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Pneumococcus remains an important cause of morbidity in pregnant women with HIV and their infants. We compared the safety and immunogenicity of PCV-10 and PPV-23 with placebo administered in pregnancy.This double-blind, multicentre, randomised controlled trial was done at eight outpatient clinics in Brazil. Eligible participants were adult women with HIV who were pregnant at a gestational age between 14 weeks and less than 34 weeks and who were taking antiretroviral therapy at study entry. Participants were randomly assigned (1:1:1) to receive either PCV-10, PPV-23, or placebo. Participants and study teams were unaware of treatment allocation. Antibodies against seven vaccine serotypes in PCV-10 and PPV-23 were measured by ELISA. The primary outcomes were maternal and infant safety assessed by the frequency of adverse events of grade 3 or higher; maternal seroresponse (defined as ≥2-fold increase in antibodies from baseline to 28 days after immunisation) against five or more serotypes; and infant seroprotection (defined as anti-pneumococcus antibody concentration of ≥0·35 μg/mL) against five or more serotypes at 8 weeks of life. The study was powered to detect differences of 20% or higher in the primary immunological outcomes between treatment groups. This trial is registered with ClinicalTrials.gov, NCT02717494.Between April 1, 2016, and Nov 30, 2017, we enrolled 347 pregnant women with HIV, of whom 116 were randomly assigned to the PCV-10 group, 115 to the PPV-23 group, and 116 to the placebo group. One participant in the PCV-10 group did not receive the vaccine and was excluded from subsequent analyses. The frequency of adverse events of grade 3 or higher during the first 4 weeks was similar in the vaccine and placebo groups (3% [90% CI 1-7] for the PCV-10 group, 2% [0-5] for the PPV-23 group, and 3% [1-8] for the placebo group). However, injection site and systemic grade 2 adverse reactions were reported more frequently during the first 4 weeks in the vaccine groups than in the placebo group (14% [9-20] for the PCV-10 group, 7% [4-12] for the PPV-23 group, and 3% [1-7] for the placebo group). The frequency of grade 3 or higher adverse effects was similar across maternal treatment groups (20% [14-27] for the PCV-10 group, 21% [14-28] for the PPV-23 group, and 20% [14-27] for the placebo group). Seroresponses against five or more serotypes were present in 74 (65%) of 114 women in the PCV-10 group, 72 (65%) of 110 women in the PPV-23 group, and none of the 113 women in the placebo group at 4 weeks post vaccination (p0·0001 for PPV-23 group vs placebo and PCV-10 group vs placebo). Seroresponse differences of 20% or higher in vaccine compared with placebo recipients persisted up to 24 weeks post partum. At birth, 76 (67%) of 113 infants in the PCV-10 group, 62 (57%) of 109 infants in the PPV-23 group, and 19 (17%) of 115 infants in the placebo group had seroprotection against five or more serotypes (p0·0001 for PPV-23 vs placebo and PCV-10 vs placebo). At 8 weeks, the outcome was met by 20 (19%) of 108 infants in the PCV-10 group, 24 (23%) of 104 infants in the PPV-23 group, and one (1%) of 109 infants in the placebo group (p0·0001). Although a difference of 20% or higher compared with placebo was observed only in the infants who received PPV-23 at 8 weeks of life, the difference between the two vaccine groups was not appreciable.PCV-10 and PPV-23 were equally safe and immunogenic in pregnant women with HIV and conferred similar levels of seroprotection to their infants. In areas in which childhood PCV administration decreased the circulation of PCV serotypes, PPV-23 administration to pregnant women with HIV might be more advantageous than PCV by virtue of including a broader range of serotypes.Eunice Kennedy Shriver National Institute of Child Health and Human Development.For the Portuguese translation of the abstract see Supplementary Materials section.

