Prolonged Tracheal Intubation and the Association Between Patent Ductus Arteriosus and Bronchopulmonary Dysplasia: A Secondary Analysis of the PDA-TOLERATE trial.

In the PDA-TOLERATE trial, persistent (even for several weeks) moderate to large patent ductus arteriosus (PDA) was not associated with an increased risk of BPD when the infant required <10 days of intubation. However, in infants requiring intubation for ≥10 days, prolonged PDA exposure (≥11 days) was associated with an increased risk of moderate/severe BPD.

Lack of Equipoise in the PDA-TOLERATE Trial: A Comparison of Eligible Infants Enrolled in the Trial and Those Treated Outside the Trial.

The PDA: TO LEave it alone or Respond And Treat Early trial compared the effects of 2 strategies for treatment of patent ductus arteriosus (PDA) in infants <280/7 weeks of gestation; however 137 potentially eligible infants were not recruited and received treatment of their PDA outside the PDA-TOLERATE trial due to "lack-of-physician-equipoise" (LPE). Despite being less mature and needing more respiratory support, infants with LPE had lower rates of mortality than enrolled infants. Infants with LPE treated before day 6 had lower rates of late respiratory morbidity than infants with LPE treated ≥day 6. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01958320.

PDA-TOLERATE Trial: An Exploratory Randomized Controlled Trial of Treatment of Moderate-to-Large Patent Ductus Arteriosus at 1 Week of Age.

OBJECTIVE: To compare early routine pharmacologic treatment of moderate-to-large patent ductus arteriosus (PDA) at the end of week 1 with a conservative approach that requires prespecified respiratory and hemodynamic criteria before treatment can be given. STUDY DESIGN: A total of 202 neonates of <28 weeks of gestation age (mean, 25.8 ± 1.1 weeks) with moderate-to-large PDA shunts were enrolled between age 6 and 14 days (mean, 8.1 ± 2.2 days) into an exploratory randomized controlled trial. RESULTS: At enrollment, 49% of the patients were intubated and 48% required nasal ventilation or continuous positive airway pressure. There were no differences between the groups in either our primary outcome of ligation or presence of a PDA at discharge (early routine treatment [ERT], 32%; conservative treatment [CT], 39%) or any of our prespecified secondary outcomes of necrotizing enterocolitis (ERT, 16%; CT, 19%), bronchopulmonary dysplasia (BPD) (ERT, 49%; CT, 53%), BPD/death (ERT, 58%; CT, 57%), death (ERT,19%; CT, 10%), and weekly need for respiratory support. Fewer infants in the ERT group met the rescue criteria (ERT, 31%; CT, 62%). In secondary exploratory analyses, infants receiving ERT had significantly less need for inotropic support (ERT, 13%; CT, 25%). However, among infants who were ≥26 weeks gestational age, those receiving ERT took significantly longer to achieve enteral feeding of 120 mL/kg/day (median: ERT, 14 days [range, 4.5-19 days]; CT, 6 days [range, 3-14 days]), and had significantly higher incidences of late-onset non-coagulase-negative Staphylococcus bacteremia (ERT, 24%; CT,6%) and death (ERT, 16%; CT, 2%). CONCLUSIONS: In preterm infants age <28 weeks with moderate-to-large PDAs who were receiving respiratory support after the first week, ERT did not reduce PDA ligations or the presence of a PDA at discharge and did not improve any of the prespecified secondary outcomes, but delayed full feeding and was associated with higher rates of late-onset sepsis and death in infants born at ≥26 weeks of gestation. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01958320.

Transcutaneous bilirubin levels in extremely preterm infants less than 30 weeks gestation.

OBJECTIVE: The primary objective of this study was to determine the relationship between transcutaneous bilirubin (TcB) levels and total serum bilirubin (TSB) levels in extremely preterm infants. STUDY DESIGN: We conducted a prospective multicenter study of extremely preterm infants less than 30 weeks gestation in California. Difference between paired TcB and TSB values were compared based on gestational age, birth weight, maternal race/ethnicity, chronological age as well as during and after phototherapy. RESULTS: TSB values ranged from 0 to 12.6 mg/dl and the TcB values ranged from 0 to 14.2 mg/dl. TSB was predicted with a high degree of accuracy at TSB = 2.37 + 0.54 (TcB) with r = 0.786. There was good correlation across gestational age, birth weight, race/ethnic, chronological age subgroups as well as during and after phototherapy. CONCLUSION: Our study supports the use of TcB as a screening tool for monitoring jaundice in extremely preterm infants.

Barriers to optimal breast milk provision in the neonatal intensive care unit.

OBJECTIVE: This study examines comprehensive patient and process factors that influence breast milk use in the NICU setting. STUDY DESIGN: We examined the association of maternal, neonatal, and family factors and lactation support systems to identify gaps in breast milk use in a retrospective study of 865 infants born in 23-41 weeks gestation admitted to the NICU. RESULTS: Breast milk at discharge for all infants was 89.3%, for extremely preterm 82.3%, moderately preterm 91.4%, late preterm 86.5%, and term 92.7%. Prematurity (OR 0.31 [0.17-0.56]), low birth weight, morbidities, Black maternal race (OR 0.20 [0.07-0.57]) and public insurance (OR 0.54 [0.34-0.85]) were associated with decreased breast milk use. Early initiation of feeds was associated with increased breast milk use. CONCLUSIONS: There is a need to increase social as well as hospital support systems to address gaps in breast milk use in the NICU.

