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1.  Human Milk Adiponectin Is Associated with Infant Growth in Two Independent Cohorts 
Breastfeeding Medicine  2009;4(2):101-109.
Adiponectin, a circulating adipocyte protein, is associated with lower obesity. We have previously shown that adiponectin is present in human milk. This study determined whether higher milk adiponectin is associated with infant growth and investigated milk adiponectin's oligomeric form.
Design and Methods
This is a study of two parallel longitudinal cohorts of breastfed infants born between 1998 and 2005. Forty-five mother–infant pairs from Cincinnati, OH and 277 mother–infant pairs from Mexico City, Mexico were analyzed. All participants were healthy, term infants breastfed at least 1 month who completed 6 months of follow-up. Monthly milk samples (n = 1,379) up to 6 months were assayed for adiponectin by radioimmunoassay. Infant weight-for-age, length-for-age, and weight-for-length Z-scores up to 6 months of age were calculated using World Health Organization standards. Repeated-measures analysis was conducted. The structural form of human milk adiponectin was assessed by western blot.
In the population studies, initial milk adiponectin was 24.0 ± 8.6 μg/L and did not differ by cohort. Over the first 6 months, higher milk adiponectin was associated with lower infant weight-for-age Z-score (−0.20 ± 0.04, p < 0.0001) and weight-for-length Z-score (−0.29 ± 0.08, p = 0.0002) but not length-for-age Z-score, adjusted for covariates, with no difference by cohort. By western blot, human milk adiponectin was predominantly in the biologically active high-molecular-weight form.
Our data suggest milk adiponectin may play a role in the early growth and development of breastfed infants.
PMCID: PMC2779028  PMID: 19500050
2.  Heightened attention to supplementation is needed to improve the vitamin D status of breastfeeding mothers and infants when sunshine exposure is restricted 
Maternal & child nutrition  2012;10(3):383-397.
Although exclusively breastfed infants are at increased risk of vitamin D (vit D) deficiency if vit D supplementation is lacking and sun exposure is limited, assessment of both risk factors in the first year of life is lacking. We evaluated contribution of vit D intake and sunlight exposure to vit D status in 120 healthy, breastfeeding mother-infant dyads, who were followed for 1 year. Vitamin D intake and skin sunlight exposure were evaluated using questionnaires. Serum 25(OH)D, PTH and ALP levels were determined postnatally in mothers at 4 weeks and in infants at 4, 26 and 52 weeks. Vitamin D supplementation was low (<20%) and sunlight exposure was common (93%) in study infants. At 4 weeks, 17% of mothers were vit D deficient (<50 nmol/L) and 49% were insufficient (50-<75 nmol/L), while 18% of infants were severely vit D deficient (<25 nmol/L) and 77% were deficient (<50 nmol/L). At 26 weeks, winter/spring birth season and shorter duration of months of exclusive breastfeeding were protective of vit D deficiency in infants. Vitamin D deficiency in infants decreased to 12% at 52 weeks with sunlight exposure. Serum PTH levels were significantly higher in severely vit D deficient than sufficient infants. Vitamin D deficiency was widespread in early postpartum breastfeeding mothers and infants and declined to 1 in 8 infants at 52 weeks due mostly to sunshine exposure. When sunlight exposure is limited or restricted intensified vit D supplementation of breastfeeding mothers and infants is needed to improve vit D status.
PMCID: PMC3461108  PMID: 22708508
Vitamin D deficiency; breastfeeding; sunlight exposure; infants; mothers
3.  Early empiric antibiotic use in preterm infants is associated with lower bacterial diversity and higher relative abundance of Enterobacter 
The Journal of pediatrics  2014;165(1):23-29.
To determine the impact of empiric ampicillin and gentamicin use in the first week of life on microbial colonization and diversity in preterm infants.
Study design
16s rDNA community profiling was used to compare the microbiota of 74 infants born ≤32 weeks gestational age by degree of antibiotic use in the first week of life. The degree of antibiotic use was classified as 0 days, 1-4 days and 5-7 days of antibiotic administration. . All of the antibiotic use was empiric, defined as treatment based solely on clinical suspicion of infection without a positive culture result.
Infants who received 5-7 days of empiric antimicrobial agents in the first week had increased relative abundance of Enterobacter (p=0.016) and lower bacterial diversity in the second and third weeks of life. Infants receiving early antibiotics also experienced more cases of NEC, sepsis or death than those not exposed to antibiotics.
Early empiric antibiotics have sustained effects on the intestinal microbiota of preterm infants. Intestinal dysbiosis in this population has been found to be associated with elevated risk of necrotizing enterocolitis, sepsis, or death.
PMCID: PMC4074569  PMID: 24529620
diversity; empiric antibiotics; microbiome; necrotizing enterocolitis; preterm infant
4.  Center Variation in Intestinal Microbiota Prior to Late-Onset Sepsis in Preterm Infants 
PLoS ONE  2015;10(6):e0130604.