Necrotizing enterocolitis (NEC) treatment remains unchanged for years. Data suggest that mild controlled hypothermia could potentially improve NEC outcomes. Our units presented unfavourable outcomes on NEC. The aim was to assess our experience with low technology, mild controlled hypothermia on NEC outcomes, and improve preterm infants' healthcare. This was a single-center quality improvement study with retrospective cohort design at the neonatal intensive care unit in the university hospital. 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 hypothermia group (2018-2020). The control group received standard treatment (fasting, abdominal decompression, and broad-spectrum antibiotics). The hypothermia group underwent cooling to 35.5 °C for 48 h after NEC diagnosis, along with conventional treatment. The primary outcomes are intestinal perforation, need for surgery, duration of parenteral nutrition, death, and extensive resection of the small intestine. There was no statistical difference in the NEC score. The hypothermia group required less surgery (aRR 0.40; 95% CI 0.19-0.85), presented less bowel perforation (aRR 0.39; 95% CI 0.18; 0.83), had a shorter duration of parenteral nutrition (aHR 5.28; 95% CI 1.88-14.89), did not need extensive intestinal resection, (0 vs 15.7%), and did not experience any deaths (0 vs 31.6%).Conclusions: In our experience, low technology, mild controlled hypothermia was feasible, not related to adverse effects, and effective treatment for NEC Modified Bell's Stage II/III. It avoided surgery, bowel perforation, and extensive intestinal resection; reduced mortality; and shortened parenteral nutrition duration. What is Known: • New approaches have been proposed to avoid enterocolitis incidence; however, the treatment of enterocolitis stage 2 has been the same for decades, and unfavourable outcomes remain despite conventional management. • Studies suggest that hypothermia can be an alternative to enterocolitis treatment. What is New: • Mild controlled hypothermia can be an additional practice to treat enterocolitis stage 2, is feasible, and is not related to adverse effects to preterm infants. • It can decrease surgery needs, duration of parenteral nutrition, and death and avoids extensive intestinal resection in preterm infants.

Maternal preconceptional cytomegalovirus (CMV) immunity does not protect the fetus from acquiring congenital CMV infection (cCMV). Nonprimary infections due to recurrence of latent infections or reinfection with new virus strains during pregnancy can result in fetal infection. Because the prevalence of cCMV increases with increasing maternal CMV seroprevalence, the vast majority of the cases of cCMV throughout the world follow nonprimary maternal infections and is more common in individuals of lower socioeconomic background. Horizontal exposures to persons shedding virus in bodily secretions (young children, sexual activity, household crowding, low income) probably increase the risk of acquisition of an exogenous nonprimary CMV infection and fetal transmission. In addition, more frequent acquisition of new antibody reactivities in transmitter mothers suggest that maternal reinfection by new viral strains could be a major source of congenital infection in such populations. However, the exact frequency of CMV nonprimary infection in seroimmune women during pregnancy and the rate of intrauterine transmission in these women are yet to be defined. Usually, the birth prevalence of cCMV is high (≥7:1000) in highly seropositive populations. There is increasing evidence that the frequency and severity of the clinical and laboratory abnormalities in infants with congenital CMV infection born to mothers with nonprimary CMV infection are similar to infants born after a primary maternal infection. This is particularly true for sensorineural hearing loss, which contributes to one third of all early-onset hearing loss in seropositive populations. This brief overview will discuss the need for more research to better clarify the natural history of cCMV in highly seropositive populations, which, in almost all populations, remains incompletely defined.

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.

