Severe Acute Respiratory Syndrome Coronavirus 2 Infection Versus Vaccination in Pregnancy: Implications for Maternal and Infant Immunity.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been associated with adverse maternal and neonatal outcomes, yet uptake of SARS-CoV-2 vaccines during pregnancy and lactation has been slow. As a result, millions of pregnant and lactating women and their infants remain susceptible to the virus. METHODS: We measured spike-specific immunoglobulin G (anti-S IgG) and immunoglobulin A (anti-S IgA) in serum and breastmilk (BM) samples from 3 prospective mother-infant cohorts recruited in 2 academic medical centers. The primary aim was to determine the impact of maternal SARS-CoV-2 immunization vs infection and their timing on systemic and mucosal immunity. RESULTS: The study included 28 mothers infected with SARS-CoV-2 in late pregnancy (INF), 11 uninfected mothers who received 2 doses of the BNT162b2 vaccine in the latter half of pregnancy (VAX-P), and 12 uninfected mothers who received 2 doses of BNT162b2 during lactation. VAX dyads had significantly higher serum anti-S IgG compared to INF dyads (P < .0001), whereas INF mothers had higher BM:serum anti-S IgA ratios compared to VAX mothers (P = .0001). Median IgG placental transfer ratios were significantly higher in VAX-P compared to INF mothers (P < .0001). There was a significant positive correlation between maternal and neonatal serum anti-S IgG after vaccination (r = 0.68, P = .013), but not infection. CONCLUSIONS: BNT161b2 vaccination in late pregnancy or lactation enhances systemic immunity through serum anti-S immunoglobulin, while SARS-CoV-2 infection induces mucosal over systemic immunity more efficiently through BM immunoglobulin production. Next-generation vaccines boosting mucosal immunity could provide additional protection to the mother-infant dyad. Future studies should focus on identifying the optimal timing of primary and/or booster maternal vaccination for maximal benefit.

Fetal and early neonatal interleukin-6 response.

In 1998, a systemic fetal cytokine response, defined as a plasma interleukin-6 (IL-6) value above 11 pg/mL, was reported to be a major independent risk factor for the subsequent development of neonatal morbid events even after adjustments for gestational age and other confounders. Since then, the body of literature investigating the use of blood concentrations of IL-6 as a hallmark of the fetal inflammatory response syndrome (FIRS), a diagnostic marker of early-onset neonatal sepsis (EONS) and a risk predictor of white matter injury (WMI), has grown rapidly. In this article, we critically review: IL-6 biological functions; current evidence on the association between IL-6, preterm birth, FIRS and EONS; IL-6 reference intervals and dynamics in the early neonatal period; IL-6 response during the immediate postnatal period and perinatal confounders; accuracy and completeness of IL-6 diagnostic studies for EONS (according to the Standards for Reporting of Diagnostic Accuracy statement); and recent breakthroughs in the association between fetal blood IL-6, EONS, and WMI.

Long-term follow-up of the "wait and see" approach to localized perinatal adrenal neuroblastoma.

BACKGROUND: Evidence-based guidelines for the management of localized perinatal adrenal neuroblastoma are not yet available. We describe our preliminary experience managing this tumor with a "wait and see" policy. METHODS: A single-center prospective study (February 2002 to December 2009) was conducted with 12 consecutive patients in whom an adrenal mass was detected antenatally or within the first 3 months of life. Diagnostic workup included the following investigations: measurement of urine catecholamine metabolites, imaging studies (ultrasonography, magnetic resonance imaging, or computed tomography), metaiodobenzylguanidine scintigraphy, and/or core needle biopsy. RESULTS: The male/female ratio was 1.4:1.0. Median tumor size at presentation was 29 mm (range 10-50 mm). Eight lesions were detected antenatally. Ten lesions were diagnosed as localized neuroblastoma. Of these ten lesions, four were excised because of parental preference (n = 2), tumor enlargement (n = 1) or tumor persistence (n = 1). The remaining six patients underwent watchful clinical observation, which showed progressive tumor shrinkage and complete regression within 10-39 months (median 12.5 months). The final two lesions were small predominantly cystic lesions without a clear-cut diagnosis. They were managed noninvasively. At an overall median follow-up of 109 months (range 30-122 months), all patients are alive and disease-free, although one patient progressed to stage 4 disease despite early excision of the primary tumor. CONCLUSIONS: Spontaneous regression of localized perinatal adrenal neuroblastoma occurs often, and a "wait and see" strategy seems justified in these small infants. Patients with enlarging or stable lesions that have persisted for several months may benefit from surgery, although prompt excision may not prevent tumor progression.

