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OBSTETRICS

Cesarean section and development of theimmune system in the offspringClara E. Cho, BSc; Mikael Norman, MD, PhD

T he worldwide rate of cesarean sec-tion (CS) has quadrupled in 2 de-cades,1,2 making CS the most commonsurgical procedure performed in womenof childbearing age today. The WorldHealth Organization recommends thatin up to 15% of deliveries, CS may beindicated. 3 However, 37 of 60 developedcountries currently exceed this recom-mendation. 4 The rate of CS is currently

25% in the United Kingdom and Can-ada, 32% in the United States, 40% inChina, and 46% in Brazil, 5-7 suggestingthat in many settings, women are under-going prelabor, elective CS without aclear medical indication.

This rapid change in mode of delivery probably reects the widespread notionthat CS is life saving and prevents injury to both the mother 8 and her baby. 9 Therise in parental requests for CS is alsoboosted bya worrying increase in fear for

childbirth 10,11 andatthesametime,bothprofessionals andparents tend to chooseCS for reasons of convenience andbettercontrol over the timing of delivery. 12,13

Finally, nancial incentives may pro-

mote hospitals and physicians to favorCS at the expense of vaginal delivery.14

Currently, the emphasis of discussionand counseling around mode of delivery is on thebenets andpotential harms forthe pregnant woman herself. 15,16 As forher infant, the risks with vaginal delivery are often underlined, whereas only 2 of 3

women are reported to have discu ssedneonatal problems after elective CS. 15,16

To date, implications of delivery modefor the future health of the offspring isseldom discussed, mainly due to a lack of existing information. With the increasingnumber of children and young adults whohave been deliveredby CS, however, this gapinknowledge needsto beaddressed.

Given the established evidence that en-vironmental inuences during early lifeshape the developmental trajectory of the

offspring and alter the risk of disease inadulthood, 17,18 it is no longer unintelligi-ble to see how changes from fetal to neo-natal life may play a role in future health.The purpose of this review is toexplore theevidence for an impact of the mode of de-livery on activation and development of the immune system in the offspring. Thefocus will be on recent epidemiologicallinks between mode of delivery and im-mune disorders in later life. We will alsohighlight some of the underlying mecha-

nisms by which the mode of delivery may shape the immune system for life.

Search methodsThis review was prepared by conductinga search in MEDLINE to identify rele-vant English-language articles publishedbefore March 2012. Search words in-cluded variations of cesarean section,delivery, immune system, asthma,allergy, diabetes, celiac disease,

skeletal disease, and cancer. Addi-tional articles were found by a manualsearch from the references cited in rele-vant reviews, letters, and editorials.

Observations in human beingsCSand later riskfor asthmaA metaanalysis of 23 studies has shownthat children and adults born by CS havea 20% higher risk of developing asthmacompared to those born vaginally. 19-28

This association remained after adjust-

ment for known confounders, such asmaternal smoking, low birthweight, andduration of breast-feeding. The overrisk of asthma in children born with CS in 2studies was conned to those diagnosedage 3-5years, suggesting that the etiol-ogy in early- and late-onset asthma may differ. 20,29 The more difcult neonatalrespiratory adaptation after CSsome-times causing neonatal lung disease 30 may possibly contribute to these nd-ings,31 but it is unclear how such

maladaptation mediates lung problemsbeyond the neonatal period. 24

From the Department of Nutritional Sciences,Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada (Ms Cho); andDepartment of Clinical Science, Interventionand Technology, Karolinska Institutet,Stockholm, Sweden (Dr Norman).Received Feb. 16, 2012; revised April 26,2012; accepted Aug. 8, 2012. The authors report no conict of interest.Reprints: Clara E. Cho, BSc, Department of Nutritional Sciences, Faculty of Medicine,University of Toronto, 150 College St., Room305, Toronto, Ontario, CanadaM5S [email protected] .0002-9378/$36.00 2013 Mosby, Inc. All rights reserved.http://dx.doi.org/10.1016/j.ajog.2012.08.009

See related editorials, pages 243

and 247

This review examines the relation between the mode of delivery and development of theimmune system in the offspring. Recent epidemiological studies provide evidence thatelective cesarean section (CS) is associated with aberrant short-term immune responsesin the newborn infant, and a greater risk of developing immune diseases such as asthma,allergies, type 1 diabetes, and celiac disease. However, it is still unknown whether CScauses a long-term effect on the immune system of the offspring that contributes tocompromised immune health. With the dramatic increase in the rate of CS today, a greateremphasis should be placed on the discussion among both professionals and childbearingwomen on potential consequences of CS on the health of the offspring.

Key words: cesarean section, delivery, immune system, offspring

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CSandlater risk for allergy Allergic rhinitis and atopy have been re-ported to be more prevalent in childrenborn by CS.26,32 Infants born by CS alsohaveahigherriskoffoodallergy,giventhatthe mother had a history of atopy. 33-35 In

contrast, other studies found no associa-tion between birth by CS and childhoodfood allergy.26,36 In a prospective cross-sectional study, infants born by CS hadgreater IgE-mediated sensitization whenintroduced to cows milk compared tothose vaginally born. 37

CSandlater risk for type1 diabetes mellitusA metaanalysis summarizing 20 studieshas shown that children born by CS have

a 23% higher risk of developing child-hood-onset type 1 diabetes compared tothose vaginally born. 38-43 This associa-tion was notaltered by adjusting forcon-founders such as maternal age, birthorder, birthweight, gestational age,breast-feeding, maternal diabetes, orfamily history.

