Purpose Built Catheters for Minimally Invasive Surfactant Therapy: Experience from a Canadian Tertiary Level Neonatal Intensive Care Unit.

Background: Minimally invasive surfactant therapy (MIST), a method of surfactant delivery via a thin catheter during spontaneous breathing, is an increasingly popular alternative to intubation and surfactant administration. Recently, purpose-built catheters for MIST received regulatory approval in Canada and became available for use. However, procedural success and user experience with such catheters have not been described. Methods: This retrospective cohort study included neonates who received MIST using purpose-built catheters between January 1, 2021, and March 31, 2022. Two types of purpose-built catheters were used in this period - SurfCath™ and BLEScath™. Procedural success, number of attempts, and adverse events in neonates receiving MIST via the two catheters were compared using chi-square or Fisher's tests. User experience was described using an ease-of-use scale. Results: Thirty-seven neonates met eligibility criteria; 22 received MIST via SurfCath™, whereas 15 received MIST via BLEScath™. Success rates were 91% in SurfCath™ and 93% in BLEScath™ (P> 0.994). Failed attempts were lower in SurfCath™ (23%) in comparison to BLEScath™ (33%), but the difference was not statistically significant (P=0.708). Among operators, 90% found SurfCath™ very easy/relatively easy to use compared to 43% of users reflecting the same degree of use with BLEScath™ (P=.021). There was no difference in adverse events. Conclusion: This is the first study in Canada to report MIST with purpose-built catheters. Overall, the success rate was equally high with both catheters. Users subjectively reported higher ease of use with SurfCath™. Commercially available purpose-built catheters should facilitate universal adaptation of the MIST method.

Role of days postdelivery on breast milk production: a secondary analysis from the EMPOWER trial.

Background: With an increasing demand for mother's own milk to be viewed as a primary source of nutritional support in the care of very small and preterm infants, mothers of preterm infants may be at risk of expressing suboptimal amounts of milk. The use of a galactogogue is often considered when these mothers are still having challenges in breast milk production. Methods: For this analysis, the study participants were the 90 mothers who participated in the EMPOWER trial and, at the time of randomization, were stratified by days post-delivery, 8-14 days and 15-21 days. The primary outcome measure was the proportion of mothers in each of the days post-delivery groups who achieved a 50% increase in breast milk volume on day 14 of the study treatment period. Results: There was no significant difference in the proportion of mothers in the 8-14 days group (75.0%) who achieved a 50% increase in breast milk volume on day 14 of the study treatment period.compared to those in the 15-21 days group (60.9%), OR 1.93 (95% CI 0.78, 4.76; p = 0.15). Because comorbidities and exposure to antenatal corticosteroids between the groups of mothers were viewed as potential confounders, a logistic regression was performed after controlling for these two variables with the adjusted OR being 1.84 (0.73, 4.64; p = 0.19). Conclusions: This secondary analysis was able to demonstrate that mothers of very preterm infants, < 30 weeks gestation at birth, were able to respond to the study treatment in a similar fashion regardless of timing of entry and exposure to domperidone. In the presence of a suboptimal breast milk production by the end of the first week postpartum, below 250 ml/kg/d based on infant birth weight, a 14 day treatment of domperidone could be considered to augment breast milk production. Trial registration: EMPOWER has been registered at http://www.clinicaltrials.gov (identifier NCT01512225) on January 10, 2012.

Evaluating the Effect of a 14-Day Course of Domperidone on Breast Milk Production: A Per-Protocol Analysis from the EMPOWER Trial.

BACKGROUND: Galactogogues are often considered when mothers of very preterm infants experience challenges in producing adequate amounts of breast milk. We conducted a per-protocol analysis of those mothers who completed a 14-day course of domperidone during the EMPOWER trial. Our primary aim was to evaluate the response to a completed course of domperidone and whether the response was affected by the timing of the initiation of intervention. METHODS: For this analysis, 83 mothers of infants ≤29 weeks gestation were included: 45 mothers who received domperidone from days 1 to 14 of the trial study treatment period and 38 mothers who received domperidone from days 15 to 28. Domperidone was given at a dose of 10 mg thrice daily for 14 days. The primary outcome was the proportion of mothers who achieved a modest 50% increase in breast milk volume from the volume at the end of the 2-week period of treatment of domperidone. RESULTS: When adjusted for the initiation of domperidone treatment, the proportion of mothers in the days 1-14 group (77.8%) was similar compared to those in the days 15-28 group (65.8%), OR 1.96 (95% CI 0.72-5.32; p = 0.19). CONCLUSION: Taking into consideration potential limitations in power, this secondary analysis was able to show that the mothers in the EMPOWER study who were identified as actually completing a 14-day treatment course responded irrespective of the timing of their initiation of domperidone and demonstrated a modest increase in breast milk volume.

