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1.  Clindamycin Pharmacokinetics and Safety in Preterm and Term Infants 
Clindamycin may be active against methicillin-resistant Staphylococcus aureus, a common pathogen causing sepsis in infants, but optimal dosing in this population is unknown. We performed a multicenter, prospective pharmacokinetic (PK) and safety study of clindamycin in infants. We analyzed the data using a population PK analysis approach and included samples from two additional pediatric trials. Intravenous data were collected from 62 infants (135 plasma PK samples) with postnatal ages of <121 days (median [range] gestational age of 28 weeks [23 to 42] and postnatal age of 17 days [1 to 115]). In addition to body weight, postmenstrual age (PMA) and plasma protein concentrations (albumin and alpha-1 acid glycoprotein) were found to be significantly associated with clearance and volume of distribution, respectively. Clearance reached 50% of the adult value at PMA of 39.5 weeks. Simulated PMA-based intravenous dosing regimens administered every 8 h (≤32 weeks PMA, 5 mg/kg; 32 to 40 weeks PMA, 7 mg/kg; >40 to 60 weeks PMA, 9 mg/kg) resulted in an unbound, steady-state concentration at half the dosing interval greater than a MIC for S. aureus of 0.12 μg/ml in >90% of infants. There were no adverse events related to clindamycin use. (This study has been registered at under registration no. NCT01728363.)
PMCID: PMC4862454  PMID: 26926644
2.  Postnatal Cytomegalovirus Infection and the Risk of Bronchopulmonary Dysplasia 
JAMA pediatrics  2015;169(12):e153785.
Postnatally acquired cytomegalovirus (CMV) is typically benign in term infants but, in very low birth weight (VLBW) infants, can cause pneumonitis and sepsis-like illness. Whether postnatal CMV infection results in long-term pulmonary sequelae in these infants is unknown.
To investigate the relationship between postnatal CMV infection and bronchopulmonary dysplasia (BPD) and mortality in a large, multicenter cohort of VLBW infants.
Propensity-matched retrospective cohort study.
348 neonatal intensive care units in the United States from 1997–2012.
Hospitalized VLBW (<1500 g) infants.
Postnatal CMV infection was defined as a diagnosis of CMV or detection of CMV from blood, urine, cerebrospinal fluid, or respiratory secretions on or after day of life 21. Infants with a CMV diagnosis or virologic detection of CMV prior to day of life 21 were not considered to have postnatal infection.
Main Outcomes and Measures
We matched infants with postnatal CMV infection 1:1 to comparison infants using propensity scores, and used Poisson regression to examine the effect of postnatal CMV on the combined risk of death or BPD at 36 weeks postmenstrual age. To describe features of postnatal CMV infection, we extracted clinical and laboratory data from 7 days before until 7 days after infants met criteria for postnatal CMV.
Of 101,111 infants, 328 (0.3%) had postnatal CMV infection. We matched a comparison infant to 303 (92%) CMV-infected infants for a final cohort of 606 infants. The median gestational age and birth weight of this cohort were 25 weeks and 730 g, respectively. Postnatal CMV infection was associated with an increased risk of death or BPD at 36 weeks postmenstrual age (risk ratio [RR]: 1.21, 95% confidence interval [CI]: 1.10–1.32) and BPD (RR: 1.33, 95% CI: 1.19–1.50). Changes in cardiorespiratory status associated with postnatal CMV infection included a new requirement for vasopressor medications (9%), intubation for mechanical ventilation (15%), a new oxygen requirement (28%), and death (1.2%).
Conclusions and Relevance
In VLBW infants, postnatal CMV infection was associated with increased risk of BPD. Further studies are needed to determine the role of preventative measures against CMV in this population.
PMCID: PMC4699399  PMID: 26642118
cytomegalovirus; bronchopulmonary dysplasia; postnatal CMV infection
3.  Comparative effectiveness and safety of indomethacin versus ibuprofen for the treatment of patent ductus arteriosus 
Early human development  2015;91(12):725-729.
Patent ductus arteriosus (PDA) is common in extremely premature infants and associated with increased morbidity and mortality. Medical management of PDA uses either indomethacin or ibuprofen. Despite numerous studies, uncertainty exists as to which drug is safer or more effective; we sought to fill this knowledge gap.
We identified infants <28 weeks gestational age discharged from neonatal intensive care units included in the Pediatrix Medical Group Clinical Data Warehouse between 2006 and 2012 who were treated with indomethacin or ibuprofen between postnatal day 2 and 14. Infants treated with both drugs or infants with a congenital malformation were excluded. We used multivariable logistic regression to determine the association of indomethacin versus ibuprofen on clinical outcomes.
Of 6349 patients who met study criteria, 1177 (19%) received ibuprofen and 5172 (81%) received indomethacin. The median gestational age was 25 weeks (interquartile range 24–26), and 2894 (46%) infants were <750 g at birth. On unadjusted analysis, infants who received ibuprofen had significantly higher incidences of death prior to discharge, surgical ligation of the PDA prior to discharge, death or spontaneous intestinal perforation within 7 days of therapy, death or surgical ligation of the PDA prior to discharge, and an elevated creatinine within 7 days of treatment. However, on multivariable analysis, no significant differences in outcomes were observed (odds ratio for death/PDA ligation for ibuprofen vs. indomethacin = 1.12 [95% CI 0.91–1.39]).
