Evolution of the Umbilical Cord Blood Proteome Across Gestational Development.

Neonatal health is dependent on early risk stratification, diagnosis, and timely management of potentially devastating conditions, particularly in the setting of prematurity. Many of these conditions are poorly predicted in real-time by clinical data and current diagnostics. Umbilical cord blood may represent a novel source of molecular signatures that provides a window into the state of the fetus at birth. In this study, we comprehensively characterized the cord blood proteome of infants born between 24 to 42 weeks using untargeted mass spectrometry and functional enrichment analysis. We determined that the cord blood proteome at birth varies significantly across gestational development. Proteins that function in structural development and growth (e.g., extracellular matrix organization, lipid particle remodeling, and blood vessel development) are more abundant earlier in gestation. In later gestations, proteins with increased abundance are in immune response and inflammatory pathways, including complements and calcium-binding proteins. Furthermore, these data contribute to the knowledge of the physiologic state of neonates across gestational age, which is crucial to understand as we strive to best support postnatal development in preterm infants, determine mechanisms of pathology causing adverse health outcomes, and develop cord blood biomarkers to help tailor our diagnosis and therapeutics for critical neonatal conditions.

Antibiotic choice for Group B Streptococcus prophylaxis in mothers with reported penicillin allergy and associated newborn outcomes.

OBJECTIVE: To evaluate the choice of antibiotic used for intrapartum Group B Streptococcus (GBS) prophylaxis in pregnant individuals with reported penicillin allergies compared to those without reported penicillin allergies and investigate whether there are associated differences in neonatal outcomes. STUDY DESIGN: This retrospective cohort study included mother-infant dyads of GBS positive pregnant individuals who labored and delivered newborns ≥ 35 weeks of gestation at a high-volume urban hospital (2005-2018). The type of antibiotic administered to the mothers for GBS prophylaxis (beta-lactam prophylaxis defined as penicillin-class drug or cefazolin; alternative prophylaxis defined as vancomycin or clindamycin) was compared between those with a penicillin allergy documented in their medical record versus those who did not. Neonatal outcomes included number of postnatal blood draws, antibiotic administration, neonatal intensive care unit (NICU) admission, bacteremia, and hospital length of stay and were compared between groups. Bivariable and multivariable analyses were performed. RESULTS: Of 11,334 mother-infant pairs, 1170 (10.3%) mothers had a penicillin allergy documented in their medical record. Of them, 49 (4.2%) received a penicillin, 259 (22.1%) received cefazolin, 449 (38.4%) received clindamycin, and 413 (35.3%) received vancomycin. Patients with a reported penicillin allergy were significantly more likely to receive alternative GBS prophylaxis compared to those without penicillin allergy (73.7% vs. 0.2%, p < 0.01). Neonates of patients who received alternative GBS prophylaxis were significantly more likely to undergo a postnatal lab draw compared to neonates of patients who received beta-lactam antibiotics (20.8% vs. 17.3%, OR 1.25 (95% CI 1.08-1.46)). This significant association persisted after adjusting for potential confounders (aOR 1.23, 95% CI 1.06-1.43). There were no other significant differences seen in other newborn outcomes. CONCLUSION: Pregnant individuals who report a penicillin allergy were more likely to receive alternative antibiotics for GBS prophylaxis compared to those without a penicillin allergy. This was associated with an increased frequency of postnatal blood draws among neonates of mothers with a reported penicillin allergy. Administration of alternative intrapartum antibiotic prophylaxis with vancomycin or clindamycin is common in individuals with self-reported penicillin allergy, and maternal alternative antibiotic administration may impact neonatal care, particularly via increased lab draws.

Patterns of diverse and changing sentiments towards COVID-19 vaccines: a sentiment analysis study integrating 11 million tweets and surveillance data across over 180 countries.

