery differ from children born vaginally including lower number of leukocytes, neutrophils, monocytes, and natural killer cells in cord blood,38,39 and likewise differences in leukocyte composition during the first year of life.40 Also, stress hormone induction in the fetus is dependent on mode of delivery with a lower production in children born by cesarean delivery,41 which may affect the immune maturation. Furthermore, pregnancy factors leading to cesarean delivery may already in utero affect the fetus and trigger the progression toward disease.

Because this is an observational study, we cannot rule out that the true casual factor underlying these associations could be a confounding factor related to cesarean delivery. Potential confounders not accounted for in the current study are lifestyle factors associated with maternal request for cesarean delivery or factors increasing the risk of cesarean delivery. Nevertheless, identification of cesarean delivery, or an associated factor, as a potential shared environmental risk factor behind several immune-related diseases is still important. It may give us lead to understand the mechanism and increasing prevalence of these diseases and eventually point to prevention. It is of interest that not all immune-related diseases were affected equally by delivery method, which might suggest different disease pathways. Opposite to some other studies, we did not find association to type 1 diabetes after adjustment for maternal disease. We demonstrated a high prevalence of cesarean delivery among women with type 1 diabetes, which may confound unadjusted results.

Our findings also support the hypotheses that perinatal life is important for later development of chronic diseases, which encourages a research strategy focusing on early life in the origins of chronic diseases.

Furthermore, research targeting the more common immune-related diseases like asthma and allergy may be a relevant approach for understanding the etiology of rare diseases where prospective studies are not feasible. Future research focusing on commonalities in mechanisms behind different disease entities may provide new mechanistic insights and understanding of lifestyle related changes in disease patterns of chronic immune-diseases.

Conclusions
Cesarean delivery is associated with increased risk of several chronic immune diseases suggesting a shared environmental risk factor in early life. Understanding the underlying disease mechanism may be a key to understanding the origin and increased prevalence of these diseases and promise a perspective for prevention.

خلصت دراسة بريطانية إلى أن الأطفال المولودين بواسطة العمليات القيصرية، يفتقدون الحماية الطبيعية ضد الجراثيم الخارقة. ويقوم الأطفال المولودون بشكل طبيعي، عند الولادة، بالتقاط المكروبات الخاص بأمهاتهم، وهي بكتيريا الأمعاء الجيدة التي تساعد في مكافحة العدوى. لكن الأطفال الذين يولدون بعمليات قيصرية لديهم مكروبات مختلفة تماما بما فيها البكتيريا المزودة بالتهابات المستشفيات.

ويقول العلماء إن دراستهم قد تساعد في تفسير ارتفاع بعض الأمراض المرتبطة بالمناعة لدى الأطفال المولودين قيصريا، بما في ذلك الحساسية والسكري من النوع الأول. وأجريت الدراسة التي استمرت سبع سنوات من قبل معهد Wellcome Sanger في لندن، وكلية جامعة لندن وجامعة برمنغهام، وحللوا خلالها 1679عينة براز من الأطفال والأمهات..

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