Association of Birth by Cesarean Delivery With Obesity and Type 2 Diabetes Among Adult Women | Obesity | JAMA Network Open | JAMA Network
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Figure 1.  Cumulative Incidence of Type 2 Diabetes Among Women Born by Vaginal vs Cesarean Delivery
Cumulative Incidence of Type 2 Diabetes Among Women Born by Vaginal vs Cesarean Delivery
Figure 2.  Associations of Birth by Cesarean Delivery With Risks of Offspring Obesity and Type 2 Diabetes Among Women in Low-Risk Categories for Cesarean Delivery Based on Maternal Characteristics
Associations of Birth by Cesarean Delivery With Risks of Offspring Obesity and Type 2 Diabetes Among Women in Low-Risk Categories for Cesarean Delivery Based on Maternal Characteristics

A, Risk of obesity among offspring in adulthood. B, Risk of type 2 diabetes among offspring in adulthood. BMI indicates body mass index (calculated as weight in kilograms divided by height in meters squared); HR, hazard ratio; and RR, relative risk.

Table 1.  Maternal and Offspring Characteristics According to Mode of Delivery
Maternal and Offspring Characteristics According to Mode of Delivery
Table 2.  Association Between Mode of Delivery With Obesity in Offspring Among 33 226 Women
Association Between Mode of Delivery With Obesity in Offspring Among 33 226 Women
Table 3.  Association Between Mode of Delivery With the Risk of Type 2 Diabetes
Association Between Mode of Delivery With the Risk of Type 2 Diabetes
1.
Martin  JA, Hamilton  BE, Osterman  MJK, Driscoll  AK.  Births: final data for 2018.   Natl Vital Stat Rep. 2019;68(13):1-47.Google Scholar
2.
Healthcare Cost and Utilization Project. McDermott KW, Freeman WJ, Elixhauser A. Statistical brief #233: overview of operating room procedures during inpatient stays in U.S. hospitals, 2014. Accessed August 22, 2018. https://www.hcup-us.ahrq.gov/reports/statbriefs/sb233-Operating-Room-Procedures-United-States-2014.pdf
3.
Woodman  M.  Mid-century trends in cesarean section.   N Engl J Med. 1950;243(14):528-530. doi:10.1056/NEJM195010052431404 PubMedGoogle ScholarCrossref
4.
Pokras  R, Kozak  LJ, McCarthy  E, Graves  EJ.  Trends in hospital utilization, 1965-86.   Am J Public Health. 1990;80(4):488-490. doi:10.2105/AJPH.80.4.488 PubMedGoogle ScholarCrossref
5.
Tita  AT.  When is primary cesarean appropriate: maternal and obstetrical indications.   Semin Perinatol. 2012;36(5):324-327. doi:10.1053/j.semperi.2012.04.014 PubMedGoogle ScholarCrossref
6.
Hannah  ME, Hannah  WJ, Hewson  SA, Hodnett  ED, Saigal  S, Willan  AR; Term Breech Trial Collaborative Group.  Planned caesarean section versus planned vaginal birth for breech presentation at term: a randomised multicentre trial.   Lancet. 2000;356(9239):1375-1383. doi:10.1016/S0140-6736(00)02840-3 PubMedGoogle ScholarCrossref
7.
Humberg  A, Härtel  C, Paul  P,  et al; German Neonatal Network (GNN).  Delivery mode and intraventricular hemorrhage risk in very-low-birth-weight infants: observational data of the German Neonatal Network.   Eur J Obstet Gynecol Reprod Biol. 2017;212:144-149. doi:10.1016/j.ejogrb.2017.03.032 PubMedGoogle ScholarCrossref
8.
Simpson  LL.  When is primary cesarean appropriate: fetal indications.   Semin Perinatol. 2012;36(5):328-335. doi:10.1053/j.semperi.2012.04.015 PubMedGoogle ScholarCrossref
9.
Liu  S, Liston  RM, Joseph  KS, Heaman  M, Sauve  R, Kramer  MS; Maternal Health Study Group of the Canadian Perinatal Surveillance System.  Maternal mortality and severe morbidity associated with low-risk planned cesarean delivery versus planned vaginal delivery at term.   CMAJ. 2007;176(4):455-460. doi:10.1503/cmaj.060870 PubMedGoogle ScholarCrossref
10.
Hansen  AK, Wisborg  K, Uldbjerg  N, Henriksen  TB.  Risk of respiratory morbidity in term infants delivered by elective caesarean section: cohort study.   BMJ. 2008;336(7635):85-87. doi:10.1136/bmj.39405.539282.BE PubMedGoogle ScholarCrossref
11.
Loebel  G, Zelop  CM, Egan  JF, Wax  J.  Maternal and neonatal morbidity after elective repeat Cesarean delivery versus a trial of labor after previous Cesarean delivery in a community teaching hospital.   J Matern Fetal Neonatal Med. 2004;15(4):243-246. doi:10.1080/14767050410001668653PubMedGoogle ScholarCrossref
12.
Barber  EL, Lundsberg  LS, Belanger  K, Pettker  CM, Funai  EF, Illuzzi  JL.  Indications contributing to the increasing cesarean delivery rate.   Obstet Gynecol. 2011;118(1):29-38. doi:10.1097/AOG.0b013e31821e5f65 PubMedGoogle ScholarCrossref
13.
Boyle  A, Reddy  UM, Landy  HJ, Huang  CC, Driggers  RW, Laughon  SK.  Primary cesarean delivery in the United States.   Obstet Gynecol. 2013;122(1):33-40. doi:10.1097/AOG.0b013e3182952242 PubMedGoogle ScholarCrossref
14.
American College of Obstetricians and Gynecologists; Society for Maternal-Fetal Medicine.  Obstetric care consensus no. 1: safe prevention of the primary cesarean delivery.   Obstet Gynecol. 2014;123(3):693-711. doi:10.1097/01.AOG.0000444441.04111.1d PubMedGoogle ScholarCrossref
15.
Black  M, Bhattacharya  S, Philip  S, Norman  JE, McLernon  DJ.  Planned cesarean delivery at term and adverse outcomes in childhood health.   JAMA. 2015;314(21):2271-2279. doi:10.1001/jama.2015.16176 PubMedGoogle ScholarCrossref
16.
Blustein  J, Liu  J.  Time to consider the risks of caesarean delivery for long term child health.   BMJ. 2015;350:h2410. doi:10.1136/bmj.h2410 PubMedGoogle ScholarCrossref
17.
Cho  CE, Norman  M.  Cesarean section and development of the immune system in the offspring.   Am J Obstet Gynecol. 2013;208(4):249-254. doi:10.1016/j.ajog.2012.08.009 PubMedGoogle ScholarCrossref
18.
Nielsen  NM, Bager  P, Stenager  E,  et al.  Cesarean section and offspring’s risk of multiple sclerosis: a Danish nationwide cohort study.   Mult Scler. 2013;19(11):1473-1477. doi:10.1177/1352458513480010PubMedGoogle ScholarCrossref
19.
Li  HT, Zhou  YB, Liu  JM.  The impact of cesarean section on offspring overweight and obesity: a systematic review and meta-analysis.   Int J Obes (Lond). 2013;37(7):893-899. doi:10.1038/ijo.2012.195 PubMedGoogle ScholarCrossref
20.
Darmasseelane  K, Hyde  MJ, Santhakumaran  S, Gale  C, Modi  N.  Mode of delivery and offspring body mass index, overweight and obesity in adult life: a systematic review and meta-analysis.   PLoS One. 2014;9(2):e87896. doi:10.1371/journal.pone.0087896 PubMedGoogle Scholar
21.
Yuan  C, Gaskins  AJ, Blaine  AI,  et al.  Association between cesarean birth and risk of obesity in offspring in childhood, adolescence, and early adulthood.   JAMA Pediatr. 2016;170(11):e162385. doi:10.1001/jamapediatrics.2016.2385 PubMedGoogle Scholar
22.
Pei  Z, Heinrich  J, Fuertes  E,  et al; Influences of Lifestyle-Related Factors on the Immune System and the Development of Allergies in Childhood plus Air Pollution and Genetics (LISAplus) Study Group.  Cesarean delivery and risk of childhood obesity.   J Pediatr. 2014;164(5):1068-1073.e2. doi:10.1016/j.jpeds.2013.12.044 PubMedGoogle ScholarCrossref
