Clinical Communications

Cesarean section and antibiotic use found to be

associated with eosinophilic esophagitis

Marcella C. Radano, MDa, Qian Yuan, MD, PhDb,Aubrey Katz, MDb, Jude T. Fleming, BSc,Stephanie Kubala, BAc, Wayne Shreffler, MD, PhDd, andCorinne A. Keet, MD, MSe

Clinical Implication

� Birth by cesarean section and early antibiotic use werefound to be associated with eosinophilic esophagitis inyoung children, which suggests that altered microbiotamay play a role in this disease.

TO THE EDITOR:

Eosinophilic esophagitis (EoE) is an emergent disease withunclear environmental causes. In the few studies of the epide-miology of EoE, male sex and white race have been identified asrisk factors.1 A recent report suggested that cesarean section andearly life antibiotic use may increase the risk of EoE, but otherstudies have not specifically looked at these factors,2 nor have theyexamined associations between early life gastrointestinal symp-toms and EoE. The aim of this study was to investigate associa-tions between EoE and dietary, environmental, and medicalexposures during infancy. Subjects and controls ages 1-5 years oldwere recruited from the pediatric clinics at the MassachusettsGeneral Hospital. EoE cases were identified by a systematicreview of pediatric gastroenterology and allergy clinic visits(by International Classification of Diseases, Ninth Revisioncodes) between March 2011 and May 2012, and a review of allage-eligible endoscopy procedure visits between January 2008and May 2012. A diagnosis of EoE was based on endoscopyfindings of �15 eosinophils in any high-powered field onesophageal biopsy specimens while the subject was on adequateproton-pump inhibitor therapy (�1 mg/kg/d for �6 weeks).

Subjects were excluded if they had known eosinophilicgastroenteritis, inflammatory bowel disease, or any systemichypereosinophilic syndromes. Control subjects were recruitedfrom the Pediatric Ambulatory Care Clinic well-child and follow-up visits. This clinic has a comparable demographic profile to thespecialty clinics, with a similar percentage of patients covered bystate-assisted health insurance. Control subjects were excluded ifthey had symptoms suggestive of undiagnosed EoE, includingfeeding difficulty, frequent vomiting, frequent chest and/orabdominal pain, or dysphagia. Frequency matching of controlswas performed for a family history of atopy and for sex. Approvalfor this study was given by the Massachusetts General HospitalInstitutional Review Board.

The parent of each subject completed a questionnaire at thetime of a clinic visit or via electronic mail. The screening andstudy questionnaire included questions extracted from the In-ternational Study of Asthma and Allergies in Childhood studyquestionnaires.3 Study data were collected and managed by usingREDCap electronic data capture tools hosted at Massachusetts

General Hospital.4 Characteristics of subjects and controls werecompared by the Fisher exact test for dichotomous variables andby the Mann-Whitney 2-sample statistic for continuous vari-ables. Odds ratios (OR) were calculated by logistic regression.The only significant demographic difference between the groupswas age; therefore, analyses were adjusted for age, and for thefrequency matching variables (atopic family history and sex). Toexplore mediators of associations found, additional analyses oftiming of dietary introduction were adjusted for history of for-mula intolerance, and analyses of mode of delivery and early lifeantibiotic use were adjusted for personal history of atopy. Cal-culations were done with STATA SE 11.2 (College Station,Texas).

Twenty-five subjects with EoE and 74 controls were enrolled;14 subjects were excluded because of symptoms that could besuggestive of undiagnosed EoE. Questionnaires were completedby 89% and 85% of approached subjects and controls, respec-tively. As seen in Table I, demographic characteristics of subjectsand controls were similar, except that the subjects were younger(median 41 vs 51 months). The subjects with EoE were morefrequently born by cesarean section than were the controls (60%vs 34%; P ¼ .03) and had a significantly higher rate of antibioticuse in the first year of life (67% vs 33%; P ¼ .004), differencesthat were significant when adjusting for age, family history ofatopy, and sex. (Tables I and II). After also adjusting for a per-sonal history of atopy, the subjects still had increased odds ofantibiotic use in the first year of life (OR 3.61 [95% CI,1.11e11.74]; P ¼ .03), although the relationship with mode ofdelivery was no longer statistically significant (OR 2.69 [95% CI,0.93e7.83]; P ¼ .07).

