T cell responses and clinical symptoms among infants with congenital cytomegalovirus infection.

BACKGROUNDCongenital cytomegalovirus (cCMV) infection can cause developmental impairment and sensorineural hearing loss (SNHL). To determine the relationship between immune responses to cCMV infection and neurologic sequelae, T cell responses were compared for their connection to clinical symptoms at birth and neurodevelopmental outcomes.METHODSThirty cCMV-infected and 15 uninfected infants were enrolled in a single-center prospective observational case-control study. T cell pp65-specific cytokine responses; CD57, CD28, and PD-1 expression; and memory subsets were compared.RESULTSInfected neonates (73% symptomatic at birth) lacked pp65-specific cytokine-secreting T cells, with elevated frequencies of CD57+, CD28-, and PD-1+CD8+ T cells and effector memory subsets. Though frequencies overlapped between cCMV symptom groups, asymptomatic infants had higher frequencies of CD57+PD-1+CD8+ T cells. Neonates with subsequent developmental delay lacked detectable CMV-specific T cell responses, with patterns resembling those of uninfected infants. Two children with progressive SNHL had high frequencies of PD-1+CD8+ T cells over the first year compared with children without progressive SNHL.CONCLUSIONSimilar to published reports, neonatal viral antigen-specific cytokine-secreting T cell responses were not detected, but overall patterns indicate that globally differentiated memory CD8+ T cell populations were induced by cCMV infection, with higher frequencies of terminally differentiated PD-1+CD8+ T cells potentially associated with asymptomatic infection. In this cohort, a lack of in utero T cell differentiation was associated with developmental delay, and high frequencies of PD-1+CD8+ T cells persisted only in children with progressive SNHL. Further work is needed to define the specificity of these T cells and their mechanistic connection to these outcomes.FUNDINGThis study was funded through an intramural research award at Nationwide Children's Hospital, the Pediatric Infectious Disease Society Fellowship Award funded by Stanley and Susan Plotkin and Sanofi Pasteur, the Abigail Wexner Research Institute at Nationwide Children's Hospital, and the Pichichero Family Foundation Vaccines for Children Initiative Research Award from the Pediatric Infectious Diseases Society Foundation.

Mucosal Site Detection of Herpes Simplex Virus in Neonates.

From 2001 to 2023, 17 (14%) of 120 neonates with confirmed herpes simplex virus infection tested positive for herpes simplex virus by polymerase chain reaction (PCR) from only mucosal sites without a clinical mucosal lesion. Whether mucosal PCR positivity reflects early infection that may lead to recognizable disease, transient colonization, or a false-positive PCR result remains a clinical conundrum and warrants further study.

Molecular testing for gastrointestinal pathogens in intestinal tissue of infants with necrotizing enterocolitis or spontaneous intestinal perforation.

OBJECTIVE: The objective of this study was to determine the frequency of common gastrointestinal bacterial, parasitic, and viral pathogen detection in necrotizing enterocolitis (NEC) or spontaneous intestinal perforation (SIP) -associated intestinal tissue. STUDY DESIGN: Retrospective cohort study examined formalin fixed, paraffin embedded (FFPE) surgical or autopsy intestinal tissue from NEC or SIP specimens. DNA and RNA were extracted and analyzed by multiplex PCR panel (GIFA Biofire). DNA or RNA from stool samples containing each pathogen were extracted for positive controls. RESULTS: The total number of intestinal tissue samples were 193 from 310 infants (156 NEC, 37 SIP). Six (3%) infants with stage III NEC tested positive for a target pathogen; 2, C. difficile; 3, Enteroaggregtive E. coli; and 1, Giardia. No gastrointestinal viral pathogens were detected. CONCLUSION: Molecular testing yielded few GI pathogens suggesting that these organisms are likely not major causes or facilitators of NEC or SIP.

