Building a growing genomic data repository for maternal and fetal health through the PING Consortium.

Background: Prenatally transmitted viruses can cause severe damage to the developing brain. There is unexplained variability in prenatal brain injury and postnatal neurodevelopmental outcomes, suggesting disease modifiers. Discordant outcomes among dizygotic twins could be explained by genetic susceptibly or protection. Among several well-recognized threats to the developing brain, Zika is a mosquito-borne, positive-stranded RNA virus that was originally isolated in Uganda and spread to cause epidemics in Africa, Asia, and the Americas. In the Americas, the virus caused congenital Zika syndrome and a multitude of neurodevelopmental disorders. As of now, there is no preventative treatment or cure for the adverse outcomes caused by prenatal Zika infection. The Prenatal Infection and Neurodevelopmental Genetics (PING) Consortium was initiated in 2016 to identify factors modulating prenatal brain injury and postnatal neurodevelopmental outcomes for Zika and other prenatal viral infections. Methods: The Consortium has pooled information from eight multi-site studies conducted at 23 research centers in six countries to build a growing clinical and genomic data repository. This repository is being mined to search for modifiers of virally induced brain injury and developmental outcomes. Multilateral partnerships include commitments with Children's National Hospital (USA), Instituto Nacional de Salud (Colombia), the Natural History of Zika Virus Infection in Gestation program (Brazil), and Zika Instituto Fernandes Figueira (Brazil), in addition to the Centers for Disease Control and Prevention and the National Institutes of Health. Discussion: Our goal in bringing together these sets of patient data was to test the hypothesis that personal and populational genetic differences affect the severity of brain injury after a prenatal viral infection and modify neurodevelopmental outcomes. We have enrolled 4,102 mothers and 3,877 infants with 3,063 biological samples and clinical data covering over 80 phenotypic fields and 5,000 variables. There were several notable challenges in bringing together cohorts enrolled in different studies, including variability in the timepoints evaluated and the collected clinical data and biospecimens. Thus far, we have performed whole exome sequencing on 1,226 participants. Here, we present the Consortium's formation and the overarching study design. We began our investigation with prenatal Zika infection with the goal of applying this knowledge to other prenatal infections and exposures that can affect brain development.

Assessment of three antibiotic combination regimens against Gram-negative bacteria causing neonatal sepsis in low- and middle-income countries.

Gram-negative bacteria (GNB) are a major cause of neonatal sepsis in low- and middle-income countries (LMICs). Although the World Health Organization (WHO) reports that over 80% of these sepsis deaths could be prevented through improved treatment, the efficacy of the currently recommended first- and second-line treatment regimens for this condition is increasingly affected by high rates of drug resistance. Here we assess three well known antibiotics, fosfomycin, flomoxef and amikacin, in combination as potential antibiotic treatment regimens by investigating the drug resistance and genetic profiles of commonly isolated GNB causing neonatal sepsis in LMICs. The five most prevalent bacterial isolates in the NeoOBS study (NCT03721302) are Klebsiella pneumoniae, Acinetobacter baumannii, E. coli, Serratia marcescens and Enterobacter cloacae complex. Among these isolates, high levels of ESBL and carbapenemase encoding genes are detected along with resistance to ampicillin, gentamicin and cefotaxime, the current WHO recommended empiric regimens. The three new combinations show excellent in vitro activity against ESBL-producing K. pneumoniae and E. coli isolates. Our data should further inform and support the clinical evaluation of these three antibiotic combinations for the treatment of neonatal sepsis in areas with high rates of multidrug-resistant Gram-negative bacteria.

High Incidence Rates of Early-onset Bacterial Sepsis in Infants Born in Two Brazilian Maternities: A 15-Year Retrospective Analysis.