Late onset sepsis (LOS) contributes to mortality and morbidity in preterm infants. We tested the hypotheses that microbes causing LOS originate from the gut, and that distortions in the gut microbial community increases subsequent risk of LOS.
Study Design
We examined the gut microbial community in prospectively collected stool samples from preterm infants with LOS and an equal number of age-matched controls at two sites (Cincinnati, OH and Birmingham, AL), by sequencing the bacterial 16S rDNA. We confirmed our findings in a subset of infants by whole genome shotgun sequencing, and analyzed the data using R and LEfSe.
Infants with LOS in Cincinnati, as compared to controls, had less abundant Actinobacteria in the first samples after birth (median 18 days before sepsis onset), and less abundant Pseudomonadales in the last samples collected prior to LOS (median 8 days before sepsis onset). Infants with LOS in Birmingham, as compared to controls, had no differences identified in the first sample microbial communities, but Lactobacillales was less abundant in the last samples prior to LOS (median 4 days before sepsis onset). Sequencing identified detectable levels of the sepsis-causative organism in stool samples prior to disease onset for 82% of LOS cases.
Translocation of gut microbes may account for the majority of LOS cases. Distortions in the fecal microbiota occur prior to LOS, but the form of distortion depends on timing and site. The microbial composition of fecal samples does not predict LOS onset in a generalizable fashion.
PMCID: PMC4482142  PMID: 26110908
5.  Longitudinal Survey of Carotenoids in Human Milk from Urban Cohorts in China, Mexico, and the USA 
PLoS ONE  2015;10(6):e0127729.
Emerging evidence indicates that carotenoids may have particular roles in infant nutrition and development, yet data on the profile and bioavailability of carotenoids from human milk remain sparse. Milk was longitudinally collected at 2, 4, 13, and 26 weeks postpartum from twenty mothers each in China, Mexico, and the USA in the Global Exploration of Human Milk Study (n = 60 donors, n = 240 samples). Maternal and neonatal plasma was analyzed for carotenoids from the USA cohort at 4 weeks postpartum. Carotenoids were analyzed by HPLC and total lipids by Creamatocrit. Across all countries and lactation stages, the top four carotenoids were lutein (median 114.4 nmol/L), β-carotene (49.4 nmol/L), β-cryptoxanthin (33.8 nmol/L), and lycopene (33.7 nmol/L). Non-provitamin A carotenoids (nmol/L) and total lipids (g/L) decreased (p<0.05) with increasing lactation stage, except the provitamin A carotenoids α- and β-cryptoxanthin and β-carotene did not significantly change (p>0.05) with lactation stage. Total carotenoid content and lutein content were greatest from China, yet lycopene was lowest from China (p<0.0001). Lutein, β-cryptoxanthin, and β-carotene, and lycopene concentrations in milk were significantly correlated to maternal plasma and neonatal plasma concentrations (p<0.05), with the exception that lycopene was not significantly associated between human milk and neonatal plasma (p>0.3). This enhanced understanding of neonatal exposure to carotenoids during development may help guide dietary recommendations and design of human milk mimetics.
PMCID: PMC4465022  PMID: 26061885
6.  Sun Exposure and Vitamin D Supplementation in Relation to Vitamin D Status of Breastfeeding Mothers and Infants in the Global Exploration of Human Milk Study 
Nutrients  2015;7(2):1081-1093.
Although vitamin D (vD) deficiency is common in breastfed infants and their mothers during pregnancy and lactation, a standardized global comparison is lacking. We studied the prevalence and risk factors for vD deficiency using a standardized protocol in a cohort of breastfeeding mother-infant pairs, enrolled in the Global Exploration of Human Milk Study, designed to examine longitudinally the effect of environment, diet and culture. Mothers planned to provide breast milk for at least three months post-partum and were enrolled at four weeks postpartum in Shanghai, China (n = 112), Cincinnati, Ohio (n = 119), and Mexico City, Mexico (n = 113). Maternal serum 25(OH)D was measured by radioimmunoassay (<50 nmol/L was categorized as deficient). Serum 25(OH)D was measured in a subset of infants (35 Shanghai, 47 Cincinnati and 45 Mexico City) seen at 26 weeks of age during fall and winter seasons. Data collected prospectively included vD supplementation, season and sun index (sun exposure × body surface area exposed while outdoors). Differences and factors associated with vD deficiency were evaluated using appropriate statistical analysis. vD deficiency in order of magnitude was identified in 62%, 52% and 17% of Mexican, Shanghai and Cincinnati mothers, respectively (p < 0.001). In regression analysis, vD supplementation (p < 0.01), obesity (p = 0.03), season (p = 0.001) and sites (p < 0.001) predicted maternal vD status. vD deficiency in order of  magnitude was found in 62%, 28%, and 6% of Mexican, Cincinnati and Shanghai infants, respectively (p < 0.001). Season (p = 0.022), adding formula feeding (p < 0.001) and a higher sun index (p = 0.085) predicted higher infant vD status. vD deficiency appears to be a global problem in mothers and infants, though the prevalence in diverse populations may depend upon sun exposure behaviors and vD supplementation. Greater attention to maternal and infant vD status starting during pregnancy is warranted worldwide.