Prospective antimicrobial stewardship interventions by multidisciplinary teams to reduce neonatal antibiotic use in South Africa: The Neonatal Antimicrobial Stewardship (NeoAMS) study.

BACKGROUND: Hospitalized neonates are vulnerable to infection and have high rates of antibiotic utilization. METHODS: Fourteen South African neonatal units (seven public, seven private sector) assembled multidisciplinary teams involving neonatologists, microbiologists, pharmacists, and nurses to implement prospective audit and feedback neonatal antimicrobial stewardship (NeoAMS) interventions. The teams attended seven online training sessions. Pharmacists conducted weekday antibiotic prescription reviews in the neonatal intensive care unit and/or neonatal wards providing feedback to the clinical teams. Anonymized demographic and NeoAMS interventions data were aggregated for descriptive purposes and statistical analysis. FINDINGS: During the 20-week NeoAMS intervention in 2022, 565 neonates were enrolled. Pharmacists evaluated seven hundred antibiotic prescription episodes; rule-out sepsis (180; 26%) and culture-negative sepsis (138; 20%) were the most frequent indications for antibiotic prescription. For infection episodes with an identified pathogen, only 51% (116/229) of empiric treatments provided adequate antimicrobial coverage. Pharmacists recommended 437 NeoAMS interventions (0·6 per antibiotic prescription episode), with antibiotic discontinuation (42%), therapeutic drug monitoring (17%), and dosing (15%) recommendations most frequent. Neonatal clinicians' acceptance rates for AMS recommendations were high (338; 77%). Mean antibiotic length of therapy decreased by 24% from 9·1 to 6·9 days (0·1 day decrease per intervention week; P = 0·001), with the greatest decline in length of therapy for culture-negative sepsis (8·2 days (95% CI 5·7-11·7) to 5·9 days (95% CI 4·6-7·5); P = 0·032). INTERPRETATION: This neonatal AMS programme was successfully implemented in heterogenous and resource-limited settings. Pharmacist-recommended AMS interventions had high rates of clinician acceptance. The NeoAMS intervention significantly reduced neonatal antibiotic use, particularly for culture-negative sepsis. FUNDING: A grant from Merck provided partial support.

"Minimally symptomatic" congenital cytomegalovirus infection: latest data and emerging concepts.

PURPOSE OF REVIEW: Universal and targeted screening of newborns for congenital cytomegalovirus (CMV) infection is increasing globally. Questions remain concerning the management of infants who have been identified with congenital CMV infection, especially those with "minimally symptomatic" or clinically inapparent infection. Our objective is to discuss current management of CMV-infected neonates with a focus on less affected infants with or without sensorineural hearing loss (SNHL). RECENT FINDINGS: Valganciclovir is being prescribed increasingly in neonates with congenital CMV infection for improvement in hearing outcomes through 2 years of age. Treatment initiated in the first month of age is recommended for clinically apparent disease. A recent study showed hearing improvement at 18-22 months of age when therapy was initiated at age 1-3 months in infants with clinically inapparent CMV infection and isolated SNHL. SUMMARY: Antiviral therapy with either ganciclovir or valganciclovir has shown moderate benefit in prevention of hearing deterioration among infants with clinically apparent CMV infection or isolated SNHL. Sustainability of benefit beyond 2 years of age remains unknown. At present, infants with clinically inapparent CMV infection (normal complete evaluation including hearing) should not receive antiviral therapy. All CMV-infected infants require close audiological and neurodevelopmental follow-up.

Neurodevelopmental Outcomes of Extremely Preterm Infants Fed Donor Milk or Preterm Infant Formula: A Randomized Clinical Trial.