BackgroundThe exact contribution of congenital cytomegalovirus infection (cCMVI) to permanent hearing loss (HL) in highly seropositive populations is unknown. We determined the contribution of cCMVI to HL and estimated the effectiveness of newborn hearing screening (HS) in identifying neonates with CMV-related HL.MethodsA total of 11 900 neonates born from a population with ≥97% maternal seroprevalence were screened for cCMVI and HL. cCMVI was confirmed by detection of CMV-DNA in saliva and urine at age ResultsOverall, 68 (0.6%; 95% confidence interval [CI], 0.4–0.7) neonates were identified with cCMVI. Of the 91 (0.8%) newborns who failed the HS, 24 (26.4%) were confirmed with HL, including 7 (29.2%; 95% CI, 17.2–59.3) with cCMVI. Another newborn with cCMVI passed the HS but was confirmed with HL at age 21 days. Of the 62 neonates with cCMVI who underwent a complete hearing evaluation, 8 (12.9%; 95% CI, 6.7–23.4) had HL and most (7/8; 87.5%; 95% CI, 46.6–99.7) were identified by HS. The rate of CMV-related HL was 8 per 11 887 neonates (0.7 per 1000 live births). The prevalence ratio of HL among neonates with cCMVI compared to CMV-uninfected neonates was 89.5 (95% CI, 39.7–202.0). No late-onset cCMVI-related HL was detected during a median follow-up of 36 months.ConclusionscCMVI is an important cause of HL in childhood in all settings. Integrating targeted cCMVI screening among neonates who fail a HS could be a reasonable, cost-effective strategy to identify newborns with early-onset cCMVI-related HL.

BACKGROUND HIV-exposed-uninfected (HEU) infants have increased infectious morbidity and mortality; little is known about their levels of inflammation and monocyte activation. METHODS Plasma samples obtained at birth and 6 months from 86 HEU mother-infant pairs enrolled in the National Institute of Child Health and Human Development cohorts in Brazil were compared with 88 HIV-unexposed mother-infant pairs. HIV-infected mothers received antiretroviral therapy during pregnancy, their infants received zidovudine prophylaxis and were not breastfed. IL-6, soluble TNFα receptor I (sTNF-RI) and II, soluble CD14, soluble CD163, IFN-γ-induced protein 10 (IP-10), vascular cell adhesion molecule, oxidized LDL, D-dimer and high-sensitivity C-reactive protein were assayed by ELISA at birth and at 6 months. sTNF-RI and IL-6 were considered coprimary endpoints. RESULTS Among HIV-infected mothers, 79% had HIV-RNA less than 400 copies/ml prior to delivery. Compared with HIV-unexposed, HEU infants had a lower mean gestational age (38.7 vs. 39.3 weeks) and weight (3.1 vs. 3.3 kg); and reached lower weight (5.9 vs. 8.5 kg) and height (53.6 vs. 68.8 cm) at 6 months. With the exception of vascular cell adhesion molecule, inflammatory markers were generally higher (P ≤ 0.005) in HEU at birth, but at 6 months only sTNF-RI and IL-6 remained higher. For HEU pairs, only IP-10 was associated with maternal levels at birth (P

Significance Human cytomegalovirus (HCMV) causes severe morbidity and mortality in immunocompromised patients and is the most commonly transmitted virus that causes developmental defects in the fetus. Currently, there is no licensed HCMV vaccine available, and prior efforts using attenuated viruses and subunit vaccines were not successful. Recently, there has been intense interest in the HCMV pentamer glycoprotein as a component of vaccines. Here, we show that transplant patients’ and pregnant mothers’ sera contain neutralizing antibodies specific for the pentamer and also for a second HCMV glycoprotein, the trimer, which is essential for HCMV entry into cells. Trimer- and pentamer-specific antibodies acted synergistically to neutralize virus and block cell–cell spread. These observations will have major implications for the future of HCMV vaccine development., Human cytomegalovirus (HCMV) causes substantial disease in transplant patients and harms the development of the nervous system in babies infected in utero. Thus, there is a major focus on developing safe and effective HCMV vaccines. Evidence has been presented that a major target of neutralizing antibodies (NAbs) is the HCMV pentamer glycoprotein gH/gL/UL128-131. In some studies, most of the NAbs in animal or human sera were found to recognize the pentamer, which mediates HCMV entry into endothelial and epithelial cells. It was also reported that pentamer-specific antibodies correlate with protection against transmission from mothers to babies. One problem with the studies on pentamer-specific NAbs to date has been that the studies did not compare the pentamer to the other major form of gH/gL, the gH/gL/gO trimer, which is essential for entry into all cell types. Here, we demonstrate that both trimer and pentamer NAbs are frequently found in human transplant patients’ and pregnant mothers’ sera. Depletion of human sera with trimer caused reductions in NAbs similar to that observed following depletion with the pentamer. The trimer- and pentamer-specific antibodies acted in a synergistic fashion to neutralize HCMV and also to prevent virus cell-to-cell spread. Importantly, there was no correlation between the titers of trimer- and pentamer-specific NAbs and transmission of HCMV from mothers to babies. Therefore, both the trimer and pentamer are important targets of NAbs. Nevertheless, these antibodies do not protect against transmission of HCMV from mothers to babies.