OBJECTIVES: Vaccines are crucial components of pandemic responses. Over 12 billion coronavirus disease 2019 (COVID-19) vaccines were administered at the time of writing. However, public perceptions of vaccines have been complex. We integrated social media and surveillance data to unravel the evolving perceptions of COVID-19 vaccines. MATERIALS AND METHODS: Applying human-in-the-loop deep learning models, we analyzed sentiments towards COVID-19 vaccines in 11 211 672 tweets of 2 203 681 users from 2020 to 2022. The diverse sentiment patterns were juxtaposed against user demographics, public health surveillance data of over 180 countries, and worldwide event timelines. A subanalysis was performed targeting the subpopulation of pregnant people. Additional feature analyses based on user-generated content suggested possible sources of vaccine hesitancy. RESULTS: Our trained deep learning model demonstrated performances comparable to educated humans, yielding an accuracy of 0.92 in sentiment analysis against our manually curated dataset. Albeit fluctuations, sentiments were found more positive over time, followed by a subsequence upswing in population-level vaccine uptake. Distinguishable patterns were revealed among subgroups stratified by demographic variables. Encouraging news or events were detected surrounding positive sentiments crests. Sentiments in pregnancy-related tweets demonstrated a lagged pattern compared with the general population, with delayed vaccine uptake trends. Feature analysis detected hesitancies stemmed from clinical trial logics, risks and complications, and urgency of scientific evidence. DISCUSSION: Integrating social media and public health surveillance data, we associated the sentiments at individual level with observed populational-level vaccination patterns. By unraveling the distinctive patterns across subpopulations, the findings provided evidence-based strategies for improving vaccine promotion during pandemics.

Placental Pathology After SARS-CoV-2 Infection in the Pre-Variant of Concern, Alpha / Gamma, Delta, or Omicron Eras.

Objectives. The goal of this study is to describe placental pathology after infection with SARS-CoV-2 before the predominance of variants of concern (pre-VOC) and during eras of predominant transmission of the Alpha & Gamma (co-circulating), Delta, and Omicron variants. Methods. We used county-level variant data to establish population-level variant proportions, SARS-CoV-2 PCR to identify cases, and IgG serology to exclude latent infections from controls and histopathologic examination to identify placental pathology. Results. We report findings in 870 placentas from pregnancies complicated by SARS-CoV-2 including 90 with infection in the Alpha/Gamma era, 60 from the Delta era and 56 from the Omicron era. Features of maternal vascular malperfusion (MVM), including decidual arteriopathy, were significantly more frequent after SARS-CoV-2 infection. The risk of these findings varied over time, with the highest rates in the Delta era. Increased COVID-19 severity and the presence of comorbidities strengthened these associations. Conclusion. MVM is a feature of SARS-CoV-2 infection in pregnancy. Lesion frequency changed with the predominant circulating virus and should be considered with new variants.

Lability of prenatal stress during the COVID-19 pandemic links to negative affect in infancy.

The association between prenatal stress and children's socioemotional development is well established. The COVID-19 pandemic has been a particularly stressful period, which may impact the gestational environment. However, most studies to-date have examined prenatal stress at a single time point, potentially masking the natural variation in stress that occurs over time, especially during a time as uncertain as the pandemic. This study leveraged dense ecological momentary assessments from a prenatal randomized control trial to examine patterns of prenatal stress over a 14-week period (up to four assessments/day) in a U.S. sample of 72 mothers and infants. We first examined whether varied features of stress exposure (lability, mean, and baseline stress) differed depending on whether mothers reported on their stress before or during the pandemic. We next examined which features of stress were associated with 3-month-old infants' negative affect. We did not find differences in stress patterns before and during the pandemic. However, greater stress lability, accounting for baseline and mean stress, was associated with higher infant negative affect. These findings suggest that pathways from prenatal stress exposure to infant socioemotional development are complex, and close attention to stress patterns over time will be important for explicating these pathways.

Maternal Antibody Response and Transplacental Transfer Following Severe Acute Respiratory Syndrome Coronavirus 2 Infection or Vaccination in Pregnancy.

