Terri Ashmeade

Development of the preterm infant gut microbiome: a research priority

The very low birth weight (VLBW) infant is at great risk for marked dysbiosis of the gut microbiome due to multiple factors, including physiological immaturity and prenatal/postnatal influences that disrupt the development of a normal gut flora. However, little is known about the developmental succession of the microbiota in preterm infants as they grow and mature. This review provides a synthesis of our understanding of the normal development of the infant gut microbiome and contrasts this with dysbiotic development in the VLBW infant. The role of human milk in normal gut microbial development is emphasized, along with the role of the gut microbiome in immune development and gastroenteric health. Current research provides evidence that the gut microbiome interacts extensively with many physiological systems and metabolic processes in the developing infant. However, to the best of our knowledge, there are currently no studies prospectively mapping the gut microbiome of VLBW infants through early childhood. This knowledge gap must be filled to inform a healthcare system that can provide for the growth, health, and development of VLBW infants. The paper concludes with speculation about how the VLBW infants’ gut microbiome might function through host-microbe interactions to contribute to the sequelae of preterm birth, including its influence on growth, development, and general health of the infant host.

Effect of carotenoid supplementation on plasma carotenoids, inflammation and visual development in preterm infants

Objective:Dietary carotenoids (lutein, lycopene and β-carotene) may be important in preventing or ameliorating prematurity complications. Little is known about carotenoid status or effects of supplementation.Study Design:This randomized controlled multicenter trial compared plasma carotenoid levels among preterm infants (n=203, <33 weeks gestational age) fed diets with and without added lutein, lycopene and β-carotene with human milk (HM)-fed term infants. We assessed safety and health.Result:Plasma carotenoid levels were higher in the supplemented group at all time points (P<0.0001) and were similar to those of term HM-fed infants. Supplemented infants had lower plasma C-reactive protein (P<0.001). Plasma lutein levels correlated with the full field electroretinogram-saturated response amplitude in rod photoreceptors (r=0.361, P=0.05). The supplemented group also showed greater rod photoreceptor sensitivity (least squares means 6.1 vs 4.1; P<0.05).Conclusion:Carotenoid supplementation for preterm infants raises plasma concentrations to those observed in HM-fed term infants. Carotenoid supplementation may decrease inflammation. Our results point to protective effects of lutein on preterm retina health and maturation.

The use of quantitative ultrasound in assessing bone status in newborn preterm infants.

OBJECTIVE: Quantitative ultrasound is increasingly used to assess bone status in adults and children; however, few studies have been carried out in neonates. Our objective was to determine if tibial bone speed of sound (SOS) correlates with gestational age and birth anthropometrics, and if bone SOS is related to maternal factors.STUDY DESIGN: We prospectively studied 95 preterm infants to assess factors related to bone status as measured by quantitative ultrasound.RESULTS: We found significant (p≤0.001) positive correlations between SOS and gestational age, birth weight, length, head circumference and tibial length. There was no significant relationship between SOS and prenatal steroid use, gestational diabetes, pre-eclampsia, race or parity.CONCLUSIONS: Quantitative ultrasound is an easy to use and inexpensive tool for assessing bone status in preterm neonates. Tibial SOS correlated with gestational age and birth anthropometrics, and was not related by few maternal factors.

Tolerance of Simulated Amniotic Fluid in Premature Neonates

OBJECTIVE: To assess the tolerance of simulated amniotic fluid enterally administered in premature neonates. DESIGN: A multicentered, Phase I, dose-escalation trial was accomplished among 30 preterm neonates. Groups of 10 patients received 5, 10, or 20 mL/kg/d enterally of the amniotic fluid solution, divided into every-3-hour dosing, for 3 days. MAIN OUTCOME MEASURES: Amount and character of emesis, stools, and gastric residuals; changes in abdominal girth; presence of a skin rash; blood pressure instability; the diagnosis of necrotizing enterocolitis (NEC) or intestinal perforation. RESULTS: Thirty patients were studied: 10 received 5 mL/kg/d, 10 received 10 mL/kg/d, and 10 received 20 mL/kg/d of amniotic solution. Gestational ages ranged from 25 to 31 weeks. The Data Safety and Monitoring Board met after each group of 10 patients completed the study, reviewed the outcome measurements, and recommended continuance of the study. Dosing was discontinued for 3 patients prior to receiving all 24 doses because of gastric residuals (n = 1; 5 mL/kg), stage I NEC (n = 1; 10 mL/kg), or symptomatic patent ductus arteriosus (n = 1; 20 mL/kg). The remaining patients completed the doses with no evidence of intolerance: specifically, no increased gastric residuals, increased abdominal girth, diarrhea, blood pressure change, rash, NEC, or intestinal perforation. CONCLUSIONS: Enteral administration of an amniotic fluid—like solution to preterm neonates is well tolerated in doses ≤20 mL/kg/d.