Importance: Maternal milk feeding of extremely preterm infants during the birth hospitalization has been associated with better neurodevelopmental outcomes compared with preterm formula. For infants receiving no or minimal maternal milk, it is unknown whether donor human milk conveys similar neurodevelopmental advantages vs preterm formula. Objective: To determine if nutrient-fortified, pasteurized donor human milk improves neurodevelopmental outcomes at 22 to 26 months' corrected age compared with preterm infant formula among extremely preterm infants who received minimal maternal milk. Design, Setting, and Participants: Double-blind, randomized clinical trial conducted at 15 US academic medical centers within the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Infants younger than 29 weeks 0 days' gestation or with a birth weight of less than 1000 g were enrolled between September 2012 and March 2019. Intervention: Preterm formula or donor human milk feeding from randomization to 120 days of age, death, or hospital discharge. Main Outcomes and Measures: The primary outcome was the Bayley Scales of Infant and Toddler Development (BSID) cognitive score measured at 22 to 26 months' corrected age; a score of 54 (score range, 54-155; a score of ≥85 indicates no neurodevelopmental delay) was assigned to infants who died between randomization and 22 to 26 months' corrected age. The 24 secondary outcomes included BSID language and motor scores, in-hospital growth, necrotizing enterocolitis, and death. Results: Of 1965 eligible infants, 483 were randomized (239 in the donor milk group and 244 in the preterm formula group); the median gestational age was 26 weeks (IQR, 25-27 weeks), the median birth weight was 840 g (IQR, 676-986 g), and 52% were female. The birthing parent's race was self-reported as Black for 52% (247/478), White for 43% (206/478), and other for 5% (25/478). There were 54 infants who died prior to follow-up; 88% (376/429) of survivors were assessed at 22 to 26 months' corrected age. The adjusted mean BSID cognitive score was 80.7 (SD, 17.4) for the donor milk group vs 81.1 (SD, 16.7) for the preterm formula group (adjusted mean difference, -0.77 [95% CI, -3.93 to 2.39], which was not significant); the adjusted mean BSID language and motor scores also did not differ. Mortality (death prior to follow-up) was 13% (29/231) in the donor milk group vs 11% (25/233) in the preterm formula group (adjusted risk difference, -1% [95% CI, -4% to 2%]). Necrotizing enterocolitis occurred in 4.2% of infants (10/239) in the donor milk group vs 9.0% of infants (22/244) in the preterm formula group (adjusted risk difference, -5% [95% CI, -9% to -2%]). Weight gain was slower in the donor milk group (22.3 g/kg/d [95% CI, 21.3 to 23.3 g/kg/d]) compared with the preterm formula group (24.6 g/kg/d [95% CI, 23.6 to 25.6 g/kg/d]). Conclusions and Relevance: Among extremely preterm neonates fed minimal maternal milk, neurodevelopmental outcomes at 22 to 26 months' corrected age did not differ between infants fed donor milk or preterm formula. Trial Registration: ClinicalTrials.gov Identifier: NCT01534481.

Oral Valganciclovir Initiated Beyond 1 Month of Age as Treatment of Sensorineural Hearing Loss Caused by Congenital Cytomegalovirus Infection: A Randomized Clinical Trial.

OBJECTIVE: The objective of this study was to determine if valganciclovir initiated after 1 month of age improves congenital cytomegalovirus-associated sensorineural hearing loss. STUDY DESIGN: We conducted a randomized, double-blind, placebo-controlled phase 2 trial of 6 weeks of oral valganciclovir at US (n = 12) and UK (n = 9) sites. Patients of ages 1 month through 3 years with baseline sensorineural hearing loss were enrolled. The primary outcome was change in total ear hearing between baseline and study month 6. Secondary outcome measures included change in best ear hearing and reduction in cytomegalovirus viral load in blood, saliva, and urine. RESULTS: Of 54 participants enrolled, 35 were documented to have congenital cytomegalovirus infection and were randomized (active group: 17; placebo group: 18). Mean age at enrollment was 17.8 ± 15.8 months (valganciclovir) vs 19.5 ± 13.1 months (placebo). Twenty (76.9%) of the 26 ears from subjects in the active treatment group did not have worsening of hearing, compared with 27 (96.4%) of 28 ears from subjects in the placebo group (P = .09). All other comparisons of total ear or best ear hearing outcomes were also not statistically significant. Saliva and urine viral loads decreased significantly in the valganciclovir group but did not correlate with change in hearing outcome. CONCLUSIONS: In this randomized controlled trial, initiation of antiviral therapy beyond the first month of age did not improve hearing outcomes in children with congenital cytomegalovirus-associated sensorineural hearing loss. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01649869.