BACKGROUND: Pregnant persons are at increased risk of severe coronavirus disease 2019 (COVID-19) and adverse obstetric outcomes. Understanding maternal antibody response, duration, and transplacental transfer after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 vaccination is important to inform public health recommendations. METHODS: This prospective observational cohort study included 351 pregnant people who had SARS-CoV-2 infection or COVID-19 vaccination during pregnancy. Immunoglobulin (Ig) G and IgM to SARS-CoV-2 S1 receptor binding domain were measured in maternal and cord blood. Antibody levels and transplacental transfer ratios were compared across (1) disease severity for those with SARS-CoV-2 infection and (2) infection versus vaccination. RESULTS: There were 252 individuals with SARS-CoV-2 infection and 99 who received COVID-19 vaccination during pregnancy. Birthing people with more severe SARS-CoV-2 infection had higher maternal and cord blood IgG levels (P = .0001, P = .0001). Median IgG transfer ratio was 0.87-1.2. Maternal and cord blood IgG were higher after vaccination than infection (P = .001, P = .001). Transfer ratio was higher after 90 days in the vaccinated group (P < .001). Modeling showed higher amplitude and half-life of maternal IgG following vaccination (P < .0001). There were no significant differences by fetal sex. CONCLUSIONS: COVID-19 vaccination in pregnancy leads to higher and longer lasting maternal IgG levels, higher cord blood IgG, and higher transfer ratio after 90 days compared with SARS-CoV-2 infection. Greater infection severity leads to higher maternal and cord blood antibodies. Maternal IgG decreases over time following both vaccination and infection, reinforcing the importance of vaccination, even after infection, and vaccine boosters for pregnant patients.

Low-level SARS-CoV-2 viremia coincident with COVID placentitis and stillbirth.

SARS-CoV-2 infection in pregnancy and COVID placentitis are associated with an increased risk of stillbirth. We sought to investigate the presence of maternal viremia in people with SARS-CoV-2 infection during pregnancy who had histologic placentitis versus those without placentitis. SARS-CoV-2 qRT-PCR was performed on plasma from 6 patients with COVID placentitis and 12 matched controls without placentitis. SARS-CoV-2 infection occurred between 4/2020-1/2021; the latency between SARS-CoV-2 diagnosis and delivery was 0-76 days. Two placentitis cases demonstrated viremia (1 stillbirth and 1 well infant), while 12/12 controls were negative. Future research may consider viremia as a possible marker of COVID placentitis.

Antibiotic resistance is common in the cultures of intraabdominal abscess drainage after appendectomy.

INTRODUCTION: Intraabdominal abscesses (IAA) are a common complication following appendectomy. Empiric antibiotic regimens may fail to prevent IAA due to changes in bacterial resistance. We aim to describe the bacteriology of pediatric patients requiring drainage of an IAA after an appendectomy for appendicitis. METHODS: We performed a retrospective study of patients ≤18 years who underwent percutaneous drainage of an IAA following appendectomy a single U.S. children's hospital between 2015 and 2018. Patient demographics, appendicitis characteristics, antibiotic regimens, and culture data were collected. RESULTS: In total, 71 patients required drainage of an IAA of which 48 (67%) were male, the average age was 9.81 (SD 3.31) years and 68 (95.7%) having complicated appendicitis. Ceftriaxone/metronidazole was the most common empiric regimen prior to IAA drainage occurring in 64 (90.1%) patients. IAA cultures isolated organisms in 34 (47.9%) patients. Of those with positive cultures, 17 (50%) cases demonstrated an antimicrobial resistant organism. Most notably, 20% of Escherichia coli was resistant to the empiric regimen. Empiric antimicrobial regimens did not appropriately cover 92.3% of Pseudomonas aeruginosa cultures or 100% of Enterococcus species cultures. Antimicrobial regimens were changed following IAA drainage in 30 (42.2%) instances with 23 (32.4%) instances due to resistance in culture results or lack of appropriate empiric antimicrobial coverage. CONCLUSIONS: IAA culture data following appendectomy for appendicitis frequently demonstrates resistance to or lack of appropriate coverage by empiric antimicrobial regimens. These data support close review of IAA culture results to identify prevalent resistant pathogens along with local changes in resistance. LEVEL OF EVIDENCE: Level III.

Maternal vs Fetal Origin of Placental Intervillous Thrombi.