23.
Hansen  S, Halldorsson  TI, Olsen  SF,  et al.  Birth by cesarean section in relation to adult offspring overweight and biomarkers of cardiometabolic risk.   Int J Obes (Lond). 2018;42(1):15-19. doi:10.1038/ijo.2017.175PubMedGoogle ScholarCrossref
24.
Bernardi  JR, Pinheiro  TV, Mueller  NT,  et al.  Cesarean delivery and metabolic risk factors in young adults: a Brazilian birth cohort study.   Am J Clin Nutr. 2015;102(2):295-301. doi:10.3945/ajcn.114.105205 PubMedGoogle ScholarCrossref
25.
Michels  KB, Willett  WC, Graubard  BI,  et al.  A longitudinal study of infant feeding and obesity throughout life course.   Int J Obes (Lond). 2007;31(7):1078-1085. doi:10.1038/sj.ijo.0803622 PubMedGoogle ScholarCrossref
26.
Tomeo  CA, Rich-Edwards  JW, Michels  KB,  et al.  Reproducibility and validity of maternal recall of pregnancy-related events.   Epidemiology. 1999;10(6):774-777. doi:10.1097/00001648-199911000-00022 PubMedGoogle ScholarCrossref
27.
McAdams  MA, Van Dam  RM, Hu  FB.  Comparison of self-reported and measured BMI as correlates of disease markers in US adults.   Obesity (Silver Spring). 2007;15(1):188-196. doi:10.1038/oby.2007.504 PubMedGoogle ScholarCrossref
28.
World Health Organization.  Physical Status: The Use and Interpretation of Anthropometry: Report of a WHO Expert Committee, WHO Technical Report Series No. 854. World Health Organization; 1995.
29.
Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.  Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.   Diabetes Care. 1997;20(7):1183-1197. doi:10.2337/diacare.20.7.1183 PubMedGoogle ScholarCrossref
30.
National Diabetes Data Group.  Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance.   Diabetes. 1979;28(12):1039-1057. doi:10.2337/diab.28.12.1039 PubMedGoogle ScholarCrossref
31.
Manson  JE, Rimm  EB, Stampfer  MJ,  et al.  Physical activity and incidence of non–insulin-dependent diabetes mellitus in women.   Lancet. 1991;338(8770):774-778. doi:10.1016/0140-6736(91)90664-B PubMedGoogle ScholarCrossref
32.
Cole  SR, Hernán  MA.  Constructing inverse probability weights for marginal structural models.   Am J Epidemiol. 2008;168(6):656-664. doi:10.1093/aje/kwn164 PubMedGoogle ScholarCrossref
33.
Xu  S, Ross  C, Raebel  MA, Shetterly  S, Blanchette  C, Smith  D.  Use of stabilized inverse propensity scores as weights to directly estimate relative risk and its confidence intervals.   Value Health. 2010;13(2):273-277. doi:10.1111/j.1524-4733.2009.00671.x PubMedGoogle ScholarCrossref
34.
Greiner  T, Bäckhed  F.  Effects of the gut microbiota on obesity and glucose homeostasis.   Trends Endocrinol Metab. 2011;22(4):117-123. doi:10.1016/j.tem.2011.01.002 PubMedGoogle ScholarCrossref
35.
Neu  J, Rushing  J.  Cesarean versus vaginal delivery: long-term infant outcomes and the hygiene hypothesis.   Clin Perinatol. 2011;38(2):321-331. doi:10.1016/j.clp.2011.03.008 PubMedGoogle ScholarCrossref
36.
Musso  G, Gambino  R, Cassader  M.  Obesity, diabetes, and gut microbiota: the hygiene hypothesis expanded?   Diabetes Care. 2010;33(10):2277-2284. doi:10.2337/dc10-0556 PubMedGoogle ScholarCrossref
37.
Biasucci  G, Benenati  B, Morelli  L, Bessi  E, Boehm  G.  Cesarean delivery may affect the early biodiversity of intestinal bacteria.   J Nutr. 2008;138(9):1796S-1800S. doi:10.1093/jn/138.9.1796S PubMedGoogle ScholarCrossref
38.
Dominguez-Bello  MG, Costello  EK, Contreras  M,  et al.  Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns.   Proc Natl Acad Sci U S A. 2010;107(26):11971-11975. doi:10.1073/pnas.1002601107 PubMedGoogle ScholarCrossref
39.
Huurre  A, Kalliomäki  M, Rautava  S, Rinne  M, Salminen  S, Isolauri  E.  Mode of delivery—effects on gut microbiota and humoral immunity.   Neonatology. 2008;93(4):236-240. doi:10.1159/000111102 PubMedGoogle ScholarCrossref
40.
Sordillo  JE, Zhou  Y, McGeachie  MJ,  et al.  Factors influencing the infant gut microbiome at age 3-6 months: findings from the ethnically diverse Vitamin D Antenatal Asthma Reduction Trial (VDAART).   J Allergy Clin Immunol. 2017;139(2):482-491. doi:10.1016/j.jaci.2016.08.045PubMedGoogle ScholarCrossref
41.
Grönlund  MM, Lehtonen  OP, Eerola  E, Kero  P.  Fecal microflora in healthy infants born by different methods of delivery: permanent changes in intestinal flora after cesarean delivery.   J Pediatr Gastroenterol Nutr. 1999;28(1):19-25. doi:10.1097/00005176-199901000-00007 PubMedGoogle ScholarCrossref
42.
Salminen  S, Gibson  GR, McCartney  AL, Isolauri  E.  Influence of mode of delivery on gut microbiota composition in seven year old children.   Gut. 2004;53(9):1388-1389. doi:10.1136/gut.2004.041640 PubMedGoogle ScholarCrossref
43.
Schlinzig  T, Johansson  S, Gunnar  A, Ekström  TJ, Norman  M.  Epigenetic modulation at birth—altered DNA-methylation in white blood cells after Caesarean section.   Acta Paediatr. 2009;98(7):1096-1099. doi:10.1111/j.1651-2227.2009.01371.x PubMedGoogle ScholarCrossref
44.
Almgren  M, Schlinzig  T, Gomez-Cabrero  D,  et al.  Cesarean delivery and hematopoietic stem cell epigenetics in the newborn infant: implications for future health?   Am J Obstet Gynecol. 2014;211(5):502.e1-502.e8. doi:10.1016/j.ajog.2014.05.014 PubMedGoogle ScholarCrossref
45.
Franz  MB, Poterauer  M, Elhenicky  M,  et al.  Global and single gene DNA methylation in umbilical cord blood cells after elective caesarean: a pilot study.   Eur J Obstet Gynecol Reprod Biol. 2014;179:121-124. doi:10.1016/j.ejogrb.2014.05.038 PubMedGoogle ScholarCrossref
46.
Virani  S, Dolinoy  DC, Halubai  S,  et al.  Delivery type not associated with global methylation at birth.   Clin Epigenetics. 2012;4(1):8. doi:10.1186/1868-7083-4-8 PubMedGoogle ScholarCrossref
47.
Horta  BL, Gigante  DP, Lima  RC, Barros  FC, Victora  CG.  Birth by caesarean section and prevalence of risk factors for non-communicable diseases in young adults: a birth cohort study.   PLoS One. 2013;8(9):e74301. doi:10.1371/journal.pone.0074301 PubMedGoogle Scholar
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    1 Comment for this article
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    Diversity and composition of the adult fecal microbiome with history of cesarean birth
    James Goedert, MD | Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health
    The article by Chavarro and colleagues, which revealed that women who had been born by cesarean delivery were 11% more likely to be obese and 46% more likely to have diabetes, is notable and well done. The setting, in the large Nurses' Health Study II cohort, provides strong support for the hypothesis that cesarean birth contributes to important metabolic disorders in adulthood.