Patients with EoE reported a significantly higher frequency ofsigns and symptoms of gastrointestinal allergy early in life. Un-expectedly, lower gastrointestinal tract disease manifestations alsowere significantly associated with EoE. Specifically, the subjectswith EoE had substantially higher rates of hematochezia (22% vs4%; P ¼ .02) and mucous in the stool (35% vs 7%; P ¼ .002)during the first year of life, although the difference in hema-tochezia was no longer significant when adjusting for age, afamily history of atopy, and sex (P ¼ .07) (Table I). No sig-nificant differences were seen between groups on measures ofbreastfeeding; timing of first solid food introduction; or timing ofintroduction of dairy, concentrated egg, wheat, meats, corn, orpeanuts. Small significant differences in timing of foods typicallyintroduced later in infancy, including baked egg products, treenuts, shellfish, and fish generally did not persist after adjustingfor the use of hypoallergenic formula, although age of intro-duction of baked egg products and fish remained higher in thesubjects than with the controls (see Tables E1 and E2 in thisarticle’s Online Repository at www.jaci-inpractice.org).

The aim of this study was to investigate the association be-tween early life exposures with the later development of EoE. Wefound that cesarean delivery and antibiotic exposure in the firstyear of life were significantly associated with the development ofEoE. The findings with regard to cesarean section and antibioticuse are of similar magnitude to another case-control study of EoEin children up to age 17 years old,2 despite the differences inages. The mode of delivery has not otherwise been linked to EoE,

1

TABLE I. Participant characteristics

Cases (n [ 25) Controls (n [ 74) P value*

Demographics

% Boys 80 67 .31

% White 68 68 >.99

Median age (IQR) (mo) 41 (25e58) 51 (36e64) .04

Median pregnancy length (IQR) (wk) (n ¼ 97) 40 (40e40) 40 (40e40) .43

Family characteristics

% Family history of atopy 76 65 .34

Median maternal age (IQR) (y) (n ¼ 81) 37 (33e40) 35 (32e39) .51

Maternal education (% with college education or higher) (n ¼ 90) 70 73 .35

% Maternal and child enrollment in Women, Infants, and Children (n ¼ 97) 17 27 .42

Allergic history

% Personal history of eczema (n ¼ 95) 75 22 <.001

% Personal history of food allergy (n ¼ 96) 67 14 <.001

Selected early life characteristics

% Birth by cesarean section (n ¼ 98) 60 34 .03

% Any antibiotics in the first year of life (n ¼ 93) 67 33 .004

% Ever breast fed (n ¼ 98) 84 84 >.99

% Use of reflux medications (n ¼ 96) 50 16 .002

% Blood in the stool (n ¼ 94) 22 4 .02

% Mucous in the stool (n ¼ 93) 35 7 .002

IQR, Interquartile range.*Calculated by using the Fisher exact test or the Wilcoxon rank sum statistics for dichotomous and continuous variables, respectively.

TABLE II. Early life exposures and gastrointestinal symptoms in infancy; EoE Cases vs controls

Variable

Unadjusted Adjusted for age, atopic family history and sex

OR (95% CI) P OR (95% CI) P

Early life exposures

Cesarean delivery (n ¼ 98) 2.94 (1.15e7.48) .02 3.21 (1.20e8.60) .02

Antibiotic use (n ¼ 93) 4.17 (1.56e11.16) .004 3.58 (1.27e10.13) .02

Feeding practices

Ever breastfed (n ¼ 98) 1.01 (0.30e3.49) .98 1.16 (0.31e4.30) .83

Early life manifestations of gastrointestinal or allergic disease

Hematochezia (n ¼ 94) 6.48 (1.41e29.69) .02 4.43 (0.089e21.98) .07

Mucus in the stool (n ¼ 93) 7.15 (2.05e24.94) .002 6.12 (1.63e23.03) .007

History of formula intolerance (n ¼ 94) 22.66 (6.89e74.53) <.001 18.60 (5.11e67.72) <.001

Diagnosis of milk and/or soy protein intolerance (n ¼ 94) 10.46 (3.06e35.66) .001 9.31 (2.47e35.05) .001

Proton-pump inhibitor use (n ¼ 96) 4.40 (1.31e14.74) .02 3.50 (1.01e12.11) .048

Use of reflux medications in the first year of life (n ¼ 96) 5.20 (1.89e14.24) .001 3.99 (1.40e11.38) .01

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although it has been identified as a risk factor for other atopicdiseases, such as asthma, allergic rhinitis, and allergic sensitiza-tion.5,6 Impressively, 60% of the subjects were born by cesareansection. After adjusting for a personal history of allergic diseases,the relationship with cesarean section but not antibiotic use wassomewhat attenuated, which suggested that atopy may explainsome, but not all, of the relationships between these factors andEoE. The association with both cesarean delivery and earlyantibiotic exposure suggests the hypothesis that dysbiosis is amechanism that contributes to the development of EoE,7,8

similar to or perhaps even more strongly than other atopic dis-eases.9,10 Children with EoE in this study had significantlyhigher rates of upper gastrointestinal symptoms early in infancythan did the controls, which is suggestive of disease onset much

earlier in life than is typically considered. The subjects with EoEalso experienced a 6-fold higher rate of allergic colitis symptoms,which suggests global mucosal allergic inflammation early in life.The link between early lower gastrointestinal diseases and lateresophageal allergic disease should be further studied.