CS and later risk forgastrointestinaldiseaseIncreased hospitalization for gastroen-teritis in infancy has been linked to birthbyCS.23 Inaddition, anincreasedrisk forceliac disease has been reported in chil-drenb orn byCScompared to vaginal de-livery.44,45 However, the risk of inam-matorybowel dis ease was not affectedby mode of delivery. 44 These ndings indi-cate that CS may impact the gastrointes-tinal function in the offspring in laterlife.

CS and later risk for skeletaldiseaseBirth by CS has been associated with a36% overrisk for later aseptic necrosis of the femoral head (Legg-Calv-Perthesdisease) in childhood, even after adjust-ingforbreechprese nta tionof the fetus atthe time of delivery. 46

CSandlater risk for cancerin the young There are some indications for an in-creased riskfor cancer (leukemia,neuro-

blastoma, testicular cancer) in childrenand young adults born by CS compared

to vaginal delivery, 47-49 although theseassociations have been uncon rmed orcontradicted in other studies. 50-52 It ispossible that the discrepancy in results isdue to various m aternal factors such asvitamin intakes53 and smoking sta-

tus54,55

during pregnancy, al tho ugh thiswas accounted for in 1 study. 47

Strengthsand limitations of theepidemiological evidenceSeveral of the observational studies inhuman beings are of high quality beingprospective, population-based, and suf-ciently large for multivariate analyses,adjusting for known confounders. Still,the strength of the epidemiological evi-dence should be considered with some

caution. Epidemiological ndings sug-gesting a long-term impact of CS on therisk of developing immune disease may be limited due to heterogeneity of study results stemmed fromconfounding vari-ables that aredifcultto control for, suchas use of anesthetic agents and antibiot-ics during CS, diet, hospital environ-ment, as well as genetic diversity of study populations. 31,56

Anesthetic drugs used during CS arethought to cross the placental barrier

and alter the immune system of the off-spring. 57 Although the physical responseof anesthetics on immune markers innewborns delivered by CS is not clear,previousreportshaveshownthat generalanesthesia lowers neutrophil respiratory burst test of cord blood compared to re-gional anesthesia. 58 Given that generalanesthesia has long since been aban-doned in many countries in favor of re-gional (spinal or epidural) anesthesia inboth elective and emergency CS, it is un-

likely that adverse effects of general an-esthesia on the immune system could bethe soleexplanation for long-termhealtheffects in the offspring.

Many studies conducted to date donot distinguish between prelabor elec-tive CS and emergency CS after onset of labor, performed in deliveries that arecomplicated by fetal distress. In studiesthat have separated the 2 types of CS, anincreased risk for later immune diseasewas conned to those deliveredby prela-

bor CS.45

Assuming that this would bevalid also for other outcomes, mixing

prelaborandemergencyCS would intro-duce a conservative bias and underesti-mate any effect of prelabor CS on laterhealth outcomes.

Mode of delivery andimmune

biomarkersSeveral studies have identied differ-ences in blood biomarkers fo llowing CScompared to vaginal birth. 59 Infantsborn by prelabor CS have be en found tohave a lower leukocyte count 60 as well aslower subpopulation counts of neutro-phil, monocyte, and natu ral killer (NK)cells in cord blood.61,62 Furthermore,cord blood leukocytes of babies born by CS had lower in vitro transmigrationability and expression of cell surface ad-

hesion molecule CD11b/CD18,63,64

andreduced levels of NK (CD3 /16 /56 )cells compared to those vaginally deliv-ered.65 In addition, the activity of leuko-cytes63,64 as well as their proinamma-tory cytokine releases, such asinterleukin (IL)-4r, IL-1 , IL-6, and tu-mor necrosis factor (TNF)- 66,67 werelower after CS compared to vaginal de-livery, thereby hampering immune cellfunctions. 68,69 However, theseresults areinconsistent with no difference observed

in fecal human -defensin 2 and TNF-concentrations of infants born by CScompared to vaginal delivery. 70

Higher risk of immune-related disor-ders following delivery byCSmay bedueto persisting differences in immunecomponents. 31 In line with this sugges-tion, 1-year-old infants born by CS havebeen found to contain a greater numberof immune cells secreting IgA and IgGcompared to those vaginally born. 59 Theatopic responder type has been charac-terized by an increased production of immunoglobulins, 71 providing a possi-ble link between CS and compromisedimmune health.

