Betamethasone treatment-to-delivery interval, retreatment, and severe intraventricular hemorrhage in infants <28 weeks' gestation.

BACKGROUND: Antenatal corticosteroids decrease the incidence of severe intraventricular hemorrhages (grades 3,4) in preterm infants. It is unclear whether their beneficial effects on intraventricular hemorrhage wane with time (as occurs in neonatal respiratory distress) and if repeat courses can restore this effect. Prior randomized controlled trials of betamethasone retreatment found no benefit on severe intraventricular hemorrhage rates. However, the trials may have included an insufficient number of infants at risk for intraventricular hemorrhage to be able to adequately address this question. Severe intraventricular hemorrhages occur almost exclusively in infants born <28 weeks, whereas only 7% (0%-16%) of the retreatment trials' populations were <28 weeks. OBJECTIVE: To determine if the risk of severe intraventricular hemorrhage in infants delivered <28 weeks increases when the betamethasone treatment-to-delivery interval increases beyond 9 days and to determine if betamethasone retreatment prior to delivery decreases the rate of hemorrhage. STUDY DESIGN: Observational study examining the incidence of intraventricular hemorrhage before (epoch 1) and after (epoch 2) a practice change that encouraged obstetricians to retreat pregnant women still at high risk of delivery before 28 weeks' gestation when >9 days elapsed from the first dose of betamethasone. Multivariable analyses with logistic regression using generalized estimating equations techniques were conducted to examine the rates of intraventricular hemorrhage among 410 infants <28 weeks' gestation who either delivered between 1-9 days (n=290) after the first 2-dose betamethasone course or delivered ≥10 days (and eligible for retreatment) (n=120). RESULTS: After adjusting for potential confounding variables, infants who delivered ≥10 days after a single betamethasone course had an increased risk of either severe intraventricular hemorrhage alone or the combined outcome severe intraventricular hemorrhage or death before 4 days (OR (95%CI): 2.8 (1.2, 6.6)) compared with infants who delivered between 1-9 days after betamethasone. Among the 120 infants who delivered ≥10 days after the first dose of betamethasone, 64 (53%) received a second/retreatment course of antenatal betamethasone. The severe intraventricular hemorrhage rate in infants whose mothers received a second/retreatment course of betamethasone was similar to the rate in infants who delivered within 1-9 days and significantly lower than in those who delivered ≥10 days without retreatment (OR (95%CI): 0.10 (0.02, 0.65). Following the change in guidelines, the rate of retreatment in infants who delivered ≥10 days after the first betamethasone course (and before 28 weeks) increased from epoch 1 to epoch 2 (25% to 87%, p<0.001) and the rate of severe intraventricular hemorrhage decreased from 22% to 0% (p<0.001). In contrast, the rate of severe intraventricular hemorrhage in infants who delivered 1-9 days after the initial betamethasone dose (who were not eligible for retreatment) did not change between epochs 1 and 2 (12% and 11%, respectively). CONCLUSIONS: Although betamethasone's benefits on severe intraventricular hemorrhage appear to wane after the first dose, retreatment with a second course appears to restore its beneficial effects. Encouraging earlier retreatment of women at high risk of delivery before 28 weeks was associated with a lower rate of severe intraventricular hemorrhages among infants delivering <28 weeks.

Correction: Accelerated weight gain, prematurity, and the risk of childhood obesity: A meta-analysis and systematic review.

[This corrects the article DOI: 10.1371/journal.pone.0232238.].

All Care is Brain Care: Neuro-Focused Quality Improvement in the Neonatal Intensive Care Unit.

Neonates requiring intensive care are in a critical period of brain development that coincides with the neonatal intensive care unit (NICU) hospitalization, placing these infants at high risk of brain injury and long-term neurodevelopmental impairment. Care in the NICU has the potential to be both harmful and protective to the developing brain. Neuro-focused quality improvement efforts address 3 main pillars of neuroprotective care: prevention of acquired injury, protection of normal maturation, and promotion of a positive environment. Despite challenges in measurement, many centers have shown success with consistent implementation of best and potentially better practices that may improve markers of brain health and neurodevelopment.

Improving the Rate of Delayed Cord Clamping in Preterm Infants: A Quality Improvement Project.