Zika virus (ZIKV) infection may adversely affect pregnancies of women living with HIV (WLHIV). Because no study to date has focused on maternal and child effects of HIV and ZIKV co-infection in pregnant women, we undertook the International Prospective Cohort Study of HIV and Zika in Infants and Pregnancy (HIV ZIP). The aims of this two-phase study of pregnant women and their infants are to compare the incidence of ZIKV infection among pregnant women with and without HIV infection and to determine the risk of adverse maternal and child outcomes associated with ZIKV/HIV co-infection at clinical sites in Brazil, Puerto Rico, and the continental United States. Phase I was designed to enroll pregnant women/infant pairs who were: (1) infected with HIV only, (2) infected with ZIKV only, (3) infected with HIV and ZIKV, and (4) not infected with either HIV or ZIKV. A key goal of this phase was to assess the feasibility of enrolling 200 women/infant pairs within a year, with a target of 150 WLHIV, 50 HIV-uninfected women, and a minimum of 20 who were co-infected with HIV and ZIKV. If the feasibility of Phase I proved successful, Phase II would enroll up to 1,800 additional pregnant women/infant pairs to the same four groups. Enrolled women in both phases were to be followed throughout their pregnancy and up to 6 weeks post-partum. Infants were also to be followed for 1 year after birth. To date, Phase 1 data collection and follow-up have been completed. Delineation of possible harmful effects of HIV/ZIKV co-infection will allow the formulation of standard-of-care recommendations to minimize adverse effects but enable the continuation of preventive HIV therapy. Furthermore, while the prospective HIV ZIP study was developed before the COVID pandemic, it is especially relevant today since it can be easily adapted to provide critically important information on the impact of COVID-19 infection or other still unrecognized new agents among pregnant women and their offspring worldwide.

BACKGROUND: Studies addressing neuroimaging findings as primary outcomes of congenital Zika virus infection are variable regarding inclusion criteria and confirmatory laboratory testing. PURPOSE: To investigate cranial US signs of prenatal Zika virus exposure and to describe frequencies of cranial US findings in infants exposed to Zika virus compared to those in control infants. MATERIALS AND METHODS: In this single-center prospective cohort study, participants were enrolled during the December 2015–July 2016 outbreak of Zika virus infection in southeast Brazil (Natural History of Zika Virus Infection in Gestation cohort). Eligibility criteria were available cranial US and laboratory findings of maternal Zika virus infection during pregnancy confirmed with RNA polymerase chain reaction testing (ie, Zika virus–exposed infants). The control group was derived from the Zika in Infants and Pregnancy cohort and consisted of infants born to asymptomatic pregnant women who tested negative for Zika virus infection during pregnancy. Two radiologists who were blinded to the maternal Zika virus infection status independently reviewed cranial US scans from both groups and categorized them as normal findings, Zika virus–like pattern, or mild findings. Associations between cranial US findings and prenatal Zika virus exposure were assessed with univariable analysis. RESULTS: Two hundred twenty Zika virus–exposed infants (mean age, 53.3 days ± 71.1 [standard deviation]; 113 boys) and born to 219 mothers infected with Zika virus were included in this study and compared with 170 control infants (mean age, 45.6 days ± 45.8; 102 boys). Eleven of the 220 Zika virus–exposed infants (5%), but no control infants, had a Zika virus–like pattern at cranial US. No difference in frequency of mild findings was observed between the groups (50 of 220 infants [23%] vs 44 of 170 infants [26%], respectively; P = .35). The mild finding of lenticulostriate vasculopathy, however, was nine times more frequent in Zika virus–exposed infants (12 of 220 infants, 6%) than in control infants (one of 170 infants, 1%) (P = .01). CONCLUSION: Lenticulostriate vasculopathy was more common after prenatal exposure to Zika virus, even in infants with normal head size, despite otherwise overall similar frequency of mild cranial US findings in Zika virus–exposed infants and in control infants. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Benson in this issue.