Incidence of Healthcare-Associated Infections in a Neonatal Intensive Care Unit before and during the COVID-19 Pandemic: A Four-Year Retrospective Cohort Study.

The COVID-19 pandemic may have had an impact on healthcare-associated infection (HAI) rates. In this study, we analyzed the occurrence of HAIs in a neonatal intensive care unit (NICU) of the Umberto I teaching hospital in Rome before and during the pandemic. All infants admitted from 1 March 2018 to 28 February 2022 were included and were divided into four groups according to their admission date: two groups before the pandemic (periods I and II) and two during the pandemic (periods III and IV). The association between risk factors and time-to-first event was analyzed using a multivariable Cox regression model. Over the four-year period, a total of 503 infants were included, and 36 infections were recorded. After adjusting for mechanical ventilation, birth weight, sex, type of delivery, respiratory distress syndrome, and previous use of netilmicin and fluconazole, the multivariable analysis confirmed that being hospitalized during the pandemic periods (III and IV) was the main risk factor for HAI acquisition. Furthermore, a change in the etiology of these infections was observed across the study periods. Together, these findings suggest that patient management during the pandemic was suboptimal and that HAI surveillance protocols should be implemented in the NICU setting promptly.

Early neurodevelopmental outcomes in children with asymptomatic congenital CMV infection.

BACKGROUND: Approximately 85-90% of congenital cytomegalovirus infections (cCMV) are asymptomatic. Few studies have investigated early and long-term neurodevelopmental outcomes in children with asymptomatic cCMV (acCMV), and the data is contradictory. In the present study, we did investigate the effect of cCMV asymptomatic infection on neurological outcomes and in cognitive, language and motor development at 6 months of age. METHODS: Fifty-six children with cCMV asymptomatic infection were followed for 6 months, as part of a long-term surveillance program, examining their neurological and developmental outcomes. Neurological examination and Bayley-III Scales were performed. RESULTS: Clinical evaluation revealed that early neurological outcomes were essentially normal, with minor neurological deficits (i.e., tone abnormalities) in a subgroup of patients. Bayley-III scores were substantially in the normal range, with 14% showing a score less than 85 (-1SD) in the Motor Scale. Children's neurological and neurodevelopmental outcomes at 6 months of age did not differ according to the trimester of infection. CONCLUSIONS: Some infants with cCMV asymptomatic infection may present minor neurological abnormalities in early stages of life. It seems useful to monitor this population for early and late neurodevelopmental sequelae.

Neonatal osteomyelitis: an Italian multicentre report of 22 cases and comparison with the inherent literature.

OBJECTIVE: The primary objective of this study is to report and compare our data with the most relevant literature of the past decade about neonatal osteomyelitis. STUDY DESIGN: We retrospectively review the data of 22 subjects aged 35 days or less who were admitted to three different sites in Italy with a radiological diagnosis of osteomyelitis. The inherent literature was searched and reviewed: five studies were considered for comparison with our data. RESULTS: All the neonates, except three (two pre-term and one post-term), were born at term. The male to female ratio was 1.75 (14 males and 8 females). The mean age at presentation was 19.5 days. The most common presenting signs of the infection were local swelling and reduced mobility of the affected segment. The most common sites of infection were the femur, humerus, and tibia. The mean duration of intravenous antibiotic therapy was 29.5 days. In most neonates the diagnosis was prompt and the antibiotic treatment immediate. A low rate of sequelae was reported. All infants survived through follow up. The data from the inherent literature showed a wide variability, probably owing to the setting and the historical period of the different studies. CONCLUSION: Neonatal osteomyelitis is an alarming yet poorly understood disease. Nonetheless, our report suggests that a quick diagnosis and treatment can be easily achieved, with good outcome on the remarkably plastic structure of neonatal bones.

Consequences of Early Separation of Maternal-Newborn Dyad in Neonates Born to SARS-CoV-2 Positive Mothers: An Observational Study.