OBJECTIVE: Delayed cord clamping (DCC) provides many benefits for preterm infants. The aim of this quality improvement project was to increase the rate of DCC by 25% within 12 months for neonates <34 weeks' gestation born at a tertiary care hospital. METHOD: A multidisciplinary team investigated key drivers and developed targeted interventions to improve DCC rates. The primary outcome measure was the rate of DCC for infants <34 weeks' gestation. Process measures were adherence to the DCC protocol and the rate of births with an experienced neonatology provider present at the bedside. Balancing measures included the degree of neonatal resuscitation, initial infant temperature, and maternal blood loss. Data were collected from chart review and a perinatal research database and then analyzed on control charts. The preintervention period was from July 2019 to June 2020 and the postintervention period was from July 2020 to December 2021. RESULTS: 322 inborn neonates born at <34 weeks' met inclusion criteria (137 preintervention and 185 postintervention). The rate of DCC increased by 63%, from a baseline of 40% to 65% (P <.001), with sustained improvement over 18 months. Significant improvement occurred for all process measures without a significant change in balancing measures. CONCLUSION: Using core quality improvement methodology, a multidisciplinary team implemented a series of targeted interventions which was associated with an increased rate of DCC in early preterm infants.

Reduction of Severe Intraventricular Hemorrhage in Preterm Infants: A Quality Improvement Project.

OBJECTIVES: The aim of this quality improvement project was to reduce the rate of severe intraventricular hemorrhage (sIVH) by 50% within 3 years for extremely preterm infants born at a children's teaching hospital. METHODS: A multidisciplinary team developed key drivers for the development of intraventricular hemorrhage in preterm infants. Targeted interventions included the development of potentially better practice guidelines, promoting early noninvasive ventilation, consistent use of rescue antenatal betamethasone, and risk-based indomethacin prophylaxis. The outcome measure was the rate of sIVH. Process measures included the rate of intubation within 24 hours and receipt of rescue betamethasone and risk-based indomethacin prophylaxis. Common markers of morbidity were balancing measures. Data were collected from a quarterly chart review and analyzed with statistical process control charts. The preintervention period was from January 2012 to March 2016, implementation period was from April 2016 to December 2018, and sustainment period was through June 2020. RESULTS: During the study period, there were 268 inborn neonates born at <28 weeks' gestation or <1000 g (127 preintervention and 141 postintervention). The rate of sIVH decreased from 14% to 1.2%, with sustained improvement over 2 and a half years. Mortality also decreased by 50% during the same time period. This was associated with adherence to process measures and no change in balancing measures. CONCLUSIONS: A multipronged quality improvement approach to intraventricular hemorrhage prevention, including evidence-based practice guidelines, consistent receipt of rescue betamethasone and indomethacin prophylaxis, and decreasing early intubation was associated with a sustained reduction in sIVH in extremely preterm infants.

Increasing Early Skin-to-Skin in Extremely Low Birth Weight Infants.

BACKGROUND: Early skin-to-skin care (SSC) has been shown to improve outcomes after preterm birth, including improved clinical stability and establishment of breastfeeding. Recent evidence suggests the most unstable infants get the most benefit, yet these infants are not consistently offered opportunities for SSC because of safety concerns and discomfort of the care team. PURPOSE: To identify barriers and implement a multidimensional approach to increase SSC within the first 72 hours of life among infants born less than 28 weeks' gestation and less than 1,000 g in a Level IV university-based regional intensive care nursery. METHODS: Using Institute of Healthcare Improvement quality improvement methodology, a multidisciplinary team identified barriers to SSC and developed targeted interventions, including a unit-specific protocol; widespread parent, staff, and provider education; and an infant readiness checklist. The primary outcome was the rate of SSC within 72 hours. The balancing measure was the rate of severe intraventricular hemorrhage (IVH). Data were collected from monthly chart review and analyzed with statistical process control charts. The aim was to increase SSC within 72 hours of birth from 7 percent to greater than 80 percent within 12 months for infants born less than 28 weeks' gestation or less than 1,000 g. RESULTS: Between June 2017 and December 2019, there were 52 extremely preterm infants included in the project (15 preintervention and 37 postintervention). The rate of SSC within the first 72 hours increased from 7 to 84 percent. There has been no increase in any or severe IVH during the project period despite the increased rate of SSC. IMPLICATIONS FOR PRACTICE: Implementation of multidimensional, multidisciplinary interventions for reducing barriers to early SSC in extremely preterm infants resulted in rapid adoption of SSC in the first 72 hours of life without increasing severe IVH in this high-risk population.

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.

Accelerated weight gain, prematurity, and the risk of childhood obesity: A meta-analysis and systematic review.

