SARS-CoV-2 neutralizing antibody titers in maternal blood, umbilical cord blood, and breast milk.

OBJECTIVE: We quantified neutralizing SARS-CoV-2 antibody against spike protein (nAb) levels after vaccination and SARS-CoV-2 infection in maternal serum, cord blood, and breast milk and determined whether they correlate with levels of spike protein binding antibody. STUDY DESIGN: Women (n = 100) were enrolled on admission for delivery. Previous SARS-CoV-2 infection was defined by anti-nucleocapsid antibodies. Levels of nAb and binding antibodies against spike receptor binding domain were measured in maternal blood, cord blood, and milk. RESULTS: Maternal nAb levels were higher after vaccine and infection than vaccine alone but waned rapidly. Levels of nAb in cord blood and milk correlated with maternal levels and were higher in cord blood than maternal. Spike protein binding antibody levels correlated with nAb. CONCLUSION: SARS-CoV-2 vaccination near delivery may boost antibody-mediated immunity in the peripartum period. Neutralizing antibodies are passed transplacentally and into milk. Spike protein binding antibody may be a feasible proxy for nAb.

Human Milk Fortifier After Neonatal Intensive Care Unit Discharge Improves Human Milk Usage Rates for Preterm Infants.

BACKGROUND: A common neonatal intensive care unit (NICU) discharge feeding strategy for preterm infants with growth failure who are fed exclusively expressed human milk (EHM) has been to enrich mother's own milk with formula powder or supplement 2-3 feeds per day with formula. However, this strategy displaces human milk from the diet. Our NICU recently adopted the standard practice of adding commercial human milk fortifier (HMF) to human milk feedings after discharge. OBJECTIVES: We aimed to compare breastfeeding rates and growth using the aforementioned 2 strategies. METHODS: Preterm infants (<34 wk of gestation at birth) exclusively feeding EHM fortified with HMF at 2 weeks before discharge were included in this retrospective study. The HMF group (n = 92) continued fortifying with HMF at home, whereas the historical comparison group (n = 35) received our previous guidance to enrich or supplement using postdischarge formula. RESULTS: Rates of human milk exclusivity after discharge decreased significantly less in the HMF group than those in the historical comparison group (to 83% compared with 39% at the first outpatient visit and 27% compared with 6%, respectively, at the second outpatient visit). Rates of any EHM feedings were also significantly higher in the HMF group. Fenton z-scores for weight, length, and head circumference were not significantly different between the groups. CONCLUSIONS: Continuing EHM fortification with HMF after NICU discharge, rather than enriching or supplementing with postdischarge infant formula, increases rates of feeding EHM for ≥3 mo but does not affect growth.

Racial and Ethnic Disparities in Phthalate Exposure and Preterm Birth: A Pooled Study of Sixteen U.S. Cohorts.

BACKGROUND: Phthalate exposures are ubiquitous during pregnancy and may contribute to racial and ethnic disparities in preterm birth. OBJECTIVES: We investigated race and ethnicity in the relationship between biomarkers of phthalate exposure and preterm birth by examining: a) how hypothetical reductions in racial and ethnic disparities in phthalate metabolites might reduce the probability of preterm birth; and b) exposure-response models stratified by race and ethnicity. METHODS: We pooled individual-level data on 6,045 pregnancies from 16 U.S. cohorts. We investigated covariate-adjusted differences in nine urinary phthalate metabolite concentrations by race and ethnicity [non-Hispanic White (White, 43%), non-Hispanic Black (Black, 13%), Hispanic/Latina (38%), and Asian/Pacific Islander (3%)]. Using g-computation, we estimated changes in the probability of preterm birth under hypothetical interventions to eliminate disparities in levels of urinary phthalate metabolites by proportionally lowering average concentrations in Black and Hispanic/Latina participants to be approximately equal to the averages in White participants. We also used race and ethnicity-stratified logistic regression to characterize associations between phthalate metabolites and preterm birth. RESULTS: In comparison with concentrations among White participants, adjusted mean phthalate metabolite concentrations were consistently higher among Black and Hispanic/Latina participants by 23%-148% and 4%-94%, respectively. Asian/Pacific Islander participants had metabolite levels that were similar to those of White participants. Hypothetical interventions to reduce disparities in metabolite mixtures were associated with lower probabilities of preterm birth for Black [13% relative reduction; 95% confidence interval (CI): -34%, 8.6%] and Hispanic/Latina (9% relative reduction; 95% CI: -19%, 0.8%) participants. Odds ratios for preterm birth in association with phthalate metabolites demonstrated heterogeneity by race and ethnicity for two individual metabolites (mono-n-butyl and monoisobutyl phthalate), with positive associations that were larger in magnitude observed among Black or Hispanic/Latina participants. CONCLUSIONS: Phthalate metabolite concentrations differed substantially by race and ethnicity. Our results show hypothetical interventions to reduce population-level racial and ethnic disparities in biomarkers of phthalate exposure could potentially reduce the probability of preterm birth. https://doi.org/10.1289/EHP12831.

