Is Maternal Methadone Dose Associated with the Severity of Neonatal Abstinence Syndrome?

OBJECTIVE: The aim of the study is to assess the correlation between maternal methadone dose and severity of neonatal abstinence syndrome (NAS) in infants that required pharmacological treatment for NAS. STUDY DESIGN: This is a retrospective analysis of 574 infants ≥35 weeks' gestation exposed to methadone in utero, born between August 2006 and May 2018, and who required pharmacological therapy for NAS. Indicators of NAS severity (duration of morphine treatment, maximum morphine dose, use of phenobarbital, and length of hospitalization) were compared between infants exposed to high (≥200 mg), intermediate (100-199 mg), and low doses (<100 mg) of methadone. Logistic and linear regression models were used to adjust for the covariates. RESULTS: Median (interquartile range) duration of medical treatment with morphine was higher in infants exposed to higher doses of methadone (low dose 23 [14-37] days, intermediate dose 31 [18-45] days, and high dose 35 [20-48] days, p < 0.001). Higher methadone doses were also predictive of longer duration of hospitalization, higher maximum morphine dose, and increased likelihood of treatment with phenobarbital. The association between maternal methadone dose and the severity of NAS persisted in multivariable regression models. CONCLUSION: Infants exposed to higher methadone doses displayed more severe NAS, as indicated by longer durations of treatment, higher maximum morphine dose, longer duration of hospitalization, and increased likelihood of phenobarbital use. KEY POINTS: · Methadone maintenance therapy is used during pregnancy to control maternal withdrawal symptoms.. · Relationship between maternal methadone dose and severity of NAS is not adequately investigated.. · Increased doses of methadone during pregnancy correlate with increased severity of NAS..

Buprenorphine for the Treatment of the Neonatal Abstinence Syndrome.

BACKGROUND: Current pharmacologic treatment of the neonatal abstinence syndrome with morphine is associated with a lengthy duration of therapy and hospitalization. Buprenorphine may be more effective than morphine for this indication. METHODS: In this single-site, double-blind, double-dummy clinical trial, we randomly assigned 63 term infants (≥37 weeks of gestation) who had been exposed to opioids in utero and who had signs of the neonatal abstinence syndrome to receive either sublingual buprenorphine or oral morphine. Infants with symptoms that were not controlled with the maximum dose of opioid were treated with adjunctive phenobarbital. The primary end point was the duration of treatment for symptoms of neonatal opioid withdrawal. Secondary clinical end points were the length of hospital stay, the percentage of infants who required supplemental treatment with phenobarbital, and safety. RESULTS: The median duration of treatment was significantly shorter with buprenorphine than with morphine (15 days vs. 28 days), as was the median length of hospital stay (21 days vs. 33 days) (P<0.001 for both comparisons). Adjunctive phenobarbital was administered in 5 of 33 infants (15%) in the buprenorphine group and in 7 of 30 infants (23%) in the morphine group (P=0.36). Rates of adverse events were similar in the two groups. CONCLUSIONS: Among infants with the neonatal abstinence syndrome, treatment with sublingual buprenorphine resulted in a shorter duration of treatment and shorter length of hospital stay than treatment with oral morphine, with similar rates of adverse events. (Funded by the National Institute on Drug Abuse; BBORN ClinicalTrials.gov number, NCT01452789 .).

Prevalence and Utility of Low Mean Corpuscular Volume in Infants Admitted to the Neonatal Intensive Care Unit.