We observed similar effectiveness and safety profiles for indomethacin and ibuprofen in the medical management of PDA in premature infants.
PMCID: PMC4662898  PMID: 26386610
premature infants; medical management; bronchopulmonary dysplasia; mortality
4.  Burden of Invasive Staphylococcus aureus Infections in Hospitalized Infants 
JAMA pediatrics  2015;169(12):1105-1111.
Staphylococcus aureus is a frequent cause of infection in hospitalized infants. These infections are associated with increased mortality and morbidity, and longer hospital stays, but data on the burden of S. aureus disease in hospitalized infants are limited.
To compare demographics and mortality of infants with invasive methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA), determine the annual proportion of S. aureus infections that were MRSA, and compare the risk of death following an invasive MRSA infection to the risk following an invasive MSSA infection.
Multicenter retrospective study of a large, nationally representative cohort.
348 neonatal intensive care units managed by the Pediatrix Medical Group.
3888 infants with an invasive S. aureus infection who were discharged between 1997 and 2012.
Invasive S. aureus infection.
Main Outcomes and Measures
Incidence of invasive S. aureus infections. Infant characteristics and mortality following MRSA or MSSA infection.
The 3888 infants had 3978 invasive S. aureus infections (2868 MSSA, 1110 MRSA). The incidence of invasive S. aureus infection was 44.8 infections/10,000 infants. The yearly proportion of invasive infections caused by MRSA increased from 1997 to 2006 and has remained relatively stable since then. Infants with invasive MRSA or MSSA infections had similar gestational ages and birth weights. Invasive MRSA infections occurred more often at a younger postnatal age. For infants with available mortality data, more infants with invasive MSSA infections died at hospital discharge (N=237) than those with invasive MRSA infections (N=110). The proportion of infants who died following invasive MSSA or MRSA infection were similar: 237/2474 (9.6%) and 110/926 (11.9%), P=.05, respectively. Adjusted risk of death at hospital discharge was similar after invasive MSSA and MRSA infections overall (risk ratio, 1.19; 95% CI, 0.96-1.49). Risks of death at 7 and 30 days after invasive infection were similar between infants with invasive MSSA and MRSA infection.
Infant mortality following invasive MRSA and MSSA infections is similar. MSSA causes more infections and more deaths in infants than MRSA. Measures to prevent S. aureus infection should include MSSA in addition to MRSA.
PMCID: PMC4694042  PMID: 26502073
5.  Survival Benefit of Empirical Therapy for Staphylococcus aureus Bloodstream Infections in Infants 
The impact of early adequate empirical antibiotic therapy on outcomes of infants in the neonatal intensive care unit (NICU) who develop Staphylococcus aureus bloodstream infection (BSI) is unknown.
Infants with S. aureus BSI discharged in 1997–2012 from 348 NICUs managed by the Pediatrix Medical Group were identified. Early adequate empirical antibiotic therapy was defined as exposure to ≥1 antibiotic with anti-staphylococcal activity on the day the first positive blood culture was obtained. All other cases were defined as inadequate empirical antibiotic therapy. We evaluated the association between inadequate empirical antibiotic therapy on outcomes controlling for gestational age, small-for-gestational-age status, gender, discharge year, mechanical ventilation, inotropic support, and use of supplemental oxygen. The primary outcome was 30-day mortality. Secondary outcomes were 7-day mortality, death before hospital discharge, and length of bacteremia.
Of the 3339 infants with S. aureus BSI, 2492 (75%) had methicillin-susceptible S. aureus (MSSA) BSI and 847 (25%) had methicillin-resistant S. aureus (MRSA) BSI. Inadequate empirical antibiotic therapy was administered in 725 (22%) cases. Inadequate empirical antibiotic therapy was associated with increased 30-day mortality (odds ratio, 2.03 [95% confidence interval, 1.08, 3.82]) among infants with MRSA BSI. Inadequate empirical antibiotic therapy was not associated with increases in mortality among infants with MSSA BSI.
After controlling for confounders, inadequate empirical antibiotic therapy was associated with a modestly increased mortality at 30 days for infants with MRSA BSI.
PMCID: PMC4604046  PMID: 26222060
infants; early empirical antibiotic therapy; Staphylococcus aureus bloodstream infection; NICU
6.  Association between positive urine cultures and necrotizing enterocolitis in a large cohort of hospitalized infants 
Early human development  2015;91(10):583-586.
We used a large research database to examine the association between urinary tract infections and necrotizing enterocolitis (NEC) in premature infants.
This retrospective data analysis included infants ≤32 weeks gestational age and ≤1500 g at birth who had urine cultures obtained at one of 322 neonatal intensive care units managed by the Pediatrix Medical Group from 1997–2012. The primary outcome was a diagnosis of NEC within 7 days after urine culture. We used multivariable conditional logistic regression conditioned on postnatal age and controlling for gestational age, inotropic support on the day of culture, and mechanical ventilation on the day of culture to evaluate the association between urine culture result and NEC.
