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Background: Breast milk reduces morbidity and mortality in infants admitted to neonatal intensive care unit (NICU). Objectives: We determined predictors of procuring mother's own milk (MOM) among N...

Background and Objectives: Exclusive breastfeeding is recommended for most newborns. However, exclusively breastfed newborns sometimes experience excess weight loss (EWL, loss ≥10% of birth weight) while lactation is being established. Our primary objective was to evaluate the sensitivity and specificity of the Newborn Weight Loss Tool (NEWT) in early identification of exclusively breastfed newborns who develop EWL; and secondarily, identify breastfeeding variables associated with an at-risk NEWT trajectory. Materials and Methods: We conducted a secondary analysis of prospective data from mother-infant dyads screened for inclusion in the U.S. site of the WHO Growth Reference Study. We excluded records if: NEWT-specific criteria not met, missing key data, or >60 mL formula consumed. We defined NEWT "test-positive" based on an in-hospital weight at about 24 hours falling within the NEWT trajectory consistent with eventual EWL. We defined cases as true EWL based on weight measured at home on day of life 4 (DoL4). Results: Of 280 original records, 60 were excluded (n = 27, NEWT-specific exclusion; n = 15, missing data; n = 18, >60 mL formula), resulting in 220 paired newborn weights measured in-hospital (17 ± 8 hours), and at DoL4 (84 ± 8 hours). NEWT status correctly identified 6/28 EWL cases (21% sensitivity [95% confidence interval, CI, 8-34%]), and 158/192 noncases (82% specificity [95% CI, 75-89%]). NEWT test-positive status was associated with greater weight loss, lower perceived breastfeeding support, and infant less often showing feeding cues on DoL4 (p

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. 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. 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. 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.

BackgroundPoliovirus vaccination induces an adaptive humoral immune response; in vitro experiments show polio-immune sera contain antibodies against the poliovirus RNA transcriptase that cross-react with SARS-CoV-2. While structural similarities between poliovirus and SARS-CoV-2 could have major implications for the COVID-19 response worldwide, polio-induced immune responses against SARS-CoV-2 have not been confirmed in prospective clinical trials.ObjectiveTo evaluate whether immune sera from adults who recently received inactivated poliovirus vaccination (IPV) can block SARS-CoV-2’s ability to synthesize RNA.InterventionIPV intramuscular injection.MeasurementsPre-inoculation and 4-weeks post-inoculation sera were tested for anti-3Dpol (RNA-dependent RNA polymerase, RdRp) antibodies using enzyme-linked immunosorbent assays (ELISA). To assess IPV’s ability to induce antibodies that inhibit SARS-CoV-2 RNA synthesis, immune-based detection assays tested RdRp enzymatic activity in polio-immune sera.Results298 of the 300 enrolled participants completed both on-site visits. Comparing pre-inoculation to 4-week samples, 85.2% of participants demonstrated an increase in anti-3Dpolantibodies against RdRp proteins. Among tested post-inoculation samples, 94.4% demonstrated inhibition of SARS-CoV-2 RNA synthesis. Few inoculation-related side effects were reported (2.0%), all were minor.LimitationsParticipants were not systematically tested for COVID-19, though known exposures were reported and positive results (1.7%) were documented.ConclusionIPV can induce antibodies that inhibit SARS-CoV-2 RNA synthesis, minimizing the risk of viral replication in infected individuals. This finding has practical implications for resource-deficient areas that may have limited access to newly developed COVID-19 vaccines and/or areas with low COVID-19 vaccination rates due to hesitancy.Funding SourcePrivate donors.RegistrationClinicalTrials.gov: NCT04639375.

OBJECTIVES: Identification of physiologic factors that impede lactation is critical for developing interventions to support milk production. Our objective was to examine the role of tumor necrosis factor–alpha (TNF-A), a potent regulator of lipid metabolism, in the suppression of human lactation. We hypothesized that mothers with very low, versus sufficient milk production, would have elevated milk TNF-A and differential expression of TNF-A signaling pathways in the mammary epithelial cells (MECs). METHODS: Among mothers in a study of low milk supply, extracellular mammary epithelial cell mRNA was isolated from fresh milk fat and submitted to RNA-sequencing. Aligned and quantified reads were examined for differentially expressed genes using t-tests (DEG, p 0.05. Serum fasting triglyceride and BMI were significantly elevated in LMP versus HMP, P

Background: Black mothers in the United States have shorter breastfeeding (BF) durations and less exclusive breastfeeding (EBF) than others. The factors underlying these disparities require investigation. Methods: Using longitudinal data from a CDC-sponsored birth cohort in Cincinnati, Ohio, we analyzed the factors mediating racial disparity in BF outcomes. Study mothers were enrolled in prenatal clinics associated with two large birth hospitals. Analysis was restricted to racial groups with sufficient numbers in the cohort, non-Hispanic Black (n = 92) and White (n = 113) mothers, followed to at least 6 months postpartum. Results: Black mothers were 25 times more likely to reside in socioeconomically deprived neighborhoods and 20 times more likely to have an annual household income

Objective: Determine if maternal obesity increases use of medically indicated or elective formula in the context of a Baby-Friendly Hospital with high prevalence of obesity. Study Design: ...