Breast Milk Production Variability Among Mothers of Preterm Infants.

Introduction: Mothers of preterm infants are at risk for inadequate milk production. Pumping logs are often used to both encourage lactation in the first week and track its efficacy. Our objectives were to determine whether mothers of preterm infants who keep pumping logs are demographically different from those who do not and to determine whether this practice affects the amount of mother's own milk (MOM) fed to their infants. We also aimed at determining whether there is a correlation between: (1) time to first breast milk expression, (2) cumulative frequency of expression in the first week, and (3) milk volume on day 7 with subsequent milk volumes and percent of infant diet consisting of MOM. Methods: Mothers of infants born ≤32 weeks and ≤1,500 g were enrolled within 48 hours of birth and encouraged to keep a pumping log. Data were collected on maternal characteristics, patterns of milk expression, and milk volumes on days 7, 14, 21, and 28 after delivery. Infant data were collected via chart review. Results: Mothers who kept pumping logs provided their own milk for a greater percentage of their infant's feeds at the time of achieving full feeds (p = 0.017). The total number of expressions in the first week was correlated with milk volume on day 21 (p = 0.016) and the provision of a higher percentage of MOM feeds at discharge (p = 0.03). Milk volume on day 7 correlated with volumes obtained at days 14, 21, and 28 (p < 0.001). Conclusions: Pumping logs may affect the availability of MOM for preterm infants. Frequency of pumping in the first week and milk volume on day 7 may impact long-term lactation success for these women.

Prediction of intrapartum fever using continuously monitored vital signs and heart rate variability.

Objectives: Neonatal early onset sepsis (EOS), bacterial infection during the first seven days of life, is difficult to diagnose because presenting signs are non-specific, but early diagnosis before birth can direct life-saving treatment for mother and baby. Specifically, maternal fever during labor from placental infection is the strongest predictor of EOS. Alterations in maternal heart rate variability (HRV) may precede development of intrapartum fever, enabling incipient EOS detection. The objective of this work was to build a predictive model for intrapartum fever. Methods: Continuously measured temperature, heart rate, and beat-to-beat RR intervals were obtained from wireless sensors on women (n = 141) in labor; traditional manual vital signs were taken every 3-6 hours. Validated measures of HRV were calculated in moving 5-minute windows of RR intervals: standard deviation of normal-to-normal intervals (SDNN) and root mean square of successive differences (RMSSD) between normal heartbeats. Results: Fever (>38.0 °C) was detected by manual or continuous measurements in 48 women. Compared to afebrile mothers, average SDNN and RMSSD in febrile mothers decreased significantly (p < 0.001) at 2 and 3 hours before fever onset, respectively. This observed HRV divergence and raw recorded vitals were applied to a logistic regression model at various time horizons, up to 4-5 hours before fever onset. Model performance increased with decreasing time horizons, and a model built using continuous vital signs as input variables consistently outperformed a model built from episodic vital signs. Conclusions: HRV-based predictive models could identify mothers at risk for fever and infants at risk for EOS, guiding maternal antibiotic prophylaxis and neonatal monitoring.

Newborn screening for Duchenne muscular dystrophy: A two-year pilot study.