PMCID: PMC4344576  PMID: 25665158
vitamin D; sun exposure; breastfeeding; supplements; mothers; infants
7.  Amniotic Fluid 
Reproductive Sciences  2014;21(1):6-19.
Our aim was to review the use of high-dimensional biology techniques, specifically transcriptomics, proteomics, and metabolomics, in amniotic fluid to elucidate the mechanisms behind preterm birth or assessment of fetal development. We performed a comprehensive MEDLINE literature search on the use of transcriptomic, proteomic, and metabolomic technologies for amniotic fluid analysis. All abstracts were reviewed for pertinence to preterm birth or fetal maturation in human subjects. Nineteen articles qualified for inclusion. Most articles described the discovery of biomarker candidates, but few larger, multicenter replication or validation studies have been done. We conclude that the use of high-dimensional systems biology techniques to analyze amniotic fluid has significant potential to elucidate the mechanisms of preterm birth and fetal maturation. However, further multicenter collaborative efforts are needed to replicate and validate candidate biomarkers before they can become useful tools for clinical practice. Ideally, amniotic fluid biomarkers should be translated to a noninvasive test performed in maternal serum or urine.
PMCID: PMC3857760  PMID: 23599373
amniotic fluid; systems biology; proteomics; transcriptomics; preterm birth
8.  Intestinal microbiota of preterm infants differ over time and between hospitals 
Microbiome  2014;2:36.
Intestinal microbiota are implicated in risk of necrotizing enterocolitis (NEC) and sepsis, major diseases of preterm infants in neonatal intensive care units (NICUs). Rates of these diseases vary over time and between NICUs, but time and NICU comparisons of the intestinal microbiota of preterm infants are lacking.
We included 66 singleton infants <29 weeks gestational age with stool samples collected between postnatal days 3 to 21 of life who survived free of NEC and sepsis. Infants were enrolled during 2010 and 2011. Twenty-six infants were enrolled at hospital 1 in Cincinnati, OH, and 40 infants were enrolled at hospital 2 in Birmingham, AL. Samples collected from days 3–9 (“week 1”) and days 10–16 (“week 2”) were compared between years and hospitals. Microbial succession was compared between hospitals in 28 infants with samples from the first 3 weeks of life. DNA extracted from stool was used to sequence the 16S rRNA gene by Illumina MiSeq using universal primers. Resulting operational taxonomic unit tables were analyzed for differences between years and hospitals using linear discriminant analysis effect size algorithm (LEfSe; significance, p < 0.05).
Significant variation was observed in infant microbiota by year and hospital. Among hospital 1 infants, week 1 samples had more phylum Firmicutes (class Bacilli, families Clostridiaceae and Enterococcaceae) in 2010 and more phylum Proteobacteria (family Enterobacteriaceae) in 2011; week 2 samples did not significantly vary over time. However, among hospital 2 infants, the week 1 shift was nearly opposite, with more Proteobacteria (Enterobacteriaceae) in 2010 and more Firmicutes (Bacilli) in 2011; week 2 samples exhibited the same pattern. Regression analysis of clinical covariates found that antibiotic use had an important influence but did not explain these observed shifts in microbiota over time and between hospitals. Microbial succession also differed by hospital, with greater change in microbiota in hospital 1 than hospital 2 infants (p < 0.01, Jaccard distance).
Colonizing microbiota differ over time and between NICUs in ways that could be relevant to disease. Multi-site, longitudinal studies are needed to reliably define the impact of intestinal microbiota on adverse outcomes of preterm infants.
PMCID: PMC4203463  PMID: 25332767
Infants; Premature; Microbiome; Geo-temporal analysis; Microbial succession
9.  Protection, Promotion, and Support and Global Trends in Breastfeeding123 
Advances in Nutrition  2013;4(2):213-219.