Does crossover treatment of control subjects invalidate results of randomized trials of patent ductus arteriosus treatment?

Optimal management of patent ductus arteriosus (PDA) in extremely preterm infants remains controversial. There is paucity of evidence on the benefits of PDA treatment in reducing mortality and morbidities in extremely preterm infants. Failure of randomized clinical trials to demonstrate beneficial effects of PDA treatment on outcomes has often been attributed to open treatment of control subjects. This perspective examines the PDA treatment trials to date, with specific focus on rates of and ages of subjects at open rescue treatment. Although these trials demonstrate that ductal closure is significantly increased with treatment, that does not translate to a significant decrease in major morbidities or mortality in premature infants, even when trials with high rates of rescue treatment of controls are excluded. Trials in which enrollment occurred after 7 days of age include insufficient numbers of subjects to evaluate this relationship.

PDA: To treat or not to treat.

Management of patent ductus arteriosus in extremely preterm infants remains a topic of debate. Treatment to produce ductal closure was widely practiced until the past decade, despite lack of evidence that it decreases morbidities or mortality. Meta-analyses of trials using nonsteroidal anti-inflammatory drugs have shown effectiveness in accelerating ductal closure, but no reduction in neonatal morbidities, regardless of agent used, indication, timing, gestational age, or route of administration. Surgical ligation closes the ductus but is associated with adverse effects. Recent experience with conservative approaches to treatment suggest improved neonatal outcomes and a high rate of spontaneous ductal closure after discharge. Careful postdischarge follow-up is important, however, because potential adverse effects of long-standing aortopulmonary shunts may be an indication for catheter-based ductal closure. Identification of extremely preterm infants at greatest risk of potential harm from a persistently patent ductus, who may benefit most from treatment are urgently needed.

Comparative effectiveness of drugs used to constrict the patent ductus arteriosus: a secondary analysis of the PDA-TOLERATE trial (NCT01958320).

OBJECTIVE: To evaluate the effectiveness of drugs used to constrict patent ductus arteriosus (PDA) in newborns < 28 weeks. METHODS: We performed a secondary analysis of the multi-center PDA-TOLERATE trial (NCT01958320). Infants with moderate-to-large PDAs were randomized 1:1 at 8.1 ± 2.1 days to either Drug treatment (n = 104) or Conservative management (n = 98). Drug treatments were assigned by center rather than within center (acetaminophen: 5 centers, 27 infants; ibuprofen: 7 centers, 38 infants; indomethacin: 7 centers, 39 infants). RESULTS: Indomethacin produced the greatest constriction (compared with spontaneous constriction during Conservative management): RR (95% CI) = 3.21 (2.05-5.01)), followed by ibuprofen = 2.03 (1.05-3.91), and acetaminophen = 1.33 (0.55-3.24). The initial rate of acetaminophen-induced constriction was 27%. Infants with persistent moderate-to-large PDA after acetaminophen were treated with indomethacin. The final rate of constriction after acetaminophen ± indomethacin was 60% (similar to the rate in infants receiving indomethacin-alone (62%)). CONCLUSION: Indomethacin was more effective than acetaminophen in producing ductus constriction.

Parents' Knowledge and Education of Retinopathy of Prematurity in Four California Neonatal Intensive Care Units.

PURPOSE: Retinopathy of prematurity (ROP) may cause visual impairment in infants with very low birth weight. Lack of parent knowledge may contribute to gaps in screening and treatment. We studied parents' knowledge and education of ROP. DESIGN: Cross-sectional study. METHODS: Setting: Four high-acuity neonatal intensive care units in California (40-84 beds). PARTICIPANTS: Total of 194 English- and Spanish-speaking parents of very low birth weight (<1500 grams) infants recruited from September 2013 to April 2015. MAIN OUTCOME MEASURES: We asked parents what they knew about ROP, how they were educated about ROP, and their experiences obtaining outpatient eye care. We used multivariate analysis to assess whether parent knowledge was associated with level of English proficiency and literacy, education modality (verbal, written, online, video), and hospital transfer status. RESULTS: Of the 194 participants, 131 (68%) completed surveys: 18% had both limited English proficiency and low literacy while overall 26% had limited English proficiency and 37% had low literacy; 17% did not know that ROP is an eye disease, and 38% did not know that very low birth weight and prematurity are both risk factors for ROP. Parents reported receiving verbal (62%) or written (56%) information; few used online resources (12%) or videos (3%). Half reported receiving information about infants' retinopathy status at discharge. No education modality was associated with higher knowledge. Limited English proficiency and low literacy were associated with lower knowledge (vs English-proficient, literate). CONCLUSIONS: Parents of infants with very low birth weight, particularly those with limited English proficiency and low health literacy, lack knowledge about ROP.

Comparative effectiveness and safety of indomethacin versus ibuprofen for the treatment of patent ductus arteriosus.

BACKGROUND: 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. METHODS: We identified infants <28weeks 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 days 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. RESULTS: Of 6349 patients who met study criteria, 1177 (19%) received ibuprofen and 5172 (81%) received indomethacin. The median gestational age was 25weeks (interquartile range 24-26), and 2894 (46%) infants were <750g 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 7days of therapy, death or surgical ligation of the PDA prior to discharge, and an elevated creatinine within 7days 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]). CONCLUSIONS: We observed similar effectiveness and safety profiles for indomethacin and ibuprofen in the medical management of PDA in premature infants.