Inhaled and systemic steroid exposure and neurodevelopmental outcome of preterm neonates.

OBJECTIVES: To compare death and/or neurodevelopmental outcomes of preterm infants exposed to inhaled and/or systemic steroids with those without exposure, and examine the impact of timing of exposure. METHODS: Retrospective study of infants born <29 weeks gestation and assessed at 18-21 months corrected age (CA). Neurodevelopmental impairment (NDI) was defined as any Bayley Scales of Infant and Toddler Development-III (BSID-III) score <85, cerebral palsy ≥ grade one, and visual or hearing impairment. Significant NDI (sNDI) was defined as any Bayley Scales of Infant Development (BSID-III) score <70, cerebral palsy ≥ grade three, or severe vision or hearing impairment. RESULTS: Of 2570 neonates, 1811 had no exposure, 125 were exposed to inhaled steroids, 522 to systemic steroids and 112 to both. Infants exposed to inhaled steroids had lower odds of bronchopulmonary dysplasia [adjusted odds ratio (AOR) 0.51, (0.33, 0.79)], and displayed no difference in death/NDI or death/significant neurodevelopmental impairment (sNDI), regardless of timing of exposure. Infants only exposed to systemic steroids before 4 weeks of age were at increased odds of death/NDI [AOR 1.83 (1.43, 2.34)] and death/sNDI [AOR 2.28 (1.76, 2.96)]. CONCLUSIONS: Exposure to inhaled steroids was not associated with increased odds of death/NDI or death/sNDI. Systemic steroids use before 4 weeks of age was associated with significantly worse outcomes.

The effect of two different domperidone doses on maternal milk production.

BACKGROUND: The benefits of breast milk to the newborn infant are well established. The Canadian Paediatric Society recommends exclusive breastfeeding for the first 6 months of life for healthy, term infants. Mothers of premature newborns, however, may have difficulty providing an adequate supply of breast milk. Domperidone is officially used as a prokinetic agent. However, it is used widely around the world as a galactogogue. Despite its widespread use as a galactogogue, only a small number of investigators have studied domperidone for this indication. AIMS: The purpose of this study was to determine an optimal dosage of domperidone as a galactogogue. METHODS: Eligible subjects were randomized to receive domperidone 10 mg 3 times daily or domperidone 20 mg 3 times daily for 4 weeks. At week 5, the frequency was decreased to twice daily in both groups, and finally once daily for week 6. RESULTS: Over the entire first 4-week period, there was a significant increase in daily milk volumes within each group (P < .01). The between-group difference over this period, although not statistically significant, was clinically significant. Additionally, there was no significant within- or between-group difference during weeks 5 and 6. CONCLUSION: A dose of domperidone of 20 mg, 3 times daily instead of 10 mg, 3 times daily was associated with a clinical, but not statistically significant, increase in milk production.

Enhancing breast milk production with Domperidone in mothers of preterm neonates (EMPOWER trial).

BACKGROUND: The use of mother's own breast milk during initial hospitalization has a positive impact not only in reducing potential serious neonatal morbidities but also contribute to improvements in neurodevelopmental outcomes. Mothers of very preterm infants struggle to maintain a supply of breast milk during their infants' prolonged hospitalization. Galactogogues are medications that induce lactation by exerting its effects through oxytocin or prolactin enhancement. Domperidone is a potent dopamine D2 receptor antagonist which stimulates the release of prolactin. Small trials have established its ability in enhancing breast milk production. EMPOWER was designed to determine the safety and efficacy of domperidone in mothers experiencing an inadequate milk supply. METHODS/DESIGN: EMPOWER is a multicenter, double masked, randomized controlled phase-II trial to evaluate the safety and effectiveness of domperidone in those mothers identified as having difficulty in breast milk production. Eligible mothers will be randomized to one of two allocated groups: Group A: domperidone 10 mg orally three times daily for 28 days; and Group B: identical placebo 10 mg orally three times daily for 14 days followed by domperidone 10 mg orally three times daily for 14 days. The primary outcome will be determined at the completion of the first 2-week period; the second 2-week period will facilitate answering the secondary questions regarding timing and duration of treatment. To detect an estimated 30% change between the two groups (from 40% to 28%, corresponding to an odds ratio of 0.6), a total sample size of 488 mothers would be required at 80% power and alpha=0.05. To account for a 15% dropout, this number is increased to 560 (280 per group). The duration of the trial is expected to be 36-40 months. DISCUSSION: The use of a galactogogue often becomes the measure of choice for mothers in the presence of insufficient breast milk production, particularly when the other techniques are unsuccessful. EMPOWER is designed to provide valuable information in guiding the practices for this high-risk group of infants and mothers. The results of this trial will also inform both mothers and clinicians about the choices available to increase and maintain sufficient breast milk. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT01512225.

Severe retinopathy of prematurity associated with FZD4 mutations.