OBJECTIVE: Duchenne muscular dystrophy (DMD) is an X-linked disorder resulting in progressive muscle weakness and atrophy, cardiomyopathy, and in late stages, cardiorespiratory impairment, and death. As treatments for DMD have expanded, a DMD newborn screening (NBS) pilot study was conducted in New York State to evaluate the feasibility and benefit of NBS for DMD and to provide an early pre-symptomatic diagnosis. METHODS: At participating hospitals, newborns were recruited to the pilot study, and consent was obtained to screen the newborn for DMD. The first-tier screen measured creatine kinase-MM (CK-MM) in dried blood spot specimens submitted for routine NBS. Newborns with elevated CK-MM were referred for genetic counseling and genetic testing. The latter included deletion/duplication analysis and next-generation sequencing (NGS) of the DMD gene followed by NGS for a panel of neuromuscular conditions if no pathogenic variants were detected in the DMD gene. RESULTS: In the two-year pilot study, 36,781 newborns were screened with CK-MM. Forty-two newborns (25 male and 17 female) were screen positive and referred for genetic testing. Deletions or duplications in the DMD gene were detected in four male infants consistent with DMD or Becker muscular dystrophy. One female DMD carrier was identified. INTERPRETATION: This study demonstrated that the state NBS program infrastructure and screening technologies we used are feasible to perform NBS for DMD. With an increasing number of treatment options, the clinical utility of early identification for affected newborns and their families lends support for NBS for this severe disease.

Video laryngoscopy-assisted less-invasive surfactant administration quality improvement initiative.

OBJECTIVE: To describe the use of quality improvement methodology in transitioning from delivery of surfactant by INSURE (INtubation-SURfactant administration-Extubation) to video laryngoscope-assisted LISA (less-invasive surfactant administration) for infants with respiratory distress syndrome (RDS) receiving non-invasive ventilatory support. SETTING: Two large neonatal intensive care units (NICUs) at Northwell Health (New Hyde Park, New York, USA). STUDY POPULATION: Infants with RDS receiving continuous positive airway pressure in the NICU and eligible for surfactant administration. RESULTS: LISA was initiated in our NICUs in January 2021, after extensive guideline development, education programmes, hands-on training and provider credentialing. Our Specific, Measurable, Achievable, Relevant and Timely aim was to deliver surfactant by LISA for 65% of total doses by 31 December 2021. This goal was achieved within 1 month of go-live. In total, 115 infants received at least one dose of surfactant during the year. Of those, 79 (69%) received it via LISA and 36 (31%) via INSURE. Two Plan-Do-Study-Act cycles contributed to improved adherence to guidelines on timely surfactant administration and both written and video documentation. CONCLUSIONS: Safe and effective introduction of LISA with the use of video laryngoscopy is achievable with careful planning, clear clinical guidelines, adequate hands-on training and comprehensive safety and quality control.

Lung ultrasound assessment of pulmonary edema in neonates with chronic lung disease before and after diuretic therapy.

INTRODUCTION: Bronchopulmonary dysplasia (BPD) is characterized by lung injury with varying degrees of disrupted alveolarization, vascular remodeling, inflammatory cell proliferation, and pulmonary edema. Diuretics are often used to ameliorate the symptoms or progression of BPD. Our primary objective was to use lung ultrasound (LUS) to determine if diuretics decrease pulmonary edema in infants with BPD. The secondary objective was to assess changes in respiratory support during the first week after initiation of diuretics. METHODS: Premature infants requiring noninvasive respiratory support and starting diuretic therapy for evolving BPD were compared with a similar group of infants not receiving diuretics (control). For the diuretic group, LUS exams were performed before and on Days 1, 3, and 6 after initiation of treatment. For the control group, LUS was performed at equivalent time points. A composite pulmonary edema severity (PES) score of 0-5 was calculated based on the total number of B-lines in six scanned areas. Respiratory support parameters (FiO2 , nasal cannula flow, or CPAP) were also recorded. RESULTS: Infants in the diuretic (n = 28) and control (n = 23) groups were recruited at median corrected gestational ages of 34.2 (33.3-35.9) and 34.0 (33.4-36.3) weeks, respectively (p = 0.82). PES scores, FiO2 , and respiratory flow support decreased significantly from Days 0 to 6 (p < 0.0001, p = 0.001, and p = 0.01, respectively) in the diuretic group, but not in the control group. CONCLUSION: Diuretic use is associated with decreased pulmonary edema and improved oxygenation in infants with BPD during the first week of treatment.