A number of case studies have shown that promotion of breastfeeding (BF) coincides with improved BF and exclusive BF (EBF) practices. We quantify the relationship between BF promotion and changes in BF practices by analyzing the relationship between implementation of the WHO/UNICEF Global Strategy for Infant and Young Child Feeding as measured by the World Breastfeeding Trends Initiative (WBTi) and trends in EBF and BF duration over the past 20 y in 22 countries in Africa, Asia, the Middle East, and Latin America. The median annual increase in EBF was 1.0%/y in countries in the upper 50th percentile of WBTi scores, indicating national policies and programs most consistent with WHO/UNICEF recommendations, whereas the median increase in EBF was only 0.2%/y in countries with the lowest WBTi scores (P = 0.01). The median annual increase in BF duration in all countries was <0.1%/ y. The annual increase in EBF was not associated with maternal demographic factors, such as urban residence, paid maternal employment, maternal education, or gross national income. Our results show that the association between BF protection, promotion, and support and improved EBF is measurable and strengthened by case studies possibly causal.
PMCID: PMC3649101  PMID: 23493537
10.  Randomized Controlled Trial of Docosahexaenoic Acid Supplementation in Midwestern U.S. Human Milk Donors 
Breastfeeding Medicine  2013;8(1):86-91.
Docosahexaenoic acid (DHA) is a long-chain polyunsaturated fatty acid important for neonatal neurodevelopment and immune homeostasis. Preterm infants fed donor milk from a Midwestern source receive only 20% of the intrauterine accretion of DHA. We tested the hypothesis that DHA supplementation of donor mothers would provide preterm infants with DHA intake equivalent to fetal accretion.
Subjects and Methods
After Institutional Review Board approval and informed consent, human milk donors to the Mother's Milk Bank of Ohio were randomized to receive 1 g of DHA (Martek® [now DSM Nutritional Lipids, Columbia, MD]) or placebo soy oil. Dietary intake data were collected and analyzed by a registered dietitian. Fatty acids were measured by gas chromatography/flame ionization detection. Statistical analysis used linear mixed models.
Twenty-one mothers were randomly assigned to either the DHA group (n=10) or the placebo group (n=11). Donor age was a median of 31 years in both groups with a mean lactational stage of 19 weeks. Dietary intake of DHA at baseline in both groups was a median of 23 mg/day (range, 0–194 mg), significantly (p<0.0001) less than the minimum recommended intake of 200 mg/day. The DHA content of milk increased in the DHA-supplemented group (p<0.05).
The women enrolled in this study had low dietary DHA intake. Supplementation with preformed DHA at 1 g/day resulted in increased DHA concentrations in the donor milk with no adverse outcomes. Infants fed donor milk from supplemented women receive dietary DHA levels that closely mimic normal intrauterine accretion during the third trimester.
PMCID: PMC3566653  PMID: 22568471
11.  Human Milk Composition: Nutrients and Bioactive Factors 
The composition of human milk is the biologic norm for infant nutrition. Human milk also contains many hundreds to thousands of distinct bioactive molecules that protect against infection and inflammation and contribute to immune maturation, organ development, and healthy microbial colonization. Some of these molecules, e.g., lactoferrin, are being investigated as novel therapeutic agents. A dynamic, bioactive fluid, human milk changes in composition from colostrum to late lactation, and varies within feeds, diurnally, and between mothers. Feeding infants with expressed human milk is increasing. Pasteurized donor milk is now commonly provided to high risk infants and most mothers in the U.S. express and freeze their milk at some point in lactation for future infant feedings. Many milk proteins are degraded by heat treatment and freeze-thaw cycles may not have the same bioactivity after undergoing these treatments. This article provides an overview of the composition of human milk, sources of its variation, and its clinical relevance.
PMCID: PMC3586783  PMID: 23178060
human milk composition; breastfeeding; infant nutrition; pasteurization; bioactive factors
12.  Fatty acid composition in the mature milk of Bolivian forager-horticulturalists: controlled comparisons with a US sample 
Maternal & child nutrition  2012;8(3):10.1111/j.1740-8709.2012.00412.x.
Breast milk fatty acid (FA) composition varies greatly among individual women, including in percentages of the long-chain polyunsaturated FAs (LCPUFA) 20:4n-6 (arachidonic acid, AA) and 22:6n-3 (docosahexaenoic acid, DHA), which are important for infant neurological development. It has been suggested that owing to wide variation in milk LCPUFA and low DHA in Western diets, standards of milk FA composition should be derived from populations consuming traditional diets. We collected breast milk samples from Tsimane women at varying lactational stages (6–82 weeks). The Tsimane are an indigenous, natural fertility, subsistence-level population living in Amazonia Bolivia. Tsimane samples were matched by lactational stage to samples from a US milk bank, and analysed concurrently for FA composition by gas-liquid chromatography. We compared milk FA composition between Tsimane (n = 35) and US (n = 35) mothers, focusing on differences in LCPUFA percentages that may be due to population-typical dietary patterns. Per total FAs, the percentages of AA, DHA, total n-3 and total n-6 LCPUFA were significantly higher among Tsimane mothers. Mean percentages of 18:2n-6 (linoleic acid) and trans FAs were significantly higher among US mothers. Tsimane mothers’ higher milk n-3 and n-6 LCPUFA percentages may be due to their regular consumption of wild game and freshwater fish, as well as comparatively lower intakes of processed foods and oils that may interfere with LCPUFA synthesis.
