Letters to the Editor Mode of delivery—impact on risk of noncommunicable diseases To the Editor: The hygiene hypothesis postulates that decreased microbial contact early in life is causally linked to a rise in the prevalence of allergic diseases. Mode of delivery, early environment, and particularly breast-feeding are key determinants of the child’s first microbial contacts.1 The modern child is faced with various elements interfering with the process of developing a healthy gut microbiota. The compositional development of the indigenous intestinal microbiota, again, coevolves with the immune system at an early age.1 Aberrant gut microbiota, dysbiosis, may thus be one factor behind the progressive increase in noncommunicable diseases (NCDs) such as allergic, autoimmune, and anti-inflammatory disorders, as well as obesity. The rate of cesarean delivery has exceeded the World Health Organization recommended share of 15% up to 52% or even more in specific environments.2 The present study set out with the hypothesis that increased rates of cesarean deliveries, although more moderate in Finland (16.3% in 2013), parallel an increase in NCDs including autism, asthma, allergy, obesity, diabetes, celiac disease, and inflammatory bowel disease. We studied an entire birth cohort, children born in 1987, linked the data to the Hospital Discharge Register and several other registers to identify NCD cases, and assessed the connection. The 1987 Birth Cohort Study was based on Finnish Medical Birth Register data on mode of delivery, complemented with follow-up information on births and deaths and health status as described in detail elsewhere.3 The 1987 Finnish Birth Cohort comprised 60,069 children born in Finland in 1987. Infants stillborn or dying during the perinatal period were excluded, and the remaining 59,476 children were included in the follow-up cohort for the years 1987 to 2008. Altogether 497 children had died and 557 had emigrated permanently during the study period, leaving a final study population of 58,430. Diagnoses of NCDs were identified from the Finnish Hospital Discharge Register, which includes all care episodes in all Finnish hospitals and all specialized-level outpatient visits.3 The register has been shown to be satisfactory for statistical and research purposes.4 The diagnosis codes applied in the present study are based on the International Classification of Diseases (International Classification of Diseases, Ninth Revision from 1987 to 1995 and International Classification of Diseases, Tenth Revision from 1996 onwards) as presented in Table I. Statistical analyses were made by logistic regression and cross-tabulation. The results were adjusted for mother’s highest educational level, child’s sex, smoking during pregnancy, and mother’s socioeconomic status. NCDs were overexpressed among children and young adults who were born by cesarean section than among those born by vaginal delivery (Table II). The distinction was due to a higher prevalence of asthma and obesity in the cesarean section group than in those vaginally delivered. The same tended to hold true for allergy, albeit reaching statistical significance only in females, 5.6% in the cesarean section group as compared with 5.0% in females vaginally delivered (P 5 .048). In like manner, the prevalence of celiac disease was higher in children born by 1398

TABLE I. Diagnosis codes for NCDs according to the International Classification of Diseases Disease

ICD-9

ICD-10

Autism

2990, 2998, 2999, 3017, 3308 493 477, 677 278 250 5790 555, 556

F84.0-F84.5, F84.9

Asthma Allergy Obesity Diabetes Celiac disease Inflammatory bowel disease

J45 J30, L20 E66 E10-E14 K90.0 K50, K51

ICD-9, International Classification of Diseases, Ninth Revision; ICD-10, International Classification of Diseases, Tenth Revision.

TABLE II. The cumulative incidence of NCDs according to the mode of delivery Disease

Neurodevelopmental disorders Autism Respiratory diseases Asthma Allergy Total Metabolic disorders Obesity Diabetes mellitus Total Bowel disorders Celiac disease IBD Total All diagnoses

Vaginal delivery

Cesarean section

P Odds value ratio

95% CI

154 (0.32)

34 (0.39)

.410 1.18

0.79-1.77

624 (7.19) .003 1.16 448 (5.17) .148 1.09 925 (10.67) .005 1.12

1.05-1.27 0.97-1.22 1.04-1.22

98 (1.13) 91 (1.04) 182 (2.10)