We identified 25,816 infants who had 43,556 urine cultures obtained; 6586 (15.1%) of the cultures were positive. A diagnosis of NEC within 7 days after culture was made in 334 (5.1%) of the 6586 positive cultures versus 1582 (4.3%) of the 36,970 negative cultures (p<0.01). On multivariable analysis, infants with any positive urine culture had increased risk of NEC (odds ratio [OR] 1.16, 95% confidence interval [CI] 1.02–1.31); the risk was higher when limited to Gram-negative organisms (OR 1.37, 95% CI 1.17–1.59). The risk of surgical NEC was increased in infants with any positive urine culture (OR 1.46, 95% CI 1.18–1.81) and was also higher when limited to Gram-negative organisms (OR 1.99, 95% CI 1.53–2.59).
Positive urine cultures were associated with increased risk of NEC within 7 days of culture.
PMCID: PMC4575648  PMID: 26226102
neonatal; necrotizing enterocolitis; urinary tract infection
7.  Solithromycin Pharmacokinetics in Plasma and Dried Blood Spots and Safety in Adolescents 
We assessed the pharmacokinetics and safety of solithromycin, a fluoroketolide antibiotic, in a phase 1, open-label, multicenter study of 13 adolescents with suspected or confirmed bacterial infections. On days 3 to 5, the mean (standard deviation) maximum plasma concentration and area under the concentration versus time curve from 0 to 24 h were 0.74 μg/ml (0.61 μg/ml) and 9.28 μg · h/ml (6.30 μg · h/ml), respectively. The exposure and safety in this small cohort of adolescents were comparable to those for adults. (This study has been registered at under registration no. NCT01966055.)
PMCID: PMC4808196  PMID: 26883693
8.  Cefepime and Ceftazidime Safety in Hospitalized Infants 
Cefepime and ceftazidime are cephalosporins used for the treatment of serious gram-negative infections. These cephalosporins are used off-label in the setting of minimal safety data for young infants.
We identified all infants discharged from 348 neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2012 who were exposed to either cefepime or ceftazidime in the first 120 days of life. We reported clinical and laboratory adverse events occurring in infants exposed to cefepime or ceftazidime and used multivariable logistic regression to compare the odds of seizures and death between the 2 groups.
A total of 1761 infants received 13,293 days of ceftazidime, and 594 infants received 4628 days of cefepime. Laboratory adverse events occurred more frequently on days of therapy with ceftazidime compared with cefepime (373 vs. 341 per 1000 infant days, p<0.001). Seizure was the most commonly observed clinical adverse event, occurring in 3% of ceftazidime-treated infants and 4% of cefepime-treated infants (p=0.52). Mortality was similar between the ceftazidime and cefepime groups (5% vs. 3%, p=0.07). There was no difference in the adjusted odds of seizure (odds ratio [OR] = 0.96 [95% confidence interval, 0.89–1.03]) or the combined outcome of mortality or seizures (OR = 1.00 [0.96–1.04]) in infants exposed to ceftazidime vs. those exposed to cefepime.
In this cohort of infants, cefepime was associated with fewer laboratory adverse events than ceftazidime, although this may have been due to a significant difference in clinical exposures and severity of illness between the 2 groups. There was no difference in seizure risk or mortality between the 2 drugs.
PMCID: PMC4573537  PMID: 26376308
9.  Neonatal Escherichia coli Bloodstream Infections: Clinical Outcomes and Impact of Initial Antibiotic Therapy 
Escherichia coli is a common cause of bloodstream infections (BSI) in infants and is associated with high mortality and morbidity among survivors. The clinical significance of antibiotic resistance and timing of appropriate antimicrobial therapy in this population is poorly understood.
We identified all infants with E. coli BSIs discharged from 77 neonatal intensive care units managed by the Pediatrix Medical Group in 2012. We used multivariable logistic regression to evaluate the association between 30-day mortality and ampicillin-resistant E. coli BSI, as well as the number of active empiric antimicrobial agents administered, controlling for gestational age, small-for-gestational age status, early- versus late-onset BSI, oxygen requirement, ventilator support, and inotropic support on the day of the first positive blood culture.
We identified 258 episodes of E. coli BSI, including 123 (48%) ampicillin-resistant isolates. Unadjusted 30-day mortality did not significantly differ between infants with ampicillin-resistant vs. -susceptible E. coli BSI (11/123 [9%] vs. 7/135 [5%]; p=0.33; adjusted odds ratio=1.37 [95% confidence interval 0.39, 4.77]). Among ampicillin-resistant E. coli BSIs, 30-day mortality was not significantly lower for infants treated with at least one empiric antimicrobial active against ampicillin-resistant E. coli vs. infants receiving no active empiric agent (adjusted odds ratio=1.50 [0.07, 33.6]).
In this population of infants with E. coli BSI, ampicillin resistance was not associated with significantly increased mortality. Among the subset of infants with ampicillin-resistant E. coli, appropriate empirical antibiotic therapy was not associated with lower mortality.
PMCID: PMC4581845  PMID: 26065862
Escherichia coli; antimicrobial resistance; early-onset sepsis; late-onset sepsis; bacteremia
10.  Effect of Catheter Dwell Time on Risk of Central Line–Associated Bloodstream Infection in Infants 
Pediatrics  2015;136(6):1080-1086.