BACKGROUND: Data on the burden and etiology of neonatal early-onset bacterial sepsis (EOBS) in low-to-middle-income countries are scarce. Surveillance is critical for optimizing prevention and treatment strategies. We aimed to estimate the incidence of EOBS in 2 large Brazilian cohorts of neonates. METHODS: Data were retrospectively obtained from 33,794 neonates born between 2009 and 2017 at low-risk (n = 17,981) and high-risk maternity centers (n = 15,813). Blood cultures were taken within 72 hours of life from neonates with perinatal risk factors for EOBS or suspected EOBS. A positive blood culture for a pathogenic microorganism and a compatible clinical evolution confirmed the diagnosis of EOBS. RESULTS: One-third of the infants born from high-risk and 18.5% from low-risk maternities were investigated for EOBS. Overall, EOBS was more incident in neonates born in the high-risk facilities [66 cases or 4.2/1000 (95% CI: 3.2-5.3)] than in the low-risk facilities [24 cases or 1.3/1000 (95% CI: 0.9-2.0)]. The incidence rate of EOBS increased with decreasing gestational age (<32 weeks: 20.5/1000; 32-36 weeks: 5.6/1000; ≥37 weeks: 1.5/1000). Group B Streptococcus (GBS) was the agent more frequently identified in high-risk and low-risk maternities: 1.8/1000 (95% CI: 1.1-2.4) and 0.4/1000 (95% CI: 0.2-0.9), respectively. EOBS's overall case fatality rate was 17.8% for all the agents and 22% for GBS. CONCLUSIONS: EOBS remains unacceptably high and is frequently fatal in preterm and term infants cared for in high- or low-risk maternities. Because GBS has emerged as the most frequent causative agent, preventive strategies are urgently needed.

Safety and Immunogenicity of a ChAd155-Vectored Respiratory Syncytial Virus Vaccine in Infants 6-7 Months of age: A Phase 1/2 Randomized Trial.

BACKGROUND: Respiratory syncytial virus (RSV) is a common cause of lower respiratory tract infections in infants. This phase 1/2, observer-blind, randomized, controlled study assessed the safety and immunogenicity of an investigational chimpanzee-derived adenoviral vector RSV vaccine (ChAd155-RSV, expressing RSV F, N, and M2-1) in infants. METHODS: Healthy 6- to 7-month-olds were 1:1:1-randomized to receive 1 low ChAd155-RSV dose (1.5 × 1010 viral particles) followed by placebo (RSV_1D); 2 high ChAd155-RSV doses (5 × 1010 viral particles) (RSV_2D); or active comparator vaccines/placebo (comparator) on days 1 and 31. Follow-up lasted approximately 2 years. RESULTS: Two hundred one infants were vaccinated (RSV_1D: 65; RSV_2D: 71; comparator: 65); 159 were RSV-seronaive at baseline. Most solicited and unsolicited adverse events after ChAd155-RSV occurred at similar or lower rates than after active comparators. In infants who developed RSV infection, there was no evidence of vaccine-associated enhanced respiratory disease (VAERD). RSV-A neutralizing titers and RSV F-binding antibody concentrations were higher post-ChAd155-RSV than postcomparator at days 31, 61, and end of RSV season 1 (mean follow-up, 7 months). High-dose ChAd155-RSV induced stronger responses than low-dose, with further increases post-dose 2. CONCLUSIONS: ChAd155-RSV administered to 6- to 7-month-olds had a reactogenicity/safety profile like other childhood vaccines, showed no evidence of VAERD, and induced a humoral immune response. Clinical Trials Registration. NCT03636906.

Fetal growth assessed via ultrasound in relation to maternal HIV infection status and antiretroviral regimens.