.001 1.51 .715 1.05 .024 1.22

1.20-1.92 0.82-1.34 1.03-1.45

.158 .420 .767 .001

0.90-1.92 0.59-1.24 0.80-1.36 1.06-1.22

2990 (6.22) 2219 (4.62) 4497 (9.36) 371 (0.77) 484 (1.01) 840 (1.75) 162 238 393 5698

(0.32) 37 (0.50) 41 (0.82) 77 (11.86) 1173

(0.43) (0.47) (0.89) (13.52)

1.31 0.86 1.04 1.136

Adjusted for mother’s highest educational level, child’s sex, smoking during pregnancy, and mother’s socioeconomic status in 2009. Values are n (%) except otherwise indicated. IBD, Inflammatory bowel disease.

cesarean section than in the vaginally delivered, though the difference failed to reach statistical significance (Table II). No association with mode of delivery was detected in other NCDs studied: autism, diabetes, and inflammatory bowel disease. In this study, we found an increased prevalence of asthma and obesity in children and young adults born by cesarean section than in those delivered vaginally. Interestingly, the disorders in question represent the earliest NCDs to manifest themselves, thus suggesting that the perinatal environment has an impact with a time-restricted window of action. In addition, our result tends to corroborate clinical data suggesting that allergy and obesity share common environmental risk factors and immunologic features and that these conditions frequently coexist.1 Maternal obesity, however, increases the risk of cesarean section delivery, which in itself has an impact on both the duration of breast-feeding and the composition of breast milk.5,6 Furthermore, maternal obesity and excessive weight gain during

LETTERS TO THE EDITOR 1399

J ALLERGY CLIN IMMUNOL VOLUME 136, NUMBER 5

pregnancy increase the risk of asthma in children.7 Excessive weight gain during pregnancy, again, is associated with aberrant gut and breast milk microbiota composition,8 and aberrancies in the mother’s microbiome may be transferred to the infant by various routes: during pregnancy, at delivery, and via breast milk.9 There would thus appear to be a triad of interacting risk factors: maternal health and weight gain during pregnancy, cesarean section delivery, and breast-feeding.1 All these elements interact with the gut microbiota composition, while the search for the primary cause continues. While calling for long-term follow-up studies in this area, with specification of the type of cesarean section, the clinical implications here are evident: we are experiencing a constantly increasing rate of cesarean section delivery for nonmedical reasons: this issue needs to be dealt with openly by health care professionals, in view of not only the attendant acute complications but also the long-term consequences for the offspring. We are very grateful to study nurses Ms Ulla-Maija Eriksson, Ms Johanna Hvitfelt-Koskelainen, and Ms Sari Laksio and also to Mr Robert MacGilleon for revision of the English text. Reetta Miettinen, BMa Henriina Hermansson, BMa Marko Merikukka, MScb Mika Gissler, PhDc,d Erika Isolauri, MD, PhDa From athe Department of Pediatrics and Adolescent Medicine, Turku University Hospital, Turku, Finland; bThe Department of Children, Young People and Families, THL National Institute for Health and Welfare, Oulu, Finland; cthe Information Department, THL National Institute for Health and Welfare, Helsinki, Finland; and d NHV Nordic School of Public Health, Gothenburg, Sweden. E-mail: [email protected]. The study was supported by a grant from the Yrj€o Jahnsson Foundation (grant no. 6543). Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. REFERENCES 1. Rautava S, Luoto R, Salminen S, Isolauri E. Microbial contact during pregnancy, intestinal colonization and human disease. Nat Rev Gastroenterol Hepatol 2012;9: 565-76. 2. Domingues RM, Dias MA, Nakamura-Pereira M, Torres JA, d’Orsi E, Pereira AP, et al. Process of decision-making regarding the mode of delivery of birth in Brazil: from the initial preference of women to the final mode of birth. Cad Saude Publica 2014;30:S1-16. 3. Paananen R, Gissler M. Cohort profile: the 1987 Finnish Birth Cohort. Int J Epidemiol 2012;41:941-5. 4. Sund R. Quality of the Finnish Hospital Discharge Register: a systematic review. Scand J Public Health 2012;40:505-15. 5. Graham LE, Brunner Huber LR, Thompson ME, Ersek JL. Does amount of weight gain during pregnancy modify the association between obesity and caesarean delivery? Birth 2014;41:93-9. 6. Kohlhuber M, Rebhan B, Schwegler U, Koletzko B, Fromme H. Breastfeeding rates and duration in Germany: a Bavarian cohort study. Br J Nutr 2008;99: 1127-32. 7. Harpsøe MC, Basit S, Bager P, Wohlfart J, Benn CS, Nøhr EA, et al. Maternal obesity, gestational weight gain, and risk of asthma and atopic disease in offspring: a study with the Danish National Birth Cohort. J Allergy Clin Immunol 2013;131: 1033-40. 8. Cabrera-Rubio R, Collado MC, Laitinen K, Salminen S, Isolauri E, Mira A. The human milk microbiome changes over lactation and is shaped by maternal weight and mode of delivery. Am J Clin Nutr 2012;96:544-51. 9. Collado MC, Isolauri E, Laitinen K, Salminen S. Effect of mother’s weight on infant’s microbiota acquisition, composition, and activity during early infancy: a prospective follow-up study initiated in early pregnancy. Am J Clin Nutr 2010;92:1023-30. Available online July 03, 2015. http://dx.doi.org/10.1016/j.jaci.2015.05.032