Summary Developmental trends between 3 and 24 months were assessed in 194 normocephalic infants with prenatal Zika virus exposure. Bayley Scales of Infant and Toddler Development Screening Test–3rd Edition cognitive scores remained in the typical range. Communication skills developed at a slower rate suggesting that neurodevelopmental delays may emerge at older ages.

Background: Neonatal sepsis is associated with high mortality, but there is limited clinical data on outcomes in hospital facilities in low and middle income countries (LMIC). The NeoOBS study aimed to determine the clinical features, pathogens and clinical outcomes of infants presenting with neonatal sepsis in hospitals globally. Methods: Infants

Objective: To define the prevalence of adverse outcomes according to the gestational age of maternal infection in a large cohort of ZIKV-infected Brazilian women and their infants. Design: Prospective, population-based cohort study. Setting: Ribeirao Preto’s region private and public health facilities. Population: All pregnant women with confirmed ZIKV-infection and their infants. Methods: Prenatal/early neonatal data were obtained for all pairs. A subgroup of infants had cranial ultrasonography, eye fundoscopy, hearing, neurological exam, and Bayley III screening test within 3 months of age. Main Outcome Measures: Prevalence of pregnancy losses, anomalies detected at birth or within 3 months according to the gestational age of infection. Results: 511 women with ZIKV were identified from a total of 1116 women with flavivirus-type symptoms. Pregnancy losses 24/511(4.7%) and/or ZIKV-related anomalies occurred in 43/511(8.4%) mothers. Microcephaly or other CNS malformations were diagnosed in 1/4(25.0%) of the stillbirths and 19/489[3.9%;CI95%:2.5-5.9] of the live-born infants, with 13/513[2.5%;CI95%:1.5-4.3] neonates presenting major signs of CZS. Fetal abnormalities were 14.0(CI95%:7.6-26.0) times more likely with gestational infection

It is still not well known, in a population with high human cytomegalovirus (HCMV) seroprevalence, whether a child with congenital infection harbors multiple viral strains at birth, and whether the prolonged viral excretion in these children is secondary to the persistence of the same viral strain. To verify the genomic diversity of HCMV detected in congenitally infected children, the nucleotide viral sequences from urine and/or saliva obtained at birth from 14 newborns with congenital infection and breast milk obtained from mothers of 5 of these children were analyzed. Among the 14 children, 10 had sequential samples until the median age of 10 months. The viral nucleotide sequences in the breast milk were compared with those identified in the respective children at birth. The differentiation of viral strains was based on the variability of 3 regions of viral genes (UL55/gB, UL144, and UL73/gN). In 13/14 children (92.8%), a single genotype was observed at birth. Different viral genotypes were found in 1 child (7.2%). Among the sequential samples from 10 children, the same genotype obtained at birth was detected in 9/10 (90%), and in 1 of them (10%), a genotype change in the urine was found. More than 1 HCMV strain in milk was observed in 2 mothers (2/5, 40%). In a population with high seroprevalence, a single genotype was found in the majority of infected children. Reinfection did not frequently occur in the first months of life. Maternal reinfection does not seem to be a rare event in transmitter mothers.