PMCID: PMC3851016  PMID: 22624983
lactation; diet; docosahexaenoic acid; arachidonic acid; breast milk; infant and child nutrition
13.  Poly-LacNAc as an Age-Specific Ligand for Rotavirus P[11] in Neonates and Infants 
PLoS ONE  2013;8(11):e78113.
Rotavirus (RV) P[11] is an unique genotype that infects neonates. The mechanism of such age-specific host restriction remains unknown. In this study, we explored host mucosal glycans as a potential age-specific factor for attachment of P[11] RVs. Using in vitro binding assays, we demonstrated that VP8* of a P[11] RV (N155) could bind saliva of infants (60.3%, N = 151) but not of adults (0%, N = 48), with a significantly negative correlation between binding of VP8* and ages of infants (P<0.01). Recognition to the infant saliva did not correlate with the ABO, secretor and Lewis histo-blood group antigens (HBGAs) but with the binding of the lectin Lycopersicon esculentum (LEA) that is known to recognize the oligomers of N-acetyllactosamine (LacNAc), a precursor of human HBGAs. Direct evidence of LacNAc involvement in P[11] binding was obtained from specific binding of VP8* with homopolymers of LacNAc in variable lengths through a glycan array analysis of 611 glycans. These results were confirmed by strong binding of VP8* to the Lec2 cell line that expresses LacNAc oligomers but not to the Lec8 cell line lacking the LacNAc. In addition, N155 VP8* and authentic P[11] RVs (human 116E and bovine B223) hemagglutinated human red blood cells that are known to express poly-LacNAc. The potential role of poly-LacNAc in host attachment and infection of RVs has been obtained by abrogation of 116E replication by the PAA-conjugated poly-LacNAc, human milk, and LEA positive infant saliva. Overall, our results suggested that the poly-LacNAc could serve as an age-specific receptor for P[11] RVs and well explained the epidemiology that P[11] RVs mainly infect neonates and young children.
PMCID: PMC3823915  PMID: 24244290
14.  Strategic Global Approaches to Improve Breastfeeding Rates123 
Advances in Nutrition  2012;3(6):829-830.
PMCID: PMC3648710  PMID: 23153740
15.  RNA Sequencing of the Human Milk Fat Layer Transcriptome Reveals Distinct Gene Expression Profiles at Three Stages of Lactation 
PLoS ONE  2013;8(7):e67531.
Aware of the important benefits of human milk, most U.S. women initiate breastfeeding but difficulties with milk supply lead some to quit earlier than intended. Yet, the contribution of maternal physiology to lactation difficulties remains poorly understood. Human milk fat globules, by enveloping cell contents during their secretion into milk, are a rich source of mammary cell RNA. Here, we pair this non-invasive mRNA source with RNA-sequencing to probe the milk fat layer transcriptome during three stages of lactation: colostral, transitional, and mature milk production. The resulting transcriptomes paint an exquisite portrait of human lactation. The resulting transcriptional profiles cluster not by postpartum day, but by milk Na:K ratio, indicating that women sampled during similar postpartum time frames could be at markedly different stages of gene expression. Each stage of lactation is characterized by a dynamic range (105-fold) in transcript abundances not previously observed with microarray technology. We discovered that transcripts for isoferritins and cathepsins are strikingly abundant during colostrum production, highlighting the potential importance of these proteins for neonatal health. Two transcripts, encoding β-casein (CSN2) and α-lactalbumin (LALBA), make up 45% of the total pool of mRNA in mature lactation. Genes significantly expressed across all stages of lactation are associated with making, modifying, transporting, and packaging milk proteins. Stage-specific transcripts are associated with immune defense during the colostral stage, up-regulation of the machinery needed for milk protein synthesis during the transitional stage, and the production of lipids during mature lactation. We observed strong modulation of key genes involved in lactose synthesis and insulin signaling. In particular, protein tyrosine phosphatase, receptor type, F (PTPRF) may serve as a biomarker linking insulin resistance with insufficient milk supply. This study provides the methodology and reference data set to enable future targeted research on the physiological contributors of sub-optimal lactation in humans.
PMCID: PMC3702532  PMID: 23861770
16.  Early microbial and metabolomic signatures predict later onset of necrotizing enterocolitis in preterm infants 
Microbiome  2013;1:13.
Necrotizing enterocolitis (NEC) is a devastating intestinal disease that afflicts 10% of extremely preterm infants. The contribution of early intestinal colonization to NEC onset is not understood, and predictive biomarkers to guide prevention are lacking. We analyzed banked stool and urine samples collected prior to disease onset from infants <29 weeks gestational age, including 11 infants who developed NEC and 21 matched controls who survived free of NEC. Stool bacterial communities were profiled by 16S rRNA gene sequencing. Urinary metabolomic profiles were assessed by NMR.