Impaired efferocytosis in human chronic granulomatous disease is reversed by pioglitazone treatment To the Editor: Patients with chronic granulomatous disease (CGD) suffer from infections and exaggerated inflammation.1 Defects in efferocytosis, the process of clearing dying cells by macrophages, may contribute to the heightened, prolonged, and granulomatous inflammation in this disease. Impaired efferocytic capability has been shown for murine CGD macrophages in vitro and in vivo,2,3 as well as human gp91phox-deficient PLB-985 cells, and in 1 study, monocyte-derived macrophages from patients with CGD.4 Efferocytosis generally leads to active suppression of inflammatory mediator production by macrophages, and this too is reportedly deficient in CGD.2,5,6 Peroxisome proliferator–activated receptor g (PPARg), a nuclear receptor activated by oxidized lipids, is a driver of metabolic programming of macrophages and enhances their ability to take up and digest dying cells.2 PPARg is ordinarily expressed at low levels in circulating monocytes, but its expression and activation are upregulated once monocytes transit into oxidant-rich inflamed tissues and begin to differentiate into macrophages. PPARg expression and activation are delayed and deficient in inflammatory macrophages derived from immigrant monocytes during inflammation in the murine model of X-linked CGD, but are restored by treatment of the animals with the PPARg agonist pioglitazone, a drug approved for type 2 diabetes.2 Treatment of mice with CGD with pioglitazone also restored the efferocytic capability of inflammatory macrophages and suppressed excessive inflammatory mediator production.2 In normal phagocytes, PPARg activation links nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity with enhanced mitochondrial reactive oxygen species (ROS) production.7 Accordingly, the lack of this upstream signaling by the NADPH oxidase and PPARg in CGD results in deficient mitochondrial ROS production in CGD phagocytes. Notably, mitochondrial ROS production was restored in murine and human CGD monocytes treated with pioglitazone, in vivo and ex vivo, respectively.7 We hypothesized that human CGD blood monocytes, precursors of inflammatory macrophages, would show impaired efferocytosis in comparison to monocytes from normal human subjects and that treatment with pioglitazone would restore CGD monocyte efferocytic capability. We investigated monocytes rather than monocyte-derived macrophages because preliminary experiments indicated that prolonged culturing required for derivation minimized differences between CGD and normal macrophages, and likely explains disparate reports of their efferocytic capability.4,5 Monocytes were isolated from PBMCs obtained from patients with CGD and healthy normal volunteers at the National Institutes of Health Clinical Center (see the Methods section and Table E1 in this article’s Online Repository at www.jacionline.org). In a first set of experiments, freshly isolated monocytes were ‘‘fed’’ fluorescently labeled apoptotic Jurkat cells or carboxylated beads, mimicking apoptotic cells. Efferocytosis was then quantified either by flow cytometry as the percentage of monocytes taking up Jurkat cells or by visual inspection of internalized beads and expressed as an efferocytic

Mode of delivery--impact on risk of noncommunicable diseases.

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