OBJECTIVE: To determine the prevalence of low mean corpuscular volume (MCV) in newborn infants admitted to the neonatal intensive care unit and to assess low MCV as a diagnostic test for alpha thalassemia. STUDY DESIGN: Retrospective analysis of all infants admitted to the neonatal intensive care unit between January 2010 and October 2018 for which a complete blood count was performed during the first 3 postnatal days. Infants with a low MCV were compared with those with a normal MCV. Infants with positive hemoglobin Bart (Hb Bart) were compared with those withnegative Hb Bart. Low MCV was also evaluated as a diagnostic test for alpha thalassemia. RESULTS: A total of 3851 infants (1386 preterm, 2465 term) met the inclusion criteria and 853 (22.2%) had a low MCV. A low MCV was more common in term (25%) compared with preterm infants (17.1%, P < .001). Hb Bart positive newborn screening was identified in 133 infants (3.5%). Hb Bart was positive in 11.1% of infants with low MCV compared with 1.3% with normal MCV (P < .001). The sensitivity, specificity, positive predictive value, and negative predictive value of low MCV for the diagnosis of alpha thalassemia were 71.4%, 79.6%, 11.3%, and 98.7%, respectively. CONCLUSIONS: As Hb Bart positive newborn screens were seen in only 11.1% of infants with microcytosis, further diagnostic investigation may be warranted in individual infants. Further research to correlate microcytosis with iron status in infants and mothers is needed as well as studies using DNA analysis for the evaluation of alpha thalassemia variants.

Car Seat Tolerance Screening in the Neonatal Intensive Care Unit: Failure Rates, Risk Factors, and Adverse Outcomes.

OBJECTIVE: To characterize the epidemiology of Car Seat Tolerance Screening (CSTS) failure and the association between test failure and all-cause 30-day postdischarge mortality or hospital readmission in a large, multicenter cohort of preterm infants receiving neonatal intensive care. STUDY DESIGN: This retrospective cohort study used the prospectively collected Optum Neonatal Database. Study infants were born at <37 weeks of gestation between 2010 and 2016. We identified independent predictors of CSTS failure and calculated the risk-adjusted odds of all-cause 30-day mortality or hospital readmission associated with test failure. RESULTS: Of 7899 infants cared for in 788 hospitals, 334 (4.2%) failed initial CSTS. Greater postmenstrual age at testing and African American race were independently associated with decreased failure risk. Any treatment with an antacid medication, concurrent use of caffeine or supplemental oxygen, and a history of failing a trial off respiratory support were associated with increased failure risk. The mean adjusted post-CSTS duration of hospitalization was 3.1 days longer (95% CI, 2.7-3.6) among the infants who failed the initial screening. Rates of 30-day all-cause mortality or readmission were higher among infants who failed the CSTS (2.4% vs 1.0%; P = .03); however, the difference was not significant after confounder adjustment (OR, 0.38; 95% CI, 0.11-1.31). CONCLUSION: CSTS failure was associated with longer post-test hospitalization but no difference in the risk-adjusted odds for 30-day mortality or hospital readmission. Whether CSTS failure unnecessarily prolongs hospitalization or results in appropriate care that prevents adverse postdischarge outcomes is unknown. Further research is needed to address this knowledge gap.

High Flow Nasal Cannula Use Is Associated with Increased Morbidity and Length of Hospitalization in Extremely Low Birth Weight Infants.

OBJECTIVE: To determine differences in the incidence of bronchopulmonary dysplasia (BPD) or death in extremely low birth weight infants managed on high flow nasal cannula (HFNC) vs continuous positive airway pressure (CPAP). STUDY DESIGN: This is a retrospective data analysis from the Alere Neonatal Database for infants born between January 2008 and July 2013, weighing ≤1000 g at birth, and received HFNC or CPAP. Baseline demographics, clinical characteristics, and neonatal outcomes were compared between the infants who received CPAP and HFNC, or HFNC ± CPAP. Multivariable regression analysis was performed to control for the variables that differ in bivariate analysis. RESULTS: A total of 2487 infants met the inclusion criteria (941 CPAP group, 333 HFNC group, and 1546 HFNC ± CPAP group). The primary outcome of BPD or death was significantly higher in the HFNC group (56.8%) compared with the CPAP group (50.4%, P < .05). Similarly, adjusted odds of developing BPD or death was greater in the HFNC ± CPAP group compared with the CPAP group (OR 1.085, 95% CI 1.035-1.137, P = .001). The number of ventilator days, postnatal steroid use, days to room air, days to initiate or reach full oral feeds, and length of hospitalization were significantly higher in the HFNC and HFNC ± CPAP groups compared with the CPAP group. CONCLUSIONS: In this retrospective study, use of HFNC in extremely low birth weight infants is associated with a higher risk of death or BPD, increased respiratory morbidities, delayed oral feeding, and prolonged hospitalization. A large clinical trial is needed to evaluate long-term safety and efficacy of HFNC in preterm infants.