BACKGROUND Perinatally HIV-infected (PHIV) children are at risk for under-vaccination and poor vaccine response at 4 years of age. Childhood vaccine coverage and immune response were compared between PHIV and HIV-exposed uninfected (HEU) children in Latin America and the Caribbean. METHODS PHIV and HEU children were enrolled prospectively at 15 sites from 2002 to 2009. Full vaccination by age 4 years was defined as: 3 hepatitis B virus vaccine doses; 4 tetanus toxoid-containing vaccine doses; 3 doses of Haemophilus influenzae type b vaccine by age 12 months or ≥1 dose given after age 12 months; one measles-containing vaccine dose; one rubella-containing vaccine dose. Immunity was defined by serum antibody titer. Fisher exact test (for categorical measures) and t test (for continuous measures) were used for comparisons. RESULTS Among 519 children seen at age 4 years, 191 had serum specimens available (137 PHIV, 54 HEU). Among those with specimens available, 29.3% initiated combination antiretroviral therapy (cART)

Background Most congenital cytomegalovirus (CMV) infections in highly seropositive populations occur in infants born to women with preexisting CMV seroimmunity. Although essential for developing prevention strategies, CMV shedding patterns in pregnant women with nonprimary infections have not been characterized. We investigated correlates of CMV shedding in a cohort of seropositive pregnant women. Methods In a prospective study, saliva, urine, vaginal swabs, and blood were collected from 120 CMV-seropositive women in the first, second, and third trimesters and 1 month postpartum. Specimens were tested for CMV DNA by polymerase chain reaction. We analyzed the contribution of the specific maternal characteristics to viral shedding. Results CMV shedding was detected at least once in 42 (35%) women. Mothers living with or providing daily care to young children (3-6 years) were twice as likely to shed CMV at least once compared to women with less exposure to young children (58% vs 26%; adjusted relative risk [aRR], 2.21; 95% confidence interval [CI], 1.37-3.56). Living in crowded households (≥2 people per room) was associated with viral shedding (64% vs 31%; aRR, 1.99; 95% CI, 1.26-3.13). Sexual activity as indicated by the number of sexual partners per year or condom use was not found to be a correlate of viral shedding. Conclusions CMV shedding is relatively frequent in seropositive pregnant women. The association between virus shedding and caring for young children as well as crowded living conditions may provide opportunities for increased exposures that could lead to CMV reinfections in seropositive women.

Cytomegalovirus (CMV) urinary shedding in pregnant women infected with human immunodeficiency virus (HIV) was evaluated to determine whether it poses an increased risk for congenital CMV infection (cCMV).A subset of mother-infant pairs enrolled in the perinatal NICHD HPTN 040 study (distinguished by no antiretroviral use before labor) was evaluated. Maternal and infant urines were tested by qualitative real-time polymerase chain reaction (RT-PCR) for CMV DNA with quantitative RT-PCR performed on positive specimens.Urine specimens were available for 260 women with 85.4% from the Americas and 14.6% from South Africa. Twenty-four women (9.2%) had detectable CMV viruria by qualitative PCR. Maternal CMV viruria was not associated with mean CD4 cell counts or HIV viral load but was associated with younger maternal age (P = .02). Overall, 10 of 260 infants (3.8%) had cCMV. Women with detectable peripartum CMV viruria were more likely to have infants with cCMV than those without: 20.8% (5/24) versus 2.1% (5/236), (P = .0001). Women with CMV viruria had significantly higher rates of HIV perinatal transmission (29.2% vs. 8.1%, P = .002). They were 5 times (adjusted odds ratio [aOR] = 5.6, 95% confidence interval [CI] 1.9-16.8) and nearly 30 times (aOR, 29.7; 95% CI, 5.4-164.2) more likely to transmit HIV and CMV to their infants, respectively. Maternal gonorrhea (aOR, 19.5; 95% CI, 2.5-151.3) and higher maternal HIV log10 viral load (OR, 2.8; 95% CI, 1.3-6.3) were also significant risk factors for cCMV.In this cohort of HIV-infected pregnant women not on antiretrovirals, urinary CMV shedding was a significant risk factor for CMV and HIV transmission to infants.NCT00099359.