The purpose of this systematic review and meta-analysis of the literature was to analyze and evaluate the impact of prematurity and accelerated weight gain on the risk of childhood and adolescent obesity. CINAHL, Embase, PubMed, and Web of Science databases were searched until December 2019 which yielded 19 studies with a total of 169,439 children enrolled were systematically reviewed. The results revealed that preterm infants had a greater likelihood of childhood obesity (defined as BMI ≥95th percentile for age-sex), than term infants (OR = 1.19, 95% CI [1.13, 1.26]). However, no difference of childhood obesity was found between "small for gestational age"(SGA) and "appropriate for gestational age"(AGA) among preterms. Accelerated weight gain (defined as weight gain velocity during first two years after birth) significantly increased the likelihood of subsequent childhood obesity among preterms (aOR = 1.87, 95% CI [1.57, 2.231]). In conclusion, accelerated weight gain at infancy among preterm children may be a critical contributor to obesity in later life. Establishing optimal growth trajectories and timely referral to health care providers may be of clinical importance.

Relationship between Duration of Infant Exposure to a Moderate-to-Large Patent Ductus Arteriosus Shunt and the Risk of Developing Bronchopulmonary Dysplasia or Death Before 36 Weeks.

OBJECTIVE: This study was aimed to examine the relationship between duration of infant exposure to a moderate-to-large patent ductus arteriosus (PDA) shunt and the risk of developing bronchopulmonary dysplasia (BPD) or death before 36 weeks (BPD/death). STUDY DESIGN: Infants <28 weeks' gestation who survived ≥7 days (n = 423) had echocardiograms performed on day 7 and at planned intervals. RESULTS: In multivariable regression models, BPD/death did not appear to be increased until infants had been exposed to a moderate-to-large PDA for at least 7-13 days: OR (95%CI) (referent = closed or small PDA): moderate-to-large PDA exposure for <7 days: 0.38 (range, 0.10-1.46); for 7 to 13 days = 2.12 (range, 1.04-4.32); for ≥14 days = 3.86 (range, 2.15-6.96). Once the threshold of 7 to 13 days had been reached, additional exposure (≥14 days) did not significantly add to the increased incidence of BPD/death: (referent exposure = 7-13 days) exposure for 14 to 27 days = 1.34 (range, 0.52-3.45); for 28 to 48 days = 2.34 (range, 0.88-6.19); for ≥49 days = 1.80 (range. 0.59-5.47). A similar relationship was found for the outcome of BPD-alone. CONCLUSION: Infants < 28 weeks' gestation required at least 7 to 13 days of exposure to a moderate-to-large PDA before a significant increase in the incidence of BPD/death was apparent. Once this threshold was reached additional exposure to a moderate-to-large PDA did not significantly add to the increased incidence of BPD/death.

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.

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.

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.

Prophylactic Indomethacin Compared with Delayed Conservative Management of the Patent Ductus Arteriosus in Extremely Preterm Infants: Effects on Neonatal Outcomes.

OBJECTIVE: To determine whether prophylactic indomethacin (PINDO) has more or less morbidity than delayed conservative management of the moderate-to-large patent ductus arteriosus (PDA). STUDY DESIGN: We performed a prospective double cohort controlled study of infants delivered at ≤276/7 weeks gestation (n = 397). From January 2005 through April 2011, all infants were treated with PINDO (n = 247). From May 2011 through August 2016, no infant was treated with indomethacin until at least 8 postnatal days (conservative epoch, n = 150). Echocardiograms were performed on day 7 and at planned intervals until the PDA was small or closed. A single neonatologist prospectively collected all data. RESULTS: The incidence of moderate-to-large PDA on day 7 and duration of exposure to moderate-to-large PDA were significantly less in the PINDO epoch (incidence = 10%, median = 2 days) than the conservative epoch (incidence = 67%, median = 14 days). Ligation rates were low in both epochs (PINDO = 14%, conservative = 5%). In multivariate analyses, PINDO infants had a significantly lower incidence of bronchopulmonary dysplasia (BPD) (risk ratio = 0.68, CI: 0.46-0.89) and BPD or death (risk ratio= 0.78, CI: 0.62-0.95) than conservative infants. There were no differences between the epochs in death, intraventricular hemorrhage grades 3 and 4, necrotizing enterocolitis, or retinopathy of prematurity receiving treatment. The effects of PINDO on BPD and BPD or death were no longer significant when analyses were adjusted for presence of a moderate-to-large PDA on day 7. The significant effects of PINDO were independent of whether or not a ligation was performed. CONCLUSIONS: PINDO decreases BPD and BPD or death compared with delayed conservative PDA management. These effects are mediated by closure of the PDA.

