Utility of Repeat Testing for Congenital Hypothyroidism in Infants with Very Low Birth Weight.

OBJECTIVE: To assess for possible missed hypothyroidism in infants of very low birth weight (VLBW) whose initial newborn screening (NBS) was within normal reference range. STUDY DESIGN: We analyzed serum thyroid-stimulating hormone (TSH) obtained at 36 weeks of corrected gestational age or at hospital discharge if earlier (retest TSH) in infants with VLBW in the neonatal intensive care unit to determine the prevalence and factors associated with retest TSH ≥5 mU/L, a concentration requiring close follow-up for hypothyroidism. Utility of alternative cut-offs for NBS TSH also was assessed. RESULTS: A total of 398 infants, median gestational age 29 (range 22-36) weeks, birth weight 1138 (470-1498) g, were included in this study. Retest TSH was obtained at 49.5 (12-137) days after birth. Median retest TSH was 3.1 (0.5-27.9) mU/L. Seventy-three (18.3%) of the cohort had retest TSH ≥5 mU/L. Adjusting NBS cut-off to ≥15 or ≥10 mU/L identified <50% of infants with TSH ≥5 mU/L, resulting in 6% false positives and >70% false negatives. Multiple regression modeling indicated that 35% of variance in retest TSH value was explained by NBS TSH concentration, birth weight, and gestational age, all P < .01. CONCLUSIONS: Retesting for hypothyroidism at 36 weeks of corrected gestational age in infants with VLBL and normal NBS could identify infants who require ongoing surveillance until thyroid function has been definitively ascertained. Adjusting NBS TSH cutoffs is not a valid option for identifying potential hypothyroidism in infants with VLBW because of lack of sensitivity and unacceptable false-positive and false-negative rates.

Epidemiological Investigation on the Current Practice of Umbilical Cord Clamping in China.

OBJECTIVE: Despite known benefits, the timing of and method used for umbilical cord clamping (UCC) in neonates remain controversial in China, as well as internationally. The objective of this study was to assess knowledge, attitudes, and practice of UCC amongst health care providers in China, as recommended by medical professional organizations. STUDY DESIGN: A web-based questionnaire on cord clamping practices was administered to midwives, obstetricians, and neonatologists in 126 hospitals from 16 provinces. The provinces were selected from seven different regions of China. RESULTS: A total of 5,005 (60.5% of eligible respondents) health care providers returned completed questionnaires. The awareness rates for immediate cord clamping (ICC) and delayed cord clamping (DCC) were over 85%, but the implementation rate for DCC was relatively low (ICC 58.3% vs. DCC 41.6%). Most neonates were placed below the introitus (92.8%) during cord clamping and this correlated with the route of delivery. The choice of UCC was impelled by different factors. Benefits for neonates influenced the choice of ICC (50%) and promoting a larger blood volume to stabilize systemic circulation influenced the choice of DCC (92.3%). Majority (91.5%) of respondents acquiesced that it was necessary to develop national clinical guidelines for UCC. CONCLUSION: The majority of obstetricians, neonatologists, and midwives who participated in this study had a positive perception of DCC. However, this did not translate to daily practice. The practice of UCC is variable and there are no standard guidelines. KEY POINTS: · The first large-scale epidemiological investigation of umbilical cord ligation is in China.. · The survey included three commonly used umbilical cord clamping methods.. · The respondents included neonatologists..

Natural Anti-Infective Pulmonary Proteins: In Vivo Cooperative Action of Surfactant Protein SP-A and the Lung Antimicrobial Peptide SP-BN.

The anionic antimicrobial peptide SP-B(N), derived from the N-terminal saposin-like domain of the surfactant protein (SP)-B proprotein, and SP-A are lung anti-infective proteins. SP-A-deficient mice are more susceptible than wild-type mice to lung infections, and bacterial killing is enhanced in transgenic mice overexpressing SP-B(N). Despite their potential anti-infective action, in vitro studies indicate that several microorganisms are resistant to SP-A and SP-B(N). In this study, we test the hypothesis that these proteins act synergistically or cooperatively to strengthen each other's microbicidal activity. The results indicate that the proteins acted synergistically in vitro against SP-A- and SP-B(N)-resistant capsulated Klebsiella pneumoniae (serotype K2) at neutral pH. SP-A and SP-B(N) were able to interact in solution (Kd = 0.4 µM), which enabled their binding to bacteria with which SP-A or SP-B(N) alone could not interact. In vivo, we found that treatment of K. pneumoniae-infected mice with SP-A and SP-B(N) conferred more protection against K. pneumoniae infection than each protein individually. SP-A/SP-B(N)-treated infected mice showed significant reduction of bacterial burden, enhanced neutrophil recruitment, and ameliorated lung histopathology with respect to untreated infected mice. In addition, the concentrations of inflammatory mediators in lung homogenates increased early in infection in contrast with the weak inflammatory response of untreated K. pneumoniae-infected mice. Finally, we found that therapeutic treatment with SP-A and SP-B(N) 6 or 24 h after bacterial challenge conferred significant protection against K. pneumoniae infection. These studies show novel anti-infective pathways that could drive development of new strategies against pulmonary infections.