As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues its spread all over the world, data on perinatal management of the maternal-infant dyad are urgent. We performed an observational study to describe the effects of the early separation of the maternal-infant dyad, in case of maternal SARS-CoV-2 infection. We reported the medical records for 37 neonates born to 37 SARS-CoV-2 positive mothers in a setting of separation of the dyad after birth. Data on neonatal infection, clinical condition, and breastfeeding rate were recorded until the first month of life. No maternal deaths were recorded; 37.8% of women had at least one pregnancy-related complication. We reported a high adherence to recommended safety measures after discharged with 84.8% of the mothers using at least one personal protective device and 51.5% using all the protective devices. We reported one case of vertical transmission and no cases of horizontal transmission. However, the separation of the dyad had a negative impact on breastfeeding because only 23.5% of the newborns received exclusively human milk during the first month of life. Despite early separation of the dyad protecting the newborns from possible horizontal transmission of SARS-CoV-2, it negatively affects breastfeeding during the first months of life.

Liver Involvement in SARS-CoV-2 Vertically Infected Newborn: A Case Report.

Neonatal SARS-CoV-2 infection can occur antenatally, peripartum, or postnatally. In the newborn, clinical manifestations may vary including fever and respiratory, gastrointestinal and neurological symptoms. Most commonly, they are subclinical. We herein present a case of vertical transmission of SARS-CoV-2 presenting with liver injury, characterized by an increase in serum transaminases.

Immune Response of Neonates Born to Mothers Infected With SARS-CoV-2.

Importance: Although several studies have provided information on short-term clinical outcomes in children with perinatal exposure to SARS-CoV-2, data on the immune response in the first months of life among newborns exposed to the virus in utero are lacking. Objective: To characterize systemic and mucosal antibody production during the first 2 months of life among infants who were born to mothers infected with SARS-CoV-2. Design, Setting, and Participants: This prospective cohort study enrolled 28 pregnant women who tested positive for SARS-CoV-2 infection and who gave birth at Policlinico Umberto I in Rome, Italy, from November 2020 to May 2021, and their newborns. Maternal and neonatal systemic immune responses were investigated by detecting spike-specific antibodies in serum, and the mucosal immune response was assessed by measuring specific antibodies in maternal breastmilk and infant saliva 48 hours after delivery and 2 months later. Exposures: Maternal infection with SARS-CoV-2 in late pregnancy. Main Outcomes and Measures: The systemic immune response was evaluated by the detection of SARS-CoV-2 IgG and IgA antibodies and receptor binding domain-specific IgM antibodies in maternal and neonatal serum. The mucosal immune response was assessed by measuring spike-specific antibodies in breastmilk and in infant saliva, and the presence of antigen-antibody spike IgA immune complexes was investigated in breastmilk samples. All antibodies were detected using an enzyme-linked immunosorbent assay. Results: In total, 28 mother-infant dyads (mean [SD] maternal age, 31.8 [6.4] years; mean [SD] gestational age, 38.1 [2.3] weeks; 18 [60%] male infants) were enrolled at delivery, and 21 dyads completed the study at 2 months' follow-up. Because maternal infection was recent in all cases, transplacental transfer of virus spike-specific IgG antibodies occurred in only 1 infant. One case of potential vertical transmission and 1 case of horizontal infection were observed. Virus spike protein-specific salivary IgA antibodies were significantly increased (P = .01) in infants fed breastmilk (0.99 arbitrary units [AU]; IQR, 0.39-1.68 AU) vs infants fed an exclusive formula diet (0.16 AU; IQR, 0.02-0.83 AU). Maternal milk contained IgA spike immune complexes at 48 hours (0.53 AU; IQR, 0.25-0.39 AU) and at 2 months (0.09 AU; IQR, 0.03-0.17 AU) and may have functioned as specific stimuli for the infant mucosal immune response. Conclusions and Relevance: In this cohort study, SARS-CoV-2 spike-specific IgA antibodies were detected in infant saliva, which may partly explain why newborns are resistant to SARS-CoV-2 infection. Mothers infected in the peripartum period appear to not only passively protect the newborn via breastmilk secretory IgA but also actively stimulate and train the neonatal immune system via breastmilk immune complexes.

Nutritional Intake Influences Zinc Levels in Preterm Newborns: An Observational Study.