    The article notes that cesarean-delivered babies differ from vaginally-delivered babies in the composition of their initial microbiota, and that this difference appears to persist up to age 7 years. They add "Whether these differences are
    sustained long-term is unknown."

    One study suggests that the cesarean-delivery difference in microbiota composition does persist into adulthood. In an analysis of the American Gut Project (EBioMedicine. 2014 Dec 1;1(2-3):167-172. DOI: 10.1016/j.ebiom.2014.11.004), that included 1097 adult volunteers (mean age 46 years) without diabetes, inflammatory bowel disease, or recent antibiotic use, of whom 92 reported their own birth by cesarean delivery, my colleagues and I found that fecal microbial composition at all taxonomic levels differed significantly with cesarean birth (P≤0.008). The cesarean-delivered volunteers had nominal differences in relative abundance for 17 fecal taxa compared to those not reporting cesarean delivery.

    The major weaknesses in both the study by Chavarro et al. and our analysis of the American Gut Project is that the indication for cesarean delivery and intrapartum use of antibiotics is unknown. Nonetheless, the findings from both studies highlight possible longterm benefits of avoiding unnecessary cesarean delivery.
    CONFLICT OF INTEREST: None Reported
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    Original Investigation
    Public Health
    April 13, 2020

    Association of Birth by Cesarean Delivery With Obesity and Type 2 Diabetes Among Adult Women

    Author Affiliations
    • 1Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
    • 2Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
    • 3Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
    • 4Department of Preventive Medicine and Public Health, University of Navarra, Pamplona, Spain
    • 5Physiopathology of Obesity and Nutrition, Carlos III Institute of Health, Madrid, Spain
    • 6Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain
    • 7Connors Center for Women’s Health and Gender Biology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
    • 8Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles
    • 9Institute for Prevention and Cancer Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg im Breisgau, Germany
    JAMA Netw Open. 2020;3(4):e202605. doi:10.1001/jamanetworkopen.2020.2605
    Key Points español 中文 (chinese)

    Question  Is birth by cesarean delivery associated with obesity and type 2 diabetes in adulthood?

    Findings  In this cohort study of 33 226 women, those born by cesarean delivery were 11% more likely to be obese as adults and had a 46% higher risk of developing type 2 diabetes than women born by vaginal delivery.

    Meaning  This study found an association between being born by cesarean delivery and increased risks of obesity and type 2 diabetes in adulthood.

    Abstract

    Importance  Cesarean delivery is associated with an increased risk of childhood obesity in offspring. However, whether this increased risk also includes obesity-associated conditions remains unclear.

    Objective  To evaluate the association of birth by cesarean delivery with offspring’s risks of obesity and type 2 diabetes in adulthood.

    Design, Setting, and Participants  This prospective cohort study compared the incidence of obesity and type 2 diabetes between birth by cesarean delivery and vaginal delivery among 33 226 women participating in the Nurses’ Health Study II who were born between 1946 and 1964, with follow-up through the end of the 2013-2015 follow-up cycle. Participants’ mothers provided information on mode of delivery and pregnancy characteristics. Participants provided information every 2 years on weight and diagnosis of type 2 diabetes. Relative risks of obesity and type 2 diabetes were estimated using log-binomial and proportional hazards regression accounting for maternal body mass index and other confounding factors. Statistical analysis was performed from June 2017 to December 2019.

    Exposure  Birth by cesarean delivery compared with birth by vaginal delivery.

    Main Outcomes and Measures  Risk of obesity and incidence of type 2 diabetes.

    Results  At baseline, the participants’ mean (SD) age was 33.8 (4.6) years (range, 24.0-44.0 years). A total of 1089 of the 33 226 participants (3.3%) were born by cesarean delivery. After 1 913 978 person-years of follow-up, 12 156 (36.6%) women were obese and 2014 (6.1%) had received a diagnosis of type 2 diabetes. Women born by cesarean delivery were more likely to be classified as obese and to have received a diagnosis of type 2 diabetes during follow-up. The multivariable-adjusted relative risk of obesity among women born by cesarean vs vaginal delivery was 1.11 (95% CI, 1.03-1.19). The multivariable-adjusted hazard ratio for type 2 diabetes among women born by cesarean vs vaginal delivery was 1.46 (95% CI, 1.18-1.81); this association remained significant after additional adjustment for participant’s own body mass index (relative risk, 1.34 [95% CI, 1.08-1.67]). These associations persisted when analyses were restricted to women at low risk of cesarean delivery based on maternal characteristics.

    Conclusions and Relevance  This study suggests that women born by cesarean delivery may have a higher risk than women born by vaginal delivery of being obese and developing type 2 diabetes during adult life.

