Capturing the antibiotic resistome of preterm infants reveals new benefits of probiotic supplementation.

BACKGROUND: Probiotic use in preterm infants can mitigate the impact of antibiotic exposure and reduce rates of certain illnesses; however, the benefit on the gut resistome, the collection of antibiotic resistance genes, requires further investigation. We hypothesized that probiotic supplementation of early preterm infants (born < 32-week gestation) while in hospital reduces the prevalence of antibiotic resistance genes associated with pathogenic bacteria in the gut. We used a targeted capture approach to compare the resistome from stool samples collected at the term corrected age of 40 weeks for two groups of preterm infants (those that routinely received a multi-strain probiotic during hospitalization and those that did not) with samples from full-term infants at 10 days of age to identify if preterm birth or probiotic supplementation impacted the resistome. We also compared the two groups of preterm infants up to 5 months of age to identify persistent antibiotic resistance genes. RESULTS: At the term corrected age, or 10 days of age for the full-term infants, we found over 80 antibiotic resistance genes in the preterm infants that did not receive probiotics that were not identified in either the full-term or probiotic-supplemented preterm infants. More genes associated with antibiotic inactivation mechanisms were identified in preterm infants unexposed to probiotics at this collection time-point compared to the other infants. We further linked these genes to mobile genetic elements and Enterobacteriaceae, which were also abundant in their gut microbiomes. Various genes associated with aminoglycoside and beta-lactam resistance, commonly found in pathogenic bacteria, were retained for up to 5 months in the preterm infants that did not receive probiotics. CONCLUSIONS: This pilot survey of preterm infants shows that probiotics administered after preterm birth during hospitalization reduced the diversity and prevented persistence of antibiotic resistance genes in the gut microbiome. The benefits of probiotic use on the microbiome and the resistome should be further explored in larger groups of infants. Due to its high sensitivity and lower sequencing cost, our targeted capture approach can facilitate these surveys to further address the implications of resistance genes persisting into infancy without the need for large-scale metagenomic sequencing. Video Abstract.

Growth and body composition trajectories in infants meeting the WHO growth standards study requirements.

BACKGROUND: While the World Health Organization (WHO) developed postnatal growth standards for infants, corresponding body composition data remains scarce. This study explores growth and body composition trajectories in infants meeting the WHO Multicentre Growth Reference Study (MGRS) eligibility criteria. STUDY DESIGN: Infants enrolled in this longitudinal cohort underwent anthropometric and body composition measurement by air displacement plethysmography (ADP) at 6 weeks, 12 weeks, and 5 months postnatally. Age and sex-specific growth and body composition percentiles were generated using GAMLSS, with extrapolated data at 5 months for those exceeding ADP weight limits. We evaluated which anthropometric measure (body mass index (BMI), weight for length or mid upper arm circumference) was most closely related to adiposity. RESULTS: Of the 225 infants with body composition measures, 187 met the WHO MGRS criteria. Their length and weight curves were comparable with WHO growth curves. Trajectory curves for fat and fat-free mass were developed. Of the anthropometric measures, BMI z score was most closely related to fat mass index z score at all timepoints. CONCLUSION: This study presents body composition trajectories for infants meeting the WHO growth standard criteria. BMI z score is the best anthropometric metric to estimate adiposity in infants. IMPACT: While postnatal growth standards derived from the WHO Multicentre Growth Reference Study (MGRS) exist for the routine clinical assessment of infant growth, this study fills the previous gap in the availability of corresponding body composition data for term-born, healthy, breastfed infants meeting the MGRS criteria. Extrapolation was used to obtain body composition values for infants exceeding the weight limit of the ADP device, to avoid construction of biased body composition curves. Sex-specific growth curves for fat mass, fat-free mass, fat mass index, and fat-free mass index are presented for a population meeting the World Health Organization growth standard criteria.

The impact of parity and maternal obesity on the fetal outcomes of a non-selected Lower Saxony population.