OBJECTIVE: To evaluate effects of maternal HIV and antiretroviral treatment (ART) on intrauterine fetal growth. DESIGN: Prospective cohort studies of HIV and ZIKA infection among women living with HIV (WLHIV) and women not living with HIV (WNLHIV) conducted in Brazil and the US from 2016 to 2020. METHODS: We evaluated fetal growth via repeated ultrasounds and calculated z scores for fetal growth measures using Intergrowth-21st standards among women with singleton pregnancies. Adjusted linear mixed models were fit for each fetal growth z score by HIV status. Among WLHIV, we compared fetal growth z scores by the most common maternal ART regimens, stratified by timing of ART initiation. RESULTS: We included 166 WLHIV and 705 WNLHIV; none had Zika infection. The z scores were similar for WLHIV and WNLHIV for femur length (latest third trimester median = 1.08) and estimated fetal weight (median ≈0.60); adjusted mean differences in fetal weight z scores by HIV status were less than 0.1 throughout gestation. Other fetal growth measurements were lower for WLHIV than WNLHIV early in gestation but increased more rapidly over gestation. Among WLHIV not on ART at conception, adjusted mean z scores were generally similar across regimens initiated during pregnancy but somewhat lower for atazanavir-based regimens for biparietal diameter compared with efavirenz-based or raltegravir-based regimens. Among WLHIV on ART at conception, mean z scores were similar across ART regimens. CONCLUSION: Within our cohorts, fetal growth was lower in WLHIV than WNLHIV early in gestation but similar by the end of gestation, which is reassuring. Among WLHIV, fetal growth measures were generally similar across ART regimens evaluated.

Maternal immunization in women living with HIV.

Thanks to widespread use of antiretroviral therapy worldwide, women living with HIV (WLWH) are becoming pregnant and giving birth to HIV-exposed but uninfected (HEU) newborns. Both pregnancy and HIV infection-related factors such as low CD4+ T-cell count or uncontrolled viral load increase the risk of severe infections such as influenza, COVID-19, and others, making maternal immunization a valuable tool to decrease maternal morbidity among WLWH. Vaccines administered during pregnancy may also benefit the health of HEU infants. Indeed, HEU infants suffer from higher risk of morbidity of infectious origin, including respiratory syncytial virus (RSV), group B streptococcus (GBS), pneumococcus and pertussis infections. Maternal pertussis immunization is recommended in various high-income countries but not in many low-middle income countries where HIV prevalence is higher. GBS and RSV vaccines to be administered during pregnancy are currently in late-phase clinical trials in HIV-uninfected women and could represent a valuable tool to decrease morbidity during infancy. Decreased transfer of vaccine-specific IgG, accelerated waning of vaccine-induced antibody responses, linked to persistent maternal immune activation, and blunting of infant immune response to vaccines could hamper vaccine effectiveness among WLWH and HEU infants. Vaccine hesitancy could limit benefits of maternal immunization and strategies to tackle vaccine hesitancy should be part of HIV routine care. The aim of this review is to summarize the current knowledge regarding the immunogenicity and efficacy of available and upcoming vaccines recommended during pregnancy of WLWH.

Incidence of Respiratory Syncytial Virus-Associated Lower Respiratory Tract Illness in Infants in Low- and Middle-Income Regions During the Coronavirus Disease 2019 Pandemic.

Background: Incidence data of respiratory syncytial virus-associated lower respiratory tract illness (RSV-LRTI) are sparse in low- and middle-income countries (LMICs). We estimated RSV-LRTI incidence rates (IRs) in infants in LMICs using World Health Organization case definitions. Methods: This prospective cohort study, conducted in 10 LMICs from May 2019 to October 2021 (largely overlapping with the coronavirus disease 2019 [COVID-19] pandemic), followed infants born to women with low-risk pregnancies for 1 year from birth using active and passive surveillance to detect potential LRTIs, and quantitative reverse-transcription polymerase chain reaction on nasal swabs to detect RSV. Results: Among 2094 infants, 32 (1.5%) experienced an RSV-LRTI (8 during their first 6 months of life, 24 thereafter). Seventeen (0.8%) infants had severe RSV-LRTI and 168 (8.0%) had all-cause LRTI. IRs (95% confidence intervals [CIs]) of first RSV-LRTI episode were 1.0 (.3-2.3), 0.8 (.3-1.5), and 1.6 (1.1-2.2) per 100 person-years for infants aged 0-2, 0-5, and 0-11 months, respectively. IRs (95% CIs) of the first all-cause LRTI episode were 10.7 (8.1-14.0), 11.7 (9.6-14.0), and 8.7 (7.5-10.2) per 100 person-years, respectively. IRs varied by country (RSV-LRTI: 0.0-8.3, all-cause LRTI: 0.0-49.6 per 100 person-years for 0- to 11-month-olds). Conclusions: RSV-LRTI IRs in infants in this study were relatively low, likely due to reduced viral circulation caused by COVID-19-related nonpharmaceutical interventions. Clinical Trials Registration: NCT03614676.