The Effects of Maternal Dietary Docosahexaenoic Acid Intake on Rat Pup Myelin and the Auditory Startle Response

We investigated the effects of maternal docosahexanoic acid (DHA) supplementation on pups’ auditory startle responses and the composition of brain myelin. Methods: Timed-pregnant rats were fed throughout pregnancy and lactation diets that contained 0, 0.3, 0.7 or 3% of total fatty acids as DHA. Milk was collected from culled pups’ stomachs on postnatal day (PND) 3, latency of the auditory startle reflex was measured on PND 15, and pups were killed and brains collected on PND 24. Results: Higher levels of DHA in maternal diet were reflected in milk and in pups’ myelin. The latency of the auditory startle response was significantly longer in offspring of dams fed higher levels of DHA. There was a positive correlation between the myelin content of DHA and the latency of the startle response (p = 0.044), and a negative correlation between the myelin content of DHA and the myelin content of cholesterol (p = 0.005). Conclusion: High levels of maternal DHA intake alter the lipid composition of rat pup myelin, and are associated with longer latencies of the auditory startle response – a myelin-dependent electrophysiologic response.

Longitudinal measurements of bone status in preterm infants

BACKGROUND Quantitative ultrasound measurement of the speed of sound (SOS) through bone has been investigated as a means of assessing bone status in preterm infants. Few studies report longitudinal measurements. OBJECTIVE To assess longitudinal changes in bone SOS in preterm infants. METHODS Sixty preterm infants with gestational ages of < 33 weeks and with birth weight appropriate for gestational age (AGA), and 48 healthy, term AGA infants were enrolled. SOS measurements of the tibia were made within the first week of life in the preterm infants, and within the first 72 hours of life in the term infants. During their hospital stay, weekly measurements of tibial SOS were made in 29 of the preterm infants, who were divided into three gestational age groups: Group 1: 24-26 weeks (n = 8), Group 2: 27-29 weeks (n = 9), and Group 3: 30-32 weeks (n = 12). RESULTS The median SOS value for the 60 newborn preterm infants was significantly lower than that for the 48 newborn term infants (2,924 versus 3,036 m/sec, p < 0.001). At each time point, SOS values for each of the preterm infant gestational age groups were significantly lower than the term newborn infant SOS values. SOS values decreased significantly over time for the entire cohort of 29 preterm infants (p < 0.001), and for Groups 1 (p = 0.015) and 2 (p = 0.003). At several time points, there was a significant negative correlation between serum alkaline phosphatase levels and SOS values, and a significant positive correlation between serum phosphorus levels and SOS values. CONCLUSION SOS measurements of the tibia decline during hospitalization in preterm infants, suggesting a progressive loss of bone strength. Longitudinal measurements of bone SOS in combination with serum alkaline phosphatase and serum phosphorus levels may identify infants at risk of developing osteopenia of prematurity.

Effects of maternal magnesium sulfate administration on intestinal blood flow velocity in preterm neonates