Central venous catheters in the NICU are associated with significant morbidity and mortality because of the risk of central line–associated bloodstream infections (CLABSIs). The purpose of this study was to determine the effect of catheter dwell time on risk of CLABSI.
Retrospective cohort study of 13 327 infants with 15 567 catheters (93% peripherally inserted central catheters [PICCs], 7% tunneled catheters) and 256 088 catheter days cared for in 141 NICUs. CLABSI was defined using National Health Surveillance Network criteria. We defined dwell time as the number of days from line insertion until either line removal or day of CLABSI. We generated survival curves for each week of dwell time and estimated hazard ratios for CLABSI at each week by using a Cox proportional hazards frailty model. We controlled for postmenstrual age and year, included facility as a random effect, and generated separate models by line type.
Median postmenstrual age was 29 weeks (interquartile range 26–33). The overall incidence of CLABSI was 0.93 per 1000 catheter days. Increased dwell time was not associated with increased risk of CLABSI for PICCs. For tunneled catheters, infection incidence was significantly higher in weeks 7 and 9 compared with week 1.
Clinicians should not routinely replace uninfected PICCs for fear of infection but should consider removing tunneled catheters before week 7 if no longer needed. Additional studies are needed to determine what daily maintenance practices may be associated with decreased risk of infection, especially for tunneled catheters.
PMCID: PMC4657598  PMID: 26574587
11.  Sedatives and Analgesics Given to Infants in Neonatal Intensive Care Units at the End of Life 
The Journal of pediatrics  2015;167(2):299-304.e3.
To describe the administration of sedatives and analgesics at the end of life in a large cohort of infants in North American neonatal intensive care units (NICUs).
Study design
Data on mortality and sedative and analgesic administration were obtained from infants who died from 1997–2012 in 348 NICUs managed by the Pediatrix Medical Group. Sedatives and analgesics of interest included opioids (fentanyl, methadone, morphine), benzodiazepines (clonazepam, diazepam, lorazepam, midazolam), central alpha-2 agonists (clonidine, dexmedetomidine), ketamine, and pentobarbital. We used multivariable logistic regression to evaluate the association between administration of these drugs on the day of death and infant demographics and illness severity.
We identified 19,726 infants who died. Of these, 6188 (31%) received a sedative or analgesic on the day of death; opioids were most frequently administered, 5366/19,726 (27%). Administration of opioids and benzodiazepines increased during the study period, from 16/283 (6%) for both in 1997 to 523/1465 (36%) and 295/1465 (20%) in 2012, respectively. Increasing gestational age, increasing postnatal age, invasive procedure within 2 days of death, more recent year of death, mechanical ventilation, inotropic support, and antibiotics on the day of death were associated with exposure to sedatives or analgesics.
Administration of sedatives and analgesics increased over time. Infants of older gestational age and those more critically ill were more likely to receive these drugs on the day of death. These findings suggest that drug administration may be driven by severity of illness.
PMCID: PMC4516679  PMID: 26012893
infant deaths; palliative care; comfort drugs
12.  Adverse Events After Routine Immunization of Extremely Low Birth Weight Infants 
JAMA pediatrics  2015;169(8):740-745.
Immunization of extremely low birth weight (ELBW) infants in the neonatal intensive care unit (NICU) is associated with adverse events including fever and apnea/bradycardia in the immediate post-immunization period. This presents a diagnostic dilemma for clinicians, leading to the potential for immunization delay and sepsis evaluations.
To compare the incidence of sepsis evaluations, need for increased respiratory support, intubation, seizures, and death among immunized ELBW infants in the 3 days pre- and post-immunization.
Multicenter retrospective cohort study.
348 NICUs managed by the Pediatrix Medical Group.
13,926 ELBW infants ≤28 weeks gestation who were discharged between 2007 and 2012.
At least one immunization between day of life 53 and 110.
Main Outcomes and Measures
Incidence of sepsis evaluations, need for increased respiratory support, intubation, seizures, and death.
Most (91%) of the infants received 3 or more immunizations. The incidence of sepsis evaluations increased from 5.4/1000 patient days in the pre-immunization period to 19.3/1000 patient days post-immunization (adjusted rate ratio [ARR], 3.7; 95% CI, 3.2–4.4). The need for increased respiratory support increased from 6.6/1000 patient days in the pre-immunization period to 14.0/1000 patient days post-immunization (ARR, 2.1; 95% CI, 1.9–2.5), and intubation increased from 2.0/1000 patient days to 3.6/1000 patient days (ARR, 1.7; 95% CI, 1.3–2.2). The post-immunization incidence of adverse events was similar across immunization types, including combination vaccines when compared to single-dose vaccines. Infants who were 23–24 weeks gestation had a higher risk of sepsis evaluation and intubation post-immunization. A prior history of sepsis was associated with higher risk of sepsis evaluation post-immunization.
ELBW infants in the NICU had an increased incidence of sepsis evaluations as well as increased respiratory support and intubation after routine immunization. Our findings provide no evidence to suggest that clinicians should not use combination vaccines in ELBW infants. Further studies are needed to determine whether timing or spacing of immunization administrations confers risk for the developing adverse events and whether a prior history of sepsis confers risk for an altered immune response in ELBW infants.