Effects of lipid emulsions on unbound bilirubin and response to phototherapy in preterm infants.

OBJECTIVE: Bilirubin-induced neurotoxicity is mediated by the fraction of total serum bilirubin (TSB) not bound to albumin (Bf). Unbound free fatty acids (FFAu) generated from lipid emulsions compete with bilirubin for albumin binding, increasing Bf. Soy-based (IL) and soy-MCT-olive-fish oil-based (SMOF) lipid emulsions contain different fatty acids with distinct albumin binding affinities. IL increases Bf in preterm infants, but the effects of SMOF on Bf are not known. Our objective was to compare changes in TSB, Bf, FFAu, and response to phototherapy in preterm infants receiving SMOF and IL. We hypothesized that SMOF would be associated with lower Bf and better response to phototherapy than IL. METHODS: Very preterm and low birth weight infants (<1500 g, <32 weeks) were infused with IL (n = 20) or SMOF (n = 20) as prescribed by providers. Phototherapy was prescribed using the standard care practice. FFAu profiles and levels, TSB, and Bf were measured on 0, 1, 2, and 3 g/kg/day of lipid infusion and at the initiation and termination of phototherapy. TSB was analyzed in the clinical laboratory using the diazo technique. FFAu and Bf were measured using fluorescent probes. RESULTS: Escalating doses of IL and SMOF increased FFAu levels and Bf, but not TSB. Phototherapy did not significantly decrease Bf for infants receiving either lipid. IL-treated infants had higher levels of unbound linoleic acid, and SMOF-treated infants had higher unbound arachidonic, oleic, and docosahexaenoic acids. CONCLUSIONS: IL and SMOF both increase Bf similarly, and phototherapy does not significantly affect Bf for infants receiving them.

Suppression of Bile Acid Synthesis in a Preterm Infant Receiving Prolonged Parenteral Nutrition.

Bile acid metabolism is altered in neonates on parenteral nutrition (PN), predisposing them to parenteral nutrition-associated liver disease. Cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme in the bile acid synthesis pathway, is repressed by fibroblast growth factor 19 (FGF19) and phytosterols (PS). We describe a case of a preterm infant who developed necrotizing enterocolitis (NEC) and received exclusive PN for over 2 months. Our objective was to serially assess CYP7A1 activity and plasma FGF19 and PS concentrations in this infant case compared to five healthy preterm infants. We found that CYP7A1 activity increased during the first 2 weeks of life in control infants but was undetectable in the infant case. FGF19 concentrations were high at birth in all infants and subsequently declined and did not differ between the case and control infants. As expected, PS concentrations were elevated in the infant case and continued to increase despite lipid minimization. In conclusion, CYP7A1 activity was gradually upregulated in healthy preterm infants but remained suppressed in the infant requiring prolonged PN. Preterm infants also had elevated FGF19 concentrations at birth, which decreased with advancing postnatal age.

Efficacy of continuous monitoring of maternal temperature during labor using wireless axillary sensors.

Neonatal early onset sepsis (EOS) occurs in 0.5-0.8/1000 live births and is a major cause of morbidity and mortality. Its presenting signs in newborns are non-specific, so risk assessment before birth is essential. Maternal fever during labor is the strongest predictor of EOS, but the current standard is for infrequent manual determinations of temperature. We aimed to determine whether continuous measurement of temperature during labor is feasible, accurate, and more effective than manual measurements for detecting fever. Women were recruited on admission in labor at > 35 weeks gestational age, with < 6 cm cervical dilation. Sensors were affixed in the axilla, which transmitted every 4 minutes by Bluetooth to a dedicated tablet. Conventional temperature measurements were taken every 3-6 hours per routine. Of 336 subjects recruited, 155 had both > 4 hours of continuous data and > 2 manual temperature measurements and were included for analysis. Continuous recordings were feasible and correlated well with manual measurements independent of mean temperature. Of 15 episodes of fever > 38 °C detected by both methods, 13 were detected earlier by continuous (9 of those more than 1 hour earlier). Manual measurements missed 32 fevers > 38 °C and 13 fevers > 38.5 °C that were identified by continuous. Continuous measurement of maternal temperature for the duration of labor is practical and accurate. It may be more sensitive for identifying infants at risk for EOS than the current practice, enabling earlier and more effective targeted treatment of affected infants.