A Cohort Comparison of Buprenorphine versus Methadone Treatment for Neonatal Abstinence Syndrome.

OBJECTIVES: To compare the duration of opioid treatment and length of stay among infants treated for neonatal abstinence syndrome (NAS) by using a pilot buprenorphine vs conventional methadone treatment protocol. STUDY DESIGN: This retrospective cohort analysis evaluated infants who received pharmacotherapy for NAS at 6 hospitals in Southwest Ohio from January 2012 through August 2014. A single neonatology provider group used a standardized methadone protocol across all 6 hospitals. However, at one of the sites, infants were managed with a buprenorphine protocol unless they had experienced chronic in utero exposure to methadone. Linear mixed models were used to calculate adjusted mean duration of opioid treatment and length of inpatient hospitalization with 95% CIs in infants treated with oral methadone compared with sublingual buprenorphine. The use of adjunct therapy was examined as a secondary outcome. RESULTS: A total of 201 infants with NAS were treated with either buprenorphine (n = 38) or methadone (n = 163) after intrauterine exposure to short-acting opioids or buprenorphine. Buprenorphine therapy was associated with a shorter course of opioid treatment of 9.4 (CI 7.1-11.7) vs 14.0 (12.6-15.4) days (P < .001) and decreased hospital stay of 16.3 (13.7-18.9) vs 20.7 (19.1-22.2) days (P < .001) compared with methadone therapy. No difference was detected in the use of adjunct therapy (23.7% vs 25.8%, P = .79) between treatment groups. CONCLUSION: The choice of pharmacotherapeutic agent is an important determinant of hospital outcomes in infants with NAS. Sublingual buprenorphine may be superior to methadone for management of NAS in infants with select intrauterine opioid exposures.

Pharmacokinetics of Oral Methadone in the Treatment of Neonatal Abstinence Syndrome: A Pilot Study.

OBJECTIVE: To characterize the population pharmacokinetics of oral methadone in neonates requiring pharmacologic treatment of neonatal abstinence syndrome and to develop a pharmacokinetic (PK) model toward an evidence-based treatment protocol. STUDY DESIGN: Based on a methadone dosing protocol, serum concentrations of methadone and its metabolites were assessed by high performance liquid chromatography-tandem mass spectrometry from dried blood spots. Population PK analysis was performed to determine the volume of distribution and clearance of oral methadone. Methadone plasma concentration-time profiles were simulated from the deduced PK model to optimize the dosing regimen. RESULTS: There was substantial interindividual variability in methadone concentrations. Blood concentrations of methadone were best described by a 1-compartment model with first-order absorption. The population mean estimates (coefficient of variation percentage) for oral clearance and volume of distribution were 8.94 (103%) L/h/70 kg and 177 (133%) L/70 kg, respectively. Optimized dosing strategies were developed based on the simulated PK profiles. We suggest a starting dose of 0.1 mg/kg per dose every 6 hours for most patients requiring pharmacologic treatment of neonatal abstinence syndrome followed by an expedited weaning phase. CONCLUSIONS: The proposed dosing regimen may reduce the cumulative dose of opioid and shorten the length of hospitalization. Future studies should aim to validate the simulated dosing schemes with clinical data and expand our understanding of the between-patient PK variability. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01754324.

Inheritance of the lysozyme inhibitor Ivy was an important evolutionary step by Yersinia pestis to avoid the host innate immune response.