Experimental evidenceCS andaltered gene expressionin theimmunesystemInvestigation into the role of CS in im-munedevelopment usinganimal modelsis limited. The paucity of experimentaldata may be due to the lack of appropri-

ate animal models or strains to study ef-fects of mode of delivery. In the piglet

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liver, prelabor CS resulted in lower geneexpression of interferon (IFN)- , NKp80,and C-reactive protein. 72 Although se-rum concentrations of inammatory markers in piglets born by CS did notdiffer signicantly compared to those

vaginally born, there was a trend forlower levels ofIFN- andhigher levelsof TNF- 73 and a reduced activ ation of proinammatory cytokine IL-6. 56 Thesendings suggest that mode of delivery can alter gene expression with a func-tional signicance for the innate im-mune system.

CS,dopamine, andimmunefunction in theratStudies using the rat have demonstrated

that the mode of deliv ery impacts thecentral nervous system, 74,75 which may alter immune function of the offspringin later life. Rats born by CS had greaterdopamine D1 receptor binding in limbicareas of the brain com pared to thoseborn by vaginal delivery. 76 Although nostudy using rodent models has directly related alterations of dopamine receptorin the brain to the immune system, do-pamine is known to be involved in theregulation of lymphocyte and T-cell ac-

tivities.77

Furthermore, dopamine may be involved in lymphocyte activation atbirth, suggested by its association withthe level of IFN- .63 Accordingly, CSmay alter the normaldevelopmental trajectory of dopamine receptors and pro-gressively increase their binding patternin adulthood, which may modulate im-mune function. 76

MechanismsMode of delivery is thought to inuencethe development of the immune systemin the offspring by several pathways,which include: (1) variation in bacterialcolonization of the intestinal tract; (2)different levelsof adaptivestressof beingborn; and (3) altered epigenetic regula-tion of gene expression ( Figure).

Mode of delivery andbacterialcolonization of thegutthehygiene hypothesisThe hygiene hypothesis proposes that

improper bacterial exposure in early lifecontributes to a greater risk of develop-

ing immune diseases. 78 It is thought thatthe bacteria that newborns are rst ex-posed to may alter their immune devel-opment. 79 Newborns deliveredvaginally arecolonized by bacteria from themoth-ers birth canal and perianal region,whereas those born by prelabor CS arepredominantly colonized by bacteriaoriginating from the hospital environ-ment and nonmaternal skin. 80-82 CS in-fants more often have longer hospitalstays and spend more time separatedfrom their mothers, resulting in delayedbreast-feeding 83 comparedto those born

vaginally, all of which alter the bacterialcolonization and growth in the neonatalgut.84,85

Neonatal intestinal bacterial coloniza-tion primes the immune system andchanges the balance between T-helpertype 1 and 2 cells.78 The deviant intesti-nal colonization of infants born by CSmay prolong postnatal immunologicalimmaturity, prevent appropriate immu-nological priming, and thereby increasethe risk for later immune disease. 86

Cross-sectional and longitudinal studieshave demonstrated that allergic children

are characterized by lower intestinal col-onization of bidobacteria and Bacte-roides species and higher colonization of clostridia compared to nonallergic chil-dren. 87 Interestingly, several reports havesuggested that children born by CS have asimilar pattern of bacterial colonization asthose with atopic dermatitis. 82,88,89

Prelabor CS decreased bacterial diver-sity and density in piglets, compared tovaginal delivery.56 Infants born by CShad a lower total count of gut bacteria at1 month of age 59 and the gut bacterialora remained disturbed for up to 6

months.82

CSwasassociated with alteredcomposition of intestinal microbes even7 years after birth, compared to vaginaldelivery.90 Accordingly, there is growingevidence that the intestinal microoraplays an essential role in the develop-ment of theimmune system. 91 The inu-ence of CS on bacterial colonization of the gut may, however, be incompletely understood using fecal samples as a sur-rogate measure for the entire gut bacte-rial population. 92 Moreover, variations

in gestational age at birth anddifferencesin postnatal diets also make interpreta-

FIGUREMechanisms by which mode of delivery may inuence immune system

Cesarean delivery may affect immune system of offspring by: (1) perturbing bacterial coloniza-tion of gut; (2) mounting poor and maladaptive stress response; and (3) altering epigeneticregulation of gene expression through DNA methylation on cytosine-phosphate-guanine (CpG)dinucleotides. Stress is also thought to inuence epigenome.CG, cytosine-guanine; Me, methylated.

Cho. Cesarean section andimmunesystem of offspring. Am J ObstetGynecol2013.

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tions difcult. 56 Finally, it is importantto note that both the motherundergoingCS and her infant are more likely to betreated with antibiotics. As antibioticscan pertur b the intestinal microora for years,93,94 antibiotic treatment in con-

junction with delivery by CS could be aconfounding factor in many epidemio-logical studies.