Lipid peroxidation products as predictors of oxidant-mediated disease in preterm infants.

BACKGROUND: Preterm infants are susceptible to "oxygen radical diseases" (ORD). 8-isoprostane (8-IP) is a bioactive eicosanoid generated by reactive oxygen species-catalyzed peroxidation of arachidonic acid. Malondialdehyde (MDA) is generated by the decomposition of oxidant-induced lipid hydroperoxides. We hypothesize that the development of ORD is associated with elevated plasma 8-IP on day 0-1, and increasing urine levels of MDA in the first month. METHODS: Preterm (<32 weeks, n = 39) and term (n = 39) infants were recruited at birth. Plasma 8-IP was quantified by ELISA on day 0-1, and urine MDA by colorimetric assay of thiobarbituric acid reactive substances (TBARS) on days 0-1, 7, 14, 21, and 28. ORD was defined as retinopathy of prematurity ≥ stage 1, pneumatosis, or oxygen requirement at 36 weeks corrected gestational age. RESULTS: Plasma 8-IP was higher on day 0-1 in preterm infants who developed ORD compared to term infants. Urine TBARS levels increased in preterm infants from day 0-1 to day 28 but were not different in infants with or without ORD. Preterm infants who developed ORD demonstrated a significant rise in urine TBARS levels from day 1 to 14. CONCLUSIONS: Elevated plasma 8-IP on day 1 is associated with ORD in preterm infants. If validated as a biomarker for ORD, it may be useful in directing antioxidant therapies to the most susceptible infants. Urine TBARS during the first month are not significantly different in term infants, preterm infants with ORD, and preterm infants without ORD, but rapid rise of TBARS in the first 2 weeks may be associated with ORD.

Ultrasound Assessment of Gastric Emptying in Premature Infants Treated With Non-Invasive Ventilatory Support.

BACKGROUND: Nasal continuous positive airway pressure (CPAP) introduces positive pressure of air into both the trachea and stomach, which may affect gastric emptying. The rate of gastric emptying can be estimated by ultrasound (US) in neonates by two validated techniques: "antral cross-sectional area" (ACSA, two-dimensional estimate of the surface area at the gastric antrum), and "spheroid gastric volume" (spheroid, three-dimensional estimate of the stomach volume). OBJECTIVE: To compare gastric emptying rates in neonates on machine-derived nasal CPAP (MD-nCPAP, Avea and RAM cannula) with those on bubble CPAP (bCPAP, Fisher Paykel and Babi.Plus nasal prongs). METHODS: Ultrasound measurements of the amount of the milk in the stomach were performed before feeding and at 1, 2, and 3 hours after the start of feeding, using both the ACSA and spheroid methods. Rates of gastric emptying were calculated during the "early" (1-2 hours) and "late" (2-3 hours) phases after feeding. RESULTS: We recruited 32 infants (25-34 weeks gestational age, full enteral tube feedings, on nasal CPAP). Seventeen infants were treated with MD-nCPAP (median birth weight 1015 g [interquartile range (IQR): 870-1300], gestational age 28 weeks [IQR: 27-29], postnatal age 20 days [IQR: 14-28]), whereas 15 infants were treated with bCPAP (median birth weight 960 g [IQR: 855-1070], gestational age 27 weeks [IQR: 26-28], postnatal age 17 days [IQR: 15-25]). Gastric emptying rates (% emptied/min) were significantly faster in the "early" compared to the "late" phase for all infants. There were no significant differences in the rates of gastric emptying (either "early" or "late") or volumes of gastric residuals between infants receiving MD-nCPAP or bCPAP, measured by either method. Although no feeding intolerance was seen in either group, the volumes of residual gastric contents measured by both methods were higher than the volumes traditionally considered abnormal when obtained by gastric tube aspiration. CONCLUSIONS: Gastric emptying is faster during the "early" compared to the "late" phase. Gastric emptying rates are not different in infants receiving MD-nCPAP versus bCPAP. The presence of large residual gastric contents in infants who are tolerating feedings challenges the value of traditional gastric aspiration for the assessment of feeding tolerance in infants.