    Introduction

    More than 1.2 million cesarean deliveries are performed yearly in the United States, making it the most common inpatient surgical procedure and accounting for nearly one-third of births nationwide.1,2 Starting at approximately 2.6% of all births in the 1930s (prior to the widespread availability of penicillin) and remaining stable around 5% between the 1950s3 and 1970s,4 the cesarean delivery rate in the United States rose to 24% in 1986,4 reaching a peak of 33% in 2009 and stabilizing around 30% thereafter,1 with primary cesarean delivery accounting for 50% of the increasing rate.5 When indicated, cesarean delivery is a lifesaving intervention to mother and fetus.5-8 Like all surgical procedures, however, cesarean deliveries are not without risks. Women without medical or obstetric risk factors for obstetric complications undergoing a planned cesarean delivery at term experience a 3-fold greater risk of major morbidity—including greater risks of cardiac arrest, hysterectomy, puerperal infection, and thromboembolism—relative to comparable women undergoing vaginal deliveries.9 For newborns, the most common immediate risk with cesarean delivery is a higher frequency of respiratory complications.10,11 Moreover, many cesarean deliveries performed in the United States do not have a clear indication,12,13 raising concerns that the excess maternal and newborn morbidity and mortality may be largely preventable. With these concerns in mind, leading professional organizations have advocated for the prevention of primary cesarean delivery as a strategy to reduce their overall frequency.13,14

    Increasing evidence also suggests that being born by cesarean delivery may have long-term consequences on the health of offspring.15-18 One of the most consistent findings to date is that birth by cesarean delivery is associated with a higher risk of childhood obesity. Two meta-analyses summarizing data from 24 studies have reported an increased risk of obesity for individuals born by cesarean delivery (pooled odds ratio, 1.33 [95% CI, 1.19-1.48]19 and 1.22 [95% CI, 1.05-1.42]20), with little difference for risk of obesity during childhood vs adolescence and suggestive evidence that the elevated risk persists in adult life (odds ratio, 1.50 [95% CI, 1.02-2.20]).19 Subsequent studies, including studies based on long-term follow-up of large populations with stringent control for maternal body mass index (BMI) and other confounders, replicated these results.21,22 It is not clear whether the increased risk of obesity may also be accompanied by an increased risk of metabolic syndrome or type 2 diabetes during adult life. In 1 study, birth by cesarean delivery was associated with higher BMI, total cholesterol, low-density lipoprotein cholesterol, and leptin levels at age 20 years,23 but other studies have not identified associations between cesarean delivery and markers of metabolic risk.24 To further investigate the long-term association of birth by cesarean delivery with obesity and metabolic risk, we evaluated the association of cesarean delivery with obesity and incidence of type 2 diabetes in an ongoing prospective cohort study followed up for nearly 3 decades.

    Methods
    Study Population

    The Nurses’ Health Study II (NHS-II) is an ongoing prospective cohort study established in 1989 when 116 671 female nurses aged 24 to 44 years enrolled in the study. Participants completed a self-administered questionnaire regarding lifestyle factors, anthropometric variables, and disease prevalence at recruitment. Updated information is collected through follow-up questionnaires every 2 years. In 2001, 39 904 mothers of NHS-II participants completed a questionnaire regarding their pregnancy with their NHS-II participant daughter and additional information regarding their daughter’s infancy, forming the Nurses’ Mothers Cohort Study.25 After excluding participants who did not provide information on height or weight, were not born of a singleton pregnancy, and whose mothers did not provide information on delivery mode, the final study sample included 33 226 NHS-II participants born between 1946 and 1964, with follow-up through the end of the 2013-2015 follow-up cycle. The study was approved by the Harvard School of Public Health and Brigham and Women’s Hospital Institutional Review Boards. In follow-up questionnaires, participants are informed in writing of the risks and benefits of participating in the study, and of their rights as participants; returning a completed questionnaire is considered evidence of informed consent. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

    Exposure Assessment

    Mode of delivery (cesarean vs vaginal delivery) was reported by the participants’ mothers in 2001. A validation study conducted among 154 women enrolled in the Collaborative Perinatal Project found perfect maternal recall of cesarean delivery at a mean of 32 years after delivery.26

    Ascertainment of Outcomes

    At baseline, participants reported their height and weight, which are validly reported by adults,27 and updated this information every 2 years. Body mass index was calculated from these data as weight in kilograms divided by height in meters squared. We defined obesity (BMI ≥30) using the World Health Organization cutoffs.28

    Participants reporting physician-diagnosed type 2 diabetes on follow-up questionnaires were mailed a supplemental questionnaire to confirm diagnoses. Cases of type 2 diabetes were confirmed based on the following American Diabetes Association criteria29: (1) 1 or more classic symptoms (excessive thirst, polyuria, weight loss, hunger, pruritus, or coma) plus elevated glucose levels (fasting plasma glucose concentration 126 mg/dL or more or random plasma glucose 200 mg/dL or more [to convert glucose to millimoles per liter, multiply by 0.0555]), or (2) no symptoms reported but 2 or more elevated plasma glucose concentrations on more than 1 occasion (fasting, 126 mg/dL or more; random, 200 mg/dL or more; or 2-hour oral glucose tolerance test, 200 mg/dL or more), or (3) treatment with insulin or an oral hypoglycemic agent. Before 1998, a fasting plasma glucose concentration of 140 mg/dL or more was used instead of 126 mg/dL or more for the diagnosis of diabetes according to the criteria of National Diabetes Data Group.30 In a validation study, a high consistency (98%) was observed comparing questionnaire-confirmed cases of type 2 diabetes against confirmation by medical record review.31 Participants were followed up from enrollment until the diagnosis of type 2 diabetes, death, or completion of the 2013-2015 follow-up cycle, whichever came first.

    Assessment of Covariates

    Information on race/ethnicity, maternal educational level, maternal prepregnancy BMI, gestational weight gain, diagnosis of gestational diabetes, preeclampsia or gestational hypertension, gestational age, birth weight, and smoking during pregnancy was reported by participants’ mothers in 2001. A validation study showed that long-term maternal recall of many pregnancy-related events, including diagnosis of pregnancy complications (hypertensive disorders of pregnancy, gestational diabetes, placental abruption, and placenta previa), offspring birth weight, gestational age at delivery, smoking status, prepregnancy anthropometry, and gestational weight gain, were very accurately reported.26 Region of residence at birth was reported by NHS-II participants. Maternal age at delivery was calculated as the difference, in years, between participants’ date of birth and their mother’s date of birth. Missing indicators were used whenever data were missing for a covariate.

    Statistical Analysis

    Statistical analysis was performed from June 2017 to December 2019. Maternal and offspring characteristics were presented according to delivery mode for which we used a Kruskal-Wallis test for continuous variables and a χ2 test for categorical variables when estimating differences between delivery modes. All P values were from 2-sided tests and results were deemed statistically significant at P < .05. To evaluate the association between cesarean delivery and offspring’s risk of obesity, we calculated relative risks (RRs) and 95% CIs using log-binomial regression models, or log-Poisson models when log-binomial models did not converge.2 To assess the association between cesarean delivery and offspring’s risk of type 2 diabetes, we calculated hazard ratios (HRs) using Cox proportional hazards regression models. We obtained crude and multivariable-adjusted estimates of these associations. The multivariable-adjusted models included terms for the following maternal variables: age at delivery (continuous, in years), race/ethnicity (white or other), educational level (≤high school or ≥college), prepregnancy BMI group (<18.5, 18.5-24.99, 25-29.99, or ≥30), gestational weight gain (continuous, in pounds), height (continuous, in inches), gestational diabetes (yes or no), preeclampsia (yes or no), pregnancy-induced hypertension (yes or no), year of birth (1946-1951, 1952-1961, or 1961-1963), gestational age at delivery (<37, 37-39, 40-42, or ≥43 weeks), birth weight group (<2.3, 2.3-3.1, 3.2-3.8, 3.9-4.4, ≥4.5 kg), smoking during pregnancy (no, first trimester, or second and third trimesters), and region of residence at birth (Northeast, Midwest, West, or South).