The stressof being born andlater immune functionAnother mechanism that may underliethe differences in immune responses be-tween CS and vaginal delivery may be al-tered levels of stress hormones at birth.Contraction of the uterus and fetal hyp-oxia during vaginal delivery normally stimulate a signicant stress response, asreected by very high catecholamin e andcortisol concentrations in neonates. 95 Incontrast, infants delivered by CS beforethe onset o f labor lack this surge of stresshormones. 96 It is well established that el-evated circulating cortisol at birth is anindicator of hypotha lamic-pituitary-ad-renal axis activation. 97 Vaginal delivery and its effects on elevating glucocortico-ids have been associated with increasedmatur ation of the organs, including thegut.56 With already shortened gesta-tional length (electiveCS is typicallyper-formed 39weeksofgestation),alackof stress hormone surge and poor activa-tion of hypothalamic-pituitary-adrenalaxis consequently result in a less matureimmune system than after vaginal deliv-ery. Furthermore, stress experienced atbirth is immediatein infants deliveredby prelabor CS,whereas it evolves gradually for those born by vaginal delivery. Thisdifference in timing could also contrib-ute to a maladaptive immune responseafter CS, which may affect the immunesystem in later life.31

Mode of delivery andepigeneticsAdverse prenatal and perinatal stressmay permanently alter neuroendocrineand behavioral responses. 98 A novelmechanism for such adaptive responsesis epigenetic regulation, in which early gene expression can be modied in re-

sponse to environmental exposur e w ith-out altering the DNA sequence. 99 The

best studied epigenetic control mecha-nism is DNA methylation, which hasbeen shown to play a crucial role duringfetal development and to be one of thedeterminants of healt hand disease in theoffspring in later life.100,101

Experimental studies on the effects of adverse neonatal stress have demon-strated epigenetic alterations via DNAmethylation of glucocorticoid receptorsin thehippocampusof matureoffspring,resulting in higher stress sensitivity thatextends into adulthood. 102 Furthermore,human infants delivered by prelabor CShad higher global DNA methylation incordblood cells atbirthc omparedto thoseborn by vaginal delivery. 103 These resultssuggest that the epigenome of a newborn

and developing infant is sensitive to expe-riences at birth. It has been suggested thatearly adversegene methylation may be in-volved in silencing the pathway that regu-lates the balance between T-helper type 1and 2 cells, which could contribute to agreater risk of developing immune dis-eases.104 However, the role of epigeneticchanges by CS in the development of theimmune system and immune disordersstill remains speculative.

ConclusionBirth may be a critical time point thatdetermines immune health of the off-spring in later life. Existing data suggestthat prelabor CS is associated with aber-rantshort-termimmune responses, suchas reduced expression of inammatory markers in the newborn infant. Childrenborn by prelabor CS also face a greaterrisk of developing immune diseases suchas asthma, allergies, type 1 diabetes, andceliac disease. However, it is still un-

known whether CS causes a long-termeffect on the immune system of the off-spring that contributes to compromisedimmune health.

The potential mechanisms by whichCS can impact the development of theimmune system may work at the level of intestine by altering bacterial coloniza-tion, or may be related to an adverse birthstress response and epigenetic modica-tion of gene expression in the immunesystem.

As for the clinical signicance of thesendings,weshould not discontinueanev-

erydayprocedurethatinanemergencycanbe truly life saving, and in many circum-stances, constitutes a preventive measurewith clear and sound cost-benet ratio.However, it is time to leave the sometimes1-sidedperspective that seems todriveand

justifythe currentepidemicofCS.A higherawareness among both professionals andchildbearing women about the associa-tions between elective CS and adversehealth of their offspring is warranted. CSshould not be recommended without aclear medical indication, orwithout a solidevaluation of harms and benets, both forthe mother and her baby. In such evalua-tion, both short- and long-term conse-quencesforthe infant and thechild shouldcarry a greaterweight than what is consid-

ered today. f

REFERENCES1. Declercq E, MenackerF, Macdorman M.Ma-ternalrisk proles andthe primary cesarean ratein the United States, 1991-2002. Am J PublicHealth 2006;96:867-72.2. Bulger T, Howden-Chapman P, Stone P. A cut above: the rising cesarean section rate inNew Zealand. N Z Med J 1998;111:30-3.3. World Health Organization. Appropriatetechnology for birth. Lancet 1985;2:436-7.4. Althabe F, Sosa C, Belizan JM, Gibbons L,

Jacquerioz F, Bergel E. Cesarean section ratesand maternal and neonatal mortality in low-,medium-, and high-income countries: an eco-logical study. Birth 2006;33:270-7.5. PatahLE, Malik AM. Modelsof childbirth careand cesarean rates in different countries. RevSaude Publica 2011;45:185-94.6. Betran AP, Merialdi M, Lauer JA, et al. Ratesof cesarean section: analysis of global, regionaland national estimates. Paediatr Perinat Epide-miol 2007;21:98-113.7. Canadian Institute for Health Research. Givingbirth in Canada: regional trends from 2001-2002to 2005-2006. Available at: https://secure.cihi.ca/cihiweb/en/downloads/Childbirth_AiB_FINAL_E.pdf . Accessed Sept. 12, 2011.8. Lee YM, DAlton ME. Cesarean delivery onmaternal request: maternal and neonatal com-plications. Curr Opin Obstet Gynecol 2008;20:597-601.9. Hankins GD, Clark SM, Munn MB. Cesareansection on request at 39 weeks: impact onshoulder dystocia, fetal trauma, neonatal en-cephalopathy, and intrauterine fetal demise.Semin Perinatol 2006;30:276-87.10. Florica M, Stephansson O, Nordstrom L.Indications associated with increased cesareansection rates in a Swedish hospital.Int J Gynae-col Obstet 2006;92:181-5.11. Wiklund I, Edman G, Andolf E. Cesareansection on maternal request: reasons for the


