Inflammatory Response in Preterm Newborns Born after Prolonged Premature Rupture of Membranes: Is There a Correlation with Placental Histological Findings?

BACKGROUND: Preterm birth is the leading cause of morbidity and mortality among neonates in the United States. Early recognition of sepsis in this population is a challenging task since overt clinical signs can be difficult to determine. C-reactive protein (CRP), one of the most frequently non-specific used laboratory test, can indirectly aid the diagnosis of neonatal sepsis. OBJECTIVES: To evaluate the relationship between histological findings in the placenta of preterm newborns born after prolonged rupture of membranes, CRP levels, and blood cultures. METHODS: Medical records were reviewed of all preterm newborns born after prolonged premature rupture of membranes at a medical center in Israel between 2011 and 2014. RESULTS: Of 128 newborns with prolonged rupture of membranes, 64 had evidence of histological chorioamnionitis (HCA). Gestational age, birth weight, and Apgar scores were significantly lower, while CRP levels (on admission and 10-12 hours post-delivery) were significantly higher in preterm newborns born to mothers with histological evidence of chorioamnionitis, but values were within normal ranges. Duration of the rupture of membranes and white blood cell counts did not differ between groups. CONCLUSIONS: CRP levels taken on admission and 10-12 hours after delivery were higher when HCA was present, but since there was a substantial overlap between those with and without HCA and the values for most were within normal range, the differences were not enough to serve as a tool to diagnose placental histological chorioamnionitis in preterm infants born after prolonged premature rupture of membranes and exposed to intrapartum antibiotics.

National Rapid Genome Sequencing in Neonatal Intensive Care.

Importance: National implementation of rapid trio genome sequencing (rtGS) in a clinical acute setting is essential to ensure advanced and equitable care for ill neonates. Objective: To evaluate the feasibility, diagnostic efficacy, and clinical utility of rtGS in neonatal intensive care units (NICUs) throughout Israel. Design, Setting, and Participants: This prospective, public health care-based, multicenter cohort study was conducted from October 2021 to December 2022 with the Community Genetics Department of the Israeli Ministry of Health and all Israeli medical genetics institutes (n = 18) and NICUs (n = 25). Critically ill neonates suspected of having a genetic etiology were offered rtGS. All sequencing, analysis, and interpretation of data were performed in a central genomics center at Tel-Aviv Sourasky Medical Center. Rapid results were expected within 10 days. A secondary analysis report, issued within 60 days, focused mainly on cases with negative rapid results and actionable secondary findings. Pathogenic, likely pathogenic, and highly suspected variants of unknown significance (VUS) were reported. Main Outcomes and Measures: Diagnostic rate, including highly suspected disease-causing VUS, and turnaround time for rapid results. Clinical utility was assessed via questionnaires circulated to treating neonatologists. Results: A total of 130 neonates across Israel (70 [54%] male; 60 [46%] female) met inclusion criteria and were recruited. Mean (SD) age at enrollment was 12 (13) days. Mean (SD) turnaround time for rapid report was 7 (3) days. Diagnostic efficacy was 50% (65 of 130) for disease-causing variants, 11% (14 of 130) for VUS suspected to be causative, and 1 novel gene candidate (1%). Disease-causing variants included 12 chromosomal and 52 monogenic disorders as well as 1 neonate with uniparental disomy. Overall, the response rate for clinical utility questionnaires was 82% (107 of 130). Among respondents, genomic testing led to a change in medical management for 24 neonates (22%). Results led to immediate precision medicine for 6 of 65 diagnosed infants (9%), an additional 2 (3%) received palliative care, and 2 (3%) were transferred to nursing homes. Conclusions and Relevance: In this national cohort study, rtGS in critically ill neonates was feasible and diagnostically beneficial in a public health care setting. This study is a prerequisite for implementation of rtGS for ill neonates into routine care and may aid in design of similar studies in other public health care systems.

Effects of 'rescue' dose of antenatal corticosteroids on placental histopathology in preterm births.

INTRODUCTION: Antenatal corticosteroids (ACS) are frequently used to reduce neonatal morbidity in preterm births (PTBs). A 'rescue' dose of ACS can be administer, if the risk of PTB remains. Some reports indicated that repeated doses of ACS might impact placental histology and possibly its function. We aimed to study whether repeated doses of ACS effect placental histopathology and pregnancy outcome. METHODS: The medical files and placental reports of all PTB, at 24-336/7 weeks, between Nov 2008-Dec 2019, were reviewed. The study population was divided into three groups; no-ACS (PTBs without ACS treatment), one-ACS (PTBs after a full or partial ACS course), and rescue-ACS (PTBs after a 'rescue' course of ACS). Placental lesions were classified according to "Amsterdam" criteria into maternal and fetal vascular malperfusion lesions, maternal and fetal inflammatory responses and chronic villitis. Placental lesions and pregnancy outcome were compared between the study groups. RESULTS: The no-ACS group (n = 58) was characterized by increased rates of PTB<28 weeks (p = 0.003), perinatal death (p < 0.001) and composite neonatal infectious morbidity (p = 0.022), as compared to the one-ACS group (n = 331) and the rescue-ACS group (n = 53). Placental MIR lesions were more common among the rescue-ACS group, compared to the one- and no-ACS groups (p = 0.022). Other placental lesions did not differ between the groups. On multivariate logistic regression analysis, MIR lesions were independently associated with rescue-ACS treatment (aOR 3.00, 95% CI 1.10-8/17, p = 0.031). DISCUSSION: Rescue course of ACS is associated with increased rate of placental maternal inflammatory response. These findings probably result from maternal stress stimuli without an adverse impact on early neonatal outcome.