BACKGROUND: Yersinia pestis (the plague bacillus) and its ancestor, Yersinia pseudotuberculosis (which causes self-limited bowel disease), encode putative homologues of the periplasmic lysozyme inhibitor Ivy and the membrane-bound lysozyme inhibitor MliC. The involvement of both inhibitors in virulence remains subject to debate. METHODS: Mutants lacking ivy and/or mliC were generated. We evaluated the mutants' ability to counter lysozyme, grow in serum, and/or counter leukocytes; to produce disease in wild-type, neutropenic, or lysozyme-deficient rodents; and to induce host inflammation. RESULTS: MliC was not required for lysozyme resistance and the development of plague. Deletion of ivy decreased Y. pestis' ability to counter lysozyme and polymorphonuclear neutrophils, but it did not affect the bacterium's ability to grow in serum or resist macrophages. Y. pestis lacking Ivy had attenuated virulence, unless animals were neutropenic or lysozyme deficient. The Ivy mutant induced inflammation to a degree similar to that of the parental strain. Last, Y. pseudotuberculosis did not require Ivy to counter lysozyme and for virulence. CONCLUSIONS: Ivy is required to counter lysozyme during infection, but its role as a virulence factor is species dependent. Our study also shows that a gene that is not necessary for the virulence of an ancestral bacterium may become essential in the emergence of a new pathogen.

Forecasting Fetal Buprenorphine Exposure through Maternal-Fetal Physiologically Based Pharmacokinetic Modeling.

Buprenorphine readily crosses the placenta, and with greater prenatal exposure, neonatal opioid withdrawal syndrome (NOWS) likely grows more severe. Current dosing strategies can be further improved by tailoring doses to expected NOWS severity. To allow the conceptualization of fetal buprenorphine exposure, a maternal-fetal physiologically based pharmacokinetic (PBPK) model for sublingual buprenorphine was developed using Simcyp (v21.0). Buprenorphine transplacental passage was predicted from its physicochemical properties. The maternal-fetal PBPK model integrated reduced transmucosal absorption driven by lower salivary pH and induced metabolism observed during pregnancy. Maternal pharmacokinetics was adequately predicted in the second trimester, third trimester, and postpartum period, with the simulated area under the curve from 0 to 12 h, apparent clearance, and peak concentration falling within the 1.25-fold prediction error range. Following post hoc adjustment of the likely degree of individual maternal sublingual absorption, umbilical cord blood concentrations at delivery (n = 21) were adequately predicted, with a geometric mean ratio between predicted and observed fetal concentrations of 1.15 and with 95.2% falling within the 2-fold prediction error range. The maternal-fetal PBPK model developed in this study can be used to forecast fetal buprenorphine exposure and would be valuable to investigate its correlation to NOWS severity.

Persistence of LPS-induced lung inflammation in surfactant protein-C-deficient mice.

Pulmonary surfactant protein-C (SP-C) gene-targeted mice (Sftpc(-/-)) develop progressive lung inflammation and remodeling. We hypothesized that SP-C deficiency reduces the ability to suppress repetitive inflammatory injury. Sftpc(+/+) and Sftpc(-/-) mice given three doses of bacterial LPS developed airway and airspace inflammation, which was more intense in the Sftpc(-/-) mice at 3 and 5 days after the final dose. Compared with Sftpc(+/+)mice, inflammatory injury persisted in the lungs of Sftpc(-/-) mice 30 days after the final LPS challenge. Sftpc(-/-) mice showed LPS-induced airway goblet cell hyperplasia with increased detection of Sam pointed Ets domain and FoxA3 transcription factors. Sftpc(-/-) type II alveolar epithelial cells had increased cytokine expression after LPS exposure relative to Sftpc(+/+) cells, indicating that type II cell dysfunction contributes to inflammatory sensitivity. Microarray analyses of isolated type II cells identified a pattern of enhanced expression of inflammatory genes consistent with an intrinsic low-level inflammation resulting from SP-C deficiency. SP-C-containing clinical surfactant extract (Survanta) or SP-C/phospholipid vesicles blocked LPS signaling through the LPS receptor (Toll-like receptor [TLR] 4/CD14/MD2) in human embryonic kidney 293T cells, indicating that SP-C blocks LPS-induced cytokine production by a TLR4-dependent mechanism. Phospholipid vesicles alone did not modify the TLR4 response. In vivo deficiency of SP-C leads to inflammation, increased cytokine production by type II cells, and persistent inflammation after repetitive LPS stimulation.

The utility of serum hepcidin as a biomarker for late-onset neonatal sepsis.