OBJECTIVES: To determine maternal vs fetal origin for blood in placental intervillous thrombi (IVTs). METHODS: We used comparative analysis of microsatellites (short tandem repeats [STRs]), sex chromosome fluorescence in situ hybridization (FISH), and immunohistochemistry (IHC) for fetal (ɑ-fetoprotein [AFP]) and maternal (immunoglobulin M [IgM]) serum proteins to distinguish the origin of IVTs. Using an informatics approach, we tested the association between IVTs and fetomaternal hemorrhage (FMH). RESULTS: In 9 of 10 cases, the preponderance of evidence showed that the thrombus was mostly or entirely maternal in origin. In 1 case, the thrombus was of mixed origins. STR testing was prone to contamination by entrapped fetal villi. FISH was useful but limited only to cases with male fetuses. IgM showed stronger staining than AFP in 9 cases, supporting maternal origin. By informatics, we found no association between IVTs and FMH. CONCLUSIONS: Evidence supports a maternal origin for blood in IVTs. IHC for IgM and AFP may be clinically useful in determining maternal vs fetal contribution to IVTs.

Outcomes from birth to 6 months of publicly insured infants born to mothers with severe acute respiratory syndrome coronavirus 2 infection in the United States.

OBJECTIVES: We evaluated inpatient management, transition to home, breastfeeding, growth, and clinical outcomes of infants born to mothers diagnosed with SARS-CoV-2 infection in pregnancy and followed in a Federally Qualified Health Center (FQHC), that serves a diverse and low-income patient population, from birth through 6 months of life. METHODS: Infants born between 4/3/20 and 7/26/20 at Prentice Women's Hospital with mothers who received prenatal care at Erie Family Health Center (Erie), the second largest FQHC in Illinois, and had confirmed SARS-CoV-2 during pregnancy were included. Data were abstracted from delivery hospital admission and outpatient follow-up appointments between 4/8/20 and 2/4/21. RESULTS: Thirty-three infants met inclusion criteria. Average gestational age was 38.9 weeks (IQR 37.6-40.4), 3 (10%) were premature and 5 (15%) required NICU admission. Nearly all (97%) mothers expressed intent to breastfeed. Outpatient follow-up rates were similar to historical cohorts and 82% (23/28) of infants were vaccination compliant. Growth parameters showed normal distributions at all time points. At 6 months, any and exclusive breast milk feeding rates were lower compared to historic cohorts (18 vs. 36%, p<0.05, 0 vs. 21%, p<0.01). Three infants (10%) received development-related referrals, one carried an underlying genetic diagnosis. Outpatient visits were predominantly face-to-face with telemedicine use comprising only 6% of visits (11/182). CONCLUSIONS: Longitudinal follow-up of 33 publicly insured infants born to mothers with SARS-CoV-2 infection in pregnancy followed in an FQHC showed high rates of follow-up and vaccination compliance, normal growth patterns and reassuring clinical status, and lower than expected rates of breastfeeding.

Mechanisms and modulation of sepsis-induced immune dysfunction in children.

Immunologic responses during sepsis vary significantly among patients and evolve over the course of illness. Sepsis has a direct impact on the immune system due to adverse alteration of the production, maturation, function, and apoptosis of immune cells. Dysregulation in both the innate and adaptive immune responses during sepsis leads to a range of phenotypes consisting of both hyperinflammation and immunosuppression that can result in immunoparalysis. In this review, we discuss components of immune dysregulation in sepsis, biomarkers and functional immune assays to aid in immunophenotyping patients, and evolving immunomodulatory therapies. Important research gaps for the future include: (1) Defining how age, host factors including prior exposures, and genetics impact the trajectory of sepsis in children, (2) Developing tools for rapid assessment of immune function in sepsis, and (3) Assessing how evolving pediatric sepsis endotypes respond differently to immunomodulation. Although multiple promising immunomodulatory agents exist or are in development, access to rapid immunophenotyping will be needed to identify which children are most likely to benefit from which therapy. Advancements in the ability to perform multidimensional endotyping will be key to developing a personalized approach to children with sepsis. IMPACT: Immunologic responses during sepsis vary significantly among patients and evolve over the course of illness. The resulting spectrum of immunoparalysis that can occur due to sepsis can increase morbidity and mortality in children and adults. This narrative review summarizes the current literature surrounding biomarkers and functional immunologic assays for immune dysregulation in sepsis, with a focus on immunomodulatory therapies that have been evaluated in sepsis. A precision approach toward diagnostic endotyping and therapeutics, including gene expression, will allow for optimal clinical trials to evaluate the efficacy of individualized and targeted treatments for pediatric sepsis.