We report 2 fatal cases of congenital Zika virus (ZIKV) infection. Brain anomalies, including atrophy of the cerebral cortex and brainstem, and cerebellar aplasia were observed. The spinal cord showed architectural distortion, severe neuronal loss, and microcalcifications. The ZIKV proteins and flavivirus-like particles were detected in cytoplasm of spinal neurons, and spinal cord samples were positive for ZIKV RNA.

Objective HIV-exposed uninfected (HEUs) infants have frequent severe infection, hospitalization, and death. We performed a serologic investigation to determine the role of common childhood respiratory pathogens in the excess incidence of infections in HEUs. Design Prospective cohort study of mother-infant pairs. Methods Among 247 HEUs and 88 HIV-unexposed uninfected (HUU) infant-mother pairs, we measured maternal antibodies to respiratory syncytial virus (RSV) and pneumococcus (PNC 1, 5, 6B, 14); infant antibodies to RSV, influenza A (flu), parainfluenza viruses (1, 2, 3), and PNC 1, 5, 6B, and 14 were measured at 0 and 6 months, and antitetanus antibodies at 6 months. Results HIV-infected mothers had higher RSV and lower PNC antibody concentrations at delivery than uninfected mothers. Transplacental transfer of maternal antibodies, particularly for RSV, was lower in HEUs compared with HUUs. At birth, HEUs had higher concentrations of anti-RSV antibodies than HUUs, but lower antibodies to the other respiratory agents. At 6 months, HEUs had significantly higher proportions of seroconversions and higher antibody concentrations against parainfluenza viruses 1, 2, and 3. There were no significant differences in seroconversions to flu and RSV, but antibody concentrations to RSV were six-fold lower in HEUs versus HUUs at 6 months. Antibody responses to at least two doses of tetanus vaccine were also six-fold lower in HEUs compared with HUUs. Conclusion Six-month-old HEUs had a higher incidence of respiratory viral infections than HUUs. In addition to the low passive protection from maternal antibodies, low antibody responses of HEUs may contribute to increased morbidity and mortality.

Background Until recently, Zika virus (ZIKV) infections were considered mild and self-limiting. Since 2015, they have been associated with an increase in microcephaly and other birth defects in newborns. While this association has been observed in case reports and epidemiological studies, the nature and extent of the relationship between ZIKV and adverse pregnancy and pediatric health outcomes is not well understood. With the unique opportunity to prospectively explore the full spectrum of issues related to ZIKV exposure during pregnancy, we undertook a multi-country, prospective cohort study to evaluate the association between ZIKV and pregnancy, neonatal, and infant outcomes. Methods At research sites in ZIKV endemic regions of Brazil (4 sites), Colombia, Guatemala, Nicaragua, Puerto Rico (2 sites), and Peru, up to 10,000 pregnant women will be recruited and consented in the first and early second trimesters of pregnancy and then followed through delivery up to 6 weeks post-partum; their infants will be followed until at least 1 year of age. Pregnant women with symptomatic ZIKV infection confirmed by presence of ZIKV RNA and/or IgM for ZIKV will also be enrolled, regardless of gestational age. Participants will be tested monthly for ZIKV infection; additional demographic, physical, laboratory and environmental data will be collected to assess the potential interaction of these variables with ZIKV infection. Delivery outcomes and detailed infant assessments, including physical and neurological outcomes, will be obtained. Discussion With the emergence of ZIKV in the Americas and its association with adverse pregnancy outcomes in this region, a much better understanding of the spectrum of clinical outcomes associated with exposure to ZIKV during pregnancy is needed. This cohort study will provide information about maternal, fetal, and infant outcomes related to ZIKV infection, including congenital ZIKV syndrome, and manifestations that are not detectable at birth but may appear during the first year of life. In addition, the flexibility of the study design has provided an opportunity to modify study parameters in real time to provide rigorous research data to answer the most critical questions about the impact of congenital ZIKV exposure. Trial registration NCT02856984. Registered August 5, 2016. Retrospectively registered.