OBJECTIVES: Maternal obesity during pregnancy is associated with adverse intrauterine events and fetal outcomes and may increase the risk of obesity and metabolic disease development in offspring. Higher parity, regardless of socioeconomic status, is associated with increased maternal body mass index (BMI). In this study, we examined the relationship between parity, maternal obesity, and fetal outcomes in a large sample of mother-neonate pairs from Lower Saxony, Germany. METHODS: This retrospective cohort study examined pseudonymized data of a non-selected singleton cohort from Lower Saxony's statewide quality assurance initiative. 448,963 cases were included. Newborn outcomes were assessed in relation to maternal BMI and parity. RESULTS: Maternal obesity was associated with an increased risk of placental insufficiency, chorioamnionitis, and fetal distress while giving birth. This effect was present across all parity groups. Fetal presentation did not differ between BMI groups, except for the increased risk of high longitudinal position and shoulder dystocia in obese women. Maternal obesity was also associated with an increased risk of premature birth, low arterial cord blood pH and low 5-min APGAR scores. CONCLUSIONS: Maternal obesity increases the risk of adverse neonatal outcomes. There is a positive correlation between parity and increased maternal BMI. Weight-dependent fetal risk factors increase with parity, while parity-dependent outcomes occur less frequently in multipara. Prevention and intervention programs for women planning to become pregnant can be promising measures to reduce pregnancy and birth complications.

Metabolic-endocrine disruption due to preterm birth impacts growth, body composition, and neonatal outcome.

Despite optimized nutrition, preterm-born infants grow slowly and tend to over-accrete body fat. We hypothesize that the premature dissociation of the maternal-placental-fetal unit disrupts the maintenance of physiological endocrine function in the fetus, which has severe consequences for postnatal development. This review highlights the endocrine interactions of the maternal-placental-fetal unit and the early perinatal period in both preterm and term infants. We report on hormonal levels (including tissue, thyroid, adrenal, pancreatic, pituitary, and placental hormones) and nutritional supply and their impact on infant body composition. The data suggest that the premature dissociation of the maternal-placental-fetal unit leads to a clinical picture similar to panhypopituitarism. Further, we describe how the premature withdrawal of the maternal-placental unit, neonatal morbidities, and perinatal stress can cause differences in the levels of growth-promoting hormones, particularly insulin-like growth factors (IGF). In combination with the endocrine disruption that occurs following dissociation of the maternal-placental-fetal unit, the premature adaptation to the extrauterine environment leads to early and fast accretion of fat mass in an immature body. In addition, we report on interventional studies that have aimed to compensate for hormonal deficiencies in infants born preterm through IGF therapy, resulting in improved neonatal morbidity and growth. IMPACT: Preterm birth prematurely dissociates the maternal-placental-fetal unit and disrupts the metabolic-endocrine maintenance of the immature fetus with serious consequences for growth, body composition, and neonatal outcomes. The preterm metabolic-endocrine disruption induces symptoms resembling anterior pituitary failure (panhypopituitarism) with low levels of IGF-1, excessive postnatal fat mass accretion, poor longitudinal growth, and failure to thrive. Appropriate gestational age-adapted nutrition alone seems insufficient for the achievement of optimal growth of preterm infants. Preliminary results from interventional studies show promising effects of early IGF-1 supplementation on postnatal development and neonatal outcomes.

Individualized Target Fortification of Breast Milk: Optimizing Macronutrient Content Using Different Fortifiers and Approaches.

Background: Native breast milk composition displays significant inter- and intra-individual variation which persists after standard fortification with fixed doses and challenges target fortification. This study aims to analyze the macronutrient composition of different commercially available fortifiers and the effect of different fortification strategies on nutritional intake of preterm infants. Methods: In 103 preterm infants, native breast milk samples were collected from 24-h feeding batches (n = 3,338) and fat, protein and carbohydrate contents were analyzed. Nutrient content was compared for breast milk that had undergone either (i) standard fortification, (ii) targeted fortification, (iii) selective batching according to breast milk composition, or (iv) partial lyophilization. For (i) eight commercially available standard fortifiers were tested. Targeted fortification (ii) involved the addition of single component modulars of either protein, fat or carbohydrates to standard fortified breast milk. Using a mathematical growth model, the combined effect of protein, fat and carbohydrate intake on growth was assessed. The best composition of standard fortifiers as the initial step for target fortification was explored assuming three clinical scenarios for milk analysis. Results: Macronutrient content was highly variable between native breast milk samples, and this variation was still present after standard fortification, however at elevated macronutrient levels. Standard fortification, breast milk batching, as well as partial lyophilization of human milk resulted in deficient and imbalanced enteral intakes in a significant proportion of infants. Target fortification reduced this variation in a, respectively, higher percentage of samples. The effect size was dependent on the number of measurements per week. The optimum composition of standard fortifiers was dependent on the clinical scenario (measurement frequency) for target fortification. Conclusions: To provide precise and accurate intakes of macronutrients, breast milk should be target fortified. Standard fortified breast milk can result in excess above recommended intakes of some macronutrients which limits the efficiency of target fortification. Standard fortifiers with improved composition are needed for target fortification.

The cumulative impact of parity on the body mass index (BMI) in a non-selected Lower Saxony population.