During postnatal days 4 to 9, samples from infants who later developed NEC tended towards lower alpha diversity (Chao1 index, P = 0.086) and lacked Propionibacterium (P = 0.009) compared to controls. Furthermore, NEC was preceded by distinct forms of dysbiosis. During days 4 to 9, samples from four NEC cases were dominated by members of the Firmicutes (median relative abundance >99% versus <17% in the remaining NEC and controls, P < 0.001). During postnatal days 10 to 16, samples from the remaining NEC cases were dominated by Proteobacteria, specifically Enterobacteriaceae (median relative abundance >99% versus 38% in the other NEC cases and 84% in controls, P = 0.01). NEC preceded by Firmicutes dysbiosis occurred earlier (onset, days 7 to 21) than NEC preceded by Proteobacteria dysbiosis (onset, days 19 to 39). All NEC cases lacked Propionibacterium and were preceded by either Firmicutes (≥98% relative abundance, days 4 to 9) or Proteobacteria (≥90% relative abundance, days 10 to 16) dysbiosis, while only 25% of controls had this phenotype (predictive value 88%, P = 0.001). Analysis of days 4 to 9 urine samples found no metabolites associated with all NEC cases, but alanine was positively associated with NEC cases that were preceded by Firmicutes dysbiosis (P < 0.001) and histidine was inversely associated with NEC cases preceded by Proteobacteria dysbiosis (P = 0.013). A high urinary alanine:histidine ratio was associated with microbial characteristics (P < 0.001) and provided good prediction of overall NEC (predictive value 78%, P = 0.007).
Early dysbiosis is strongly involved in the pathobiology of NEC. These striking findings require validation in larger studies but indicate that early microbial and metabolomic signatures may provide highly predictive biomarkers of NEC.
PMCID: PMC3971624  PMID: 24450576
Microbiome; Premature infants; Necrotizing enterocolitis; Dysbiosis
17.  Human milk adiponectin impacts infant weight trajectory during the second year of life 
Serum adiponectin (APN) is associated with lower childhood obesity, and APN concentration in human milk is associated with slower growth during active breastfeeding. Here, we examine infant weight gain in the second year of life after exposure to high or low levels of mother’s milk APN.
Breastfeeding mother-infant pairs were recruited in Mexico City and followed for 2 years; 192 infants with ≥12 months’ follow-up were analyzed. Monthly milk samples were assayed for APN; mothers were classified as producing high or low levels of milk APN. Infant and maternal serum APN were assessed during year 1. Infant anthropometry was measured monthly (year 1) or bi-monthly (year 2), and WHO Z-scores calculated. Longitudinal adjusted models assessed weight-for-age (WEI) and weight-for-length (WFL) Z-score trajectories from 1 to 2 years.
Maternal serum APN modestly correlated with milk APN (r=0.37, p<0.0001) and infant serum APN (r=0.29, p=0.01). Infants exposed to high milk APN experienced increasing WEI and WFL Z-scores between age 1 and 2 years in contrast to low milk APN exposure (p for group*time=0.02 and 0.054, respectively), adjusting for growth in the first 6 months and other covariates. In contrast, infant serum APN in year 1 was not associated with rate of weight gain in year 2.
High human milk APN exposure was associated with accelerated weight trajectory during the second year of life suggesting its role in catch up growth after slower weight gain during the first year of life.
PMCID: PMC3299902  PMID: 22094897
adiponectin; human milk; breastfeeding; weight gain; infancy
18.  Prolonged Initial Empirical Antibiotic Treatment is Associated with Adverse Outcomes in Premature Infants 
The Journal of pediatrics  2011;159(5):720-725.
To investigate the outcomes following prolonged empirical antibiotic administration to premature infants in the first week of life, concluding subsequent late onset sepsis (LOS), necrotizing enterocolitis (NEC), and death.
Study design
Study infants were ≤32 weeks gestational age and ≤ 1500 grams birth weight who survived free of sepsis and NEC for 7 days. Multivariable logistic regression was conducted to determine independent relationships between prolonged initial empirical antibiotic therapy (≥ 5 days) and study outcomes controlling for birth weight, gestational age, race, prolonged premature rupture of membranes, days on high frequency ventilation in 7 days, and the amount of breast milk received in the first 14 days of life.
Of the 365 premature infants surviving 7 days free of sepsis or NEC, 36% received prolonged initial empirical antibiotics, which was independently associated with subsequent outcomes: LOS (odds ratio [OR] 2.45, 95% confidence interval [CI] 1.28–4.67) and the combination of LOS, NEC, or death (OR 2.66, 95% CI 1.12–6.3).