OBJECTIVE: To assess the utility of hepcidin, a potent regulator of host defense and inflammation, in the diagnosis of late-onset sepsis in very low birth weight infants. STUDY DESIGN: We compared the diagnostic performance of hepcidin with C-reactive protein from the serum concentrations in acute and convalescent blood specimens obtained from 44 infants suspected of late-onset sepsis. The predictive accuracies were assessed from the areas under receiver operating characteristic curves and the cutoffs that differentiated infants with and without sepsis were identified using classification and regression tree analysis. RESULTS: Seventeen of the enrolled infants in this study were bacteremic and/or received antibiotics for neonatal sepsis for ≥ 5 days (infants with sepsis). The concentrations of hepcidin were increased 4-fold in infants with compared with infants without sepsis (P < .0001) and returned to similar levels following therapy. The areas under receiver operating characteristic curves of hepcidin was 0.93 compared with 0.83 for C-reactive protein, P = .06. Hepcidin concentration >92.2 ng/mL correctly classified 91% of all infants (positive predictive value: 100%, negative predictive value: 87%, specificity: 100%, and sensitivity: 76%). CONCLUSION: Serum hepcidin concentration may be a useful adjunct test, in addition to blood culture and other markers of infection, in the evaluation of late-onset sepsis in very low birth weight infants.

Fatty acids regulate stress resistance and virulence factor production for Listeria monocytogenes.

Fatty acids (FAs) are the major structural component of cellular membranes, which provide a physical and chemical barrier that insulates intracellular reactions from environmental fluctuations. The native composition of membrane FAs establishes the topological and chemical parameters for membrane-associated functions and is therefore modulated diligently by microorganisms especially in response to environmental stresses. However, the consequences of altered FA composition during host-pathogen interactions are poorly understood. The food-borne pathogen Listeria monocytogenes contains mostly saturated branched-chain FAs (BCFAs), which support growth at low pH and low temperature. In this study, we show that anteiso-BCFAs enhance bacterial resistance against phagosomal killing in macrophages. Specifically, BCFAs protect against antimicrobial peptides and peptidoglycan hydrolases, two classes of phagosome antimicrobial defense mechanisms. In addition, the production of the critical virulence factor, listeriolysin O, was compromised by FA modulation, suggesting that FAs play a key role in virulence regulation. In summary, our results emphasize the significance of FA metabolism, not only in bacterial virulence regulation but also in membrane barrier function by providing resistance against host antimicrobial stress.

The Pseudomonas aeruginosa flagellum confers resistance to pulmonary surfactant protein-A by impacting the production of exoproteases through quorum-sensing.

Surfactant protein-A (SP-A) is an important antimicrobial protein that opsonizes and permeabilizes membranes of microbial pathogens in mammalian lungs. Previously, we have shown that Pseudomonas aeruginosa flagellum-deficient mutants are preferentially cleared in the lungs of wild-type mice by SP-A-mediated membrane permeabilization, and not by opsonization. In this study, we report a flagellum-mediated mechanism of P. aeruginosa resistance to SP-A. We discovered that flagellum-deficient (ΔfliC) bacteria are unable to produce adequate amounts of exoproteases to degrade SP-A in vitro and in vivo, leading to its preferential clearance in the lungs of SP-A(+/+) mice. In addition, ΔfliC bacteria failed to degrade another important lung antimicrobial protein lysozyme. Detailed analyses showed that ΔfliC bacteria are unable to upregulate the transcription of lasI and rhlI genes, impairing the production of homoserine lactones necessary for quorum-sensing, an important virulence process that regulates the production of multiple exoproteases. Thus, reduced ability of ΔfliC bacteria to quorum-sense attenuates production of exoproteases and limits degradation of SP-A, thereby conferring susceptibility to this major pulmonary host defence protein.

Surfactant protein B propeptide contains a saposin-like protein domain with antimicrobial activity at low pH.

Surfactant protein B (SP-B) proprotein contains three saposin-like protein (SAPLIP) domains: a SAPLIP domain corresponding to the mature SP-B peptide is essential for lung function and postnatal survival; the function of SAPLIP domains in the N-terminal (SP-BN) and C-terminal regions of the proprotein is not known. In the current study, SP-BN was detected in the supernatant of mouse bronchoalveolar lavage fluid (BALF) and in nonciliated bronchiolar cells, alveolar type II epithelial cells, and alveolar macrophages. rSP-BN indirectly promoted the uptake of bacteria by macrophage cell lines and directly killed bacteria at acidic pH, consistent with a lysosomal, antimicrobial function. Native SP-BN isolated from BALF also killed bacteria but only at acidic pH; the bactericidal activity of BALF at acidic pH was completely blocked by SP-BN Ab. Transgenic mice overexpressing SP-BN and mature SP-B peptide had significantly decreased bacterial burden and increased survival following intranasal inoculation with bacteria. These findings support the hypothesis that SP-BN contributes to innate host defense of the lung by supplementing the nonoxidant antimicrobial defenses of alveolar macrophages.