PMCID: PMC4523398  PMID: 26030302
13.  Medication use in the neonatal intensive care unit 
American journal of perinatology  2013;31(9):811-822.
We provide an update on medication use in infants admitted to the neonatal intensive care unit (NICU) in the United States and examine how use has changed over time.
Study Design
We performed a retrospective review (2005–2010) of a large prospectively collected administrative database.
Medications most commonly administered during the study period were ampicillin, gentamicin, caffeine citrate, vancomycin, beractant, furosemide, fentanyl, dopamine, midazolam, and calfactant (56–681 exposures per 1000 infants). Those with the greatest relative increase in use included azithromycin, sildenafil, and milrinone. Medications with the greatest relative decrease in use included theophylline, metoclopramide, and doxapram.
Medication use in the NICU has changed substantially over time, and only 35% of the most commonly prescribed medications are FDA-approved in infants.
PMCID: PMC4061287  PMID: 24347262
pharmacotherapy; trends over time
14.  Right ventricular echocardiographic indices predict poor outcomes in infants with persistent pulmonary hypertension of the newborn 
Infants with persistent pulmonary hypertension of the newborn (PPHN) have elevated pulmonary vascular resistance that can lead to right ventricular (RV) failure and death. Clinicians must decide which infants will fail conventional therapy and require transfer to extra corporeal membrane oxygenation (ECMO) centres, but accurate echocardiographic predictors have not been identified. We assessed echocardiographic measurements of RV pressure and function in predicting progression to death or ECMO in infants with PPHN.
Methods and results
Echocardiograms for infants ≥35-week gestation with a clinical diagnosis of PPHN were retrospectively reviewed. Traditional and strain echocardiographic measures were compared for those with or without the primary outcome of ECMO/cardiovascular death. Receiver operator curves identified cut points for measures that were significantly different. Of the 86 subjects analysed, 25 (29%) of the patients had the primary outcome of ECMO/death. The ECMO/death group had diminished tricuspid annular plane systolic excursion (TAPSE; P = 0.002) and RV global longitudinal peak strain (GLPS; P = 0.03), a predominant right-to-left shunt across the patent ductus arteriosus (PDA; P = 0.05), and an elevated oxygenation index (OI; P < 0.001). Sensitivity/specificity for TAPSE <4 mm was 56 and 85%, and for GLPS greater than or equal to −9% was 52 and 77%.
TAPSE, GLPS, and right-to-left PDA shunting were associated with progression to death/ECMO. RV free wall strain was not associated with the outcome, suggesting that diminished global strain better reflects clinical outcomes in this group. These thresholds may assist in the decision-making to transfer high-risk infants to ECMO centres.
PMCID: PMC4609160  PMID: 25851325
persistent pulmonary hypertension; echocardiogram; mortality; ECMO; strain
15.  Safety of octreotide in hospitalized infants 
Early human development  2015;91(7):387-392.
Octreotide is used off-label in infants for treatment of chylothorax, congenital hyperinsulinism, and gastrointestinal bleeding. The safety profile octreotide in hospitalized infants has not been described; we sought to fill this information gap.
We identified all infants exposed to at least 1 dose of octreotide from a cohort of 887,855 infants discharged from 333 neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2012. We collected laboratory and clinical information while infants were exposed to octreotide and described the frequency of baseline diagnoses, laboratory abnormalities, and adverse events (AEs).
A total of 428 infants received 490 courses of octreotide. The diagnoses most commonly associated with octreotide use were chylothorax (50%), pleural effusion (32%), and hypoglycemia (22%). The most common laboratory AEs that occurred during exposure to octreotide were thrombocytopenia (47/1000 infant-days), hyperkalemia (21/1000 infant-days), and leukocytosis (20/1000 infant-days). Hyperglycemia occurred in 1/1000 infant-days and hypoglycemia in 3/1000 infant-days. Hypotension requiring pressors (12%) was the most common clinical AE that occurred during exposure to octreotide. Necrotizing enterocolitis was observed in 9/490 (2%) courses, and death occurred in 11 (3%) infants during octreotide administration.
Relatively few AEs occurred during off-label use of octreotide in this cohort of infants. Additional studies are needed to further evaluate the safety, dosing, and efficacy of this medication in infants.
PMCID: PMC4450124  PMID: 25968047
octreotide; safety; infant; drug toxicity
16.  Management Practice and Mortality for Infants with Congenital Diaphragmatic Hernia 
American journal of perinatology  2015;32(9):887-894.
Congenital diaphragmatic hernia (CDH) is fatal in 20–40% of cases, largely due to pulmonary dysmaturity, lung hypoplasia, and persistent pulmonary hypertension. Evidence for survival benefit of inhaled nitric oxide (iNO), extracorporeal membrane oxygenation (ECMO), and other medical interventions targeting pulmonary hypertension is lacking. We assessed medical interventions and mortality over time in a large multicenter cohort of infants with CDH.