Normocephalic Children Exposed to Maternal Zika Virus Infection Do Not Have a Higher Risk of Neurodevelopmental Abnormalities around 24 Months of Age than Unexposed Children: A Controlled Study.

Although very few controlled studies are available, in utero Zika virus (ZIKV)-exposed children are considered at risk for neurodevelopmental abnormalities. We aimed to identify whether there is an excess risk of abnormalities in non-microcephalic children born to mothers with confirmed ZIKV infection compared with ZIKV-unexposed children from the same population. In a cross-sectional study nested in two larger cohorts, we compared 324 ZIKV-exposed children with 984 unexposed controls. Outcomes were assessed using the Bayley Screening Test III applied around 24 months of age. Relative risks for classifying children as emergent or at-risk for neurodevelopmental delay in at least one of five domains were calculated, adjusting for covariates. In four of the five domains, few children were classified as emergent (4-12%) or at-risk (0.3-2.16%) but for the expressive communication domain it was higher for emergent (19.1-42.9%). ZIKV-exposed children were half as frequently classified as emergent, including after adjusting for covariates [RR = 0.52 (CI 95% 0.40; 0.66)]. However, no difference was detected in the at-risk category [RR = 0.83 (CI 95% 0.48; 1.44)]. Normocephalic children exposed to the Zika virus during pregnancy do not have a higher risk of being classified as at risk for neurodevelopmental abnormalities at two years of age.

Vaccine value profile for cytomegalovirus.

Cytomegalovirus (CMV) is the most common infectious cause of congenital malformation and a leading cause of developmental disabilities such as sensorineural hearing loss (SNHL), motor and cognitive deficits. The significant disease burden from congenital CMV infection (cCMV) led the US National Institute of Medicine to rank CMV vaccine development as the highest priority. An average of 6.7/1000 live births are affected by cCMV, but the prevalence varies across and within countries. In contrast to other congenital infections such as rubella and toxoplasmosis, the prevalence of cCMV increases with CMV seroprevalence rates in the population. The true global burden of cCMV disease is likely underestimated because most infected infants (85-90 %) have asymptomatic infection and are not identified. However, about 7-11 % of those with asymptomatic infection will develop SNHL throughout early childhood. Although no licensed CMV vaccine exists, several candidate vaccines are in development, including one currently in phase 3 trials. Licensure of one or more vaccine candidates is feasible within the next five years. Various models of CMV vaccine strategies employing different target populations have shown to provide substantial benefit in reducing cCMV. Although CMV can cause end-organ disease with significant morbidity and mortality in immunocompromised individuals, the focus of this vaccine value profile (VVP) is on preventing or reducing the cCMV disease burden. This CMV VVP provides a high-level, comprehensive assessment of the currently available data to inform the potential public health, economic, and societal value of CMV vaccines. The CMV VVP was developed by a working group of subject matter experts from academia, public health groups, policy organizations, and non-profit organizations. All contributors have extensive expertise on various elements of the CMV VVP and have described the state of knowledge and identified the current gaps. The VVP was developed using only existing and publicly available information.

Challenges in the Implementation of the NeoOBS Study, a Global Pragmatic Observational Cohort Study, to Investigate the Aetiology and Management of Neonatal Sepsis in the Hospital Setting.