Neonatal intensive care unit admissions before and after the adoption of the baby friendly hospital initiative.

BACKGROUND: The Baby Friendly Hospital initiative (BFHI) is a global initiative of the World Health Organization developed in 1991 to promote and support successful breastfeeding. It has led to increased rates of exclusive breastfeeding. Exclusive breastfeeding may increase risk for hypoglycemia, hyperbilirubinemia, and dehydration requiring higher level of neonatal care. OBJECTIVE: To determine if there was a change in admissions to the Neonatal Intensive Care Unit (NICU) from the newborn nursery after the adoption of BFHI in a large urban hospital. METHODS: This is a retrospective analysis of all neonates admitted to the NICU from the newborn nursery between January 2007 and December 2016 at Thomas Jefferson University Hospital, in Philadelphia, PA, USA. Demographics, clinical characteristics and primary diagnosis for admission were compared between those admitted before (January 2007 to December 2011) and after (January 2012 to December 2016) the initiation of BFHI. RESULTS: A total of 20,124 infants were born and 3,684 infants (18.3%) were admitted to NICU. 570 infants (2.8% of live birth) were admitted to the NICU from the newborn nursery, 282 (49.5%) were born before and 288 (50.5%) born after BFHI. There was no significant difference in the number of infants admitted from the newborn nursery either as a percentage of total deliveries (2.8 versus 2.9%, p = .6) or percentage of total NICU admissions (15.5 versus 15.5%, p = 1.0) before and after the BFHI. Additionally, there was no difference in number of infants admitted with a diagnosis of possible sepsis, hypoglycemia, neonatal abstinence syndrome (NAS) and hyperbilirubinemia between the two groups. However, significantly more infants admitted with hypoglycemia required IV fluids for hypoglycemia after the initiation of BFHI (8 out of 27 versus 21 out of 28, p .001). The age of admission was higher and the duration of NICU stay was shorter in infants admitted after the initiation of the BFHI. CONCLUSIONS: The BFHI has not led to a significant change in the number of infants admitted to NICU from the newborn nursery or reasons for their admissions. However, since its adoption, there has been an increase in the use of IV fluids for treatment of hypoglycemia. These findings suggest a role for additional treatments other than formula to prevent IV fluid use, such as glucose gel. Change in NICU guidelines for the management of possible sepsis and NAS may have impacted the duration of hospitalization in infants born after BFHI.

Do extremely preterm infants need retinopathy of prematurity screening earlier than 31 weeks postmenstrual age?

OBJECTIVE: To evaluate the utility of screening all extremely preterm infants for retinopathy of prematurity (ROP) at 4 weeks chronologic age, which is earlier than recommended by the 2018 AAP guidelines. STUDY DESIGN: Retrospective analysis of infants <27 weeks gestation from two tertiary NICUs between 2006 and 2018 who survived until first eye examination. RESULTS: 550 infants (gestational age 25.1 ± 1.2 weeks and birth weight 758 ± 323 g) had 1310 examinations performed by 32 weeks postmenstrual age (PMA), and 676 (51.6%) of these were prior to 31 weeks PMA. No examinations in infants prior to 31 weeks PMA met the criteria for laser therapy. Of 87/550 infants (15.8%) who required laser therapy, none did so prior to 32 weeks PMA. CONCLUSIONS: No infants born <27 weeks gestation were found to have severe ROP prior to 31 weeks PMA, supporting the most recent AAP recommendation of initiating ROP screening at 31 weeks PMA for extremely preterm infants.