Study Design
We identified all infants ≥34 weeks gestation with CDH discharged from 29 neonatal intensive care units between 1999 and 2012 with an average of ≥2 CDH admissions per year. We examined mortality and the proportion of infants exposed to medical interventions, comparing 4 periods of time: 1999–2001, 2002–2004, 2005–2007, and 2008–2012.
We identified 760 infants with CDH. From 1999–2001 to 2008–2012, use of iNO increased from 20% of infants to 50%, sildenafil use increased from 0% to 14%, and milrinone use increased from 0% to 22% (p<0.001). Overall mortality (28%) did not significantly change over time compared with the earliest time period.
Despite changing use of iNO, sildenafil, and milrinone, CDH mortality has not significantly decreased in this population of infants.
PMCID: PMC4516623  PMID: 25715314
infants; congenital diaphragmatic hernia; lung dysmaturity; lung hypoplasia; pulmonary hypertension; respiratory management
17.  Necrotizing Enterocolitis in Infants with Ductal-Dependent Congenital Heart Disease 
American journal of perinatology  2014;32(7):633-638.
Infants with congenital heart disease (CHD) receiving prostaglandins (PGE) may be at increased risk for necrotizing enterocolitis (NEC). Enteral feeding may further increase risk of NEC in these patients. We evaluated the incidence of NEC and its association with enteral feeding in infants with ductal-dependent CHD.
Study Design
We examined a cohort of infants with CHD receiving PGE in neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2010. We used logistic regression to evaluate the association between NEC and enteral feeding, as well as other risk factors including antacid medications, inotropic and ventilator support, and anatomic characteristics, controlling for gestational age.
We identified 6710 infants with ductal-dependent CHD receiving PGE for 17,158 infant days. NEC occurred in 21 of 6710 (0.3%) infants, of whom 12/21(57%) were <37 weeks gestational age. The incidence of NEC was 1.2/1000 infant days while on enteral feeds versus 0.4/1000 infant days while not on enteral feeds (p=0.27). Enteral feeding was not associated with a statistically significant increased odds of NEC on the day of diagnosis (odds ratio [OR] 2.08; 95% confidence interval [CI] 0.38, 11.7). Risk factors associated with a significant increased odds of NEC included a diagnosis of single-ventricle heart defect (OR 2.82; 95% CI 1.23, 6.49), although the overall risk in this population remained low (8/1631, 0.5%).
The incidence of NEC in our cohort of infants with ductal-dependent CHD on PGE therapy was low and did not increase with enteral feeding.
PMCID: PMC4449801  PMID: 25486286
single-ventricle anomaly; neonatal intensive care; prostaglandin E1; NPO
18.  No Survival Benefit with Empirical Vancomycin Therapy for Coagulase-negative Staphylococcal Bloodstream Infections in Infants 
Coagulase-negative Staphylococcus (CoNS) is the most common cause of bloodstream infections (BSI) in hospitalized infants. CoNS BSI is most reliably treated with vancomycin; however, concerns about side effects and promoting resistance often delay empirical vancomycin therapy until culture results become available.
All infants with CoNS BSI discharged from 348 neonatal intensive care units managed by the Pediatrix Medical Group from 1997–2012 were identified. Empirical vancomycin therapy was defined as vancomycin exposure on the day of the first positive blood culture. Delayed vancomycin therapy was defined as vancomycin exposure 1–3 days after the first positive blood culture. We used multivariable logistic regression with random effects for site to evaluate the association between the use of empirical vancomycin therapy vs. delayed vancomycin therapy and 30-day mortality, controlling for gestational age, small-for-gestational age status, postnatal age on the day of the first positive culture, oxygen requirement, ventilator support, and inotropic support on the day the first positive culture was obtained.
Of the 4364 infants with CoNS BSI, 2848 (65%) were treated with empirical vancomycin. The median postnatal age at first positive culture was 14 days (interquartile range: 9, 21). Unadjusted 30-day mortality was similar for infants treated with empirical vancomycin and infants treated with delayed vancomycin therapy (166/2848 [6%] vs. 69/1516 [4%]; p=0.08). There was no significant difference in 30-day mortality on multivariable analysis (odds ratio: 1.14 [0.84, 1.56]). The median duration of bacteremia was 1 day longer for infants with delayed vancomycin therapy (4 days [interquartile range 2, 6] vs. 3 days [2, 5]; p<0.0001).
The median duration of bacteremia was 1 day longer in infants with CoNS BSI who received delayed vancomycin therapy. Despite this finding, empirical vancomycin therapy for CoNS BSI was not associated with improved mortality.
PMCID: PMC4357312  PMID: 25760564
late-onset sepsis; NICU
19.  Use and safety of erythromycin and metoclopramide in hospitalized infants 
Prokinetic medications are used in premature infants to promote motility and decrease time to full enteral feeding. Erythromycin and metoclopramide are the most commonly used prokinetic medications in the neonatal intensive care unit (NICU), but their safety profile is not well defined.
We conducted a large retrospective cohort study using data from 348 NICUs managed by the Pediatrix Medical Group. All infants exposed to ≥1 dose of erythromycin, metoclopramide, or both, from a cohort of 887,910 infants discharged between 1997 and 2012 were included. We collected laboratory and clinical information while infants were exposed to erythromycin or metoclopramide and described the frequency of laboratory abnormalities and clinical adverse events.
