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

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 1,420g; 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.

Keywords: Human milk cytokines; Low-birth weight infants; Pregnancy complications.

Figure 1. Percentage of samples with detectable levels of human milk cytokines

The total number of samples tested was 440, including 223 colostrum and 217 mature milk samples. The frequency of detectability was significantly different between colostrum and mature milk for 6 cytokines: IL-12, P≤0.001; IL-4, P<0.001; IL-1ra, P<0.001; IFN-γ, P=0.01; IL-10, P=0.01; IL-2, P=0.02. Statistical significance was calculated using the Chi square test. * indicates P values <0.05.

Figure 2. Comparison of colostrum and mature human milk cytokine levels between women with and without peripartum infections

Women with documented peripartum infections or fever (n=97) were compared to women without infections (n=203). A set of 4 cytokines were decreased in colostrum of women with infections: (a) MIP-1β, (b) IL-8, (c) IL-1ra, (d) IFN-γ. Two cytokines (e) IL-12 and (f) TGF-β3, conversely, were slightly higher in mature milk samples. Col-I, colostrum samples from women with infections; Col-U, colostrum samples from women without infections; Mat-I, mature milk samples from women with infections; Mat-U, mature milk samples from women without infections. *P<0.05; **P<0.01. Statistical significance was calculated using the Mann-Whitney U test.

Figure 3. Comparison of human milk cytokine levels between women with and without pregnancy-related hypertensive disorders

Women with pregnancy-related hypertensive disorders (n=101) were compared to women without hypertensive disorders (n=199). Women with hypertensive disorders had higher levels of (a) IL-6, (b) TNF, (c) IL-8, (d) MIP-1β, (e) MCP-1, (f) IL-4, (g) IFN-γ, and (h) TGF-β3 in their colostrum and mature milk. Col-HTN, colostrum from hypertensive mothers; Col-No HTN, colostrum of mothers with no hypertension; Mat-HTN, mature milk from hypertensive mothers; Mat-No HTN, mature milk from mothers with no hypertension. *P<0.05; **P<0.01. Statistical significance was calculated using the Mann-Whitney U test

Figure 4. Human milk concentration of selected cytokines among women delivering Very Low Birth Weight (VLBW) babies versus Low Birth Weight (LBW) babies

Colostrum (Col) and mature (Mat) milk of mothers of VLBW newborns had higher levels of (a) IP-10, (e) IL-17 and (f) G-CSF, while (b) IL-8, (c) MIP-1β, (d) MCP-1, (g) TGF-β1 and (h) TGF-β2 were higher only in mature samples; *P<0.05; **P<0.01. Statistical significance was calculated using the Mann-Whitney U test.