Maternal and pregnancy-related factors affecting human milk cytokines among Peruvian mothers bearing low-birth-weight neonates

https://doi.org/10.1016/j.jri.2017.04.001Get rights and content

Highlights

  • A core of 12 cytokines is detected in human milk across different lactation stages.

  • Specific pregnancy complications are associated with distinct breast milk cytokine signatures.

  • Mothers of very small neonates have higher concentrations of many cytokines in their breast milk.

Abstract

Several cytokines have been detected in human milk but their relative concentrations differ among women and vary over time in the same person. The drivers of such differences have been only partially identified, while the effect of luminal cytokines in the fine-regulation of the intestinal immune system is increasingly appreciated. The aim of this study was to investigate the associations between obstetrical complications and human milk cytokine profiles in a cohort of Peruvian women giving birth to Low Birth Weight (LBW) infants.

Colostrum and mature human milk samples were collected from 301 Peruvian women bearing LBW infants. The concentration of twenty-three cytokines was measured using the Luminex platform.

Ninety-nine percent of women had at least one identified obstetrical complication leading to intra-uterine growth restriction and/or preterm birth. Median weight at birth was 1,420 g; median gestational age 31 weeks.

A core of 12 cytokines, mainly involved in innate immunity and epithelial cell integrity, was detectable in most samples. Maternal age, maternal infection, hypertensive disorders, preterm labor, and premature rupture of membranes were associated with specific cytokine profiles both in colostrum and mature human milk. Mothers of Very LBW (VLBW) neonates had significantly higher concentrations of chemokines and growth factor cytokines both in their colostrum and mature milk compared with mothers of larger neonates. Thus, maternal conditions affecting pregnancy duration and in utero growth are also associated with specific human milk cytokine signatures.

Introduction

Human milk is regarded as the premier source of nutrition for infants until at least 6 months of age (AAP, 2012, WHO, 2003). It contains the nutrients necessary to promote adequate growth and bioactive substances essential for maturation of the neonatal immune system and intestinal function (Agarwal et al., 2011). Animal and in vitro studies suggest that cytokines may have an important role in the proliferation and migration of intestinal epithelial cells and in modulation of the mucosal immune system (Nguyen et al., 2014, Parigi et al., 2015, Rautava et al., 2012). Their effect could be especially important in low birth weight (LBW) infants (birth weight equal to or below 2500 g), a population at increased risk of mortality and complications like sepsis or necrotizing enterocolitis (Neu and Walker, 2011, Stoll et al., 2002). Among small infants, the intake of human milk is directly associated with decreased mortality and morbidity but the underlying mechanisms are unclear (Corpeleijn et al., 2012, Meinzen-Derr et al., 2009, Sisk et al., 2007).

This study is an exploratory analysis conducted on samples and data from a large randomized controlled trial evaluating supplemental lactoferrin for the prevention of late onset sepsis in neonates. The aim of this analysis was to characterize the cytokine profile of human milk in a cohort of mothers of LBW neonates from poor neighborhoods of Lima, Peru. These women are exposed to a high burden of infectious diseases throughout their lives and have a low intake of animal foods and high quality proteins, with potentially significant effects on their immune systems. As many obstetrical complications leading to intrauterine growth restriction and/or preterm birth may be associated with perturbations of the maternal immune system, we hypothesized that specific pregnancy disorders would be associated with distinctive human milk cytokine profiles and affect the newborn’s growth even after birth.

Section snippets

Study participants

Participants were recruited at Hospital Nacional Cayetano Heredia, Hospital Nacional Almenara, and Hospital Nacional Sabogal in Lima, Peru. Infants were eligible if they weighed between 500 and 2,000 g and were admitted to the Neonatal Intensive Care Unit within the first 72 h of life. Exclusion criteria included severe underlying problems preventing oral feeding, family history of cow milk allergy or chronic conditions potentially affecting growth (for example chromosomal abnormalities, anatomic

Clinical and demographic information

Demographic and clinical data were available on 300 of the 301 mothers with milk samples available for cytokine analysis (Table 1). The median maternal age was 30 years (IQR 24, 34). The median monthly household income was 1000 Peruvian Soles (approximately US $300), with a median of 4 people (IQR 3, 6) per household. Median gestational age, assessed either by obstetrical ultrasounds, Ballard clinical score or reliable date of last menstrual period was 31 weeks (IQR 29, 33). Only 4/300 (1.3%)

Discussion

Despite the changes in human milk throughout lactation, the function of its immunological constituents, drivers of inter-individual differences and the implications for the neonate remain unclear. In this population of women living in a resource-limited setting who delivered LBW babies, we found that: 1) A core of 12 cytokines (TGF-β1-3, IL-1β, IL-6, IL-7 and TNF) and chemokines (MCP-1, MIP-1β, IP-10, IL-8, RANTES) was present in virtually all colostrum and mature human milk samples; 2)

Conclusion

Complications of pregnancy influence the concentration of cytokines and chemokines in human milk, potentially affecting the initial priming of the neonatal immune system. In depth understanding of the interplay between human milk immune components and the intestinal mucosa system could open the way for innovative approaches to neonatal health.

Funding

This work was funded by the Grand Challenges Explorations Grant from Bill & Melinda Gates Foundation, Grant OPP1015669 (T.J.O.), by the Public Health Service award R01-HD067694-01A1 from the National Institute of Child Health and Human Development (NICHD), USA (T.J.O.), and by the Center for Tropical Diseases-Institute for Human Infections and Immunity at the University of Texas Medical Branch at Galveston (N.S.U.). The content is solely the responsibility of the authors and does not

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    These authors have contributed equally to the work.

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