Determinants of the lung microbiome in intubated premature infants at risk for bronchopulmonary dysplasia.

BACKGROUND: Airway dysbiosis in premature infants may be associated with bronchopulmonary dysplasia (BPD). Early oropharyngeal colostrum (OPC) administration alters the oral microbiome, which may impact the lung microbiome. We aim to compare the oral and tracheal microbiota during the first week of life, and to determine whether early OPC administration affects microbial diversity or leukocyte inflammatory activity in the lung. METHODS: Intubated premature infants (n = 42) were evaluated. The oral microbiome was characterized on day of life (DOL) 3, and the tracheal microbiome on DOL 3 and DOL 7, using 16S ribosomal DNA sequencing. Gene expression for inflammatory markers was quantified in airway leukocytes by real-time q-PCR. RESULTS: The oral and tracheal microbiota were significantly different on DOL 3, but the tracheal microbiome on DOL 7 was more similar to the oral from DOL 3. Tracheal bacterial diversity decreased from DOL 3 to DOL 7. Longer time to first OPC administration tended to be associated with lower bacterial diversity in the airways. CONCLUSIONS: The tracheal microbiome in intubated premature infants in the first week is likely determined, in part, by the composition of the oral microbiome. Bacterial diversity in intubated babies decreases during the first week of life, a pattern that could be consistent with risk for BPD. Decreased bacterial diversity and increased inflammatory activity in the lung may also be associated with delayed administration of OPC.

A Quality Improvement Project to Standardize Surfactant Delivery in the Era of Noninvasive Ventilation.

INTRODUCTION: Continuous positive airway pressure (CPAP) and surfactant both improve outcomes for premature infants with respiratory distress syndrome. However, prolonged trials of CPAP, as well as observation periods after intubation, may delay the administration of surfactant. Late surfactant treatment likely increases the incidence of bronchopulmonary dysplasia, which leads to significant morbidity and healthcare utilization. METHODS: We aimed to decrease time from meeting standard criteria (start of a continuous run of FiO2 > 40% or PaCO2 > 65 for >90 min) to intubation, and from intubation to surfactant administration, for infants <1,500 g or younger than 32 weeks gestation. Retrospective data collection from the electronic medical record assessed those process measures as the primary endpoints. Balancing measures were the adverse outcomes of asymmetric lung disease, the inappropriate position of the endotracheal tube, or pneumothorax on the first x-ray (within 24 h) after surfactant. RESULTS: Mean time to intubation for infants 28-32 weeks gestation decreased from 321 to 81 minutes in response to a literature review for physicians and free-text orders for notification. Time to intubation for infants younger than 28 weeks gestation did not change. Administration of surfactant within 1 hour of intubation improved from 78% to 100% after a program for trainees and coordination with radiology. There were no adverse occurrences. CONCLUSIONS: Educational interventions and targeted process change can successfully implement standard criteria for intubation and surfactant administration for premature infants. Determination of an acceptable range of evidence-based practice is essential for the engagement of medical staff. Timely intubation and surfactant may decrease bronchopulmonary dysplasia.

Unbound bilirubin levels in phototherapy-treated preterm infants receiving soy-based lipid emulsion.

BACKGROUND: Phototherapy is an effective treatment for neonatal jaundice. Treatment indication uses total serum bilirubin (TSB), although unbound bilirubin (Bf) more accurately predicts disability risk. The goals of this investigation were to examine the response of Bf and TSB to phototherapy in preterm infants, and we hypothesized that (i) TSB and Bf respond differently; (ii) the relationship between TSB and Bf is altered; and (iii) unexpected Bf elevations are found. METHODS: One hundred and seventeen preterm infants <2 kg at birth and receiving (IL) were enrolled; and measurements of TSB and Bf were obtained. TSB was measured by the diazo method and Bf with a fluorescent Bf sensor BL22P1B11-Rh. RESULTS: Initial mean (± SD) TSB and Bf levels (41.4 ± 6.9 h) were 8.0 ± 9.0 mg/dL and 16.9 ± 12.4 nmol/L (P < 0.05). The rates of rise (ROR) were 0.21 ± 0.10 mg/dL/h for TSB and 0.38 ± 0.33 nmol/L/h for Bf. Phototherapy reduced TSB from 8.0 ± 9.0 to 5.8 ± 9.4 mg/dL (P = 0.068) but Bf did not change (16.9 ± 12.4 to 14.1 ± 9.4 nmol/L P = n.s.). Bf levels were >11 nmol/L in 64, >17 nmol/L in 18, and >22 nmol/L in 7 infants. CONCLUSIONS: Bf and TSB responded differently. While TSB and Bf correlated well before phototherapy, they did not correlate during phototherapy. TSB showed a trend toward a reduction with treatment, Bf did not. While TSB ROR information is not helpful, ROR Bf data can be utilized to anticipate treatment. Potentially high Bf levels existed before and after phototherapy and the mean Bf level at phototherapy termination remained elevated in a significant proportion of infants.