Neonatal sepsis is a significant cause of mortality and morbidity in low- and middle-income countries. To deliver high-quality data studies and inform future trials, it is crucial to understand the challenges encountered when managing global multi-centre research studies and to identify solutions that can feasibly be implemented in these settings. This paper provides an overview of the complexities faced by diverse research teams in different countries and regions, together with actions implemented to achieve pragmatic study management of a large multi-centre observational study of neonatal sepsis. We discuss specific considerations for enrolling sites with different approval processes and varied research experience, structures, and training. Implementing a flexible recruitment strategy and providing ongoing training were necessary to overcome these challenges. We emphasize the attention that must be given to designing the database and monitoring plans. Extensive data collection tools, complex databases, tight timelines, and stringent monitoring arrangements can be problematic and might put the study at risk. Finally, we discuss the complexities added when collecting and shipping isolates and the importance of having a robust central management team and interdisciplinary collaborators able to adapt easily and make swift decisions to deliver the study on time and to target. With pragmatic approaches, appropriate training, and good communication, these challenges can be overcome to deliver high-quality data from a complex study in challenging settings through a collaborative research network.

Neonatal invasive candidiasis in low- and middle-income countries: Data from the NeoOBS study.

Neonatal invasive candidiasis (NIC) has significant morbidity and mortality. Reports have shown a different profile of those neonates affected with NIC and of fluconazole-resistant Candida spp. isolates in low- and middle-income countries (LMICs) compared to high-income countries (HICs). We describe the epidemiology, Candida spp. distribution, treatment, and outcomes of neonates with NIC from LMICs enrolled in a global, prospective, longitudinal, observational cohort study (NeoOBS) of hospitalized infants <60 days postnatal age with sepsis (August 2018-February 2021). A total of 127 neonates from 14 hospitals in 8 countries with Candida spp. isolated from blood culture were included. Median gestational age of affected neonates was 30 weeks (IQR: 28-34), and median birth weight was 1270 gr (interquartile range [IQR]: 990-1692). Only a minority had high-risk criteria, such as being born <28 weeks, 19% (24/127), or birth weight <1000 gr, 27% (34/127). The most common Candida species were C. albicans (n = 45, 35%), C. parapsilosis (n = 38, 30%), and Candida auris (n = 18, 14%). The majority of C. albicans isolates were fluconazole susceptible, whereas 59% of C. parapsilosis isolates were fluconazole-resistant. Amphotericin B was the most common antifungal used [74% (78/105)], followed by fluconazole [22% (23/105)]. Death by day 28 post-enrollment was 22% (28/127). To our knowledge, this is the largest multi-country cohort of NIC in LMICs. Most of the neonates would not have been considered at high risk for NIC in HICs. A substantial proportion of isolates was resistant to first choice fluconazole. Understanding the burden of NIC in LMIC is essential to guide future research and treatment guidelines.

Our study describes neonates from low- and middle-income countries with neonatal invasive candidiasis (NIC). Most of them were outside the groups considered at high risk for NIC described in high-income countries. Candida spp. epidemiology was also different. The mortality was high (22%). Further research in these settings is required.

Risk of adverse outcomes in offspring with RT-PCR confirmed prenatal Zika virus exposure: An individual participant data meta-analysis of 13 cohorts in the Zika Brazilian Cohorts Consortium.

Background: Knowledge regarding the risks associated with Zika virus (ZIKV) infections in pregnancy has relied on individual studies with relatively small sample sizes and variable risk estimates of adverse outcomes, or on surveillance or routinely collected data. Using data from the Zika Brazilian Cohorts Consortium, this study aims, to estimate the risk of adverse outcomes among offspring of women with RT-PCR-confirmed ZIKV infection during pregnancy and to explore heterogeneity between studies. Methods: We performed an individual participant data meta-analysis of the offspring of 1548 pregnant women from 13 studies, using one and two-stage meta-analyses to estimate the absolute risks. Findings: Of the 1548 ZIKV-exposed pregnancies, the risk of miscarriage was 0.9%, while the risk of stillbirth was 0.3%. Among the pregnancies with liveborn children, the risk of prematurity was 10,5%, the risk of low birth weight was 7.7, and the risk of small for gestational age (SGA) was 16.2%. For other abnormalities, the absolute risks were: 2.6% for microcephaly at birth or first evaluation, 4.0% for microcephaly at any time during follow-up, 7.9% for neuroimaging abnormalities, 18.7% for functional neurological abnormalities, 4.0% for ophthalmic abnormalities, 6.4% for auditory abnormalities, 0.6% for arthrogryposis, and 1.5% for dysphagia. This risk was similar in all sites studied and in different socioeconomic conditions, indicating that there are not likely to be other factors modifying this association. Interpretation: This study based on prospectively collected data generates the most robust evidence to date on the risks of congenital ZIKV infections over the early life course. Overall, approximately one-third of liveborn children with prenatal ZIKV exposure presented with at least one abnormality compatible with congenital infection, while the risk to present with at least two abnormalities in combination was less than 1.0%.