Metoclopramide use increased from 1997–2005 and decreased from 2005–2012, while erythromycin use remained stable. Erythromycin use was most often associated with a diagnosis of feeding problem (40%), while metoclopramide was most often associated with a diagnosis of gastroesophageal reflux (59%). The most common laboratory adverse event during exposure to erythromycin or metoclopramide was hyperkalemia (8.6/1000 infant days on erythromycin and 11.0/1000 infant days on metoclopramide). Incidence of pyloric stenosis was greater with erythromycin than with metoclopramide (10/1095, 0.9% vs. 76/19,001, 0.4%, p=0.01), but odds were not significantly increased after adjusting for covariates (odds ratio=0.52 [95% CI: 0.26, 1.02], p=0.06). More infants experienced an adverse event while treated with metoclopramide than with erythromycin (odds ratio=1.21 [95% CI: 1.03, 1.43]).
Metoclopramide was associated with increased risk of adverse events compared to erythromycin. Studies are needed to confirm safety and effectiveness of both drugs in infants.
PMCID: PMC4553109  PMID: 25806675
20.  Anaerobic Antimicrobial Therapy After Necrotizing Enterocolitis in VLBW Infants 
Pediatrics  2015;135(1):e117-e125.
To evaluate the effect of anaerobic antimicrobial therapy for necrotizing enterocolitis (NEC) on clinical outcomes in very low birth weight (≤1500 g) infants.
We identified very low birth weight infants with NEC from 348 US NICUs from 1997 to 2012. Anaerobic antimicrobial therapy was defined by antibiotic exposure on the first day of NEC. We matched (1:1) infants exposed to anaerobic antimicrobial therapy with infants who were not exposed by using a propensity score stratified by NEC severity (medical and surgical). The primary composite outcome was in-hospital death or intestinal stricture. We assessed the relationship between anaerobic antimicrobial therapy and outcome by using a conditional logistic regression on the matched cohort.
A total of 1390 infants exposed to anaerobic antimicrobial therapy were matched with 1390 infants not exposed. Mean gestational age and birth weight were 27 weeks and 946 g, respectively, and were similar in both groups. We found no significant difference in the combined outcome of death or strictures, but strictures as a single outcome were more common in the anaerobic antimicrobial therapy group (odds ratio 1.73; 95% confidence interval, 1.11–2.72). Among infants with surgical NEC, mortality was less common with anaerobic antimicrobial therapy (odds ratio 0.71; 95% confidence interval, 0.52–0.95).
Anaerobic antimicrobial therapy was not associated with the composite outcome of death or strictures but was associated with an increase in intestinal strictures. This higher incidence of intestinal strictures may be explained by the fact that death is a competing outcome for intestinal strictures, and mortality was slightly lower in the anaerobic cohort. Infants with surgical NEC who received anaerobic antimicrobial therapy had lower mortality.
PMCID: PMC4279070  PMID: 25511117
necrotizing enterocolitis; very low birth weight infants; anaerobes; antibiotics; mortality; intestinal strictures
21.  Dosing in neonates: Special considerations in physiology and trial design 
Pediatric research  2014;77(0):2-9.
Determining the right dose for drugs used to treat neonates is critically important. Neonates have significant differences in physiology affecting drug absorption, distribution, metabolism, and elimination that makes extrapolating dosages from adults and older children inappropriate. In spite of recent legislative efforts requiring drug studies in this population, most drugs given to neonates remain insufficiently studied. Many ethical and logistical concerns make designing studies in this age group difficult. Fortunately, specialized analytical techniques, such as the use of dried blood spots, scavenged sampling, population pharmacokinetics analyses, and sparse sampling, have helped investigators better define doses that maximize efficacy and safety. Through the use of these methods, successful clinical trials have resulted in recent changes to drug dosing in this population.
PMCID: PMC4268272  PMID: 25268145
22.  Baseline Urinary Glucose Tetrasaccharide Concentrations in Patients with Infantile- and Late-Onset Pompe Disease Identified by Newborn Screening 
JIMD Reports  2015;19:67-73.
Purpose: The urinary glucose tetrasaccharide, Glcα1-6Glcα1-4Glcα1-4Glc (Glc4), is a biomarker of glycogen accumulation and tissue damage and is elevated in patients with Pompe disease. We report baseline urinary Glc4 concentrations for patients with classic infantile-onset or late-onset Pompe disease, and those with a pseudodeficiency of acid alpha-glucosidase (GAA), identified through newborn screening (NBS) in Taiwan.
Methods: Infants identified through NBS with (1) classic infantile-onset Pompe disease (NBS-IOPD) (n = 7) defined as patients with evidence for hypertrophic cardiomyopathy by EKG, X-ray, and echocardiogram, (2) a late-onset phenotype (NBS-LOPD) (n = 13) defined as patients without evidence for cardiomyopathy, (3) a GAA pseudodeficiency (n = 58), and (4) one patient with LOPD diagnosed in infancy due to family history were consented to the study. Four infants diagnosed after the onset of clinical symptoms (CLIN-IOPD) were included for comparison. Glc4 concentrations in dried urine samples on filter paper were determined using tandem mass spectrometry.