(1) Background: Zinc is a key element for protein synthesis in preterm newborns. Early aggressive nutrition, promoting protein synthesis, may increase zinc consumption; (2) Methods: We performed a prospective observational study, to assess the relationship between early macronutrients intake and serum zinc levels, in preterm newborns with Gestational Age (GA) of 24-35 weeks, consecutively observed in Neonatal Intensive Care Unit (NICU). (3) Results: We enrolled 130 newborns (GA 31.5 ± 2.8). A significant negative correlation between serum zinc level at 28 days of life and energy (r -0.587, p < 0.001) and protein intake (r -0.556, p < 0.001) in the first week of life was observed. Linear regression analysis showed that zinc levels depended on energy (ß -0.650; p < 0.001) and protein (ß -0.669; p < 0.001) intake given through parenteral nutrition (PN) in the first week of life; (4) Conclusions: zinc status of preterm neonates was influenced by early protein and energy intake. An additional zinc supplementation should be considered when high protein and energy intake are received by preterm newborns in the first week of life.

Isolated auditory neuropathy at birth in congenital cytomegalovirus infection.

BACKGROUND: Congenital cytomegalovirus (cCMV) infection is the most frequent non-genetic cause of sensorineural hearing-loss (SNHL) (i.e., hearing loss due to a cochlear and/or auditory nerve damage). It is widely accepted that SNHL at birth, when associated to cCMV symptomatic infection involving the central nervous system, benefits from antiviral therapy started in the neonatal period. Conversely, there is no consensus for antiviral treatment in congenitally infected infants diagnosed with isolated SNHL (i.e., SNHL in an otherwise asymptomatic infant) at birth. Our aim was to assess the frequency and the auditory outcome of isolated SNHL at birth due to auditory neuropathy (AN) (i.e., SNHL in a patient with normal cochlear function and auditory nerve dysfunction) in infants with cCMV infection. METHODS: We retrospectively reviewed the clinical history of 60 infants, born at term, with cCMV asymptomatic infection, without additional risk factors for SNHL, and exhibiting bilateral "pass" otoacustic emissions (OAE). None of them underwent antiviral therapy. Hearing thresholds were assessed by means of Auditory Brainstem Responses (ABR). AN affected children were followed up until possible normalization of the hearing thresholds or definitive diagnosis of AN. Each infant diagnosed with monolateral or bilateral AN was classified according to the worst ear threshold. RESULTS: In our population, the first ABR was performed at a mean age of 5.00 ± 2.79 (SD) months and AN was diagnosed in 16/60 (26.67%) infants; in 4 infants the AN was defined as mild (4/4 monolateral), moderate in 11 (5/11 bilateral), and severe in 1 (bilateral). The mean age at first ABR was 3.69 ± 2.80 (SD) months in the 16 babies with AN and 5.48 ± 2.66 (SD) months in the 44 infants with normal hearing (p = 0.007). All AN cases spontaneously recovered a normal auditory threshold over time. The mean length of the audiological follow-up was 32.44 ± 17.58 (SD) months (range 5-60 months). CONCLUSION: A delayed maturation of the auditory pathways should be considered when a mild/moderate isolated AN at birth is detected in cCMV infected infants. Prospective studies conducted on larger populations, and with a longer audiological follow-up, are needed to confirm our findings.

Rescue of Replication-Competent ZIKV Hidden in Placenta-Derived Mesenchymal Cells Long After the Resolution of the Infection.

The Zika virus (ZIKV) genome, its negative-strand viral proteins, and virus-like particles were detected in placenta-derived mesenchymal cells (MSCs), indicating that ZIKV persists after virus clearance from maternal blood and can be rescued by in vitro cultivation. We report for the first time the presence of replication-competent ZIKV in MSCs from an asymptomatic woman who acquired infection during pregnancy.

Strategies for Prevention of Mother-to-Child Transmission Adopted in the "Real-World" Setting: Data From the Italian Register for HIV-1 Infection in Children.