Social distancing and extremely preterm births in the initial COVID-19 pandemic period.

HYPOTHESIS: Increased social distancing was associated with a lower incidence of extremely preterm live births (EPLB) during the initial COVID-19 pandemic period. STUDY DESIGN: Prospective study at the NICHD Neonatal Research Network sites comparing EPLB (220/7-286/7 weeks) and extremely preterm intrapartum stillbirths (EPIS) rates during the pandemic period (March-July, weeks 9-30 of 2020) with the reference period (same weeks in 2018 and 2019), correlating with state-specific social distancing index (SDI). RESULTS: EPLB and EPIS percentages did not significantly decrease (1.58-1.45%, p = 0.07, and 0.08-0.06%, p = 0.14, respectively). SDI was not significantly correlated with percent change of EPLB (CC = 0.29, 95% CI = -0.12, 0.71) or EPIS (CC = -0.23, 95% CI = -0.65, 0.18). Percent change in mean gestational age was positively correlated with SDI (CC = 0.49, 95% CI = 0.07, 0.91). CONCLUSIONS: Increased social distancing was not associated with change in incidence of EPLB but was associated with a higher gestational age of extremely preterm births. GOV ID: Generic Database: NCT00063063.

Trends in Age and Disease Severity in Children Hospitalized With RSV Infection Before and During the COVID-19 Pandemic.

This cohort study evaluates respiratory syncytial virus (RSV)­related hospitalizations and disease severity from 2012 to 2023 in children younger than 5 years.

Use of the Pfizer Respiratory Syncytial Virus Vaccine During Pregnancy for the Prevention of Respiratory Syncytial Virus-Associated Lower Respiratory Tract Disease in Infants: Recommendations of the Advisory Committee on Immunization Practices - United States, 2023.

Respiratory syncytial virus (RSV) is the leading cause of hospitalization among U.S. infants. Nirsevimab (Bevfortus, Sanofi and AstraZeneca) is recommended to prevent RSV-associated lower respiratory tract infection (LRTI) in infants. In August 2023, the Food and Drug Administration (FDA) approved RSVpreF vaccine (Abrysvo, Pfizer Inc.) for pregnant persons as a single dose during 32-36 completed gestational weeks (i.e., 32 weeks and zero days' through 36 weeks and 6 days' gestation) to prevent RSV-associated lower respiratory tract disease in infants aged <6 months. Since October 2021, CDC's Advisory Committee on Immunization Practices (ACIP) RSV Vaccines Pediatric/Maternal Work Group has reviewed RSV epidemiology and evidence regarding safety, efficacy, and potential economic impact of pediatric and maternal RSV prevention products, including RSVpreF vaccine. On September 22, 2023, ACIP and CDC recommended RSVpreF vaccine using seasonal administration (i.e., during September through end of January in most of the continental United States) for pregnant persons as a one-time dose at 32-36 weeks' gestation for prevention of RSV-associated LRTI in infants aged <6 months. Either maternal RSVpreF vaccination during pregnancy or nirsevimab administration to the infant is recommended to prevent RSV-associated LRTI among infants, but both are not needed for most infants. All infants should be protected against RSV-associated LRTI through use of one of these products.

Tissue Oxygenation Changes After Transfusion and Outcomes in Preterm Infants: A Secondary Near-Infrared Spectroscopy Study of the Transfusion of Prematures Randomized Clinical Trial (TOP NIRS).