We recognize several limitations of this study. Restrictingrecruitment to young children limits the generalizability of ourfindings to EoE in older patients, and, because this populationwas generally white with well educated parents, the results maynot generalize to other demographic groups. Excluding controlchildren with ongoing gastrointestinal issues could have biasedour results, especially those results that link early life gastroin-testinal symptoms to later EoE. Recall bias is inherent in retro-spective studies but it is unlikely that mode of delivery is affected

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by recall bias. Strengths of the study design include matching fora family history of atopy to ensure maximum similarity betweenthe subjects and the controls. Finally, we drew subjects andcontrols from clinics with similar referral patterns to minimizeselection bias and had a high response rate, thus reducing se-lection bias.

In summary, this case-control study identified cesarean de-livery and antibiotic use in the first year of life as having a strongassociation with EoE, which suggests a role for altered microbiotain this disease. In addition, in this subset of young children withEoE, disease began in infancy for many subjects and includedlower gastrointestinal symptoms. Although genetic risk factorsfor EoE have received significant attention, given the apparentincreasing prevalence, environmental factors are likely to beequally important and deserve more study. Analysis of thesefindings suggests several operational hypotheses that should beaddressed in larger, prospective studies.

aDivision of Gastroenterology, Massachusetts General Hospital (MGH), and HarvardMedical School, Boston, Mass

bDivision of Gastroenterology, The Food Allergy Center at MGH, MGH, andHarvard Medical School, Boston, Mass

cThe Food Allergy Center at MGH; MGH and Harvard Medical School, Boston,Mass

dDivision of Allergy and Immunology, The Food Allergy Center at MGH; Depart-ment of Pediatrics, MGH, and Harvard Medical School, Boston, Mass

eDivision of Allergy and Immunology, Department of Pediatrics, Johns HopkinsUniversity School of Medicine, Baltimore, Md

The study described was made possible in part by grant 1K23AI103187-01 (toC.A.K.) from the National Institute of Allergy and Infectious Diseases, acomponent of the National Institutes of Health; this study received support fromthe Demarest Lloyd Jr Foundation.

Conflicts of interest: M. C. Radano has received research support from the NationalInstitutes of Health (NIH). J. T. Fleming was employed by Partners MGH as asummer research assistant. Q. Yuan received research support from The DemarestLloyd Jr. Foundation in the form of a private donation to Dr Qian Yuan and theMGH Food Allergy Center. C. A. Keet has received research support from theNIH. W. Shreffler has received research support from National Institute of Allergy

and Infectious Diseases. The rest of the authors declare that they have no relevantconflicts of interest.

Received for publication December 10, 2013; revised January 16, 2014; accepted forpublication February 21, 2014.

Corresponding author: Corinne A. Keet, MD, MS, Department of Pediatrics,Johns Hopkins Hospital, CMSC 1102, 600 N Wolfe St, Baltimore, MD 21287.E-mail: ckeet1@jhmi.edu.

2213-2198/$36.00� 2014 American Academy of Allergy, Asthma & Immunologyhttp://dx.doi.org/10.1016/j.jaip.2014.02.018

REFERENCES

1. Franciosi JP, Tam V, Liacouras CA, Spergel JM. A case-control study ofsociodemographic and geographic characteristics of 335 children with eosino-philic esophagitis. Clin Gastroenterol Hepatol 1996;7:415-9.

2. Jensen ET, Kappelman MD, Kim HP, Ringel-Kulka T, Dellon ES. Early lifeexposures as risk factors for pediatric eosinophilic esophagitis: a pilot andfeasibility study. J Pediatr Gastroenterol Nutr 2013;57:67-71.

3. Asher MI, Keil U, Anderson HR, Beasley R, Crane J, Martinez F, et al. Inter-national Study of Asthma and Allergy in Childhood (ISAAC): rationale andmethods. Eur Respir J 1995;8:483-91.

4. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Researchelectronic data capture (REDCap): a metadata-driven methodology and work-flow process for providing translational research informatics support. J BiomedInform 2009;42:377-81.

5. Pistiner M, Gold D, Abdulkerim H, Benn CS, Westergaard T. Birth by cesareansection, allergic rhinitis, and allergic sensitization among children with aparental history of atopy. J Allergy Clin Immunol 2008;22:274-9.

6. Bager P, Melbye M, Rostgaard K, Benn CS, Westergaard T. Mode of deliveryand risk of allergic rhinitis and asthma. J Allergy Clin Immunol 2003;11:51-6.