Prolonged administration of empirical antibiotics to premature infants with sterile cultures in the first week of life is associated with subsequent severe outcomes. Judicious restriction of antibiotic use should be investigated as a strategy to reduce severe outcomes for premature infants.
PMCID: PMC3193552  PMID: 21784435
prolonged antibiotic treatment; death; human milk; late-onset sepsis; necrotizing enterocolitis; premature infant
19.  Fucosyltransferase 2 non-secretor and low secretor status predicts severe outcomes in premature infants 
The Journal of pediatrics  2011;158(5):745-751.
To investigate secretor gene fucosyltransferase2 (FUT2) polymorphism and secretor phenotype in relation to outcomes of prematurity.
Study design
Study infants were ≤32 weeks gestational age. Secretor genotype was determined from salivary DNA. Secretor phenotype was measured by H antigen, the carbohydrate produced by secretor gene enzymes, in saliva samples collected on day 9±5. The optimal predictive cut-point in salivary H values was identified by Classification and Regression Tree analysis. Study outcomes were death, necrotizing enterocolitis (NEC, Bell’s stage II/III), and confirmed sepsis.
There were 410 study infants, 26 deaths, 30 cases of NEC, and 96 cases of sepsis. Analyzed by genotype, 13% of 95 non-secretors, 5% of 203 heterozygotes, and 2% of 96 infants who were secretor dominant died (p=0.01). Analyzed by phenotype, 15% of 135 infants with low secretor phenotype died, compared with 2% of 248 infants with high secretor phenotype (predictive value=76%, p<0.001). Low secretor phenotype was associated (P<.05) with NEC, and non-secretor genotype was associated (P=.05) with gram negative sepsis. Secretor status remained significant after controlling for multiple clinical factors.
Secretor genotype and phenotype may provide strong predictive biomarkers of adverse outcomes in premature infants.
PMCID: PMC3412418  PMID: 21256510
20.  Lactation and Neonatal Nutrition: Defining and Refining the Critical Questions 
This paper resulted from a conference entitled “Lactation and Milk: Defining and refining the critical questions” held at the University of Colorado School of Medicine from January 18–20, 2012. The mission of the conference was to identify unresolved questions and set future goals for research into human milk composition, mammary development and lactation. We first outline the unanswered questions regarding the composition of human milk (Section I) and the mechanisms by which milk components affect neonatal development, growth and health and recommend models for future research. Emerging questions about how milk components affect cognitive development and behavioral phenotype of the offspring are presented in Section II. In Section III we outline the important unanswered questions about regulation of mammary gland development, the heritability of defects, the effects of maternal nutrition, disease, metabolic status, and therapeutic drugs upon the subsequent lactation. Questions surrounding breastfeeding practice are also highlighted. In Section IV we describe the specific nutritional challenges faced by three different populations, namely preterm infants, infants born to obese mothers who may or may not have gestational diabetes, and infants born to undernourished mothers. The recognition that multidisciplinary training is critical to advancing the field led us to formulate specific training recommendations in Section V. Our recommendations for research emphasis are summarized in Section VI. In sum, we present a roadmap for multidisciplinary research into all aspects of human lactation, milk and its role in infant nutrition for the next decade and beyond.
PMCID: PMC3428522  PMID: 22752723
Lactation; Infant nutrition; Human milk; Breastfeeding; Mammary gland development; Human nutrition; Preterm birth; Obesity; Undernutrition; Lactational programming; Milk
21.  Genetic Diversity and Histo-Blood Group Antigen Interactions of Rhesus Enteric Caliciviruses▿  
Journal of Virology  2010;84(17):8617-8625.
Recently, we reported the discovery and characterization of Tulane virus (TV), a novel rhesus calicivirus (CV) (T. Farkas, K. Sestak, C. Wei, and X. Jiang, J. Virol. 82:5408-5416, 2008). TV grows well in tissue culture, and it represents a new genus within Caliciviridae, with the proposed name of Recovirus. We also reported a high prevalence of CV antibodies in macaques of the Tulane National Primate Research Center (TNPRC) colony, including anti-norovirus (NoV), anti-sapovirus (SaV), and anti-TV (T. Farkas, J. Dufour, X. Jiang, and K. Sestak, J. Gen. Virol. 91:734-738, 2010). To broaden our knowledge about CV infections in captive nonhuman primates (NHP), 500 rhesus macaque stool samples collected from breeding colony TNPRC macaques were tested for CVs. Fifty-seven (11%) samples contained recovirus isolates. In addition, one NoV was detected. Phylogenetic analysis classified the recovirus isolates into two genogroups and at least four genetic types. The rhesus NoV isolate was closely related to GII human NoVs. TV-neutralizing antibodies were detected in 88% of serum samples obtained from primate caretakers. Binding and plaque reduction assays revealed the involvement of type A and B histo-blood group antigens (HBGA) in TV infection. Taken together, these findings indicate the zoonotic potential of primate CVs. The discovery of a genetically diverse and prevalent group of primate CVs and remarkable similarities between rhesus enteric CVs and human NoVs opens new possibilities for research involving in vitro and in vivo models of human NoV gastroenteritis.