    We conducted sensitivity analyses to address the possibility of residual confounding and evaluate the robustness of the findings. We fitted marginal structural models where the probability of cesarean delivery was assessed for each woman based on baseline characteristics and subsequently used to weight each observation using stabilized weights.32,33 In addition, we fitted models where we adjusted for maternal BMI with a linear and a quadratic term (instead of categories), restricted the obesity case definition to individuals who remained obese during follow-up, and allowed obesity status to vary over time. When assessing the association of cesarean delivery with the risk of type 2 diabetes, we additionally adjusted for offspring breastfeeding and fit log-binomial models for risk. To evaluate whether BMI explained any association between cesarean delivery and type 2 diabetes, the multivariable-adjusted model was additionally adjusted for offspring BMI during follow-up. We also conducted analyses restricted to participants in low-risk categories for cesarean delivery based on maternal characteristics (ie, maternal prepregnancy BMI <25, no gestational diabetes, no hypertensive disorders of pregnancy, no smoking during pregnancy, maternal age <30 years, gestational age at delivery between 37 and 42 weeks, and birth weight between 2.3 and 4.4 kg). All analyses were conducted using SAS software, version 9.2 (SAS Institute Inc).

    Results

    At baseline, the participants’ mean (SD) age was 33.8 (4.6) years (range, 24.0-44.0 years). Of the 33 226 participants in the study, 1089 (3.3%) were born by cesarean delivery. Participants’ mothers who delivered by cesarean method had a higher mean (SD) prepregnancy BMI than those who delivered vaginally (21.7 [3.0] vs 21.2 [2.5]), were older (mean [SD] age at delivery, 28.2 [5.6] vs 26.2 [4.9] years), and were more likely to have preeclampsia (54 of 1089 [5.0%] vs 1018 of 32 137 [3.2%]), pregnancy-induced hypertension (55 of 1089 [5.1%] vs 1089 of 32 137 [3.4%]), preterm birth (64 [9.2%] vs 757 [4.1%]), and low birth weight (94 of 1089 [8.6%] vs 1903 of 32 137 [5.9%]) (Table 1). They were also less likely than those who delivered vaginally to smoke during pregnancy (249 of 1089 [22.9%] vs 8394 of 32 137 [26.1%]) and to breastfeed their participant daughters (350 of 1089 [32.1%] vs 14 820 of 32 137 [46.1%]). We documented 12 156 cases of obesity and 2014 new cases of type 2 diabetes during 1 913 978 person-years of follow-up. The cumulative risk of obesity through the end of follow-up was 36.5% (11 722 of 32 137) among women born by vaginal delivery and 39.9% (434 of 1089) among women born by cesarean delivery. The incidence of type 2 diabetes per 10 000 person-years was 10.4 among participants born by vaginal delivery and 14.1 among participants born by cesarean delivery.

    Being born by cesarean delivery was associated with a higher risk of obesity (RR, 1.09 [95% CI, 1.01-1.18]) (Table 2). This association persisted in multivariable-adjusted analyses (adjusted RR, 1.11 [95% CI, 1.03-1.19]) and was similar across strata of age. Results were also similar when analyzing data using marginal structural models (RR, 1.11 [95% CI, 1.03-1.19]), when maternal prepregnancy BMI was modeled as a continuous variable (RR, 1.11 [95% CI, 1.03-1.19]), when case definition was restricted to women whose BMI remained ≥30 in all follow-up cycles after obesity was first documented (RR, 1.13 [95% CI, 1.05-1.22]), and when obesity status was allowed to change in each follow-up cycle (RR, 1.18 [95% CI, 1.08-1.29]).

    The incidence of type 2 diabetes was also higher among women born by cesarean delivery than among women born by vaginal delivery (Figure 1). The HR for type 2 diabetes in women born by cesarean vs vaginal delivery was 1.42 (95% CI, 1.14-1.76) (Table 3). This association persisted after multivariable adjustment (HR, 1.46 [95% CI, 1.18-1.81]), when analyzing data using marginal structural models (HR, 1.19 [95% CI, 0.96-1.50]), when maternal prepregnancy BMI was modeled as a continuous variable (HR, 1.47 [95% CI, 1.18-1.82]), and when risk of obesity was modeled using log-binomial models (HR, 1.49 [95% CI, 1.19-1.87]). Adjustment for breastfeeding did not change the association (HR, 1.45 [95% CI, 1.17-1.80]). Adjustment for updated offspring BMI status attenuated the association by 12% but the association remained statistically significant (HR, 1.34 [95% CI, 1.08-1.67]).

    The associations of cesarean delivery with risks of obesity and type 2 diabetes were of comparable magnitude across each of the low-risk categories for cesarean delivery based on maternal characteristics, separately and when all were simultaneously considered (Figure 2). However, estimates were no longer statistically significant when analyses were restricted to women in all 8 low-risk groups.

    Discussion

    In this prospective cohort of women aged of 24 to 66 years during the entire follow-up period, we found that being born by cesarean delivery was associated with an 11% higher risk of obesity and a 46% higher risk of type 2 diabetes. The association of cesarean delivery with type 2 diabetes persisted after adjustment for BMI during follow-up, suggesting that the association with type 2 diabetes is only partly mediated by elevated BMI. Findings were consistent across multiple strategies to account for confounding, suggesting that these associations are consistent with a true biological association of birth by cesarean delivery. Whether these findings are applicable to men or to individuals born today, when cesarean delivery rates are substantially higher, is uncertain.