Proteomic analysis of lamellar bodies isolated from amniotic fluid: implications for function.

Lamellar body count (LBC) in amniotic fluid is a well-established method for assessing fetal lung maturity. However, the biogenesis and function of lamellar bodies (LBs) secreted into the amniotic fluid have not been formally assessed. We purified LBs from amniotic fluids obtained from term gestation pregnancies that had been determined to have mature LBC. Using tandem mass spectrometry, we identified 122 unique proteins in the LB preparations from the amniotic fluids. There was minimal overlap between the proteins identified in amniotic fluid LB and those reported for human epidermis LB. In contrast, there was >40% concordance with the proteome of rat lung LBs despite species differences. Classification of the identified proteins into functional bins demonstrated that the preponderance of amniotic fluid LB proteins was associated with host defense or anti-inflammatory functions. These data suggest that amniotic fluid LBs are derived from lung secretions and may play an important role in innate host defense of the fetus.

Antibiotic exposure prevents acquisition of beneficial metabolic functions in the preterm infant gut microbiome.

BACKGROUND: Aberrations in the preterm microbiome following antibiotic therapy have been reported in previous studies. The objective of this study was to probe potential underlying mechanisms between this observation and susceptibility to adverse prematurity-related outcomes. RESULTS: Metagenomic shotgun sequencing was performed on 133 stool and 253 skin samples collected at 1 and 3 weeks of age from 68 infants born at <36 weeks postmenstrual age and birth weight <2000 g. After accounting for gestational age and maternal antibiotics, the distribution of organisms in all samples and the corresponding metabolic pathway abundance were compared between infants exposed to postnatal antibiotics and antibiotics-naïve infants. In antibiotic-naïve infants, gestational and postnatal age imparted similar trajectories on maturation of the microbial community and associated metabolic functional capacity, with postnatal age exerting greater contribution. Antibiotic exposure was associated with reversal in maturation trajectory from the first week to the third week of age (p< 0.001). Butyrate-producing genera, including Clostridium and Blautia, were significantly more abundant in antibiotic-naïve neonates at 3 weeks postnatal age. Correspondingly, metabolic pathways required for short-chain fatty acid synthesis were significantly increased in antibiotic-naïve infants, but not in antibiotic-exposed neonates, at 3 weeks after birth. CONCLUSIONS: Early brief antibiotic exposure markedly disrupts developmental trajectory of the neonatal microbiome and its corresponding functional capacity. Our findings may provide a mechanistic explanation for the known associations between antibiotic use and adverse outcomes in preterm infants. Video Abstract.

A review of pregnancy-induced changes in opioid pharmacokinetics, placental transfer, and fetal exposure: Towards fetomaternal physiologically-based pharmacokinetic modeling to improve the treatment of neonatal opioid withdrawal syndrome.

Physiologically-based pharmacokinetic (PBPK) modeling has emerged as a useful tool to study pharmacokinetics (PK) in special populations, such as pregnant women, fetuses, and newborns, where practical hurdles severely limit the study of drug behavior. PK in pregnant women is variable and everchanging, differing greatly from that in their nonpregnant female and male counterparts typically enrolled in clinical trials. PBPK models can accommodate pregnancy-induced physiological and metabolic changes, thereby providing mechanistic insights into maternal drug disposition and fetal exposure. Fueled by the soaring opioid epidemic in the United States, opioid use during pregnancy continues to rise, leading to an increased incidence of neonatal opioid withdrawal syndrome (NOWS). The severity of NOWS is influenced by a complex interplay of extrinsic and intrinsic factors, and varies substantially between newborns, but the extent of prenatal opioid exposure is likely the primary driver. Fetomaternal PBPK modeling is an attractive approach to predict in utero opioid exposure. To facilitate the development of fetomaternal PBPK models of opioids, this review provides a detailed overview of pregnancy-induced changes affecting the PK of commonly used opioids during gestation. Moreover, the placental transfer of these opioids is described, along with their disposition in the fetus. Lastly, the implementation of these factors into PBPK models is discussed. Fetomaternal PBPK modeling of opioids is expected to provide improved insights in fetal opioid exposure, which allows for prediction of postnatal NOWS severity, thereby opening the way for precision postnatal treatment of these vulnerable infants.