PMCID: PMC2919043  PMID: 20554772
22.  Characteristics and potential functions of human milk adiponectin 
The Journal of pediatrics  2010;156(2 Suppl):S41-S46.
Adiponectin is a protein hormone produced by adipose tissue whose circulating levels are inversely related to adiposity and inflammation. Adiponectin circulates as oligomers, from the low molecular weight trimer to the high molecular weight octodecamer (18mer) Each oligomer has distinct biological activities, which include enhancement of insulin sensitivity and metabolic control, and suppression of inflammation. Adiponectin occurs in human milk at higher concentrations than leptin. The adiponectin in human milk is almost entirely of the high molecular weight form, the form with the highest activity in controlling many types of metabolic processes. Human adiponectin fed to infant mice is transported across the intestinal mucosa into the serum. An inverse relationship between adiponectin levels in milk and adiposity (weight-for-height) of the breastfed infant was observed, and could be due to modulation of infant metabolism by milk adiponectin, and may be related to the observed protection against obesity by breastfeeding. Human milk may be a medium whereby the hormonal milieu (in response to internal factors and the environment) of the mother can be used to communicate with the breastfed infant to modify infant metabolic processes. Transmission of information from mother to infant through milk may allow adaptation to fluctuating environmental conditions.
PMCID: PMC2875873  PMID: 20105665
infant development; body weight; BMI; adiposity
23.  Response to Brody et al. 
Breastfeeding Medicine  2009;4(2):123.
PMCID: PMC2932547  PMID: 19500056
24.  Epidemiology of Necrotizing Enterocolitis Temporal Clustering in Two Neonatology Practices 
The Journal of pediatrics  2008;154(5):656-661.
To develop a statistical method for defining clusters of necrotizing enterocolitis (NEC) cases in the neonatal intensive care unit (NICU).
Study design
2782 infants, between 1996–2004, weighing 401–1500 grams at birth were included. NEC was defined as Bell stage II or III. Two statistical methods used to define “disease clusters” were: (1) modified scan test; (2) comparison of observed and expected incidence density rates (IDR) of NEC at each NICU.
The proportion of infants with NEC was similar between NICUs (7.1% vs. 7.7%; p=0.6) as was the expected IDR of NEC (1.39/1000 patient-days vs. 1.32/1000 patient-days, p=0.72). Twelve temporal clusters of NEC were identified in the NICUs combined, comprising 18% of 203 total NEC cases during the study period. No seasonal/secular trends were noted for NEC rates or identified clusters. Potential NEC clusters of ≥3 cases at either NICU had >75% chance of being a true NEC cluster.
No operational definition of NEC cluster exists. This study introduced methods to be employed for prospective surveillance and guide studies to investigate etiologic relevance. Utilizing the proposed methods, statistically significant clusters (potential outbreaks) of NEC within NICUs can be identified early, providing early opportunity to implement cluster investigation protocols.
PMCID: PMC2700364  PMID: 19111317
disease clusters; outbreaks; neonatal intensive care unit; very low birth weight infants
25.  Use of a body proportionality index for growth assessment of preterm infants 
The Journal of pediatrics  2008;154(4):486-491.
We evaluated the utility of weight-for-length (defined as gm/cm3, “ponderal index”) as a complementary measure of growth in infants in neonatal intensive care units (NICUs).
Study design
Secondary analysis of infants (n=1214) 26-29 weeks at birth, included in a registry database (1991-2003), who had growth data at birth and discharge. Weight-for-age and weight-for-length were categorized as small (<10th percentile), appropriate or large (>90th percentile).
Statistical agreement between the weight-for-age and weight-for-length measures was poor (kappa=0.02 at birth, 0.10 at discharge, Bowker test for symmetry p<0.0001). From birth to discharge, the percent of small-for-age infants increased from 12% to 21%, and the percent of small-for-length infants decreased from 10% to 4%; the percent of large-for-age infants remained similar (<1%), and the percent of large-for-length infants increased from 5% to 17%. At discharge, 92% of small-for-age infants were appropriate or large-for-length, and 19% of appropriate-for-age infants were large-for-length.
Weight-for-age and weight-for-length are complementary measures. Weight-for-length or other measure of body proportionality should be considered for inclusion in routine growth monitoring of infants in the NICU.
PMCID: PMC2745983  PMID: 19041096
Growth status; growth; weight-for-age; weight/length3; ponderal index; weight/length ratio; obesity; overweight; underweight; small-for-gestational age; nutrition

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