    Although the mechanisms for the development of obesity and type 2 diabetes in adulthood among individuals born by cesarean delivery remains unclear, growing evidence points to the hygiene theory and changes in the offspring’s gut microbiota.34,35 Gut microbiota can modulate host energy harvest from the diet and bacterial lipopolysaccharide-induced chronic inflammation. Thus, changes in gut microbiota can be associated with host adiposity and glucose metabolism.36 Mode of delivery is associated with the diversity in gut microbiota of the offspring.37-40 Vaginally delivered neonates are rapidly colonized by microbes from their mother’s birth canal and feces, while neonates delivered by cesarean delivery are colonized by environmental microbes.36 As a result, neonates born by cesarean delivery harbor a less diverse gut microbiota, particularly less Bifidobacteria and less Bacteroides spp, which have shown to be protective against obesity.36,40 Differences in gut microbiota composition by mode of delivery have been described in infants40,41 and children up to 7 years of age.42 Whether these differences are sustained long-term is unknown. Differences in DNA methylation patterns between children born by cesarean delivery and those born by vaginal delivery have also been proposed as a biological explanation underlying long-term health outcomes of cesarean delivery, but data are scarce.43-46 Higher global DNA methylation has been reported in infants born by cesarean delivery,43,44 including a study in which a genome-wide analysis identified 343 loci that were nominally (P < .01) differentially methylated between infants born by cesarean delivery and those born by vaginal delivery.44 Other studies, however, have found no difference in DNA methylation between children born by vaginal delivery or cesarean delivery.45,46

    We found that, compared with those born by vaginal delivery, offspring born by cesarean delivery had an 11% higher risk of obesity and a 46% higher risk of type 2 diabetes in adulthood. Our finding of an association with obesity in adulthood is in agreement with the results of 2 meta-analyses, which reported an increased risk in offspring obesity of 22%20 and 50%,19 and with more recent prospective cohorts that included young adults and reported associations of similar magnitude to that reported here.21 However, to our knowledge, an association of birth by cesarean delivery with risk of type 2 diabetes has not been previously described. Two prospective cohort studies24,47 previously reported that cesarean delivery was not associated with metabolic risk factors in offspring after 20 to 23 years of follow-up. On the other hand, a recent prospective cohort study23 found that, compared with those born by vaginal delivery, young adults born by cesarean delivery showed a more adverse cardiometabolic risk profile. More important, participants in these 3 studies were all in their early 20s and the prevalence of type 2 diabetes may not have been sufficiently high to identify differences in prevalence by mode of delivery. In fact, the incidence data from our study (Figure 1) suggest that differences in risk of type 2 diabetes may not become evident until the fourth decade of life. Although, to our knowledge, our study has the largest sample size and longest duration of follow-up of all studies addressing the association of cesarean delivery with type 2 diabetes to date, these findings should be interpreted with caution given that it is the first time that an association with type 2 diabetes is reported and very few studies have examined the association with obesity-related metabolic abnormalities. Further research is needed to replicate the association with type 2 diabetes and address the biological mechanisms underlying the association of cesarean delivery with the increased risk of offspring obesity and type 2 diabetes in adulthood.

    Limitations and Strengths

    Our study has some limitations. The most important limitation is the lack of data on indications for cesarean delivery. Historical data3 suggest that the most common indications of cesarean delivery during the time period in which participants in this study were born were cephalopelvic disproportion, previous cesarean delivery, and placenta previa, jointly accounting for approximately 80% of cesarean deliveries.3 These data further suggest that no less than 30% and as much as half of all cesarean deliveries during this period were planned and presumably performed before the onset of labor. Although we cannot determine whether these figures apply to our study participants, they do highlight the importance of our analyses restricted to low-risk groups, as these analyses may have eliminated many cesarean deliveries performed owing to cephalopelvic disproportion. Moreover, other common indications of cesarean delivery during this period, namely labor arrest and breech presentation, are not known risk factors for offspring obesity and are therefore unlikely to be important confounders of the association of cesarean delivery with offspring obesity or type 2 diabetes. The individuals in this study are nurses participating in a long-term health study; while this facilitated long-term follow-up and the prospective collection of high-quality detailed data, it may hamper the generalizability of the findings to the general population. The fact that maternal report of mode of birth and other pregnancy-related information was retrospective and thus subject to recall bias could be reasonably identified as a major potential limitation. However, cesarean delivery rates in this cohort are comparable to cesarean delivery rates in the general population at the time participants were born4 and, as previously mentioned, past studies have shown perfect recall of cesarean delivery and highly accurate reporting of other pregnancy events and important potential confounders (including smoking status during pregnancy, prepregnancy weight, and gestational weight gain) decades later.26 An additional limitation is the underrepresentation of minorities in our cohort. However, there are no a priori reasons to believe these associations would differ across race or ethnicity. We also acknowledge the possibility of residual confounding owing to the lack of information about potentially relevant covariates such as the use of antibiotics during pregnancy or intrapartum and birth order. We also lacked information on offspring gut microbiota, DNA methylation patterns, or other potential biological mediators to further explore the underlying mechanisms.

    It is also important to consider the generalizability of the findings to current practice in light of the differences in cesarean delivery rates at the time of the study and today. As this is an observational study, further research is needed before causality can be assumed. Nevertheless, the current study has multiple strengths and was able to address the most salient limitations of previous studies. The prospective study design, large sample size, and long-term follow-up allowed us to examine the associations of cesarean delivery and the risk of obesity and type 2 diabetes of the offspring in adulthood, and to provide precise estimates of these associations. The availability of key prepregnancy and pregnancy information allowed for multiple sensitivity analyses aimed at addressing residual confounding.

    Conclusions

    We observed associations of cesarean delivery with increased risks of obesity and type 2 diabetes of the offspring in adulthood. Most important, the association remained significant in most of the analyses restricted to participants in low-risk categories for cesarean delivery based on maternal characteristics. Greater evidence from large, prospective studies with high-quality data on prepregnancy, pregnancy, and delivery information (particularly information regarding the timing of cesarean delivery relative to the onset of labor or rupture of membranes), as well as data from studies with sibling pairs discordant in delivery mode, is needed to address if these findings are generalizable and to investigate whether offspring born by cesarean delivery are at a higher risk of developing other adverse metabolic and cardiovascular outcomes.

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    Article Information

    Accepted for Publication: February 12, 2020.

    Published: April 13, 2020. doi:10.1001/jamanetworkopen.2020.2605

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Chavarro JE et al. JAMA Network Open.

    Corresponding Author: Jorge E. Chavarro, MD, ScD, Harvard T.H. Chan School of Public Health, 655 Huntington Ave, Building II, Third Floor, Boston, MA 02115 (jchavarr@hsph.harvard.edu).

    Author Contributions: Drs Chavarro and Yuan had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Chavarro, Martin-Calvo.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Chavarro, Martin-Calvo, Arvizu.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Chavarro, Martin-Calvo, Yuan, Arvizu.

    Obtained funding: Chavarro.

    Administrative, technical, or material support: Arvizu, Michels, Sun.

    Supervision: Chavarro, Arvizu.

    Conflict of Interest Disclosures: Dr Chavarro reported receiving grants from the National Institutes of Health during the conduct of the study. Dr Sun reported receiving ad hoc consulting fees from Emavant Solutions GmbH. No other disclosures were reported.

    Funding/Support: This study was supported by grants R01-HD093761, U01-HL145386, UM1-CA176726, R01-DK112940, and P30-DK046200 from the National Institutes of Health.

    Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    References
    1.
    Martin  JA, Hamilton  BE, Osterman  MJK, Driscoll  AK.  Births: final data for 2018.   Natl Vital Stat Rep. 2019;68(13):1-47.Google Scholar
    2.
    Healthcare Cost and Utilization Project. McDermott KW, Freeman WJ, Elixhauser A. Statistical brief #233: overview of operating room procedures during inpatient stays in U.S. hospitals, 2014. Accessed August 22, 2018. https://www.hcup-us.ahrq.gov/reports/statbriefs/sb233-Operating-Room-Procedures-United-States-2014.pdf
    3.
    Woodman  M.  Mid-century trends in cesarean section.   N Engl J Med. 1950;243(14):528-530. doi:10.1056/NEJM195010052431404 PubMedGoogle ScholarCrossref
    4.
    Pokras  R, Kozak  LJ, McCarthy  E, Graves  EJ.  Trends in hospital utilization, 1965-86.   Am J Public Health. 1990;80(4):488-490. doi:10.2105/AJPH.80.4.488 PubMedGoogle ScholarCrossref
    5.
    Tita  AT.  When is primary cesarean appropriate: maternal and obstetrical indications.   Semin Perinatol. 2012;36(5):324-327. doi:10.1053/j.semperi.2012.04.014 PubMedGoogle ScholarCrossref
    6.
    Hannah  ME, Hannah  WJ, Hewson  SA, Hodnett  ED, Saigal  S, Willan  AR; Term Breech Trial Collaborative Group.  Planned caesarean section versus planned vaginal birth for breech presentation at term: a randomised multicentre trial.   Lancet. 2000;356(9239):1375-1383. doi:10.1016/S0140-6736(00)02840-3 PubMedGoogle ScholarCrossref
    7.
    Humberg  A, Härtel  C, Paul  P,  et al; German Neonatal Network (GNN).  Delivery mode and intraventricular hemorrhage risk in very-low-birth-weight infants: observational data of the German Neonatal Network.   Eur J Obstet Gynecol Reprod Biol. 2017;212:144-149. doi:10.1016/j.ejogrb.2017.03.032 PubMedGoogle ScholarCrossref
    8.
    Simpson  LL.  When is primary cesarean appropriate: fetal indications.   Semin Perinatol. 2012;36(5):328-335. doi:10.1053/j.semperi.2012.04.015 PubMedGoogle ScholarCrossref
    9.
    Liu  S, Liston  RM, Joseph  KS, Heaman  M, Sauve  R, Kramer  MS; Maternal Health Study Group of the Canadian Perinatal Surveillance System.  Maternal mortality and severe morbidity associated with low-risk planned cesarean delivery versus planned vaginal delivery at term.   CMAJ. 2007;176(4):455-460. doi:10.1503/cmaj.060870 PubMedGoogle ScholarCrossref
    10.
    Hansen  AK, Wisborg  K, Uldbjerg  N, Henriksen  TB.  Risk of respiratory morbidity in term infants delivered by elective caesarean section: cohort study.   BMJ. 2008;336(7635):85-87. doi:10.1136/bmj.39405.539282.BE PubMedGoogle ScholarCrossref
    11.
    Loebel  G, Zelop  CM, Egan  JF, Wax  J.  Maternal and neonatal morbidity after elective repeat Cesarean delivery versus a trial of labor after previous Cesarean delivery in a community teaching hospital.   J Matern Fetal Neonatal Med. 2004;15(4):243-246. doi:10.1080/14767050410001668653PubMedGoogle ScholarCrossref
    12.
    Barber  EL, Lundsberg  LS, Belanger  K, Pettker  CM, Funai  EF, Illuzzi  JL.  Indications contributing to the increasing cesarean delivery rate.   Obstet Gynecol. 2011;118(1):29-38. doi:10.1097/AOG.0b013e31821e5f65 PubMedGoogle ScholarCrossref
    13.
    Boyle  A, Reddy  UM, Landy  HJ, Huang  CC, Driggers  RW, Laughon  SK.  Primary cesarean delivery in the United States.   Obstet Gynecol. 2013;122(1):33-40. doi:10.1097/AOG.0b013e3182952242 PubMedGoogle ScholarCrossref
    14.
    American College of Obstetricians and Gynecologists; Society for Maternal-Fetal Medicine.  Obstetric care consensus no. 1: safe prevention of the primary cesarean delivery.   Obstet Gynecol. 2014;123(3):693-711. doi:10.1097/01.AOG.0000444441.04111.1d PubMedGoogle ScholarCrossref
    15.
    Black  M, Bhattacharya  S, Philip  S, Norman  JE, McLernon  DJ.  Planned cesarean delivery at term and adverse outcomes in childhood health.   JAMA. 2015;314(21):2271-2279. doi:10.1001/jama.2015.16176 PubMedGoogle ScholarCrossref
    16.
    Blustein  J, Liu  J.  Time to consider the risks of caesarean delivery for long term child health.   BMJ. 2015;350:h2410. doi:10.1136/bmj.h2410 PubMedGoogle ScholarCrossref
    17.
    Cho  CE, Norman  M.  Cesarean section and development of the immune system in the offspring.   Am J Obstet Gynecol. 2013;208(4):249-254. doi:10.1016/j.ajog.2012.08.009 PubMedGoogle ScholarCrossref
    18.
    Nielsen  NM, Bager  P, Stenager  E,  et al.  Cesarean section and offspring’s risk of multiple sclerosis: a Danish nationwide cohort study.   Mult Scler. 2013;19(11):1473-1477. doi:10.1177/1352458513480010PubMedGoogle ScholarCrossref
    19.
    Li  HT, Zhou  YB, Liu  JM.  The impact of cesarean section on offspring overweight and obesity: a systematic review and meta-analysis.   Int J Obes (Lond). 2013;37(7):893-899. doi:10.1038/ijo.2012.195 PubMedGoogle ScholarCrossref
    20.
    Darmasseelane  K, Hyde  MJ, Santhakumaran  S, Gale  C, Modi  N.  Mode of delivery and offspring body mass index, overweight and obesity in adult life: a systematic review and meta-analysis.   PLoS One. 2014;9(2):e87896. doi:10.1371/journal.pone.0087896 PubMedGoogle Scholar
    21.
    Yuan  C, Gaskins  AJ, Blaine  AI,  et al.  Association between cesarean birth and risk of obesity in offspring in childhood, adolescence, and early adulthood.   JAMA Pediatr. 2016;170(11):e162385. doi:10.1001/jamapediatrics.2016.2385 PubMedGoogle Scholar
    22.
    Pei  Z, Heinrich  J, Fuertes  E,  et al; Influences of Lifestyle-Related Factors on the Immune System and the Development of Allergies in Childhood plus Air Pollution and Genetics (LISAplus) Study Group.  Cesarean delivery and risk of childhood obesity.   J Pediatr. 2014;164(5):1068-1073.e2. doi:10.1016/j.jpeds.2013.12.044 PubMedGoogle ScholarCrossref
    23.
    Hansen  S, Halldorsson  TI, Olsen  SF,  et al.  Birth by cesarean section in relation to adult offspring overweight and biomarkers of cardiometabolic risk.   Int J Obes (Lond). 2018;42(1):15-19. doi:10.1038/ijo.2017.175PubMedGoogle ScholarCrossref