Physiologically-Based Pharmacokinetic Modeling to Investigate the Effect of Maturation on Buprenorphine Pharmacokinetics in Newborns with Neonatal Opioid Withdrawal Syndrome.

Neonatal opioid withdrawal syndrome (NOWS) is a major public health concern whose incidence has paralleled the opioid epidemic in the United States. Sublingual buprenorphine is an emerging treatment for NOWS, but given concerns about long-term adverse effects of perinatal opioid exposure, precision dosing of buprenorphine is needed. Buprenorphine pharmacokinetics (PK) in newborns, however, is highly variable. To evaluate underlying sources of PK variability, a neonatal physiologically-based pharmacokinetic (PBPK) model of sublingual buprenorphine was developed using Simcyp (version 19.1). The PBPK model included metabolism by cytochrome P450 (CYP) 3A4, CYP2C8, UDP-glucuronosyltransferase (UGT) 1A1, UGT1A3, UGT2B7, and UGT2B17, with additional biliary excretion. Maturation of metabolizing enzymes was incorporated, and default CYP2C8 and UGT2B7 ontogeny profiles were updated according to recent literature. A biliary clearance developmental profile was outlined using clinical data from neonates receiving sublingual buprenorphine as NOWS treatment. Extensive PBPK model validation in adults demonstrated good predictability, with geometric mean (95% confidence interval (CI)) predicted/observed ratios (P/O ratios) of area under the curve from zero to infinity (AUC0-∞ ), peak concentration (Cmax ), and time to reach peak concentration (Tmax ) equaling 1.00 (0.74-1.33), 1.04 (0.84-1.29), and 0.95 (0.72-1.26), respectively. In neonates, the geometric mean (95% CI) P/O ratio of whole blood concentrations was 0.75 (95% CI 0.64-0.87). PBPK modeling and simulation demonstrated that variability in biliary clearance, sublingual absorption, and CYP3A4 abundance are likely important drivers of buprenorphine PK variability in neonates. The PBPK model could be used to guide development of improved buprenorphine starting dose regimens for the treatment of NOWS.

Opioid Treatment for Neonatal Opioid Withdrawal Syndrome: Current Challenges and Future Approaches.

Chronic intrauterine exposure to psychoactive drugs often results in neonatal opioid withdrawal syndrome (NOWS). When nonpharmacologic measures are insufficient in controlling NOWS, morphine, methadone, and buprenorphine are first-line medications commonly used to treat infants with NOWS because of in utero exposure to opioids. Research suggests that buprenorphine may be the leading drug therapy used to treat NOWS when compared with morphine and methadone. Currently, there are no consensus or standardized treatment guidelines for medications prescribed for NOWS. Opioids used to treat NOWS exhibit large interpatient variability in pharmacokinetics (PK) and pharmacodynamic (PD) response in neonates. Organ systems undergo rapid maturation after birth that may alter drug disposition and exposure for any given dose during development. Data regarding the PK and PD of opioids in neonates are sparse. Pharmacometric methods such as physiologically based pharmacokinetic and population pharmacokinetic modeling can be used to explore factors predictive of some of the variability associated with the PK/PD of opioids in newborns. This review discusses the utility of pharmacometric techniques for enhancing precision dosing in infants requiring opioid treatment for NOWS. Applying these approaches may contribute to optimizing the outcome by reducing cumulative drug exposure, mitigating adverse drug effects, and reducing the burden of NOWS in neonates.

Impact of Institutional Breastfeeding Support in Very Low-Birth Weight Infants.