Background: Metformin improves insulin action, but feasibility in treating low milk supply is unknown. Research aim: To determine the feasibility of a metformin- versus-placebo definitive randomized clinical trial in women with low milk production and signs of insulin resistance. Methods: Pilot trial criteria included: Mother 1–8 weeks postpartum (ideally 1–2 weeks), low milk production, and ≥1 insulin resistance sign; and singleton, healthy, term infant. Eligible mothers were randomly assigned 2:1 (metformin:placebo) and instructed in frequent milk removal for 28 days with option to stop at 14 days. Results: From 02/2015 through 06/2016, we screened 114 women, completed baseline assessments on 46, and trialed 15 (median, 36 days postpartum). Comparing metformin-assigned ( n = 10) to placebo ( n = 5), 70% versus 80% continued to day 28; peak median change in milk output was +8 versus –58 mL/24 hr ( p = .31) and 80% peaked at Day 14 for both groups; 0% versus 20% desired to continue assigned drug after study completion; 44% versus 0% reported nausea/vomiting. Post-hoc, median peak change in milk output was +22 (metformin completers, n = 8) versus –58 mL/24 hr (placebo + non-completers, n = 7, p = .07). At baseline assessment, median milk production was significantly lower in those with ( n = 31), versus those without ( n = 15) signs of insulin resistance ( p = .002). Conclusions: Although results trend toward hypothesized direction, trial feasibility concerns include late enrollment and only 20% of metformin-assigned participants sustaining improved milk output to Day 28, with none perceiving metformin worthwhile. Better tools are needed to identify and treat metabolically-driven low milk production. Registered at ClinicalTrials.gov (NCT02179788) on 02/JUL/2014.

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.

Background: The benefits of breastfeeding are unparalleled. Unfortunately, obesity and diabetes are fueling a rise in the number of mothers who are physiologically unable to produce sufficient breast milk. Our aim was to identify gene expression signatures for mammary epithelial cells (MEC) during lactation that characterize insufficient breast milk production in obese women with elevated plasma triglycerides. Methods: …

The COVID-19 pandemic upended “life as we knew it” seemingly overnight. However, for public health professionals, the vulnerability of our systems and subsequent devastating outcomes did not come as much of a surprise. This commentary aims to reveal the untapped potential of Doctorate in Public Health (DrPH) professionals and their role in contributing to the future mitigation of public health crises. In this context, “DrPH professionals” are defined as doctoral awardees (or current students) of the advanced, terminal degree in pursuit of a career in public health practice and leadership. Research suggests the importance of public health interventions in reducing the burden of disease, but the opportunities and visibility of DrPH professionals specifically over the past year have been limited. By working to include these professionals at all levels of proverbial planning tables, future public health pandemic responses will be all the better for it. Public health has never been as visible—and the need for trained public health leaders has never been as critical—as it is today. In this commentary, we recommend actions that should be championed by DrPH practitioners to improve the resiliency of our global health care systems.

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 ...

Necrotizing enterocolitis (NEC) is a devastating intestinal disease in premature infants. Local rates of NEC were unacceptably high. We hypothesized that utilizing quality improvement methodology to standardize care and apply evidence-based practices would reduce our rate of NEC. A multidisciplinary team used the model for improvement to prioritize interventions. Three neonatal intensive care units (NICUs) developed a standardized feeding protocol for very low birth weight (VLBW) infants, and employed strategies to increase the use of human milk, maximize intestinal perfusion, and promote a healthy microbiome. The primary outcome measure, NEC in VLBW infants, decreased from 0.17 cases/100 VLBW patient days to 0.029, an 83% reduction, while the compliance with a standardized feeding protocol improved. Through reliable implementation of evidence-based practices, this project reduced the regional rate of NEC by 83%. A key outcome and primary driver of success was standardization across multiple NICUs, resulting in consistent application of best practices and reduction in variation.