    24.
    Bernardi  JR, Pinheiro  TV, Mueller  NT,  et al.  Cesarean delivery and metabolic risk factors in young adults: a Brazilian birth cohort study.   Am J Clin Nutr. 2015;102(2):295-301. doi:10.3945/ajcn.114.105205 PubMedGoogle ScholarCrossref
    25.
    Michels  KB, Willett  WC, Graubard  BI,  et al.  A longitudinal study of infant feeding and obesity throughout life course.   Int J Obes (Lond). 2007;31(7):1078-1085. doi:10.1038/sj.ijo.0803622 PubMedGoogle ScholarCrossref
    26.
    Tomeo  CA, Rich-Edwards  JW, Michels  KB,  et al.  Reproducibility and validity of maternal recall of pregnancy-related events.   Epidemiology. 1999;10(6):774-777. doi:10.1097/00001648-199911000-00022 PubMedGoogle ScholarCrossref
    27.
    McAdams  MA, Van Dam  RM, Hu  FB.  Comparison of self-reported and measured BMI as correlates of disease markers in US adults.   Obesity (Silver Spring). 2007;15(1):188-196. doi:10.1038/oby.2007.504 PubMedGoogle ScholarCrossref
    28.
    World Health Organization.  Physical Status: The Use and Interpretation of Anthropometry: Report of a WHO Expert Committee, WHO Technical Report Series No. 854. World Health Organization; 1995.
    29.
    Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.  Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.   Diabetes Care. 1997;20(7):1183-1197. doi:10.2337/diacare.20.7.1183 PubMedGoogle ScholarCrossref
    30.
    National Diabetes Data Group.  Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance.   Diabetes. 1979;28(12):1039-1057. doi:10.2337/diab.28.12.1039 PubMedGoogle ScholarCrossref
    31.
    Manson  JE, Rimm  EB, Stampfer  MJ,  et al.  Physical activity and incidence of non–insulin-dependent diabetes mellitus in women.   Lancet. 1991;338(8770):774-778. doi:10.1016/0140-6736(91)90664-B PubMedGoogle ScholarCrossref
    32.
    Cole  SR, Hernán  MA.  Constructing inverse probability weights for marginal structural models.   Am J Epidemiol. 2008;168(6):656-664. doi:10.1093/aje/kwn164 PubMedGoogle ScholarCrossref
    33.
    Xu  S, Ross  C, Raebel  MA, Shetterly  S, Blanchette  C, Smith  D.  Use of stabilized inverse propensity scores as weights to directly estimate relative risk and its confidence intervals.   Value Health. 2010;13(2):273-277. doi:10.1111/j.1524-4733.2009.00671.x PubMedGoogle ScholarCrossref
    34.
    Greiner  T, Bäckhed  F.  Effects of the gut microbiota on obesity and glucose homeostasis.   Trends Endocrinol Metab. 2011;22(4):117-123. doi:10.1016/j.tem.2011.01.002 PubMedGoogle ScholarCrossref
    35.
    Neu  J, Rushing  J.  Cesarean versus vaginal delivery: long-term infant outcomes and the hygiene hypothesis.   Clin Perinatol. 2011;38(2):321-331. doi:10.1016/j.clp.2011.03.008 PubMedGoogle ScholarCrossref
    36.
    Musso  G, Gambino  R, Cassader  M.  Obesity, diabetes, and gut microbiota: the hygiene hypothesis expanded?   Diabetes Care. 2010;33(10):2277-2284. doi:10.2337/dc10-0556 PubMedGoogle ScholarCrossref
    37.
    Biasucci  G, Benenati  B, Morelli  L, Bessi  E, Boehm  G.  Cesarean delivery may affect the early biodiversity of intestinal bacteria.   J Nutr. 2008;138(9):1796S-1800S. doi:10.1093/jn/138.9.1796S PubMedGoogle ScholarCrossref
    38.
    Dominguez-Bello  MG, Costello  EK, Contreras  M,  et al.  Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns.   Proc Natl Acad Sci U S A. 2010;107(26):11971-11975. doi:10.1073/pnas.1002601107 PubMedGoogle ScholarCrossref
    39.
    Huurre  A, Kalliomäki  M, Rautava  S, Rinne  M, Salminen  S, Isolauri  E.  Mode of delivery—effects on gut microbiota and humoral immunity.   Neonatology. 2008;93(4):236-240. doi:10.1159/000111102 PubMedGoogle ScholarCrossref
    40.
    Sordillo  JE, Zhou  Y, McGeachie  MJ,  et al.  Factors influencing the infant gut microbiome at age 3-6 months: findings from the ethnically diverse Vitamin D Antenatal Asthma Reduction Trial (VDAART).   J Allergy Clin Immunol. 2017;139(2):482-491. doi:10.1016/j.jaci.2016.08.045PubMedGoogle ScholarCrossref
    41.
    Grönlund  MM, Lehtonen  OP, Eerola  E, Kero  P.  Fecal microflora in healthy infants born by different methods of delivery: permanent changes in intestinal flora after cesarean delivery.   J Pediatr Gastroenterol Nutr. 1999;28(1):19-25. doi:10.1097/00005176-199901000-00007 PubMedGoogle ScholarCrossref
    42.
    Salminen  S, Gibson  GR, McCartney  AL, Isolauri  E.  Influence of mode of delivery on gut microbiota composition in seven year old children.   Gut. 2004;53(9):1388-1389. doi:10.1136/gut.2004.041640 PubMedGoogle ScholarCrossref
    43.
    Schlinzig  T, Johansson  S, Gunnar  A, Ekström  TJ, Norman  M.  Epigenetic modulation at birth—altered DNA-methylation in white blood cells after Caesarean section.   Acta Paediatr. 2009;98(7):1096-1099. doi:10.1111/j.1651-2227.2009.01371.x PubMedGoogle ScholarCrossref
    44.
    Almgren  M, Schlinzig  T, Gomez-Cabrero  D,  et al.  Cesarean delivery and hematopoietic stem cell epigenetics in the newborn infant: implications for future health?   Am J Obstet Gynecol. 2014;211(5):502.e1-502.e8. doi:10.1016/j.ajog.2014.05.014 PubMedGoogle ScholarCrossref
    45.
    Franz  MB, Poterauer  M, Elhenicky  M,  et al.  Global and single gene DNA methylation in umbilical cord blood cells after elective caesarean: a pilot study.   Eur J Obstet Gynecol Reprod Biol. 2014;179:121-124. doi:10.1016/j.ejogrb.2014.05.038 PubMedGoogle ScholarCrossref
    46.
    Virani  S, Dolinoy  DC, Halubai  S,  et al.  Delivery type not associated with global methylation at birth.   Clin Epigenetics. 2012;4(1):8. doi:10.1186/1868-7083-4-8 PubMedGoogle ScholarCrossref
    47.
    Horta  BL, Gigante  DP, Lima  RC, Barros  FC, Victora  CG.  Birth by caesarean section and prevalence of risk factors for non-communicable diseases in young adults: a birth cohort study.   PLoS One. 2013;8(9):e74301. doi:10.1371/journal.pone.0074301 PubMedGoogle Scholar
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