https://secure.cihi.ca/cihiweb/en/downloads/Childbirth_AiB_FINAL_E.pdfhttps://secure.cihi.ca/cihiweb/en/downloads/Childbirth_AiB_FINAL_E.pdfhttps://secure.cihi.ca/cihiweb/en/downloads/Childbirth_AiB_FINAL_E.pdfhttps://secure.cihi.ca/cihiweb/en/downloads/Childbirth_AiB_FINAL_E.pdfhttps://secure.cihi.ca/cihiweb/en/downloads/Childbirth_AiB_FINAL_E.pdfhttps://secure.cihi.ca/cihiweb/en/downloads/Childbirth_AiB_FINAL_E.pdfhttps://secure.cihi.ca/cihiweb/en/downloads/Childbirth_AiB_FINAL_E.pdf


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request, self-estimated health, expectations,experience of birth and signs of depressionamongrst-timemothers. Acta Obstet GynecolScand 2007;86:451-6.12. Hopkins K. Are Brazilian women reallychoosing to deliver by cesarean? Soc Sci Med2000;51:725-40.13. McFarlin BL. Elective cesarean birth: issuesand ethics of an informed decision. J MidwiferyWomens Health 2004;49:421-9.14. Michaluk CA. Cesarean delivery by mater-nal request: what neonatal nurses need toknow. Neonatal Netw 2009;28:145-50.15. Bettes BA, Coleman VH, Zinberg S, et al.Cesarean delivery on maternal request: obste-trician-gynecologists knowledge, perception,and practice patterns. Obstet Gynecol 2007;109:57-66.16. Coleman VH, Lawrence H, Schulkin J. Ris-ingcesarean delivery rates: theimpact of cesar-ean delivery on maternal request. Obstet Gyne-col Surv 2009;64:115-9.17. Barker DJ, Gluckman PD, Godfrey KM,Harding JE, Owens JA, Robinson JS. Fetal nu-trition and cardiovascular disease in adult life.Lancet 1993;341:938-41.18. Hales CN,Barker DJ.Type 2 (non-insulin-de-pendent) diabetes mellitus: the thrifty phenotypehypothesis. Diabetologia 1992;35:595-601.19. Thavagnanam S, Fleming J, Bromley A,Shields MD, Cardwell CR. A meta-analysis of the association between cesarean section andchildhood asthma. Clin Exp Allergy 2008;38:629-33.20. MaitraA, Sherriff A, Strachan D, HendersonJ. Mode of delivery is not associated with

asthma or atopy in childhood. Clin Exp Allergy2004;34:1349-55.21. McKeever TM,Lewis SA,Smith C, HubbardR. Mode of delivery and risk of developing aller-gic disease. J Allergy Clin Immunol 2002;109:800-2.22. Kero J, Gissler M, Gronlund MM, et al.Mode of delivery andasthmais therea connec-tion? Pediatr Res 2002;52:6-11.23. Hakansson S, Kallen K. Cesarean sectionincreases the risk of hospital care in childhoodfor asthma and gastroenteritis. Clin Exp Allergy2003;33:757-64.24. Smith GC, Wood AM, White IR, Pell JP,Cameron AD, Dobbie R. Neonatal respiratorymorbidity at term and the risk of childhoodasthma. Arch Dis Child 2004;89:956-60.25. Debley JS, Smith JM, Redding GJ, Critch-low CW. Childhood asthma hospitalization risk after cesarean delivery in former term and pre-mature infants. Ann Allergy Asthma Immunol2005;94:228-33.26. Renz-Polster H, David MR, Buist AS, et al.Cesarean section delivery andthe risk of allergicdisorders in childhood. Clin Exp Allergy 2005;35:1466-72.27. Salam MT, Margolis HG, McConnell R,McGregor JA, Avol EL, Gilliland FD. Mode of delivery is associated with asthma and allergy

occurrences in children. Ann Epidemiol 2006;16:341-6.

28. Rusconi F, Galassi C, Forastiere F, et al.Maternal complications and procedures inpregnancy and at birth and wheezing pheno-types in children. Am J Respir Crit Care Med2007;175:16-21.29. Metsala J, Kilkkinen A, Kaila M, et al. Peri-natal factors and the risk of asthma in child-hooda population-based register study in Fin-land. Am J Epidemiol 2008;168:170-8.30. Levine EM, Ghai V, Barton JJ, Strom CM.Mode of delivery andrisk of respiratory diseasesin newborns. Obstet Gynecol 2001;97:439-42.31. HydeMJ,Mostyn A,Modi N, KempPR. Thehealth implications of birth by cesarean section.Biol Rev Camb Philos Soc 2012;87:229-43.32. Pistiner M, Gold DR, Abdulkerim H, Hoff-man E, Celedon JC. Birth by cesarean section,allergic rhinitis, and allergic sensitization amongchildren with a parental history of atopy. J Al-lergy Clin Immunol 2008;122:274-9.33. Eggesbo M, Botten G, Stigum H, NafstadP, Magnus P. Is delivery by cesarean section a