Hypertonic saline/epinephrine treatment in hospitalized infants with viral bronchiolitis reduces hospitalization stay: 2 years experience.

BACKGROUND: We recently published preliminary evidence on the effectiveness of hypertonic saline in infants with viral bronchiolitis. OBJECTIVE: To further establish the efficacy of nebulized hypertonic saline in these infants. METHODS: In a continuing, second-year randomized, doubleblind controlled trial, an additional 41 infants (age 2.6 +/- 1 months) hospitalized with viral bronchiolitis were recruited during the winter of 2001-2002. The infants received inhalation of 1.5 mg epinephrine dissolved either in 4 ml normal (0.9%) saline (Group I, n=20) or 4 ml hypertonic (3%) saline (Group II, n=22). The therapy was repeated three times daily until discharge. Pooling our 2 years of experience (2000-2002), a total of 93 hospitalized infants with viral bronchiolitis were recruited; 45 were assigned to Group I and 48 to Group II. RESULTS: The clinical scores at baseline were 7.6 +/- 0.7 for Group I vs. 7.4 +/- 1.3 for Group II (P = NS). However, the clinical scores at days 1 and 2 after inhalation differed significantly between the two groups, invariably favoring Group II: 7 +/- 1 vs. 6.25 +/- 1.1 (P< 0.05), 6.45 +/- 1 vs. 5.35 +/- 1.35 (P< 0.05), respectively. Adding aerosolized 3% saline to 1.5 mg epinephrine reduced the hospitalization stay from 3.5 +/- 1.7 days in Group I to 2.6 +/- 1.4 in Group II (P< 0.05). The pooled data of both years revealed that adding 3% saline to the inhalation mixture decreased hospitalization stay from 3.6 +/- 1.6 to 2.8 +/- 1.3 days (P< 0.05). CONCLUSIONS: This second-year experience and our 2 year pooled data analysis strengthen the evidence that the combination of 3% saline/1.5 mg epinephrine benefits hospitalized infants with viral bronchiolitis.

Aerosol delivery in respiratory syncytial virus bronchiolitis: hood or face mask?

OBJECTIVES: To compare the utility of the hood versus the face mask for delivery of inhaled medications to infants hospitalized with viral bronchiolitis. STUDY DESIGN: Randomized, double-blinded, controlled trial; 49 hospitalized infants with viral bronchiolitis, age 2.75 +/- 2.2 months (mean +/- SD), were grouped to either the hood (n = 25) or the mask (n = 24). Each subject received inhalation treatments with the use of both devices. Half of the Hood Group received the active drug treatment (1.5 mg epinephrine in 4 mL saline [3%]) via hood followed immediately by placebo treatment (normal saline) via mask, whereas the other half received the opposite order. Half of the Mask Group received the active drug treatment via mask followed immediately by placebo treatment via hood, whereas the other half received the opposite order. Therapy was repeated 3 times daily until discharge. Outcome measures included clinical scores and parental preference. RESULTS: Percent improvement in clinical severity scores after inhalation was significant in both groups on days 1, 2, and 3 after admission (Hood Group: 15%, 15.4%, and 16.4%, respectively; Mask Group: 17.5%, 12.1%, and 12.7%, respectively; P < .001). No significant difference in clinical scores improvement between groups was observed. Eighty percent (39/49) of parents favored the hood over the mask; 18% (9/49) preferred the mask and 2% (1/49) were indifferent. CONCLUSIONS: In infants hospitalized with viral bronchiolitis and in whom aerosol treatment is considered, aerosol delivery by hood is as effective as by mask. However, according to parents, the tolerability of the hood is significantly better than that of a mask.

Association between common Toll-like receptor 4 mutations and severe respiratory syncytial virus disease.

BACKGROUND: The clinical spectrum of respiratory syncytial virus (RSV) bronchiolitis in previously healthy infants is extremely variable. Thus, it is likely that factors such as genetic heterogeneity contribute to disease severity. Toll-like receptor 4 (TLR4) and CD14 are part of a receptor complex involved in the innate immune response to RSV. METHODS: The association of the TLR4 mutations (Asp299Gly and Thr399Ile) and the CD14/-159 polymorphism were analyzed in 99 infants hospitalized with severe RSV bronchiolitis (group I). Eighty-two ambulatory infants with mild RSV bronchiolitis (group II) and 90 healthy adults (group III) composed the 2 control groups. The TLR4 mutations and the CD14/-159 polymorphism were genotyped by use of reverse-transcriptase polymerase chain reaction and restriction fragment-length polymorphism analysis, respectively. RESULTS: Each of the TLR4 mutations, either alone or in cosegregation, were associated with severe RSV bronchiolitis: the Asp299Gly and Thr399Ile mutations were significantly overrepresented in group I, compared with groups II and III. No association between the CD14/-159 polymorphism and RSV bronchiolitis was found. CONCLUSIONS: These findings suggest that TLR4 mutations, but not the CD14/-159 polymorphism, are associated with an increased risk of severe RSV bronchiolitis in previously healthy infants.