Effects of Prophylactic Indomethacin on Vasopressor-Dependent Hypotension in Extremely Preterm Infants.

OBJECTIVE: To determine whether a moderate-to-large patent ductus arteriosus (PDA) is responsible for vasopressor-dependent hypotension, occurring at the end of the first postnatal week. STUDY DESIGN: We performed a retrospective, double cohort controlled study of infants delivered at ≤27+6 weeks' gestation (n = 313). From January 2004 through April 2011, all infants were treated with prophylactic indomethacin ([PINDO] epoch). From May 2011 through December 2015, no infant was treated with indomethacin until at least 8 postnatal days (conservative epoch). Echocardiograms were performed on postnatal days 6 or 7. Hypotension was managed by a predefined protocol. The primary outcome was the incidence of dopamine-dependent hypotension, defined as having received at least 6 µg/kg/min dopamine for at least 24 hours during postnatal days 4-7. RESULTS: As expected, the incidence of moderate-to-large PDA at the end of the first week differed significantly between epochs (PINDO = 8%; conservative = 64%). In multivariate analyses, infants in the PINDO epoch had a significantly lower incidence of vasopressor-dependent hypotension (11%) than infants in the conservative epoch (21%; OR = 0.40, 95% CI 0.20-0.82). Infants in the PINDO epoch also required less mean airway pressure, had a lower respiratory severity score, and lower mode of ventilation score than infants in the conservative epoch during postnatal days 4-7. The effects of PINDO on both the incidence of vasopressor-dependent hypotension and the need for respiratory support were no longer significant when analyses were adjusted for "presence or absence of a moderate-to-large PDA." CONCLUSION: PINDO decreases vasopressor-dependent hypotension and the need for respiratory support at the end of the first postnatal week. These effects are mediated by closure of the PDA.

Antenatal Betamethasone: A Prolonged Time Interval from Administration to Delivery Is Associated with an Increased Incidence of Severe Intraventricular Hemorrhage in Infants Born before 28 Weeks Gestation.

OBJECTIVE: To examine the effects of antenatal steroids on severe intraventricular hemorrhage (IVH) in infants born during the IVH vulnerable period (<28 weeks gestational age) and to evaluate rates of IVH correlated with the time interval between treatment or retreatment and birth. STUDY DESIGN: A total of 429 infants (<28 weeks gestation), who delivered ≥24 hours after the first betamethasone (BMZ) course (2 doses), were divided into groups based on the interval between the first course of BMZ and delivery: <10 days or ≥10 days. The primary outcome was severe IVH. Multiple regression analyses were performed to adjust for potential confounders. RESULTS: Three hundred ninety-two infants delivered after a single BMZ course (312 delivered <10 days; 80 ≥10 days). The incidence of severe IVH was 17% for infants delivered ≥10 days and 7% for those delivered <10 days after a single BMZ course (aOR 4.16; 95% CI 1.59-10.87, P = .004); 37 infants (born ≥10 days from the first BMZ course) received a second/rescue BMZ course. The incidence of severe IVH among infants receiving a second/rescue course was 8%, which was similar to the incidence among infants born <10 days (aOR 1.7; 95% CI 0.41-6.6, P = .48). CONCLUSIONS: In infants born before 28 weeks gestation, delivery ≥10 days from the first BMZ course is associated with a higher incidence of severe IVH; a second/rescue course may reverse this effect.

Predicting the Need for Home Oxygen Therapy in Preterm Infants Born Before 28 Weeks' Gestation.

OBJECTIVE: To discover a predictor, that could be used at least 3 to 4 weeks' before discharge, to identify infants who would need home oxygen therapy. We hypothesized that infants requiring a high level of respiratory support at 34 weeks' postmenstrual age (PMA) would require home oxygen. STUDY DESIGN: Single center retrospective study of 143 infants less than 28 weeks' gestation. We determined when infants weaned from each level of respiratory support (mechanical ventilation, nasal continuous airway pressure [nCPAP] or biphasic positive pressure, nasal cannula flow ≥ 2 L/min, nasal cannula flow < 2 L/min or no respiratory support). Our primary outcome was need for home oxygen. RESULT: Infants who required nCPAP at 34 weeks' PMA had a 100% positive predictive value for home oxygen therapy. CONCLUSION: Higher levels of respiratory support at 34 weeks' PMA can predict the need for home oxygen and is useful in preparing patients and families for discharge.