The Interplay of Cesarean-Section Delivery and First-Birth Order as Risk Factors in Acute Lymphoblastic Leukemia

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Abstract

Background:

Childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has been associated with early-life exposures, including birth by cesarean section (C-section), and a deficit of social exposure (first child). These exposures as proxies for microbiome acquisition in infancy are essential to prime the immune system and restrain later dysregulated immune responses that can trigger ALL in susceptible individuals. We tested risk factors pertaining to immune stimulation that may impact BCP-ALL development.

Methods:

Cases comprised 1,126 children (0–12 years) with ALL (BCP-ALL: 78.5%) from the EMiLI study group in Brazil (2002–2020). Age- and sex-matched controls (n = 2,252) were randomly selected from healthy children whose mothers participated in the National Placental and Umbilical Cord Blood Bank donation. Multiple logistic regression was run fitted and adjusted for selected covariates models.

Results:

C-section delivery was associated with increased risk for ALL [odds ratio (OR) ALL: 1.10; 95% confidence intervals (CI), 1.04–1.15; ORBCP-ALL: 1.09; 95% CI, 1.03–1.14], as well as being the firstborn child. Interaction analysis showed a significant effect of first birth on the observed C-section associations (P < 0.0001). Indeed, high-risk children, namely, firstborn children delivered via C-section were at increased risk for ALL (OR: 2.33; 95% CI, 2.40–4.84) compared with non-first, vaginally born children. An increased risk was found for firstborn children delivered by C-section and non-breastfed with ALL (ORALL: 2.32; 95% CI, 1.27–4.24; ORBCP-ALL: 2.37; 95% CI, 1.18–4.76).

Conclusions:

Our observations are in accord with the prediction that exposures determining microbiome composition and adrenal pathway in infancy contribute to the risk of BCP-ALL.

Impact:

These findings encourage the exploration of potential preventive interventions.

See related commentary by Wiemels and Gallant, p. 292

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Most cited references 43

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Breastfeeding in the 21st century: epidemiology, mechanisms, and lifelong effect.

Cesar Victora, Rajiv Bahl, Aluísio Barros … (2016)

The importance of breastfeeding in low-income and middle-income countries is well recognised, but less consensus exists about its importance in high-income countries. In low-income and middle-income countries, only 37% of children younger than 6 months of age are exclusively breastfed. With few exceptions, breastfeeding duration is shorter in high-income countries than in those that are resource-poor. Our meta-analyses indicate protection against child infections and malocclusion, increases in intelligence, and probable reductions in overweight and diabetes. We did not find associations with allergic disorders such as asthma or with blood pressure or cholesterol, and we noted an increase in tooth decay with longer periods of breastfeeding. For nursing women, breastfeeding gave protection against breast cancer and it improved birth spacing, and it might also protect against ovarian cancer and type 2 diabetes. The scaling up of breastfeeding to a near universal level could prevent 823,000 annual deaths in children younger than 5 years and 20,000 annual deaths from breast cancer. Recent epidemiological and biological findings from during the past decade expand on the known benefits of breastfeeding for women and children, whether they are rich or poor.

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Dynamics and Stabilization of the Human Gut Microbiome during the First Year of Life.

Fredrik Bäckhed, Josefine Roswall, Yangqing Peng … (2015)

The gut microbiota is central to human health, but its establishment in early life has not been quantitatively and functionally examined. Applying metagenomic analysis on fecal samples from a large cohort of Swedish infants and their mothers, we characterized the gut microbiome during the first year of life and assessed the impact of mode of delivery and feeding on its establishment. In contrast to vaginally delivered infants, the gut microbiota of infants delivered by C-section showed significantly less resemblance to their mothers. Nutrition had a major impact on early microbiota composition and function, with cessation of breast-feeding, rather than introduction of solid food, being required for maturation into an adult-like microbiota. Microbiota composition and ecological network had distinctive features at each sampled stage, in accordance with functional maturation of the microbiome. Our findings establish a framework for understanding the interplay between the gut microbiome and the human body in early life.

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How colonization by microbiota in early life shapes the immune system.

Thomas Gensollen, Shankar S. Iyer, Dennis Kasper … (2016)

Microbial colonization of mucosal tissues during infancy plays an instrumental role in the development and education of the host mammalian immune system. These early-life events can have long-standing consequences: facilitating tolerance to environmental exposures or contributing to the development of disease in later life, including inflammatory bowel disease, allergy, and asthma. Recent studies have begun to define a critical period during early development in which disruption of optimal host-commensal interactions can lead to persistent and in some cases irreversible defects in the development and training of specific immune subsets. Here, we discuss the role of early-life education of the immune system during this "window of opportunity," when microbial colonization has a potentially critical impact on human health and disease.