Importance: Preterm infants with varying degrees of anemia have different tissue oxygen saturation responses to red blood cell (RBC) transfusion, and low cerebral saturation may be associated with adverse outcomes. Objective: To determine whether RBC transfusion in preterm infants is associated with increases in cerebral and mesenteric tissue saturation (Csat and Msat, respectively) or decreases in cerebral and mesenteric fractional tissue oxygen extraction (cFTOE and mFTOE, respectively) and whether associations vary based on degree of anemia, and to investigate the association of Csat with death or neurodevelopmental impairment (NDI) at 22 to 26 months corrected age. Design, Setting, and Participants: This was a prospective observational secondary study conducted among a subset of infants between August 2015 and April 2017 in the Transfusion of Prematures (TOP) multicenter randomized clinical trial at 16 neonatal intensive care units of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Preterm neonates with gestational age 22 to 28 weeks and birth weight 1000 g or less were randomized to higher or lower hemoglobin thresholds for transfusion. Data were analyzed between October 2020 and May 2022. Interventions: Near-infrared spectroscopy monitoring of Csat and Msat. Main Outcomes and Measures: Primary outcomes were changes in Csat, Msat, cFTOE, and mFTOE after transfusion between hemoglobin threshold groups, adjusting for age at transfusion, gestational age, birth weight stratum, and center. Secondary outcome at 22 to 26 months was death or NDI defined as cognitive delay (Bayley Scales of Infant and Toddler Development-III score <85), cerebral palsy with Gross Motor Function Classification System level II or greater, or severe vision or hearing impairment. Results: A total of 179 infants (45 [44.6%] male) with mean (SD) gestational age 25.9 (1.5) weeks were enrolled, and valid data were captured from 101 infants during 237 transfusion events. Transfusion was associated with a significant increase in mean Csat of 4.8% (95% CI, 2.7%-6.9%) in the lower-hemoglobin threshold group compared to 2.7% (95% CI, 1.2%-4.2%) in the higher-hemoglobin threshold group, while mean Msat increased 6.7% (95% CI, 2.4%-11.0%) vs 5.6% (95% CI, 2.7%-8.5%). Mean cFTOE and mFTOE decreased in both groups to a similar extent. There was no significant change in peripheral oxygen saturation (SpO2) in either group (0.2% vs -0.2%). NDI or death occurred in 36 infants (37%). Number of transfusions with mean pretransfusion Csat less than 50% was associated with NDI or death (odds ratio, 2.41; 95% CI, 1.08-5.41; P = .03). Conclusions and Relevance: In this secondary study of the TOP randomized clinical trial, Csat and Msat were increased after transfusion despite no change in SpO2. Lower pretransfusion Csat may be associated with adverse outcomes, supporting further investigation of targeted tissue saturation monitoring in preterm infants with anemia. Trial Registration: ClinicalTrials.gov Identifier: NCT01702805.

Use of Nirsevimab for the Prevention of Respiratory Syncytial Virus Disease Among Infants and Young Children: Recommendations of the Advisory Committee on Immunization Practices - United States, 2023.

Respiratory syncytial virus (RSV) is the leading cause of hospitalization among U.S. infants. In July 2023, the Food and Drug Administration approved nirsevimab, a long-acting monoclonal antibody, for passive immunization to prevent RSV-associated lower respiratory tract infection among infants and young children. Since October 2021, the Advisory Committee on Immunization Practices (ACIP) Maternal and Pediatric RSV Work Group has reviewed evidence on the safety and efficacy of nirsevimab among infants and young children. On August 3, 2023, ACIP recommended nirsevimab for all infants aged <8 months who are born during or entering their first RSV season and for infants and children aged 8-19 months who are at increased risk for severe RSV disease and are entering their second RSV season. On the basis of pre-COVID-19 pandemic patterns, nirsevimab could be administered in most of the continental United States from October through the end of March. Nirsevimab can prevent severe RSV disease among infants and young children at increased risk for severe RSV disease.