Background Although there is an increasing trend for more mothers to initiate breastfeeding in the US, there is a rapid decline after initiation, and racial disparities persist. A multidisciplinary team comprised of pediatricians, neonatologists, prenatal lactation providers, primary care lactation experts, and members of the community partnered to address the cessation of breastfeeding before the first “Newborn” visit at our institution’s busy primary care safety net clinics, using Quality Improvement methodology. Methods The aim of this project was to increase the number of babies presenting to the safety net primary …

OBJECTIVES: Insulin resistance may contribute to the association between maternal obesity and lactation difficulties. Our objective was to examine differential expression of genes involved in insulin-sensitive and prolactin-sensitive signaling in the mammary glands of women with very low, versus sufficient, milk production. METHODS: Among a subset of mothers in a study of low milk supply, extracellular mammary epithelial cell mRNA was isolated from fresh milk fat and submitted for RNA-sequencing. Aligned and quantified reads were examined for differentially expressed genes by t-test (DEG, p

Multiple health organizations, including the American Academy of Pediatrics,1 endorse the recommendation for exclusive breastfeeding for the first 6 months of life. In the United States, most women initiate breastfeeding, but a majority do not meet their intended goals of duration.2 There is a complex interplay of factors that impact breastfeeding outcomes, which include sociodemographic variables, psychosocial issues, maternal health, and infant conditions. However, hospital practices also play a significant role in a mother’s experience during the birth hospitalization and can be critical in setting the stage for breastfeeding success after discharge.2 In this issue of Pediatrics , Nguyen et al3 noted that in 2014, New York had the highest national rate of formula supplementation in breastfed newborns in the first 2 days of life. These authors sought to determine the factors that influence this finding. By using birth certificate data, they included 176 764 … Address correspondence to Laura P. Ward, MD, IBCLC, Division of Neonatology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, MLC 7009, Cincinnati, OH 45229-3039. E-mail: laura.ward{at}cchmc.org

BACKGROUND AND OBJECTIVE: Breastfeeding has many well-established health benefits for infants and mothers. There is greater risk reduction in health outcomes with exclusive breastfeeding (EBF). Our urban academic facility has had long-standing low EBF rates, serving a population with breastfeeding disparities. We sought to improve EBF rates through a Learning Collaborative model by participating in the Best Fed Beginnings project. METHODS: Formal improvement science methods were used, including the development of a key driver diagram and plan–do–study–act cycles. Improvement activities followed the Ten Steps to Successful Breastfeeding. RESULTS: We demonstrated significant improvement in the median adherence to 2 process measures, rooming in and skin-to-skin after delivery. Subsequently, the proportion of infants exclusively breastfed at hospital discharge in our facility increased from 37% to 59%. We demonstrated an increase in sustained breastfeeding in a subset of patients at a postpartum follow-up visit. These improvements led to Baby-Friendly designation at our facility. CONCLUSIONS: This quality improvement initiative resulted in a higher number of infants exclusively breastfed in our patient population at “high risk not to breastfeed.” Other hospitals can use these described methods and techniques to improve their EBF rates.

Twin anemia polycythemia sequence is a rare condition in monochorionic twin pregnancies that has only recently been described. It can occur spontaneously or as a result of fetoscopic laser surgery for twin to twin transfusion syndrome. The size of the placental connections and the flow of blood between tiny anastomoses allow for chronic changes in the hemodynamic states of each fetus. The chronic nature of the pathophysiology leads to reticulocytosis in the donor twin and limits the fluid-level discrepancies between amniotic sacs, which differentiates it from twin to twin transfusion syndrome, which is thought to be an acute process. Several in utero procedures have been described to treat this condition; however, because of the rarity of the condition, data are limited. Postnatal treatment includes packed red blood cell transfusion for the donor twin and partial exchange transfusion for the recipient twin, along with standard medical neonatal care. Long-term outcomes data are limited; however, one study revealed normal neurodevelopment in a small cohort of patients.

To determine acceptance of donor human milk (DM) for feeding preterm infants and whether offering DM, alters mothers' milk (MM) feeding.Infant feeding data were collected from medical records of 650 very preterm infants enrolled between 2006-2011 in two hospital level III neonatal intensive care units (NICUs) in Cincinnati, Ohio. The study was conducted during the implementation of a program offering 14 days of DM.From 2006-2011, any DM use increased from 8 to 77% of infants, largely replacing formula for the first 2 weeks of life; provision of MM did not change. DM was more likely to be given in the first 2 weeks of life, if infants never received MM or were1000 g birth weight, but DM use did not differ by sociodemographic factors.Offering DM dramatically increased human milk feeding and decreased formula use, but did not alter MM feeding in hospital.