Background: Antenatal MgSO4 administration is used extensively as a tocolytic agent and to treat preeclampsia. Various effects on the fetus and newborn have been reported, and MgSO4 has well-documented vasoactive effects. Objective: To determine if antenatal MgSO4 administration affects intestinal blood flow velocity in newborn preterm infants. Methods: Peak, mean and end-diastolic velocities in the superior mesenteric artery were measured on day 1 of life. Maternal medical records were reviewed to identify infants whose mothers had been administered MgSO4 for preterm labor or preeclampsia within 24 h of delivery. Result: Fifty-six infants were studied: 27 were exposed and 29 were not exposed to antenatal MgSO4. Mean birth weight (1,371 ± 349 and 1,401 ± 469 g, respectively), gestational age (29.7 ± 2.0 and 30.0 ± 2.9 weeks, respectively) and infant hemodynamic and clinical variables (other than clinical indication for antenatal MgSO4 administration) were similar between groups. There were no significant differences between the exposed and unexposed groups in intestinal blood flow velocities. For the exposed group, however, there was a significant negative correlation between mean velocity and the number of hours from birth to the time superior mesenteric artery blood flow velocity measurements were made (p = 0.002); there was no correlation for the unexposed group (p = 0.852). Conclusion: Group mean values indicate that antenatal exposure to MgSO4 does not significantly affect intestinal blood flow velocity in newborn preterm infants. However, the significant negative relationship between mean blood flow velocity and time from birth to blood flow velocity measurement in exposed infants suggests that there may be measurable effects of MgSO4 exposure within the hours immediately after birth. Trials that prospectively evaluate the development of intestinal blood flow velocities are needed to further clarify potential effects of antenatal MgSO4 on the gastrointestinal tract of preterm infants.

Outcomes of a Neonatal Golden Hour Implementation Project

The objective of this study was to implement and evaluate a quality improvement project (the golden hour pathway [GHP]) aimed at improving the quality and efficiency of care delivered to extremely low birth weight (ELBW) infants <28 weeks gestation and/or <1000 g birth weight during the first hour of life. Process improvement and patient data collected during the quality improvement cycles were compared with retrospective data for ELBW infants admitted to the study neonatal intensive care unit during the 2 years prior to GHP implementation. GHP implementation resulted in improvements compared with past internal performance in time to surfactant administration, time to administration of dextrose and amino acids, body temperature at admission, odds of developing chronic lung disease, and odds of developing retinopathy of prematurity. A standardized interdisciplinary approach to the care of ELBW infants in the first hour of life can lead to more efficient care delivery and contribute to improved outcomes.

Cytokines, Chemokines, and Growth Factors in Banked Human Donor Milk for Preterm Infants

Background: There has been a recent increase in availability of banked donor milk for feeding of preterm infants. This milk is pooled from donations to milk banks from carefully screened lactating women. The milk is then pasteurized by the Holder method to remove all microbes. The processed milk is frozen, banked, and sold to neonatal intensive care units (NICUs). The nutrient bioavailability of banked donor milk has been described, but little is known about preservation of immune components such as cytokines, chemokines, and growth factors (CCGF). Objective: The objective was to compare CCGF in banked donor milk with mother’s own milk (MOM). Methods: Aliquots (0.5 mL) were collected daily from MOM pumped by 45 mothers of NICU-admitted infants weighing < 1500 grams at birth. All daily aliquots of each mother’s milk were pooled each week during 6 weeks of an infant’s NICU stay or for as long as the mother provided MOM. The weekly pooled milk was measured for a panel of CCGF through multiplexing using magnetic beads and a MAGPIX instrument. Banked donor milk samples (n = 25) were handled and measured in the same way as MOM. Results: Multiplex analysis revealed that there were levels of CCGF in banked donor milk samples comparable to values obtained from MOM after 6 weeks of lactation. Conclusion: These data suggest that many important CCGF are not destroyed by Holder pasteurization.

Red blood cell transfusions increase fecal calprotectin levels in premature infants.

Objective:We hypothesized that red blood cell (RBC) transfusions influence intestinal inflammation in very low birth weight (VLBW) infants. We also suspected that hematocrit (Hct) at transfusions and RBC storage time correlate with intestinal inflammation.Study Design:VLBW infants, without major congenital defects, intestinal perforation or necrotizing enterocolitis, were enrolled prospectively. Fecal calprotectin (FC) levels were measured from stool samples collected before and after RBC transfusions. Data on Hct and RBC storage time were collected.Result:Data from 42 RBC transfusions given to 26 infants revealed that FC levels increased faster than baseline after RBC transfusions (P=0.018) and were higher in multiple-transfused infants (0 to 48 and >48 h post transfusion, P=0.007 and P=0.005, respectively). Lower Hct and RBC storage >21 days correlated with higher FC levels (P=0.044 and P=0.013, respectively).Conclusion:RBC transfusions, anemia and prolonged RBC storage were associated with an increase in intestinal inflammation.