BACKGROUND: Strategies for prevention of HIV-1 mother-to-child transmission (PMTCT) have been continuously optimized. However, cases of vertical transmission continue to occur in high-income countries. OBJECTIVES: To investigate changes in PMTCT strategies adopted by Italian clinicians over time and to evaluate risk factors for transmission. METHODS: Data from mother-child pairs prospectively collected by the Italian Register, born in Italy in 1996-2016, were analyzed. Risk factors for MTCT were explored by logistic regression analyses. RESULTS: Six thousand five hundred three children (348 infections) were included. In our cohort, the proportion of children born to foreign mothers increased from 18.3% (563/3078) in 1996%-2003% to 66.2% (559/857) in 2011-2016 (P < 0.0001). Combination neonatal prophylaxis use significantly (P < 0.0001) increased over time, reaching 6.3% (56/857) after 2010, and it was largely (4.2%) adopted in early preterm infants. The proportion of vaginal deliveries in women with undetectable viral load (VL) increased over time and was 9.9% (85/857) in 2011-2016; no infection occurred among them. In children followed up since birth MTCT, rate was 3.5% (96/2783) in 1996-2003; 1.4% (36/2480) in 2004-2010; and 1.1% (9/835) in 2011-2016. At a multivariate analysis, factors associated with MTCT were vaginal delivery with detectable or missing VL or nonelective caesarean delivery, prematurity, breastfeeding, lack of maternal or neonatal antiretroviral therapy, detectable maternal VL, and age at first observation. Previously described increased risk of offspring of immigrant women was not confirmed. CONCLUSIONS: Risk of MTCT in Italy is ongoing, even in recent years, underling the need for implementation of the current screening program in pregnancy. Large combination neonatal prophylaxis use in preterm infants was observed, even if data on safety and efficacy in prematures are poor.

Ganciclovir penetrates into the cerebrospinal fluid of an infant with congenital cytomegalovirus infection.

Currently, there is no evidence whether ganciclovir, or its oral prodrug valganciclovir, penetrates into the cerebrospinal fluid of human infants treated for congenital cytomegalovirus infection. Here, we report a case study providing evidence that ganciclovir, administered as valganciclovir, reaches the infant's cerebrospinal fluid when used at the currently recommended dose for congenital cytomegalovirus infection.

Procalcitonin in pediatrics.

Over the past two decades, the body of literature on the clinical usefulness of procalcitonin (PCT) in adults has grown rapidly. Although this approach has led to increased insight, it has also prompted debate regarding its potential use in diagnosis and management of severe infection. Clinicians, however, are less familiar with the use of PCT in pediatric populations. In this review, we examine PCT as a marker of severe clinical pediatric conditions including its role in systemic inflammation, infection, and sepsis.

Cervical insufficiency: a new issue for guidelines on prevention of perinatal group B streptococcal disease?

The updated Guidelines on Prevention of Perinatal Group B Streptococcal Disease, issued by the Centers for Disease Control and Prevention, actually represent the mainstay in the prevention of neonatal early-onset group B streptococcal (GBS) sepsis. According to these guidelines, patients with possible preterm delivery are screened for GBS colonization and offered intrapartum prophylaxis only if they enter preterm labor or experience preterm premature rupture of the membranes. Nonetheless, the fulfillment of these recommendations seems to be suboptimal in clinical practice, as it is heavily influenced by the knowledge of the colonization status. We report here 2 cases of blood culture-proven, early-onset neonatal GBS sepsis involving preterm infants delivered by mothers who had midtrimester cervical insufficiency and bulging membranes. Midtrimester acute cervical insufficiency strongly predicts preterm delivery. These women are liable to miss intrapartum antibiotic prophylaxis because they typically have shorter labor, and the test results for GBS status are unlikely to be available before delivery. We believe that women with midtrimester cervical insufficiency and bulging membranes should be screened for GBS infection soon after hospital admittance if the gestational age is close to the threshold of fetal viability. A timely diagnosis of GBS colonization may not only increase the number of patients receiving targeted intrapartum antibiotic prophylaxis but would also allow consideration of the administration of antepartum antibiotic prophylaxis. Indeed, as further outlined in this report, GBS intraamniotic infection may dramatically occur before the onset of preterm labor or preterm premature rupture of the membranes.

Early onset sepsis in very low birth weight newborn infants.

Early onset sepsis (EOS) is a severe problem affecting very low birth weight (VLBW) infants and is associated with a threefold increased risk of mortality. Although advances in perinatal care have led to improved survival of VLBW infants over recent decades, survival without major neonatal morbidity has not increased. The authors reviewed the current literature on EOS, focusing on the peculiarities concerning risk factors, etiology, diagnosis, treatment and outcome in very low birth weight infants, and on the recent advances in the management of this condition.