Developmental regulation of the gut-liver (FGF19-CYP7A1) axis in neonates.

Introduction: Fibroblast growth factor 19 (FGF19) is a gut-derived hormone that regulates the expression of CYP7A1, the rate-limiting enzyme in bile acid (BA) synthesis pathway. Dysregulation of the FGF19-CYP7A1 (gut-liver) axis is associated with cholestatic liver disease. Infants, especially preterm infants and those with intestinal failure are at high risk for developing cholestatic liver disease. The activity of the gut-liver axis has not been characterized in this population. Our objective was to assess relationships between circulating FGF19 concentrations and CYP7A1 activity in neonates.Materials and methods: Plasma samples were obtained longitudinally from term and preterm infants (22-41-week gestation) hospitalized in a neonatal intensive care unit. Infants with congenital and acquired gastrointestinal disorders were excluded. Plasma levels of 7α-hydroxy-4-cholesten-3-one (C4), a marker of CYP7A1 activity, were quantified using HPLC-MS/MS. Plasma FGF19 concentrations were quantified by ELISA. Data were analyzed using linear regression models and structural equation modeling.Results: One hundred eighty-one plasma samples were analyzed from 62 infants. C4 concentrations were undetectable prior to 30 weeks' gestation and, thereafter, increased with advancing gestational age and with volume of enteral feeds. They did not correlate with serum FGF19 concentrations, which decreased with advancing gestational age and volume of enteral feeds.Discussion: The activity of CYP7A1, the rate-limiting BA synthetic enzyme in adults, is developmentally regulated and undetectable in newborns less than 30 weeks' gestation. FGF19 concentrations do not correlate with CYP7A1 activity, suggesting that the gut-liver axis is not functional in infants. High FGF19 concentrations at birth in infants less than 37 weeks' gestation is a novel finding, and its source and role in preterm infants warrants further investigation.Rationale: The intestinal hormone, fibroblast growth factor 19 (FGF19), is a major regulator of CYP7A1, the rate limiting enzyme in bile acid (BA) synthesis. Recently, dysregulation of the gut-liver (FGF19-CYP7A1) axis has been implicated in adult cholestatic liver disease, and animal studies have shown that exogenous FGF19 protects against liver injury. Given the therapeutic potential related to this signaling pathway, we sought to characterize the association between CYP7A1 and FGF19 in term and preterm infants. We conducted a prospective, observational study that measured in vivo CYP7A1 activity and FGF19 concentrations in 62 term and preterm infants (n = 181 samples). We found that CYP7A1 activity is developmentally regulated; its activity is undetectable prior to 30 weeks' gestation and increases with advancing gestational age and volume of enteral feeds. Contrary to expectation, we demonstrated that FGF19 is expressed at birth in preterm infants and decreases over time, even as enteral feeds increase. Using structural equation modeling, we were able to show that CYP7A1 activity does not correlate with FGF19 concentrations. Our results suggest that the gut-liver axis is not upregulated in preterm and term infants and that neonates with cholestatic liver disease will unlikely benefit from supplemental FGF19. We also report novel findings of elevated FGF19 concentrations in preterm infants at birth and speculate that there may be an extra-intestinal source of FGF19 that is developmentally expressed in these infants.

Determination of optimal endotracheal tube tip depth from the gum in neonates by X-ray and ultrasound.