Use of term reference infants in assessing the developmental outcome of extremely preterm infants: lessons learned in a multicenter study.

OBJECTIVE: Extremely preterm (EP) impairment rates are likely underestimated using the Bayley III norm-based thresholds scores and may be better assessed relative to concurrent healthy term reference (TR) infants born in the same hospital. STUDY DESIGN: Blinded, certified examiners in the Neonatal Research Network (NRN) evaluated EP survivors and a sample of healthy TR infants recruited near the 2-year assessment age. RESULTS: We assessed 1452 EP infants and 183 TR infants. TR-based thresholds showed higher overall EP impairment than Bayley norm-based thresholds (O.R. = 1.86; [95% CI 1.56-2.23], especially for severe impairment (36% vs. 24%; p ≤ 0.001). Difficulty recruiting TR patients at 2 years extended the study by 14 months and affected their demographics. CONCLUSION: Impairment rates among EP infants appear to be substantially underestimated from Bayley III norms. These rates may be best assessed by comparison with healthy term infants followed with minimal attrition from birth in the same centers. GOV ID: Term Reference (under the Generic Database Study): NCT00063063.

The Mortality of Congenital Syphilis.

OBJECTIVES: To document the case-fatality rate (CFR) of congenital syphilis diagnosed by molecular tools and rabbit infectivity testing (RIT) of clinical specimens in addition to standard evaluation and to compare that with the CFR using the Centers for Disease Control and Prevention (CDC) surveillance case definition. STUDY DESIGN: Prospective, single site, cohort study of all cases of syphilis among mothers and their infants from 1984 to 2002. The diagnosis of congenital syphilis was determined using IgM immunoblotting, polymerase chain reaction, and RIT of fetal or infant specimens in addition to clinical, laboratory, and radiographic criteria. Data were retrospectively reviewed to ascertain fetal and neonatal mortality. RESULTS: During the 18-year study, there were 191 cases of congenital syphilis confirmed by abnormalities on clinical, laboratory, or radiographic evaluation and/or positive serum IgM immunoblot, blood polymerase chain reaction, or blood/cerebrospinal fluid RIT. Of the 191 cases, 59 died for a CFR of 31%. Of the 59 deaths, 53 (90%) were stillborn and 6 (10%) died in the neonatal period. The majority (74%, 39/53) of stillbirths occurred in the third trimester. The CDC surveillance case definition correctly identified all infants with congenital syphilis, but the CDC CFR was 10% which underestimated the CFR by more than 300%. CONCLUSIONS: Our findings corroborate the high sensitivity of the CDC surveillance definition for congenital syphilis but highlight its poor estimation of its associated mortality. The CFR among infected progeny of pregnant women with syphilis was 31%, due mostly to demise in the third trimester and as such highlights the need for detection and appropriate treatment of syphilis during pregnancy.

Short-course antibiotic therapy for pneumonia in the neonatal intensive care unit.

OBJECTIVE: To determine the adherence and safety outcomes of a 5-day antibiotic course with a "time-out" for treatment of "blood culture-negative" pneumonia in the NICU. STUDY DESIGN: Prospective surveillance of all infants diagnosed with pneumonia at 7 NICUs from 8/2020-12/2021. Safety outcomes were defined a priori by re-initiation of antibiotic therapy within 14 days after discontinuation and overall and sepsis-related mortality. RESULTS: 128 infants were diagnosed with 136 episodes of pneumonia; 88% (n = 119) were treated with 5 days of definitive antibiotic therapy. Antibiotics were restarted within 14 days in 22 (16%) of the 136 pneumonia episodes. However, only 3 (3%) of the 119 episodes of pneumonia treated for 5 days had antibiotics restarted for pneumonia. Mortality was 5% (7/128); 5 of the 7 deaths were assessed as sepsis-related. CONCLUSION: Adherence to the 5-day definitive antibiotic treatment for "culture-negative" pneumonia was high and the intervention seemed safe.