Congenital ocular toxoplasmosis in consecutive siblings / Toxoplasmose ocular congênita em irmãos consecutivos

ABSTRACT Toxoplasma gondii infection can cause ocular manifestations after acquired and congenital disease. We report two cases of symptomatic congenital toxoplasmosis with ocular involvement in non-twin siblings, with a 2-year interval between pregnancies. Vertical transmission of toxoplasmosis in successive pregnancies, which was once considered impossible, is now found to be plausible even in immunocompetent subjects.

RESUMO A infecção pelo Toxoplasma gondii pode causar manifestações oculares tanto após a sua forma congênita quanto a sua forma adquirida. Reportamos aqui dois casos de toxoplasmose congênita sintomática com envolvimento ocular em irmãos não gêmeos, com intervalo de 2 anos entre gestações. A transmissão vertical da toxoplasmose em gestações sucessivas, outrora considerada impossível, é um evento plausível mesmo em indivíduos imunocompetentes.

Impaired functionality of antigen presenting cells in HIV- exposed uninfected infants in the first six months of life.

HIV-exposed uninfected infants (HEU) have increased morbidity and mortality due to infections in the first 6 months of life that tapers down to 2 years of life. The underlying immunologic defects remain undefined. We investigated antigen-presenting cells (APC) by comparing the phenotype of unstimulated APC, responses to toll-like receptor (TLR) stimulation, and ability to activate natural killer (NK) cells in 24 HEU and 64 HIV-unexposed infants (HUU) at 1-2 days of life (birth) and 28 HEU and 45 HUU at 6 months of life. At birth, unstimulated APC showed higher levels of activation and cytokine production in HEU than HUU and stimulation with TLR agonists revealed lower expression of inflammatory cytokines and activation markers, but similar expression of IL10 regulatory cytokine, in APC from HEU compared to HUU. Differences were still present at 6 months of life. From birth to 6 months, APC underwent extensive phenotypic and functional changes in HUU and minimal changes in HEU. TLR stimulation also generated lower NK cell expression of CD69 and/or IFNγ in HEU compared with HUU at birth and 6 months. In vitro experiments showed that NK IFNγ expression depended on APC cytokine secretion in response to TLR stimulation. Ex vivo IL10 supplementation decreased APC-mediated NK cell activation measured by IFNγ expression. We conclude that APC maturation was stunted or delayed in the first 6 months of life in HEU compared with HUU. Deficient inflammatory APC responses and/or the imbalance between inflammatory and regulatory responses in HEU may play an important role in their increased susceptibility to severe infections.

Gamma variant vertically transmitted from a mild symptomatic pregnant woman associated with fatal neonatal COVID.

Herein we describe a mild symptomatic real-time reverse transcriptase- polymerase chain reaction-confirmed coronavirus 2 (SARS-CoV-2) infection in a pregnant woman who gave birth to a preterm infant, 32 weeks gestational age. The neonate was immediately isolated after delivery and developed severe respiratory disease that progressed to multisystem inflammatory syndrome and death on the seventh day of life. Genome sequencing detected the P.1 (gamma) variant in samples obtained at hospital admission (mother) and on the first (10h) and 13th days of life (neonate). Complete homology (mother's and newborn's sequences) confirmed vertical transmission. To our knowledge, this is the first report of vertically-transmitted SARS-CoV-2 P.1 (gamma) variant in a mild symptomatic infection in pregnancy associated with fatal COVID in a neonate.