Background/objective: Proper placement of endotracheal tube (ETT) in the midtrachea is essential. Initial depth of placement of oral ETT from the lips is commonly estimated based on weight ("7-8-9 rule"), gestational age, or nasal-tragus distance. However, these measurements can be altered by superficial factors and the mobility of the lips relative to the airway, so the upper alveolar ridge (gum) may provide a superior landmark. Also, confirmation of ETT tip position by point of care ultrasound (POC-US) is noninvasive and may enable localization of the ETT tip in real time. The objective of this study is to define optimal initial ETT depth from the gum in infants relative to weight, and to compare the efficacy of POC-US with standard chest X-ray (CXR) for confirming ETT tip position.Methods: Neonates requiring oral intubation were enrolled. At the time of CXR that were obtained for clinical indications, the position of the ETT at both the lip and gum were recorded. "Optimal" ETT placement in midtrachea (from lip and gum) was calculated based on the observed measurements and the distance of the ETT tip from the carina on CXR. Linear regression was used to model ideal placement of ETT, as a function of weight. POC-US was performed using a 10 MHz cardiac probe and high parasternal view. Distance from the ETT bevel to the superior aspect of the right pulmonary artery, which is at the level of carina, was measured using electronic calipers.Results: Infants were recruited at a median age of 3 days (n = 75), weight 1300 g, and corrected gestational age 31.6 ± 5.8 weeks. The regression equation for optimal placement from the gum (in cm) was 5.21 + 1.03 × weight (kg). Using estimates of 5 or 5.5 cm + weight (kg) to the gum yielded accuracy similar or superior to the 7-8-9 rule to the lip. Most of the variability in ideal placement of ETT tip from the gum was determined by weight (R2 = 0.83). The difference between optimal placement using lip and gum was 0.51 ± 0.24 cm. ETT location by POC-US (n = 40) was in substantial agreement with CXR (intraclass correlation coefficient 0.95, 95% CI: 0.92, 0.98).Conclusions: Marking oral ETT placement to the gum is feasible, with optimal depth of about 5.2 cm + weight (kg), across all weight categories. POC-US can be used for rapid confirmation of continued ideal ETT tip location, with accuracy similar to CXR. Further studies will be needed to determine whether marking ETT depth to the gum or using POC-US achieves the goal of decreased complications of ETT misplacement or displacement.

Plasma unbound free fatty acid profiles in premature infants before and after intralipid infusion.

Background: Unbound free fatty acids (FFAu) are the bioactive fraction of plasma free fatty acids (FFA). Most plasma FFA are bound to albumin. Only when FFA dissociate from albumin, do they become biologically active.Objective: To measure the first FFAu profiles in human infants and to measure these profiles before and during intravenous administration of the soybean lipid, intralipid (IL).Study design: The study population was 16 premature infants, from a parent study of 130 infants with birth weights 500-2000 g and gestational age 23-34 weeks. The infants chosen had plasma samples of ≥120 µL (volume needed for each FFAu profile measurement) in the first day of life. Infants received IL infusions starting in the second day of life at 1 g/kg/day, increasing by 1-g/kg/day daily up to 3 g/kg/day. FFAu profiles were determined during IL infusion when plasma was available. Profiles are the concentrations of the nine most abundant long-chain FFAu and were determined using novel fluorescent probes.Results: Before intralipid infusion unbound myristic acid was the dominant FFAu, as high as 78% of the total FFAu (sum of the 9 FFAu). In contrast, unbound linoleic acid was 0% in all infants. With increasing infusion of IL to 3 g/kg/day, unbound linoleic increased to 26% of the total FFAu, with unbound oleic, myristic, and linolenic acid the second, third and fourth most abundant. The average total FFAu concentration also increased from 4 nM before intralipid to 53 nM at 3 g/kg/day. During IL infusion the FFAu profiles approached the fatty acid composition of intralipid at 3 g/kg/day.Conclusions: This first study of FFAu profiles in neonates revealed that before IL infusion unbound linoleic acid was zero in all 16 infants and levels of myristic acid were exceptionally large, as much as 78% of the total FFAu profile. These results suggest important and previously unrecognized roles of lipid metabolism in early development. Zero unbound linoleic acid before IL infusion may help promote closure of the ductus arteriosus but after IL infusion, synthesis of arachidonic from linoleic acid may tend to promote patency. The high levels of unbound myristate may be needed for immediate neonatal energy needs.