Increasing rates of sars-cov-2 infection in newborns during the omicron variant epoch.

PROBLEM: Transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from infected pregnant individuals to the fetus or newborn occurs from 1.2% to 4.3%. Our aim was to determine the rate of positivity among newborns delivered to infected mothers during epochs of different variants predominance. METHOD OF STUDY: This is a single academic center retrospective cohort study where we reviewed the electronic health records of pregnant individuals who tested positive for SARS-CoV-2 infection and their newborns from March 2020 through January 2022. Infants born to SARS-CoV-2-positive mothers at the time of delivery or within 10 days of admission were tested for SARS-CoV-2 infection at 24-36 h of age. RESULTS: A total of 195 mothers were positive at delivery or within 10 days of admission and had their newborns tested for SARS-CoV-2. Seven newborns (3.6%) were positive. All positive infants were asymptomatic and born to unvaccinated mothers. Newborn positivity for SARS-CoV-2 was highest during the Omicron epoch (9.4%, p = .01). CONCLUSION: Increasing positivity rate was seen during the Omicron variant predominance. This could be attributed to postnatal acquisition of the virus, as Omicron has been associated with higher transmissibility in older children and adults.

Update on nonpolio enterovirus and parechovirus infections in neonates and young infants.

PURPOSE OF REVIEW: To review the epidemiology, clinical manifestations, and treatment strategies of nonpolio enterovirus and parechovirus (PeV) infections, and identify research gaps. RECENT FINDINGS: There is currently no approved antiviral agent for enterovirus or PeV infections, although pocapavir may be provided on a compassionate basis. Elucidation of the structure and functional features of enterovirus and PeV may lead to novel therapeutic strategies, including vaccine development. SUMMARY: Nonpolio human enterovirus and PeV are common childhood infections that are most severe among neonates and young infants. Although most infections are asymptomatic, severe disease resulting in substantial morbidity and mortality occurs worldwide and has been associated with local outbreaks. Long-term sequelae are not well understood but have been reported following neonatal infection of the central nervous system. The lack of antiviral treatment and effective vaccines highlight important knowledge gaps. Active surveillance ultimately may inform preventive strategies.

The Influence of Mediators on the Relationship Between Antenatal Opioid Agonist Exposure and the Severity of Neonatal Opioid Withdrawal Syndrome.

OBJECTIVES: (1) To evaluate the direct (un-mediated) and indirect (mediated) relationship between antenatal exposure to opioid agonist medication as treatment for opioid use disorder (MOUD) and the severity of neonatal opioid withdrawal syndrome (NOWS), and (2) to understand the degree to which mediating factors influence the direct relationship between MOUD exposure and NOWS severity. METHODS: This cross-sectional study includes data abstracted from the medical records of 1294 opioid-exposed infants (859 MOUD exposed and 435 non-MOUD exposed) born at or admitted to one of 30 US hospitals from July 1, 2016, to June 30, 2017. Regression models and mediation analyses were used to evaluate the relationship between MOUD exposure and NOWS severity (i.e., infant pharmacologic treatment and length of newborn hospital stay (LOS)) to identify potential mediators of this relationship in analyses adjusted for confounding factors. RESULTS: A direct (un-mediated) association was found between antenatal exposure to MOUD and both pharmacologic treatment for NOWS (aOR 2.34; 95%CI 1.74, 3.14) and an increase in LOS (1.73 days; 95%CI 0.49, 2.98). Delivery of adequate prenatal care and a reduction in polysubstance exposure were mediators of the relationship between MOUD and NOWS severity and as thus, were indirectly associated with a decrease in both pharmacologic treatment for NOWS and LOS. CONCLUSIONS FOR PRACTICE: MOUD exposure is directly associated with NOWS severity. Prenatal care and polysubstance exposure are potential mediators in this relationship. These mediating factors may be targeted to reduce the severity of NOWS while maintaining the important benefits of MOUD during pregnancy.