Early Identification and Management of Congenital Cytomegalovirus.

Congenital cytomegalovirus (cCMV) is the most common nongenetic cause of sensorineural hearing loss. Despite its prevalence, universal screening for cCMV is not currently performed. Hearing loss caused by cCMV is most often severe to profound, often bilateral, and may be fluctuating or progressive. Infants with hearing loss at birth and confirmed cCMV might benefit from antiviral therapy. Roughly half of hearing loss cases owing to cCMV are delayed in onset, and consequently, these children pass newborn hearing screening. Children with cCMV require close audiologic monitoring, require appropriate management with hearing aids, and should be monitored for cochlear implant candidacy.

Congenital Cytomegalovirus Infection: Epidemiology, Timely Diagnosis, and Management.

Congenital cytomegalovirus (cCMV) infection is common because of the ubiquitous nature of the virus and the lack of an effective prevention strategy during pregnancy. Most infants with cCMV are asymptomatic, although a notable subset can have sequelae including, most commonly, sensorineural hearing loss and neurodevelopmental disability, which may not be present at birth. Timely screening for cytomegalovirus in the first weeks after birth is critical to appropriately diagnose congenital infection, evaluate affected infants, and determine the treatment course. Antiviral therapy with valganciclovir can optimize end hearing and neurodevelopmental outcomes in symptomatic infants. This review discusses the epidemiology and clinical manifestations of cCMV, targeted and universal screening approaches, and treatment and monitoring of infants with cCMV.

Laboratory analysis of symptomatic and asymptomatic pregnant patients with SARS-CoV-2 infection.

BACKGROUND: Inflammatory biomarkers have been used to portend disease severity in nonpregnant individuals with SARS-CoV-2 infection. However, currently, limited data are available, and with mixed results, to elucidate which inflammatory biomarkers may be most associated with clinical phenotype in pregnant patients. OBJECTIVE: We aimed to compare laboratory findings among pregnant patients with SARS-CoV-2 infection by symptom status and disease severity. STUDY DESIGN: We retrospectively evaluated pregnant patients with positive SARS-CoV-2 infection, confirmed through polymerase chain reaction testing, at an urban academic US hospital between March 2020 and October 2020, performed for reported symptoms or universal screening on admission. In our hospital, all patients with SARS-CoV-2 infection were recommended to have baseline laboratory testing, including leukocyte, neutrophil, and lymphocyte counts; aspartate aminotransferase and alanine aminotransferase; high-sensitivity C-reactive protein; procalcitonin; lactate dehydrogenase; D-dimer; and ferritin. We performed multivariable logistic regression to evaluate peak laboratory abnormalities significantly associated with symptomatic SARS-CoV-2 infection and disease severity with gestational age at diagnosis, maternal age, and obesity as covariates. The sensitivity and specificity of laboratory abnormalities were calculated to identify symptomatic vs asymptomatic infection and severe to critical disease vs mild to moderate disease. RESULTS: We identified 175 pregnant patients with SARS-CoV-2 infection, of whom 100 (57%) were symptomatic; 17 (17%) of those who were symptomatic had a severe to critical disease. Laboratory data were available for 128 patients, of whom 67 (52%) were symptomatic. Compared with asymptomatic individuals, symptomatic individuals were more likely to exhibit elevated high-sensitivity C-reactive protein levels after adjusting for gestational age (adjusted odds ratio, 5.67; 95% confidence interval, 1.42-22.52; sensitivity, 81%; specificity, 43%). In symptomatic individuals, transaminitis (adjusted odds ratio, 5.67; 95% confidence interval, 1.27-25.43), elevated procalcitonin levels (adjusted odds ratio, 16.60; 95% confidence interval, 2.61-105.46), and elevated lactate dehydrogenase levels (adjusted odds ratio, 17.55; 95% confidence interval, 2.51-122.78) were independently associated with severe to critical disease rather than mild to moderate disease after adjusting for maternal age and obesity. For differentiating disease severity, sensitivity rates for transaminitis, procalcitonin elevation, and lactate dehydrogenase elevation were 47%, 87%, and 53%, respectively, whereas the specificity rates were 89%, 63%, and 90%, respectively. CONCLUSION: Inflammatory biomarkers in pregnant patients with SARS-CoV-2 infection exhibited vast heterogeneity, poor discriminative ability, and thereby limited clinical utility. Larger registry studies should evaluate which inflammatory biomarkers may be most useful for risk stratification and prognostication of pregnant patients with SARS-CoV-2 infection, taking into account the physiology of pregnancy.