Mild controlled hypothermia for necrotizing enterocolitis treatment to preterm neonates: low technology technique description and safety analysis.

We performed a quality improvement project to necrotizing enterocolitis (NEC) and published our results about the initiative in 2021. However, aspects on the safety of the cooling and how to do therapeutic hypothermia with low technology to preterm infants are not described in this previous reporter. Thus, we aim to describe the steps and management to apply hypothermia in preterm infants using low technology and present the safety aspects regarding the initiative. We performed a quality improvement project to NEC in a reference hospital for neonatology (intensive care unit). Forty-three preterm infants with NEC (modified Bell's stage II/III) were included: 19 in the control group (2015-2018) and 24 in the hypothermic group (2018-2020). The control group received standard treatments. The hypothermia group received standard treatment and underwent passive cooling (35.5 °C, used for 48 h after NEC diagnosis). We reported cooling safety to NEC, assessing hematological and gasometrical parameters, coagulation disorders, clinical instability, and neurological disorders. We described how to perform cooling to preterm infants using incubators' servo-control and the occurrence and management of dysthermia during the cooling. We turn-off the incubator and used the esophageal probe to monitor the temperature every 15 min; if the temperature dropped, the incubator was turned on with a rewarming speed of 0.5 °C/h. The participants' average weights and gestational ages were 1186 g and 32 weeks, respectively. There were no differences among hematological indices, serum parameters (sodium, potassium, creatinine, lactate, and bicarbonate), pH, pCO2, and pO2/FiO2 between the groups during treatment and after rewarming. We did not observe dysthermia, bradycardia, hemodynamic instability, apnea, seizure, bleeding, peri-intraventricular hemorrhage, or any alterations in ventilatory parameters due to the cooling technique in preterm babies. This simple technique was performed without intercurrences through a rigorous team evaluation, with a target cooling speed of 0.5 °C/h. The target temperature was successfully reached between the second and third hours of life with the incubator control in 21 children; ice bags were used in only three cases. The temperature was maintained at the expected level during the programmed cooling period. CONCLUSION: Mild controlled hypothermia for preterm infants with NEC is safe. The cooling of preterm infants could be performed through passive methods, using the servo-control of the incubators for temperature management. WHAT IS KNOWN: • Mild controlled hypothermia to NEC treatment is feasible and associated with a decrease in NEC surgery, short bowel, and death. • Mild controlled hypothermia to preterm is feasible and can be performed through low technology and passive cooling. WHAT IS NEW: • Mild controlled hypothermia to preterm is safe and does not associate with safety adverse effects during and after the cooling. • Preterm infants can be cooled through passive methods by just using the servo control of the incubator, presenting acceptable temperature variance, without dysthermia, achieving and remaining at the target temperature with a proper cooling speed. Mild controlled temperature for preterm infants does not need an additional cooling device.

Congenital ocular toxoplasmosis in consecutive siblings.

Toxoplasma gondii infection can cause ocular manifestations after acquired and congenital disease. We report two cases of symptomatic congenital toxoplasmosis with ocular involvement in non-twin siblings, with a 2-year interval between pregnancies. Vertical transmission of toxoplasmosis in successive pregnancies, which was once considered impossible, is now found to be plausible even in immunocompetent subjects.

Effect of Maternal Immunization With 10-Valent Pneumococcus Conjugate Vaccine (PCV-10), 23-Valent Pneumococcus Polysaccharide Vaccine, or Placebo on the Immunogenicity of PCV-10 in Human Immunodeficiency Virus-Exposed Uninfected Infants: A Randomized Clinical Trial.

