The effect of histological and subclinical chorioamnionitis and funisitis on breathing effort in premature infants at birth: a retrospective cohort study.

Antenatal inflammation in the form of chorioamnionitis (fetal membranes; HCA) and funisitis (umbilical vessels; FUN) is a major risk factor for preterm birth. Exposure to HCA + FUN affects infants by releasing mediators that may suppress respiratory drive. While the association between clinical chorioamnionitis (CCA) and (depressed) spontaneous breathing has been described, we have investigated the association between breathing and HCA + FUN. Infants born < 30 weeks' gestation with available placental pathology assessments were included. Infants were compared at multiple levels: infants with vs without HCA + FUN (comparison 1) and infants with subclinical HCA + FUN vs infants without any chorioamnionitis (comparison 2). The primary outcome was breathing effort, defined as minute volume (MV) of spontaneous breathing in the first 5 min after birth. We also assessed tidal volume (Vt), respiratory rate (RR), heart rate (HR), oxygen saturation (SpO2) and oxygen requirement (FiO2). Regression analyses were performed to control for confounding factors. One hundred eighty-six infants were included (n = 75 infants with HCA + FUN vs. n = 111 infants without HCA + FUN). Comparison 1: Infants with HCA + FUN had lower gestational ages 26+5 (25+0-28+1; median (IQR) and lower birthweights (mean ± SD; 943 ± 264) compared to infants without HCA + FUN (28+4 (27+0-29+1) weeks, p < 0.001 and 1023 ± 270 g, p = 0.049). Comparison 2: Subclinical HCA + FUN was diagnosed in 46/75 HCA + FUN infants. Infants with subclinical HCA + FUN had lower gestational ages (26+6 (25+1-28+3) vs. 28+4 (27+2-29+1) weeks, p < 0.001) without significant differences for birthweights (987 ± 248 vs. 1027 ± 267 g, p = 0.389) compared to infants without any chorioamnionitis (n = 102 infants). After adjustment, HCA + FUN was associated with lower MV (p = 0.025), but subclinical HCA + FUN was not (p = 0.226). HCA + FUN and subclinical HCA + FUN were associated with lower Vt (p = 0.003; p = 0.014), SpO2 at 5 min (p = 0.021; 0.036) and SpO2/FiO2 ratio (p = 0.028; p = 0.040). CONCLUSION: HCA + FUN and subclinical HCA + FUN are associated with reduced oxygenation and parameters that reflect breathing effort in premature infants at birth. WHAT IS KNOWN: • Acute antenatal inflammation, in the form of chorioamnionitis (fetal membranes) and funisitis (umbilical vessels), affects a large proportion of premature infants. • Clinical chorioamnionitis is associated with reduced breathing effort and oxygenation in premature infants at birth. WHAT IS NEW: • Histological and subclinical chorioamnionitis and funisitis are associated with reduced breathing effort parameters and oxygenation in premature infants at birth.

The influence of chorioamnionitis on respiratory drive and spontaneous breathing of premature infants at birth: a narrative review.

Most very premature infants breathe at birth but require respiratory support in order to stimulate and support their breathing. A significant proportion of premature infants are affected by chorioamnionitis, defined as an umbrella term for antenatal inflammation of the foetal membranes and umbilical vessels. Chorioamnionitis produces inflammatory mediators that potentially depress the respiratory drive generated in the brainstem. Such respiratory depression could maintain itself by delaying lung aeration, hampering respiratory support at birth and putting infants at risk of hypoxic injury. This inflammatory-mediated respiratory depression may contribute to an association between chorioamnionitis and increased requirement of neonatal resuscitation in premature infants at birth. This narrative review summarises mechanisms on how respiratory drive and spontaneous breathing could be influenced by chorioamnionitis and provides possible interventions to stimulate spontaneous breathing.  Conclusion: Chorioamnionitis could possibly depress respiratory drive and spontaneous breathing in premature infants at birth. Interventions to stimulate spontaneous breathing could therefore be valuable. What is Known: • A large proportion of premature infants are affected by chorioamnionitis, antenatal inflammation of the foetal membranes and umbilical vessels. What is New: • Premature infants affected by chorioamnionitis might be exposed to higher concentrations of respiratory drive inhibitors which could depress breathing at birth. • Premature infants affected by chorioamnionitis seem to be associated with a higher and more extensive requirement of resuscitation at birth.

Doxapram versus placebo in preterm newborns: a study protocol for an international double blinded multicentre randomized controlled trial (DOXA-trial).