Objective: The goal of this study was to evaluate risk factors for readmission among late-preterm (34–36 weeks’ gestation) infants in clinical practice. Methods: This was a retrospective, matched case-control study of late-preterm infants receiving care across 8 regional hospitals in 2009 in the United States. Those readmitted within 28 days of birth were matched to non-readmitted infants at a ratio of 1:3 according to birth hospital, birth month, and gestational age. Step-wise modeling with likelihood ratio tests were used to develop a multivariable logistic regression model. A subgroup analysis of hyperbilirubinemia readmissions was also performed. Results: Of 1861 late-preterm infants delivered during the study period, 67 (3.6%) were readmitted within 28 days of birth. These were matched to 201 control infants, for a final sample of 268 infants. In multivariable regression, each additional day in length of stay was associated with a significantly reduced odds ratio (OR) for readmission (0.57, P = .004); however, for those infants delivered vaginally, there was no significant association between length of stay and readmission (adjusted OR: 1.08, P = .16). A stronger inverse relationship was observed in subgroup analysis for hyperbilirubinemia readmissions, with the adjusted OR associated with increased length of stay 0.40 (P = .002) for infants born by cesarean delivery but 1.14 (P = .27) for those delivered vaginally. Conclusions: Infants born via cesarean delivery with longer length of hospital stay have a decreased risk for readmission. As hospitals implement protocols to standardize length of stay, mode of delivery may be a useful factor to identify late-preterm infants at higher risk for readmission.

Neonatal abstinence syndrome (NAS) comprises a constellation of drug withdrawal symptoms that result from chronic intrauterine exposure to a variety of substances, including opioids, benzodiazepines, barbiturates, selective serotonin reuptake inhibitors, ethanol, nicotine and caffeine. Most non-opioid fetal drug exposures result in limited clinical presentation, respond well to supportive care measures and rarely require pharmacologic intervention [1, 2]. Chronic in utero exposure to opioids is well characterized and is particularly problematic because of its high prevalence and frequent need for pharmacotherapy to mitigate withdrawal signs, especially when the opioid exposure is in the broader context of maternal polysubstance consumption.

Objective To evaluate the efficacy of a universal maternal drug testing protocol for all mothers in a community hospital setting that experienced a 3-fold increase in neonatal abstinence syndrome (NAS) over the previous 5 years. Study design We conducted a retrospective cohort study between May 2012 and November 2013 after the implementation of universal maternal urine drug testing. All subjects with positive urine tests were reviewed to identify a history or suspicion of drug use, insufficient prenatal care, placental abruption, sexually transmitted disease, or admission from a justice center, which would have prompted urine testing using our previous risk-based screening guidelines. We also reviewed the records of infants born to mothers with a positive toxicology for opioids to determine whether admission to the special care nursery was required. Results Out of the 2956 maternal specimens, 159 (5.4%) positive results were recorded. Of these, 96 were positive for opioids, representing 3.2% of all maternity admissions. Nineteen of the 96 (20%) opioid-positive urine tests were recorded in mothers without screening risk factors. Seven of these 19 infants (37%) required admission to the special care nursery for worsening signs of NAS, and 1 of these 7 required pharmacologic treatment. Conclusion Universal maternal drug testing improves the identification of infants at risk for the development of NAS. Traditional screening methods underestimate in utero opioid exposure.

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.

Cocaine has become a popular illicit drug in our society, and pregnant women are not immune from this epidemic. Recently, there have been several references in the literature describing an association between prenatal cocaine exposure and the subsequent development of necrotizing enterocolitis in the neonate, but the mechanism underlying this relationship remains speculative. Because alpha-2 adrenergic receptors are thought to play a role in the autoregulatory mechanism in the newborn intestine that responds to hypoxia and ischemia, we examined the expression of this receptor in the intestine of embryonic rats exposed to low- and high-dose cocaine in utero. Pregnant Sprague Dawley rats were injected daily with either saline, low-dose cocaine, or high-dose cocaine beginning on embryonic d 5 (E 5) and continuing to E 20. Mothers were killed on E 16, E 17, E 18, E 19, and E 20. Embryos were frozen and stored at -80 degrees C. In situ hybridization was performed on 20- micro m sections with 35S-labeled oligonucleotide probes specific for the alpha-2A adrenergic receptor subtype. Densitometric analysis revealed a significant decrease in the alpha-2A receptor expression in the intestine of both the low-dose and high-dose cocaine-exposed animals compared with controls. This down-regulation was demonstrated by E 17, and continued through the remainder of gestation. These changes may limit the normal adaptation to vasoconstriction, thus exacerbating the already insufficient compensatory mechanisms for responding to ischemic injury, and thus may be one of the important factors predisposing cocaine-exposed infants to necrotizing enterocolitis.

Alpha-2A Adrenergic Receptor Gene Expression in the Embryonic Rat Intestine after Low and High Dose Cocaine Exposure In Utero