Results: Baseline Glc4 concentrations were at or above the 90th centile of the age-matched reference range for the NBS-IOPD cohort. The median Glc4 level for this group was lower than that of the CLIN-IOPD group, although not at the level of significance (p = 0.07), but was significantly higher than that of the NBS-LOPD group (p < 0.05). Baseline Glc4 was not elevated for the NBS-LOPD and GAA pseudodeficiency cohorts and remained low for late-onset patients that did not require treatment before the age of three years.
Conclusion: Baseline urinary Glc4 is elevated in neonates with infantile-onset Pompe disease identified through NBS.
Electronic supplementary material
The online version of this chapter (doi:10.1007/8904_2014_366) contains supplementary material, which is available to authorized users.
PMCID: PMC4501239  PMID: 25681082
Biomarker; Glucose tetrasaccharide; Newborn screening; Pompe disease; Tandem mass spectrometry
23.  Treatment of supraventricular tachycardia in infants: analysis of a large multicenter database 
Early human development  2015;91(6):345-350.
Supraventricular tachycardia (SVT) is the most common arrhythmia in infants. Infants are typically treated with antiarrhythmic medications, but there is a lack of evidence guiding management, thus exposing infants to risks of both inadequate therapy and medication adverse events. We used data from a large clinical database to better understand current practices in SVT management, safety of commonly used medications, and outcomes of hospitalized infants treated for SVT.
This retrospective data analysis included all infants discharged from Pediatrix Medical Group neonatal intensive care units between 1998 and 2012 with a diagnosis of SVT who were treated with antiarrhythmic medications. We categorized infants by presence of congenital heart disease other than patent ductus arteriosus. Medications were categorized as abortive, acute, or secondary prevention therapies. We used descriptive statistics to describe medication use, adverse events, and outcomes including SVT recurrence and mortality.
A total of 2848 infants with SVT were identified, of whom 367 (13%) had congenital heart disease. Overall, SVT in-hospital recurrence was high (13%), and almost one fifth of our cohort (18%) experienced an adverse event. Mortality was 2% in the overall cohort and 6% in the congenital heart disease group (p<0.001). Adenosine was the most commonly used abortive therapy, but there was significant practice variation in therapies used for acute treatment and secondary prevention of SVT.
Conclusion and Practice Implication
Significant variation in SVT treatment and suboptimal outcomes warrant future clinical trials to determine best practices in treating SVT in infants.
PMCID: PMC4433846  PMID: 25933212
supraventricular tachycardia; infants; anti-arrhythmic
24.  Sildenafil and Retinopathy of Prematurity Risk in Very Low Birth Weight Infants 
To examine the effect of sildenafil therapy on development of severe retinopathy of prematurity (ROP) requiring surgical intervention in premature infants.
Study Design
We identified premature infants who were discharged from Pediatrix Medical Group neonatal intensive care units from 2003–2012 and who received an ophthalmologic exam. We matched each infant exposed to sildenafil prior to first eye exam to three non-exposed infants using propensity scoring to control for differences in baseline infant characteristics. We evaluated the association between sildenafil exposure and development of severe ROP using conditional logistic regression.
Of the 57815 infants meeting inclusion criteria, 88 were exposed to sildenafil. We matched 81/88 (92%) sildenafil-exposed with 243 non-exposed infants. There was no difference in the proportion of infants who developed severe ROP in the sildenafil-exposed vs. non-exposed groups (17/81 [21%] vs. 38/243 [16%], P=0.27). On adjusted analysis, there was no difference in severe ROP in the sildenafil-exposed versus non-exposed infants (odds ratio=1.46, 95% confidence interval=0.76–2.82, P=0.26).
We did not observe an association between risk of severe ROP and sildenafil exposure prior to first eye exam in this cohort of premature infants.
PMCID: PMC4731250  PMID: 26491852
25.  Late-Onset Bloodstream Infections in Hospitalized Term Infants 
The epidemiology and incidence of late-onset bloodstream infections (BSIs) in premature infants has been described, but studies describing late-onset BSI in term infants are sparse. We sought to describe the pathogens, incidence, risk factors, and mortality of late-onset BSI in hospitalized term infants.
A cohort study was conducted of infants ≥37 weeks gestational age and ≤120 days old discharged from Pediatrix Medical Group neonatal intensive care units from 1997–2010. We examined all cultures obtained from day of life (DOL) 4–120 and used multivariable regression to assess risk factors for late-onset BSI.
We found a total of 206,019 infants cared for between DOL 4 and 120, and the incidence of late-onset BSI was 2.7/1000 admissions. We identified Gram-positive organisms in 64% of the cultures and Gram-negative organisms in 26%. We found a decreased risk of late-onset BSI in infants with the following characteristics: small for gestational age, delivery by Cesarean section, antenatal antibiotic use, and discharged in the later years of the study. Late-onset BSI increased the risk of death after controlling for confounders (odds ratio 8.43 [95% confidence interval 4.42, 16.07]).
Our data highlight the importance of late-onset BSI in hospitalized term infants. We identified Gram-positive organisms as the most common pathogen, and late-onset BSI was an independent risk factor for death.
PMCID: PMC4160433  PMID: 24618934
sepsis; infant; term birth; infection

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