risk factor for food allergy? J Allergy Clin Immu-nol 2003;112:420-6.34. Eggesbo M, Botten G, Stigum H, Samu-elsen SO, Brunekreef B, Magnus P. Cesareandelivery and cow milk allergy/intolerance. Al-lergy 2005;60:1172-3.35. LaubereauB, Filipiak-Pittroff B, von Berg A,et al. Cesarean section and gastrointestinalsymptoms, atopic dermatitis, and sensitizationduring the rst year of life. Arch Dis Child2004;89:993-7.36. KoplinJ, Allen K, GurrinL, Osborne N, TangML, Dharmage S. Is cesarean delivery associ-ated with sensitization to food allergens and

IgE-mediated food allergy: a systematic review.Pediatr Allergy Immunol 2008;19:682-7.37. Sanchez-Valverde F, GilF, Martinez D, et al. The impact of cesarean delivery and type of feeding on cows milk allergy in infants andsub-sequent development of allergic march in child-hood. Allergy 2009;64:884-9.38. Cardwell CR, Stene LC, Joner G, et al. Ce-sarean section is associated with an increasedriskof childhood-onsettype 1 diabetes mellitus:a meta-analysis of observational studies. Dia-betologia 2008;51:726-35.39. Dahlquist G, Kallen B. Maternal-child bloodgroup incompatibility and other perinatal eventsincrease the risk for early-onset type 1 (insulin-dependent) diabetes mellitus. Diabetologia1992;35:671-5.40. SteneLC,Magnus P,LieRT, SovikO, JonerG. No association between preeclampsiaor ce-sareansection and incidenceof type 1 diabetesamong children: a large, population-based co-hort study. Pediatr Res 2003;54:487-90.41. Cardwell CR, Carson DJ, Patterson CC.Parental ageat delivery,birth order,birthweightand gestational age areassociated with the risk of childhood type 1 diabetes: a UK regional ret-rospective cohort study. Diabet Med 2005;22:200-6.42. Bache I, Bock T, Volund A, Buschard K.

Previous maternal abortion, longer gestation,and younger maternal age decrease the risk of

type1 diabetes among maleoffspring.DiabetesCare 1999;22:1063-5.43. Malcova H, Sumnik Z, Drevinek P, Venha-cova J, Lebl J, Cinek O. Absence of breast-feeding is associated with the risk of type 1 di-abetes: a case-control study in a populationwith rapidly increasing incidence. Eur J Pediatr2006;165:114-9.44. Decker E, Engelmann G, Findeisen A, et al.Cesarean delivery is associated with celiac dis-ease butnot inammatoryboweldisease in chil-dren. Pediatrics 2010;125:e1433-40.45. Marild K, Stephansson O, Montgomery S,Murray JA, LudvigssonJF. Pregnancyoutcomeand risk of celiac disease in offspring: a nation-wide case-control study. Gastroenterology2012;142:39-45.e3.46. Bahmanyar S, Montgomery SM, Weiss RJ,Ekbom A. Maternal smoking during pregnancy,other prenatal andperinatal factors, andthe risk of Legg-Calve-Perthes disease. Pediatrics2008;122:e459-64.47. Cnattingius S, Zack M, Ekbom A, Gunnar-skog J, Linet M, Adami HO. Prenatal and neo-natal risk factors for childhood myeloid leuke-mia. Cancer Epidemiol Biomarkers Prev 1995;4:441-5.48. McLaughlin CC, Baptiste MS, SchymuraMJ, Zdeb MS, Nasca PC. Perinatal risk factorsfor neuroblastoma. Cancer Causes Control2009;20:289-301.49. Cook MB, Graubard BI, Rubertone MV, Er-ickson RL, McGlynn KA. Perinatal factors andthe risk of testicular germ cell tumors. Int J Can-cer 2008;122:2600-6.50. Bluhm E, McNeil DE, Cnattingius S, Gridley

G, El Ghormli L, Fraumeni JF Jr. Prenatal andperinatal risk factors for neuroblastoma. Int JCancer 2008;123:2885-90.51. Johnson KJ, Soler JT, Puumala SE, RossJA, Spector LG. Parental and infant character-istics and childhood leukemia in Minnesota.BMC Pediatr 2008;8:7.52. Podvin D, Kuehn CM, Mueller BA, WilliamsM. Maternal and birth characteristics in relationto childhood leukemia. Paediatr Perinat Epide-miol 2006;20:312-22.53. Bunin GR, Kuijten RR, Buckley JD, RorkeLB, Meadows AT. Relation between maternaldiet and subsequent primitive neuroectodermalbrain tumors in young children. N Engl J Med1993;329:536-41.54. Pettersson A, Kaijser M, RichiardiL, AsklingJ, Ekbom A, Akre O. Women smoking and tes-ticular cancer: one epidemic causing another?Int J Cancer 2004;109:941-4.55. Stavrou EP, Baker DF, Bishop JF. Maternalsmoking during pregnancy and childhood can-cer in NewSouth Wales: a record linkage inves-tigation. Cancer Causes Control 2009;20:1551-8.56. Siggers RH, Thymann T, Jensen BB, et al.Elective cesarean delivery affects gut matura-tion and delays microbial colonization but doesnot increase necrotizing enterocolitis in preterm

pigs. Am J Physiol Regul Integr Comp Physiol2008;294:R929-38.