Prolonging gavage feeds for reduction of gastroesophageal reflux in infants.

OBJECTIVE: To determine if prolonging gavage feedings in infants for ≥60 min is associated with decreased gastroesophageal reflux (GER) compared with bolus feeding using multiple-channel intraluminal impedance with pH probe (MII-pH). STUDY DESIGN: Retrospective analysis of infants who underwent MII-pH between October 2009 and July 2018 and received gavage feedings. Infants were divided into two groups: bolus (<30 min) or prolonged (≥60 min). Symptoms, number of reflux events and percent time pH < 4 was compared. RESULT: Fifty-eight infants underwent evaluation. Thirty-one (54%) received bolus gavage feedings and 27 (46%) received prolonged feedings. Groups differed in postmenstrual age. Total reflux episodes were significantly lower with prolonged feeding (median 19 vs. 28 episodes, p = 0.015), with no difference in acid exposure time. There was no significant difference in GER symptoms between the two groups. CONCLUSION: Prolongation of gavage feedings was associated with decreased total numbers of GER events without reduction in GER symptoms.

Maternal breast milk feeding and length of treatment in infants with neonatal abstinence syndrome.

OBJECTIVE: The objective of this study is to assess whether infants with neonatal abstinence syndrome (NAS), who receive maternal breast milk (BM), have shorter pharmacological treatment durations and lengths of stay compared with formula-fed infants. STUDY DESIGN: Retrospective data analysis from Optum Neonatal Database for infants born between 1 January 2010 and 21 November 2016, who received treatment for NAS. Clinical characteristics and outcomes were compared between infants who received any amount of BM and those exclusively formula-fed. RESULT: Infants (1738) were analyzed. Median length of pharmacological treatment was significantly lower in infants who received any BM (14 days) compared with "no BM" group (17 days, p = 0.04). Similarly, median length of hospitalization was significantly reduced in "any BM" group (19 days vs. 20 days), which remained significant after adjustment for confounders (p = 0.01). There was no difference in hospital re-admission rates. CONCLUSION: Feeding any BM to infants with NAS was associated with both decreased lengths of pharmacological treatment and hospital stay compared with exclusively formula-fed infants.

Adverse effects of small for gestational age differ by gestational week among very preterm infants.

OBJECTIVE: To characterise the excess risk for death, grade 3-4 intraventricular haemorrhage (IVH), bronchopulmonary dysplasia (BPD) and stage 3-5 retinopathy of prematurity independently associated with birth small for gestational age (SGA) among very preterm infants, stratified by completed weeks of gestation. METHODS: Retrospective cohort study using the Optum Neonatal Database. Study infants were born <32 weeks gestation without severe congenital anomalies. SGA was defined as a birth weight <10th percentile. The excess outcome risk independently associated with SGA birth among SGA babies was assessed using adjusted risk differences (aRDs). RESULTS: Of 6708 infants sampled from 717 US hospitals, 743 (11.1%) were SGA. SGA compared with non-SGA infants experienced higher unadjusted rates of each study outcome except grade 3-4 IVH among survivors. The excess risk independently associated with SGA birth varied by outcome and gestational age. The highest aRD for death (0.27; 95% CI 0.13 to 0.40) occurred among infants born at 24 weeks gestation and declined as gestational age increased. In contrast, the peak aRDs for BPD among survivors (0.32; 95% CI 0.20 to 0.44) and the composites of death or BPD (0.35; 95% CI 0.24 to 0.46) and death or major morbidity (0.35; 95% CI 0.24 to 0.45) occurred at 27 weeks gestation. The risk-adjusted probability of dying or developing one or more of the evaluated morbidities among SGA infants was similar to that of non-SGA infants born approximately 2-3 weeks less mature. CONCLUSION: The excess risk for neonatal morbidity and mortality associated with being born SGA varies by adverse outcome and gestational age.