7. Droste JH, Wieringa MH, Weyler JJ, Nelen VJ, Vermeire PA, Van Bever HP.Does the use of antibiotics in early childhood increase the risk of asthma andallergic disease? Clin Exp Allergy 2000;30:1548-53.

8. Johnson CC, Ownby DR, Alford SH, Havstad SL, Williams LK, Zoratti EM,et al. Antibiotic exposure in early infancy and risk for childhood atopy.J Allergy Clin Immunol 2005;115:1218-24.

9. VanNimwegen FA, Penders J, Stobberingh EE, Postma DS, Koppelman GH,Kerkhof M, et al. Mode and place of delivery, gastrointestinal microbiota andtheir influence on asthma and atopy. J Allergy Clin Immunol 2011;28:948-55.

10. Penders J, Thijs C, van den Brandt PA, Snijders B, Stelma F, et al. Gutmicrobiota composition and development of atopic manifestations in infancy:the KOALA Birth Cohort Study. Gut 2007;56:661-7.

TABLE E1. Timing of food introduction by case-control status

Median (IQR) age of introduction in cases (mo) Median (IQR) age of Introduction in controls (mo) P

Breast feeding

Duration of exclusive breastfeeding 1 (0.5e5) 3 (0.5e5) .24

Duration of any breastfeeding 5 (3e8) 6 (2e11) .48

Food introductions

Cow’s milk (including formula) 2 (0.5e5.5) 3 (0.5e7) .37

Introduction of solids 5 (4e6) 5 (4e6) .76

Wheat 9 (7.5e12) 9 (6e11) .12

Chicken 10 (8e11.5) 9 (6e12) .31

Beef 10 (8e12) 10 (8e12) .95

Corn 11.5 (8.5 to >13.5) 11 (8 to >12) .86

Baked egg 12 (9.5e12.5) 9 (6.5e11.5) .003

Concentrated egg 12 (9 to >12) 12 (9 to >12) .19

Soy (including formula) >12 (8 to >12) >12 (10.5 to >12) .26

Tree nuts >12 (>12 to >12) >12 (12 to >12) .02

Peanut >12 (>12 to >12) > 12 (12 to >12) .052

Shellfish >12 (>12 to >12) >12 (>12 to >12) .05Fish >12 (>12 to >12) >12 (11 to >12) .001

IQR, Interquartile range.Bold values represent statistically significant differences.

TABLE E2. Comparison of timing of food introduction between cases and controls

Unadjusted OR

(per mo of introduction)

Adjusted OR for age, family

history of atopy, and sex

Adjusted OR for age, family history of atopy,

sex, and use of hypoallergenic formula

OR (95% CI) P OR (95% CI) P OR (95% CI) P

Breast feeding

Duration of exclusive breastfeeding 0.88 (0.72e1.06) .17 0.88 (0.72e1.08) .22 0.99 (0.79e1.24) .91

Duration of any breastfeeding 0.95 (0.86e1.05) .33 0.97 (0.87e1.08) .53 1.04 (0.91e1.19) .55

Introduction of Foods

Cow’s milk (including formula) 0.93 (0.82e1.06) .26 0.93 (0.81e1.06) .29 0.96 (0.82e1.13) .65

Introduction of Solids 0.47 (0.70e1.23) .60 0.98 (0.74e1.30) .90 1.05 (0.75e1.47) .77

Wheat 1.13 (0.95e1.36) .15 1.13 (0.94e1.36) .20 1.20 (0.96e1.51) .11

Chicken 1.09 (0.90e1.32) .36 1.08 (0.88e1.32) .46 1.24 (0.96e1.60) .11

Beef 1.00 (0.84e1.20) .95 1.02 (0.85e1.23) .83 1.17 (0.93e1.50) .18

Corn 1.02 (0.85e1.21) .86 1.03 (0.86e1.25) .71 1.10 (0.87e1.40) .43

Baked egg 1.36 (1.10e1.69) .005 1.39 (1.10e1.75) .006 1.44 (1.10e1.90) .008

Concentrated egg 1.14 (0.92e1.42) .23 1.17 (0.92e1.49) .19 1.15 (0.88e1.52) .31

Soy (including formula) 0.92 (0.82e1.04) .19 0.94 (0.83e1.07) .35 1.11 (0.93e1.32) .24

Tree nuts 4.26 (0.96e19.11) .057 4.23 (0.90e19.92) .07 4.11 (0.70e24.21) .12

Peanut 2.60 (0.80e8.43) .11 2.35 (0.67e8.19) .18 2.81 (0.59e13.28) .19

Shellfish 4.62 (0.64e33.12) .13 4.51 (0.58e34.86) .15 6.61 (0.55e79.48) .14

Fish 3.57 (1.18e10.80) .02 3.39 (1.04e11.00) .04 6.06 (1.12e32.86) .04

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