Background and Objectives: Feeding of human milk is associated with improved health outcomes in preterm infants. Mothers of preterm infants have difficulty establishing and maintaining an adequate milk supply. Our institution participated in Best Fed Beginnings (BFB), a national breastfeeding quality improvement collaborative, in 2012. Although most practice changes targeted healthy term infants, we hypothesized that mother's milk feeding (MMF) to preterm infants would also improve. Our objective was to compare MMF in very low-birth weight (VLBW) infants at discharge before and after our participation in BFB. Materials and Methods: We completed a retrospective chart review of VLBW infants born between January 2006 and June 2016. The primary outcome measure was the percentage of VLBW infants receiving MMF at hospital discharge. We used Fisher's exact test to determine the difference before and after 2012 and performed the Kruskal-Wallis test to determine changes in median time to pump initiation in mothers of VLBW infants. Multiple logistic regression was used to determine variables associated with the primary outcome. Results: A total of 1,077 VLBW infants were eligible. After launching BFB, MMF at discharge increased in VLBW infants, from 35.2% to 46.0%, p < 0.001. Median time to pump initiation decreased from 11 to 5 hours after 2012, p = 0.0001. Factors significantly associated with receiving MMF at discharge included birth post-BFB; private insurance; non-Black race; shorter length of stay; older maternal age; and mother's milk as first feeding. Conclusions: Hospital culture supportive of breastfeeding impacts not only healthy term infants but also VLBW infants. Earlier initiation of milk expression significantly improves provision of MMF to preterm infants at discharge.

Physiologic Indirect Response Modeling to Describe Buprenorphine Pharmacodynamics in Newborns Treated for Neonatal Opioid Withdrawal Syndrome.

BACKGROUND AND OBJECTIVE: Buprenorphine has been shown to be effective in treating infants with neonatal opioid withdrawal syndrome. However, an evidence-based buprenorphine dosing strategy has not been established in the treatment of neonatal opioid withdrawal syndrome because of a lack of exposure-response data. The aim of this study was to develop an integrated pharmacokinetic and pharmacodynamic model to predict buprenorphine treatment outcomes in newborns with neonatal opioid withdrawal syndrome. METHODS: Clinical data were obtained from 19 newborns with a median (range) gestational age of 37 (34-41) weeks enrolled in a pilot pharmacokinetic study of buprenorphine. Sparse blood sampling, comprising three specimens obtained around the second dose of buprenorphine, was performed using heel sticks with dried blood spot technology. Standardized neonatal opioid withdrawal syndrome severity scores (Finnegan scores) were collected every 3-4 h based on symptoms by bedside nursing staff. Mean Finnegan scores were used as a pharmacodynamic marker in the exposure-response modeling. The blood concentration-Finnegan score relationship was described using a physiologic indirect response model with inclusion of natural disease remission. RESULTS: A total of 52 buprenorphine blood concentrations and 780 mean Finnegan scores were available for the pharmacokinetic/pharmacodynamic modeling and exposure-response analysis. A one-compartment model with first-order absorption adequately described the pharmacokinetic data. The buprenorphine blood concentration at 50% of maximum effect for the inhibition of disease progression was 0.77 ng/mL (95% confidence interval 0.32-1.2). The inclusion of natural disease remission described as a function of postnatal age significantly improved the model fit. CONCLUSIONS: A buprenorphine pharmacokinetic/pharmacodynamic model was successfully developed. The model could facilitate model-informed optimization of the buprenorphine dosing regimen in the treatment of neonatal opioid withdrawal syndrome.

Pharmacotherapy of neonatal opioid withdrawal syndrome: a review of pharmacokinetics and pharmacodynamics.

INTRODUCTION: Neonatal opioid withdrawal syndrome (NOWS) often arises in infants born to mothers who used opioids during pregnancy. Morphine, methadone, and buprenorphine are the most common first-line treatments, whereas clonidine and phenobarbital are generally reserved for adjunctive therapy. These drugs exhibit substantial pharmacokinetic (PK) and pharmacodynamic (PD) variability. Current pharmacological treatments for NOWS are based on institutional protocols and largely rely on empirical treatment of patient symptoms. AREAS COVERED: This article reviews the PK/PD of NOWS pharmacotherapies with a focus on the implication of physiological development and maturation. Body size-standardized clearance is consistently low in neonates, except for methadone. This can be ascribed to underdeveloped metabolic and elimination pathways. The effects of pharmacogenetics have been clarified especially for morphine. The PK/PD relationship of medications used in the treatment of NOWS is generally understudied. EXPERT OPINION: Providing an appropriate opioid dose in neonates is challenging. Advancements in quantitative pharmacology and PK/PD modeling approaches facilitate identification of key factors driving PK/PD variability and characterization of exposure-response relationships. PK/PD model-informed simulations have been widely employed to define age-appropriate pediatric dosing regimens. The model-informed approach holds promise to aid more rational use of medications in the treatment of NOWS.