www.AJOG.org Obstetrics Expert Reviews



6/6

57. Rizzo A, CampanileD, SpedicatoM, MinoiaG, Sciorsci RL. Update on anesthesia and theimmune response in newborns delivered by ce-sarean section. Immunopharmacol Immuno-toxicol 2011;33:581-5.58. Gasparoni A, Ciardelli L, De Amici D, et al.Effect of general and epidural anesthesia onthyroid hormones and immunity in neonates.Paediatr Anaesth 2002;12:59-64.59. Huurre A, Kalliomaki M, Rautava S, RinneM, Salminen S, Isolauri E. Mode of deliveryeffects on gut microbiota and humoral immu-nity. Neonatology 2008;93:236-40.60. Nikischin W, Peter M, Oldigs HD. The inu-ence of mode of delivery on hematologic valuesin the umbilical vein. Gynecol Obstet Invest1997;43:104-7.61. Gronlund MM, Nuutila J, Pelto L, et al.Mode of delivery directs the phagocyte func-tions of infants for the rst 6 months of life. ClinExp Immunol 1999;116:521-6.62. Thilaganathan B, Meher-Homji N, Nico-laides KH. Labor: an immunologically benecialprocess for the neonate. Am J Obstet Gynecol1994;171:1271-2.63. Yektaei-Karin E, Moshfegh A, Lundahl J,Berggren V, Hansson LO, Marchini G. Thestress of birth enhances in vitro spontaneousand IL-8-induced neutrophil chemotaxis in thehuman newborn. Pediatr Allergy Immunol2007;18:643-51.64. Gessler P, Dahinden C. Increased respira-tory burst and increased expression of comple-ment receptor-3 (CD11b/CD18) and of IL-8 re-ceptor-A in neutrophil granulocytes fromnewborns after vaginal delivery. Biol Neonate2003;83:107-12.65. Bili H, Fleva A, Pados G, et al. Regulatory Tau-cell differentiation between maternal andcord blood samples in pregnancies with spon-taneous vaginal deliveryandwithelectivecesar-ean section. Am J Reprod Immunol 2011;65:173-9.66. Malamitsi-Puchner A, Protonotariou E,BoutsikouT, Makrakis E, Sarandakou A, Creat-sas G. The inuence of the mode of delivery oncirculating cytokine concentrations in the peri-natal period. Early Hum Dev 2005;81:387-92.67. Zanardo V, Solda G, Trevisanuto D. Electivecesarean section and fetal immune-endocrine

response. Int J GynaecolObstet 2006;95:52-3.68. Baggiolini M, Loetscher P, Moser B. Inter-leukin-8 and the chemokine family. Int J Immu-nopharmacol 1995;17:103-8.69. Hagnevik K, Faxelius G, Irestedt L, Lager-crantz H, Lundell B, Persson B. Catecholaminesurge and metabolic adaptation in the newbornafter vaginal delivery and cesarean section. Acta Paediatr Scand 1984;73:602-9.70. Richter M, Topf HG, Groschl M, et al. Inu-ence of gestational age, cesarean section, andtype of feeding on fecal human beta-defensin 2and tumor necrosis factor-alpha. J Pediatr Gas-troenterol Nutr 2010;51:103-5.

71. Guarner F, Malagelada J-R. Gut ora inhealth and disease. Lancet 2003;360:512-9.72. Hyde MJ, Grifn JL, Herrera E, Byrne CD,Clarke L, Kemp PR. Delivery by cesarean sec-tion, rather than vaginal delivery, promotes he-patic steatosis in piglets. Clin Sci (Lond)2010;118:47-59.73. Daniel JA, Carroll JA, Keisler DH, KojimaCJ. Evaluation of immune system function inneonatal pigs born vaginally or by cesareansection. Domest Anim Endocrinol 2008;35:81-7.74. Ng PC.The fetal andneonatal hypothalamic-pituitary-adrenalaxis. ArchDis Child Fetal Neona-tal Ed 2000;82:F250-4.75. HerleniusE, Lagercrantz H. Development of neurotransmitter systems during critical peri-ods. Exp Neurol 2004;190(Suppl):S8-21.76. El-Khodor B, Boksa P. Cesarean sectionbirth produces long term changes in dopamineD1 receptors and in stress-induced regulationof D3 and D4 receptors in the rat brain. Neuro-