BACKGROUND: The effect of pneumococcal vaccination of mothers with human immunodeficiency virus (HIV) on infant responses to childhood vaccination has not been studied. We compared the immunogenicity of 10-valent pneumococcus conjugate vaccine (PCV-10) in HIV-exposed uninfected infants born to mothers who received PCV-10, 23-valent pneumococcus polysaccharide vaccine (PPV-23), or placebo during pregnancy. METHODS: Antibody levels against 7 serotypes were measured at birth, before the first and second doses of PCV-10m and after completion of the 2-dose regimen in 347 infants, including 112 born to mothers who received PPV-23, 112 who received PCV-10, and 119 who received placebo during pregnancy. Seroprotection was defined by antibody levels ≥0.35 µg/mL. RESULTS: At birth and at 8 weeks of life, antibody levels were similar in infants born to PCV-10 or PPV-23 recipients and higher than in those born to placebo recipient. After the last dose of PCV-10, infants in the maternal PCV-10 group had significantly lower antibody levels against 5 serotypes than those in the maternal PPV-23 group and against 3 serotypes than those in the maternal placebo group, and they did not have higher antibody levels against any serotype. The seroprotection rate against 7 serotypes was 50% in infants in the maternal PCV-10 group, compared with 71% in both of the maternal PPV-23 and placebo groups (P < .001). CONCLUSIONS: Administration of PCV-10 during pregnancy was associated with decreased antibody responses to PCV-10 and seroprotection rates in infants. Considering that PCV-10 and PPV-23 had similar immunogenicity in pregnant women with HIV and that administration of PPV-23 did not affect the immunogenicity of PCV-10 in infants, PPV-23 in pregnancy may be preferred over PCV-10.

Immunogenicity of Conjugated and Polysaccharide Pneumococcal Vaccines Administered During Pregnancy or Postpartum to Women With HIV.

BACKGROUND: Pneumococcal vaccination is recommended in people with HIV, prioritizing PCV. We compared the immunogenicity of PCV-10 and PPV-23 administered antepartum or postpartum. METHODS: This double-blind study randomized 346 pregnant women with HIV on antiretrovirals to PCV-10, PPV-23, or placebo at 14-34 weeks gestational age. Women who received placebo antepartum were randomized at 24 weeks postpartum to PCV-10 or PPV-23. Antibodies against 7 serotypes common to both vaccines and 1 serotype only in PPV-23 were measured by ELISA/chemiluminescence; B- and T-cell responses to serotype 1 by FLUOROSPOT; and plasma cytokines/chemokines by chemiluminescence. RESULTS: Antibody responses were higher after postpartum versus antepartum vaccination. PCV-10 generated lower antibody levels than PPV-23 against 4 and higher against 1 of 7 common serotypes. Additional factors associated with high postvaccination antibody concentrations were high prevaccination antibody concentrations and CD4+ cells; low CD8+ cells and plasma HIV RNA; and several plasma cytokines/chemokines. Serotype 1 B- and T-cell memory did not increase after vaccination. CONCLUSIONS: Antepartum immunization generated suboptimal antibody responses, suggesting that postpartum booster doses may be beneficial and warrant further studies. Considering that PCV-10 and PPV-23 had similar immunogenicity, but PPV-23 covered more serotypes, use of PPV-23 may be prioritized in women with HIV on antiretroviral therapy. CLINICAL TRAILS REGISTRATION: NCT02717494.

Gamma variant vertically transmitted from a mild symptomatic pregnant woman associated with fatal neonatal COVID

ABSTRACT Herein we describe a mild symptomatic real-time reverse transcriptase- polymerase chain reaction-confirmed coronavirus 2 (SARS-CoV-2) infection in a pregnant woman who gave birth to a preterm infant, 32 weeks gestational age. The neonate was immediately isolated after delivery and developed severe respiratory disease that progressed to multisystem inflammatory syndrome and death on the seventh day of life. Genome sequencing detected the P.1 (gamma) variant in samples obtained at hospital admission (mother) and on the first (10h) and 13th days of life (neonate). Complete homology (mother's and newborn's sequences) confirmed vertical transmission. To our knowledge, this is the first report of vertically-transmitted SARS-CoV-2 P.1 (gamma) variant in a mild symptomatic infection in pregnancy associated with fatal COVID in a neonate.