OBJECTIVES: During the last decade obesity has been continuously rising in adults in industrial countries. The increased occurrence of perinatal complications caused by maternal obesity poses a major challenge for obstetricians during pregnancy and childbirth. This study aims to examine the association between parity, pregnancy, birth risks, and body mass index (BMI) of women from Lower Saxony, Germany. METHODS: This retrospective cohort study examined pseudonymized data of a non-selected singleton cohort from Lower Saxony's statewide quality assurance initiative. Mothers were categorized according to BMI as normal weight (18.5 to <25 kg/m2) or obese (≥30 kg/m2). RESULTS: Most of the mothers in this study population were either in their first (33.9%) or second pregnancy (43.4%). The mean age of women giving birth for the first time was 28.3 years. Maternal age increased with increasing parity. The proportion of pregnant women with a BMI over 30 was 11% in primiparous women, 14.3% in second para, 17.3% in third para and 24.1% in fourth para or more women. Increasing parity was positively correlated with the incidence of classical diseases related to obesity, namely diabetes mellitus, gestational diabetes, hypertension, pregnancy-related hypertension and urinary protein excretion. An increased risk of primary or secondary cesarean section was observed in the obese women, particularly during the first deliveries. CONCLUSIONS: There is a positive and significant correlation between parity and increased maternal BMI. The highest weight gain happens during the first pregnancy. The rate of operative deliveries and complications during delivery is increased in obese pregnant women.

Persistence of Suspected Probiotic Organisms in Preterm Infant Gut Microbiota Weeks After Probiotic Supplementation in the NICU.

Probiotics are becoming a prevalent supplement to prevent necrotizing enterocolitis in infants born preterm. However, little is known about the ability of these live bacterial supplements to colonize the gut or how they affect endogenous bacterial strains and the overall gut community. We capitalized on a natural experiment resulting from a policy change that introduced the use of probiotics to preterm infants in a single Neonatal Intensive Care Unit. We used amplicon sequence variants (ASVs) derived from the v3 region of the 16S rRNA gene to compare the prevalence and abundance of Bifidobacterium and Lactobacillus in the gut of preterm infants who were and were not exposed to a probiotic supplement in-hospital. Infants were followed to 5 months corrected age. In the probiotic-exposed infants, ASVs belonging to species of Bifidobacterium appeared at high relative abundance during probiotic supplementation and persisted for up to 5 months. In regression models that controlled for the confounding effects of age and antibiotic exposure, probiotic-exposed infants had a higher abundance of the suspected probiotic bifidobacteria than unexposed infants. Conversely, the relative abundance of Lactobacillus was similar between preterm groups over time. Lactobacillus abundance was inversely related to antibiotic exposure. Furthermore, the overall gut microbial community of the probiotic-exposed preterm infants at term corrected age clustered more closely to samples collected from 10-day old full-term infants than to samples from unexposed preterm infants at term age. In conclusion, routine in-hospital administration of probiotics to preterm infants resulted in the potential for colonization of the gut with probiotic organisms post-discharge and effects on the gut microbiome as a whole. Further research is needed to fully discriminate probiotic bacterial strains from endogenous strains and to explore their functional role in the gut microbiome and in infant health.

Fat and Fat-Free Mass of Preterm and Term Infants from Birth to Six Months: A Review of Current Evidence.

To optimize infant nutrition, the nature of weight gain must be analyzed. This study aims to review publications and develop growth charts for fat and fat-free mass for preterm and term infants. Body composition data measured by air displacement plethysmography (ADP) and dual energy X-ray absorptiometry (DXA) in preterm and term infants until six months corrected age were abstracted from publications (31 December 1990 to 30 April 2019). Age-specific percentiles were calculated. ADP measurements were used in 110 studies (2855 preterm and 22,410 term infants), and DXA was used in 28 studies (1147 preterm and 3542 term infants). At term age, preterm infants had higher percent-fat than term-born infants (16% vs. 11%, p < 0.001). At 52 weeks postmenstrual age (PMA), both reached similar percent-fat (24% vs. 25%). In contrast, at term age, preterm infants had less fat-free mass (2500 g vs. 2900 g) by 400 g. This difference decreased to 250 g by 52 weeks, and to 100 g at 60 weeks PMA (5000 g vs. 5100 g). DXA fat-free mass data were comparable with ADP. However, median percent-fat was up to 5% higher with DXA measurements compared with ADP with PMA > 50 weeks. There are methodological differences between ADP and DXA measures for infants with higher fat mass. The cause of higher fat mass in preterm infants at term age needs further investigation.