PURPOSE: To determine whether mutations in the FZD4 gene are a risk factor for developing severe ROP. METHODS: Three Canadian tertiary care centers recruited premature infants prospectively and retrospectively, and assigned affectation status based on the maximum degree of severity of ROP recorded in both eyes. Mutation screening of the FZD4 gene was performed using direct sequencing. All sequence changes were evaluated for functional significance. RESULTS: Two novel FZD4 mutations (Ala370Gly or Lys203Asn) were identified in two infants from the severe ROP group (n=71). No mutation was detected in the mild to no ROP group (n=33), and the two novel mutations were absent in 173 random Caucasian samples. Mutation Ala370Gly was also found in one sibling and one parent of the affected infant, but no signs of familial exudative vitreoretinopathy (FEVR), a condition with phenotypic overlap with ROP known to be caused by FZD4 mutations, were present in either family member. CONCLUSIONS: Mutations in the FZD4 gene in this group of premature infants supports a role for the FZD4 pathway in the development of severe ROP and accounts for approximately 3% of severe ROP in Caucasian premature infants.

Effect of maternal depression and anxiety on use of health services for infants.

OBJECTIVE: To evaluate the association between postpartum maternal depressive symptoms or maternal anxiety and health services utilization (HSU) for infants. DESIGN: Telephone survey. SETTING: London-Middlesex region of Ontario. PARTICIPANTS: Mothers of infants 2 to 12 months of age between 2004 and 2005 (N = 655). This sample was drawn from a larger longitudinal cohort of mothers recruited during pregnancy. MAIN OUTCOME MEASURES: Maternal depressive symptoms were measured using the Center for Epidemiologic Studies Depression Scale. Anxiety was measured using the State-Trait Anxiety Inventory. Infant HSU outcomes included number of primary care provider (PCP) visits for infants < 6 months of age, number of PCP visits for infants 6 to 12 months of age, emergency department (ED) use, and walk-in clinic (WIC) use. RESULTS: Multivariable regression methods were used to compare HSU for infants. After adjustment for confounders, no significant associations were observed between postpartum maternal depressive symptoms and PCP visits, ED use, or WIC use. Similarly, no significant associations were observed for maternal anxiety and PCP visits, ED use, or WIC use. CONCLUSION: In contrast to some previous studies, this study found no association between postpartum maternal depressive symptoms or anxiety and HSU for infants.

Preterm histologic chorioamnionitis: impact on cord gas and pH values and neonatal outcome.

OBJECTIVE: The purpose of this study was to further delineate the impact of preterm chorioamnionitis on a spectrum of neonatal outcomes using a large tertiary hospital population. STUDY DESIGN: The perinatal/neonatal and placental pathology databases of St. Joseph's Health Care, London, Ontario, Canada, were used to obtain the umbilical cord gas and pH values, incidence of adverse neonatal outcomes, patient demographics, and placental pathology reports for all preterm (25 to 34 weeks of gestation), singleton, liveborn infants with no major anomalies who were delivered with spontaneous onset of labor or for suspected chorioamnionitis between November 1, 1995, and October 31, 2003. Patient groupings on the basis of placental inflammation and clinical chorioamnionitis were studied by a comparison of mean values and incidences for those neonatal outcomes that were available from the database with the use of linear and logistic regression analysis and controlling for potentially confounding variables. RESULTS: There were 660 infants who met the inclusion criteria and had placental pathology available of whom 368 (56%) had no placental inflammation, 114 (17%) had placental chorioamnionitis, and 178 (27%) had placental funisitis. Umbilical cord partial pressure oxygen and base excess values were generally higher in the placental inflammation/clinical chorioamnionitis groups, in keeping with enhanced oxygen delivery and an overall decrease in the metabolic contribution to acidosis attributed to altered lactate metabolism in these infants. After adjusting for confounders (primarily differences in gestational age), the incidence of respiratory distress syndrome was significantly decreased in the placental inflammation/clinical chorioamnionitis groups, in keeping with cytokine-induced synthesis of surfactant proteins in these infants. Although the incidence of bronchopulmonary dysplasia, intraventricular hemorrhage, and periventricular leukomalacia was generally unchanged among the groups studied, that for intraventricular hemorrhage and periventricular leukomalacia was lowest in the placental inflammation/no clinical chorioamnionitis patients and highest in the placental inflammation/clinical chorioamnionitis patients, suggesting a differential effect of clinical chorioamnionitis for these outcomes. CONCLUSION: Overall, infants born preterm with intrauterine infection were better oxygenated and showed less metabolic acidosis at birth and had incidences of respiratory distress syndrome and intraventricular hemorrhage, which were variably lower. Although there are likely threshold levels of inflammatory cytokines that do give rise to adverse outcome, a minimal level of cytokines may also be beneficial for the transition at birth from intrauterine to extrauterine existence when preterm pending the circumstances (ie, exposure to antenatal steroids) and emphasizing the complex relationship among preterm birth, infection, and adverse neonatal outcome.