BACKGROUND: Apnoea of prematurity (AOP) is one of the most common diagnoses among preterm infants. AOP often leads to hypoxemia and bradycardia which are associated with an increased risk of death or disability. In addition to caffeine therapy and non-invasive respiratory support, doxapram might be used to reduce hypoxemic episodes and the need for invasive mechanical ventilation in preterm infants, thereby possibly improving their long-term outcome. However, high-quality trials on doxapram are lacking. The DOXA-trial therefore aims to investigate the safety and efficacy of doxapram compared to placebo in reducing the composite outcome of death or severe disability at 18 to 24 months corrected age. METHODS: The DOXA-trial is a double blinded, multicentre, randomized, placebo-controlled trial conducted in the Netherlands, Belgium and Canada. A total of 396 preterm infants with a gestational age below 29 weeks, suffering from AOP unresponsive to non-invasive respiratory support and caffeine will be randomized to receive doxapram therapy or placebo. The primary outcome is death or severe disability, defined as cognitive delay, cerebral palsy, severe hearing loss, or bilateral blindness, at 18-24 months corrected age. Secondary outcomes are short-term neonatal morbidity, including duration of mechanical ventilation, bronchopulmonary dysplasia and necrotising enterocolitis, hospital mortality, adverse effects, pharmacokinetics and cost-effectiveness. Analysis will be on an intention-to-treat principle. DISCUSSION: Doxapram has the potential to improve neonatal outcomes by improving respiration, but the safety concerns need to be weighed against the potential risks of invasive mechanical ventilation. It is unknown if the use of doxapram improves the long-term outcome. This forms the clinical equipoise of the current trial. This international, multicentre trial will provide the needed high-quality evidence on the efficacy and safety of doxapram in the treatment of AOP in preterm infants. TRIAL REGISTRATION: ClinicalTrials.gov NCT04430790 and EUDRACT 2019-003666-41. Prospectively registered on respectively June and January 2020.

Automated oxygen control for very preterm infants and neurodevelopmental outcome at 2 years-a retrospective cohort study.

Faster resolution of hypoxaemic or hyperoxaemic events in preterm infants may reduce long-term neurodevelopmental impairment. Automatic titration of inspiratory oxygen increases time within the oxygen saturation target range and may provide a more prompt response to hypoxic and hyperoxic events. We assessed routinely performed follow-up at 2 years of age after the implementation of automated oxygen control (AOC) as standard care and compared this with a historical cohort. Neurodevelopmental outcomes at 2 years of age were compared for infants born at 24-29 weeks gestational age before (2012-2015) and after (2015-2018) the implementation of AOC as standard of care. The primary outcome was a composite outcome of either mortality or severe neurodevelopmental impairment (NDI), and other outcomes assessed were mild-moderate NDI, Bayley-III composite scores, cerebral palsy GMFCS, and CBCL problem behaviour scores. A total of 289 infants were included in the pre-AOC epoch and 292 in the post-AOC epoch. Baseline characteristics were not significantly different. Fifty-one infants were lost to follow-up (pre-AOC 6.9% (20/289), post-implementation 10.6% (31/292). The composite outcome of mortality or severe NDI was observed in 17.9% pre-AOC (41/229) vs. 24.0% (47/196) post-AOC (p = 0.12). No significant differences were found for the secondary outcomes such as mild-moderate NDI, Bayley-III composite scores, cerebral palsy GMFCS, and problem behaviour scores, with the exception of parent-reported readmissions until the moment of follow-up which was less frequent post-AOC than pre-AOC. CONCLUSION: In this cohort study, the implementation of automated oxygen control in our NICU as standard of care for preterm infants led to no statistically significant difference in neurodevelopmental outcome at 2 years of age. WHAT IS KNOWN: • Neurodevelopmental outcome is linked to hypoxemia, hyperoxaemia and choice of SpO2 target range. • Automated titration of inspired oxygen may provide a faster resolution of hypoxaemic and hyperoxaemic events. WHAT IS NEW: • This cohort study did not find a significant difference in neurodevelopmental outcome at two years of age after implementing automated oxygen control as standard of care.

Comparing pulse rate measurement in newborns using conventional and dry-electrode ECG monitors.

AIM: Heart rate (HR) is the most important parameter to evaluate newborns' clinical condition and to guide intervention during resuscitation at birth. The present study aims to compare the accuracy of NeoBeat dry-electrode ECG for HR measurement with conventional ECG and pulse oximetry (PO). METHODS: Newborns with a gestational age ≥32 weeks and/or birth weight ≥1.5 kg were included when HR evaluation was needed. HR was simultaneously measured for 10 min with NeoBeat, PO and conventional ECG. RESULTS: A total of 18 infants were included (median (IQR) gestational age 39 (36-39) weeks and birth weight 3 150 (2 288-3 859) grams). Mean (SD) duration until NeoBeat obtained a reliable signal was 2.5 (9.0) s versus 58.5 (171.0) s for PO. Mean difference between NeoBeat and ECG was 1.74 bpm (LoA -4.987-8.459 and correlation coefficient 0.98). Paired HR measurements over 30-s intervals revealed no significant difference between NeoBeat and ECG. The positive predictive value of a detected HR <100 bpm by NeoBeat compared with ECG was 54.84%, negative predictive value 99.99%, sensitivity 94.44%, specificity 99.99% and accuracy 99.85%. CONCLUSIONS: HR measurement with NeoBeat dry-electrode ECG at birth is reliable and accurate.