Chorioamnionitis and Risk for Maternal and Neonatal Sepsis: A Systematic Review and Meta-analysis.

OBJECTIVE: To estimate the risk of maternal and neonatal sepsis associated with chorioamnionitis. DATA SOURCES: PubMed, BIOSIS, and ClinicalTrials.gov databases were systematically searched for full-text articles in English from inception until May 11, 2020. METHODS OF STUDY SELECTION: We screened 1,251 studies. Randomized controlled trials, case-control, or cohort studies quantifying a relationship between chorioamnionitis and sepsis in mothers (postpartum) or neonates born at greater than 22 weeks of gestation were eligible. Studies were grouped for meta-analyses according to exposures of histologic or clinical chorioamnionitis and outcomes of maternal or neonatal sepsis. TABULATION, INTEGRATION, AND RESULTS: One hundred three studies were included, and 55 met criteria for meta-analysis (39 studies of preterm neonates, 10 studies of general populations of preterm and term neonates, and six studies of late preterm and term neonates). Study details and quantitative data were abstracted. Random-effects models were used to generate pooled odds ratios (ORs); most studies only reported unadjusted results. Histologic chorioamnionitis was associated with confirmed and any early-onset neonatal sepsis (unadjusted pooled ORs 4.42 [95% CI 2.68-7.29] and 5.88 [95% CI 3.68-9.41], respectively). Clinical chorioamnionitis was also associated with confirmed and any early-onset neonatal sepsis (unadjusted pooled ORs 6.82 [95% CI 4.93-9.45] and 3.90 [95% CI 2.74-5.55], respectively). Additionally, histologic and clinical chorioamnionitis were each associated with higher odds of late-onset sepsis in preterm neonates. Confirmed sepsis incidence was 7% (early-onset) and 22% (late-onset) for histologic and 6% (early-onset) and 26% (late-onset) for clinical chorioamnionitis-exposed neonates. Three studies evaluated chorioamnionitis and maternal sepsis and were inconclusive. CONCLUSION: Both histologic and clinical chorioamnionitis were associated with early- and late-onset sepsis in neonates. Overall, our findings support current guidelines for preventative neonatal care. There was insufficient evidence to determine the association between chorioamnionitis and maternal sepsis. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42020156812.

Umbilical cord miRNAs to predict neonatal early onset sepsis.

OBJECTIVE: To determine if miRNA (miR) expression in umbilical cord blood and umbilical cord tissue differs between neonates with early onset sepsis (EOS) versus neonates without true infection. METHODS: Retrospective case-control study design of human patients with EOS (n = 8), presumed sepsis (N = 12) and non-infected control patients (N = 21). Differential expression of >300 miRs was examined using the MIHS-3001ZE-miScript miRNA PCR Array Human miFinder 384HC. Expression levels of miRs were normalized using the global Ct mean of expressed miR and compared between groups. Data analysis was performed using GeneGlobe data analysis software. Ratios of over and under-expressed miRs were calculated and compared between groups using receiver operating characteristic (ROC) curves. RESULTS: Both umbilical cord plasma and umbilical cord tissue revealed several miRs with differential expression with little overlap between the two specimen types. The most overexpressed miR in plasma of EOS patients was miR-211-5p and the most overexpressed in EOS cord tissue was miR-223-5p. ROC curves comparing the ratios of over and under-expressed miRs for EOS patients and controls resulted in an area under the curve of 0.787 for cord plasma (miR-211-5p/miR-142-3p) and 0.988 for umbilical cord tissue (miR-223-5p/miR-22-3p), indicating good discrimination. CONCLUSIONS: miRs show differential expression in EOS versus non-infected controls and presumed sepsis. A ratio of over and under-expressed miRs can provide a potentially sensitive and specific diagnostic test for EOS.