Assessment of neonatal ventilation during high-frequency oscillatory ventilation.

OBJECTIVE: To determine alterations in high-frequency oscillatory ventilation (HFOV) performance during clinical ventilator management. DESIGN: Clinical investigation. SETTING: Two level III intensive care nurseries in Wilmington, Delaware, and Philadelphia, Pennsylvania. PATIENTS: Thirty infants 1.49 +/- 1.01 kg with respiratory distress receiving HFOV. INTERVENTIONS: Due to the demonstrated benchtop load sensitivity of the HFOV (SensorMedics 3100), we hypothesized that measured tidal volume (Vt/kg) and high-frequency minute ventilation (HFMV) would vary inversely with respiratory rate adjustments and that ventilator performance will be affected with endotracheal tube (ETT) suctioning. Both Vt/kg and HFMV were recorded using a novel hot-wire anemometry technique at the time of ETT suctioning or changes in ventilator settings. MEASUREMENTS AND MAIN RESULTS: During HFOV it was found that Vt/kg = 2.52 +/- 0.68 mL/kg and HFMV = 69 +/- 45 ([mL/kg]2 x Hz); effective ventilation was observed in the range of HFMV = 29-113 ([mL/kg]2 x Hz). HFMV decreased with an increase in breathing frequency. Although there was a significant increase in the mean Vt/kg after suctioning events, there was no difference in Vt/kg or HFMV after disconnection of the ETT alone. There were significant alterations in HFOV performance as a result of clinical adjustments in respiratory rate and suctioning. In addition, we found that measured Vt during clinically effective HFOV is at least equivalent to expected deadspace. CONCLUSIONS: Measurement of tidal volume and HFMV may be clinically important in optimizing HFOV performance both during ETT suctioning and adjustments to breathing frequency.

Physiologic implications of helium as a carrier gas for inhaled nitric oxide in a neonatal model of Bethanecol-induced bronchoconstriction.

OBJECTIVE: To compare heliox to nitrogen-oxygen (nitrox) as a carrier gas for inducible nitric oxide (iNO) in the presence of pharmacologically inhaled bronchoconstriction. We hypothesized that respiratory resistance and gas exchange would improve when iNO is delivered with heliox. DESIGN: Interventional laboratory study. SETTING: An academic medical research facility in the northeastern United States. SUBJECTS: Sedated, ventilated newborn piglets. INTERVENTIONS: Newborn piglets (n = 16; 2.3 +/- 0.1 kg) were placed on a flow-controlled ventilator and given intravenous Bethanecol (2 x 1 mg/kg followed by 1 mg/kg/hr) to induce bronchoconstriction. Piglets were randomized to heliox or nitrox (Fio2 = 0.3) and given 80 ppm iNO. MEASUREMENTS AND MAIN RESULTS: Hemodynamics, blood chemistry, and pulmonary mechanics were recorded at 30-min intervals for 2 hrs. Bethanecol dosing increased inspiratory respiratory resistance (cm H2O/L/min; p < .01) and decreased respiratory compliance (mL/cm H2O/kg; p < .01). Following carrier gas assignment, hemodynamics and respiratory compliance were similar between groups and respiratory resistance decreased (p < .01) in the heliox group. Over 2 hrs with iNO therapy, Paco2 increased (p < .01) whereas blood pH decreased (p < .01) in the heliox group. Respiratory resistance trended downward, oxygenation index improved (p < .01), and blood methemoglobin levels trended higher for nitrox compared with heliox. CONCLUSIONS: The INOvent was effective for controlling heliox delivery of iNO. Despite marked reduction in respiratory resistance with heliox gas ventilation in a neonatal model of pharmacologic bronchoconstriction, nitrox might perform better as a delivery vehicle for iNO.