psychopharmacology 2001;25:423-39.77. Watanabe Y, Nakayama T, Nagakubo D, etal. Dopamine selectively induces migration andhoming of naive CD8 T cells via dopamine re-ceptor D3. J Immunol 2006;176:848-56.78. Strachan DP. Hay fever, hygiene, andhousehold size. BMJ 1989;299:1259-60.79. Neu J, Rushing J. Cesarean versus vaginaldelivery: long-term infant outcomes and the hy-giene hypothesis. Clin Perinatol 2011;38:321-31.80. Dominguez-Bello MG, Costello EK, Contre-ras M, et al. Delivery mode shapes the acquisi-tion andstructure of theinitial microbiota acrossmultiple body habitats in newborns. Proc Natl Acad Sci U S A 2010;107:11971-5.81. Bezirtzoglou E. The intestinal microoraduring the rst weeks of life. Anaerobe1997;3:173-7.82. Gronlund MM, Lehtonen OP,Eerola E, KeroP. Fecal microora in healthy infants born bydifferent methods of delivery: permanentchanges in intestinal ora after cesarean deliv-ery. J Pediatr Gastroenterol Nutr 1999;28:19-25.83. Prior E, Santhakumaran S, Gale C, PhilippsLH, Modi N, Hyde MJ. Breastfeeding after ce-sarean delivery: a systematic review and meta-analysis of world literature. Am J Clin Nutr2012;95:1113-35.84. Vestermark V, Hogdall CK, Birch M, PlenovG, Toftager-Larsen K. Inuence of the mode of delivery on initiation of breast-feeding.Eur J Ob-stet Gynecol Reprod Biol 1991;38:33-8.85. Rowe-Murray HJ, Fisher JR. Baby friendlyhospital practices: cesarean section is a persis-tent barrier to early initiation of breastfeeding.Birth 2002;29:124-31.86. Ly NP, Ruiz-Perez B, Onderdonk AB, et al.Mode of delivery and cord blood cytokines: abirth cohort study. Clin Mol Allergy 2006;4:13.87. BjorkstenB, Sepp E, Julge K,Voor T, Mikel-saar M. Allergy development and the intestinal

microora during the rst year of life. J AllergyClin Immunol 2001;108:516-20.88. Bennet R, Nord CE. Development of thefecal anaerobic microora after cesarean sec-tion and treatment with antibiotics in newborninfants. Infection 1987;15:332-6.89. Neut C, Bezirtzoglou E, Romond C, Beer-ens H, Delcroix M, Noel AM. Bacterial coloniza-tion of the large intestine in newborns deliveredby cesarean section. Zentralbl Bakteriol Mikro-biol Hyg A 1987;266:330-7.90. Salminen S, Gibson GR, McCartney AL,Isolauri E. Inuence of mode of delivery on gutmicrobiota composition in seven year old chil-dren. Gut 2004;53:1388-9.91. Bjorksten B. Effects of intestinal microoraand the environment on the development of asthma and allergy. Springer Semin Immuno-pathol 2004;25:257-70.92. Magne F, Suau A, Pochart P, Desjeux JF.Fecal microbial community in preterm infants.J Pediatr Gastroenterol Nutr 2005;41:386-92.93. Jernberg C, Lofmark S, Edlund C, JanssonJK. Long-term ecological impacts of antibioticadministration on the human intestinal microbi-ota. ISME J 2007;1:56-66.94. Jakobsson HE, Jernberg C, Andersson AF,Sjolund-Karlsson M, Jansson JK, Engstrand L.Short-term antibiotic treatment has differinglong-termimpacts on thehuman throat andgutmicrobiome. PLoS One 2010;5:e9836.95. Lagercrantz H. Stress, arousal and geneactivation at birth. News Physiol Sci 1996;11:214-8.96. Lagercrantz H, Slotkin TA. The stress of being born. Sci Am 1986;254:100-7.97. Gitau R, Menson E, Pickles V, Fisk NM,Glover V, MacLachlan N. Umbilical cortisol lev-elsas an indicatorof thefetalstress response toassisted vaginal delivery. Eur J Obstet GynecolReprod Biol 2001;98:14-7.98. Welberg LA, Seckl JR. Prenatal stress, glu-cocorticoids and the programming of the brain.J Neuroendocrinol 2001;13:113-28.99. Murphy SK, Jirtle RL. Imprinting evolutionand the price of silence. Bioessays 2003;25:577-88.100. Razin A, Shemer R. DNA methylation inearly development. Hum Mol Genet 1995;4:1751-5.101. Jirtle RL, Skinner MK. Environmental epig-enomics and disease susceptibility. Nat RevGenet 2007;8:253-62.102. Weaver IC, Cervoni N, Champagne FA, etal. Epigenetic programming by maternalbehav-ior. Nat Neurosci 2004;7:847-54.103. Schlinzig T, Johansson S, Gunnar A, Ek-strom TJ, Norman M. Epigenetic modulation atbirthaltered DNA-methylation in white bloodcells after cesarean section. Acta Paediatr2009;98:1096-9.104. Martino DJ, Prescott SL. Silent mysteries:epigenetic paradigms could hold the key toconquering theepidemic of allergy and immunedisease. Allergy 2010;65:7-15.



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