A cohort study found that white blood cell count and endocrine markers predicted preterm birth in symptomatic women.

OBJECTIVE: This cohort study investigated potential clinical and biochemical predictors of subsequent preterm birth in women presenting with threatened preterm labor. STUDY DESIGN AND SETTING: Subjects were 218 pregnant women admitted to hospital with a diagnosis of threatened preterm labor at 22-36 weeks gestation. Exclusion criteria were multiple pregnancy, fetal anomalies, diabetes mellitus, abruptio placenta, preeclampsia, intrauterine growth restriction, cervical dilatation > 4 cm, and clinical signs of infection. Analyses used logistic regression. RESULTS: The presence of ruptured membranes was the best predictor of birth within 48 hours. Other important predictors were maternal white blood cell count at 22-27 weeks gestation and maternal adrenocorticotropin and corticotropin-releasing hormone concentrations at 28-36 weeks gestation. CONCLUSION: Subclinical infection may be an important etiologic factor in preterm births of gestational age < 28 weeks. For those at > or = 28 weeks gestation, the findings support the etiologic role of activation of the fetal and/or maternal hypothalamic pituitary adrenal axis leading to preterm birth.

The impact of labor at term on measures of neonatal outcome.

OBJECTIVE: The purpose of this study was to determine risk assessments for a spectrum of neonatal outcomes with elective cesarean delivery versus a trial of labor for previous cesarean section and otherwise healthy patients who deliver at term. STUDY DESIGN: The perinatal/neonatal database of St. Joseph's Health Care, London, Ontario, Canada, was used to obtain the umbilical cord pH and base excess values, incidence of adverse neonatal outcomes, and patient demographics for all term (> or =37 weeks of gestation), singleton, liveborn, or intrapartum demise infants with no major anomalies who were delivered between January 1992 and March 2002 (n = 33,709 infants). Patient groupings (all patient, patient with previous cesarean delivery, and low-risk patient) with no labor versus labor were studied by a comparison of mean values/incidences for those neonatal outcomes that were available from the database with the use of linear and logistic regression analysis and controlling for potentially confounding variables. RESULTS: Labor was associated with a small drop in umbilical artery pH from approximately 7.27 to 7.25 and base excess from approximately -3.1 to -5.4 mmol/L, but this was generally well tolerated, with no difference in the incidence of 5-minute Apgar scores of <7 for any of the patient population groupings. Neonatal respiratory morbidity was increased generally in the group of elective cesarean delivery patients, which resulted in increased neonatal intensive care unit triage/admission even out to 7 days; some of this risk was likely to persist even with a policy of elective cesarean delivery after 39 weeks of gestation. Although we found no significant difference in the incidence of pathologic acidemia at birth with an umbilical artery pH <7.00, there was a risk for intrapartum/neonatal death that could be attributed to labor events per se that ranged from 1 of 882 for the patients with previous cesarean delivery to 1 of 3406 for the low-risk patients. CONCLUSION: For otherwise healthy patients at term, the risk of adverse neonatal outcomes is low, with the choice between elective cesarean delivery and trial of labor in general balancing the low risk of increased respiratory morbidity and thereby neonatal intensive care unit triage/admission against the extremely low risk of labor-related infant death and severe morbidity. However, this balance for the patients with previous cesarean delivery appears shifted, with less benefit from a trial of labor in terms of reduced respiratory morbidity and neonatal intensive care unit triage/admission and with increased labor-related severe morbidity/death, albeit with all of these still at a low level.

Perinatal mortality in term and preterm twin and singleton births.

Although, in general, twins have higher perinatal mortality rates than singletons, preterm twins have lower perinatal mortality rates than singletons of the same birth weight or gestational age. This study investigated the hypotheses that this paradoxical twin advantage: 1) is due to gestational age distribution differences between the singleton and twin populations, and 2) is due to increased likelihood of birth having occurred in a tertiary perinatal center. A pre-existing, time-limited data set of all births in the province of Ontario in odd years between 1979 and 1985 was chosen for this study because of the large sample size (n = 618,579). Multivariable logistic regression of the relationship between perinatal mortality and twin status was controlled for mother's age, hospital level and gestational age. Findings confirm the lower mortality of preterm twins. After controlling for level of hospital of birth this difference remained, suggesting that level of hospital of birth was not a major factor responsible for the twin advantage. Analyses in which gestational age was standardized indicate that, for those whose gestational age was less than 2 SD below the mean for their particular group (twin or singleton), twins were actually at higher risk than singletons. These results support hypothesis 1 and do not strongly support hypothesis 2. The results also support earlier authors' suggestions that the definition of term birth should be different for twins and singletons