National Council for Scientific and Technological Development (Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico? CNPq) (grant number 404861/2018-0); Wellcome Trust and the United Kingdom?s Department for International Development (grant numbers: 205377/Z/16/Z; 201870/Z/16/Z). European Union?s Horizon 2020 research and innovation programme under ZikaPLAN (grant number 734584). Wellcome Trust - Research Enrichment in Epidemic Situation (grant number 107779/Z/15/Z; with ER1505 & ER1601). Medical Research Council on behalf of the Newton Fund and Wellcome Trust (grant number MC_PC_15088). National Institutes of Health/National Institute of Allergy and Infectious Diseases (grant number RO1/AI140718). Fondation Christophe et Rodolphe M?rieux. National Council for Scientific and Technological Development (Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico?CNPq) (grant numbers 443875/2018-9; 440573/2016-5; 441098/2016-9; 305090/2016-0; 307282/2017-1; 304476/2018- 8; 465549/2014-4; 440763/2016-9; 309722/2017-9; 306708/2014-0; 440577/2016-0). Coordination for the improvement of Higher Education Personnel (Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior-Capes) (grant numbers 88881.130813/2016-01; 88887.116627/2016-01; 88887.136366/2017-00). Ministry of Health of Brazil-Emergency Response in Public Health-Zika virus and Microcephaly (Minist?rio da Sa?de de Brasil-Resposta ? Emerg?ncia em Sa?de P?blica?Zika v?rus e Microcefalia) (grant number 837058/2016). Department of Science and Technology (Departamento de Ci?ncia e TecnologiaDECIT) (grant numbers 25000.072811/2016-19; 440839/2016-5). Foundation of Research Support of the State of S?o Paulo (Funda??o de Amparo ? Pesquisa do Estado de S?o Paulo?FAPESP) (grant numbers 2016/08578-0; 2017/21688-1; 2013/21719-3; 2016/15021-1; 2015/12295-0; 2016/05115-9). Foundation of Research Support of the State of Rio de Janeiro (Funda??o de Amparo ? Pesquisa do Estado do Rio de Janeiro ?FAPERJ) (grant numbers E-26/201.351/2016; E-18/2015TXB; E-26/202.862/2018; E-26/010.002477/2016). Foundation of Support for Research and Scientific and Technological Development of Maranh?o (Funda??o de Amparo ? Pesquisa e ao Desenvolvimento Cient?fico e Tecnol?gico do Maranh?o?FAPEMA) (grant number 008/2016). Brazilian Ministry of Health (Minist?rio da Sa?de?MS) (grant number 929698560001160-02). Evandro Chagas Institute/Brazilian Ministry of Health (Instituto Evandro Chagas/Minist?rio da Sa?de). Foundation of Research Support of the State of Goi?s (Funda??o de Amparo ? Pesquisa do Estado de Goi?s?FAPEG) (number grant 2017/10267000531). Foundation of Research Support of the State of Rio Grande do Sul (Funda??o de Amparo ? Pesquisa do Estado do Rio Grande do Sul?FAPERGS) (grant number 17/2551-0000521-0). Foundation to Support Teaching, Research and Assistance at Hospital das Cl?nicas, Faculty of Medicine of Ribeir?o Preto (Funda??o de Apoio ao Ensino, Pesquisa e Assist?ncia do Hospital das Cl?nicas da Faculdade de Medicina de Ribeir?o Preto) and S?o Paulo State Department of Health (Secretaria de Sa?de do Estado de S?o Paulo). Support Foundation of Pernambuco Science and Technology (Funda??o de Amparo ? Ci?ncia e Tecnologia de Pernambuco?FACEPE) (grant numbers APQ-0172-4.01/16; APQ-0192-4.01/17; APQ-0793-4.01/17). Funda??o de Medicina Tropical Doutor Heitor Vieira Dourado. Manaus, AM, Brasil. Universidade Federal de Campina Grande. Campina Grande, PB, Brasil / Instituto de Medicina Integral Professor Fernando Figueira. Recife, PE, Brazil. Universidade Federal de Pernambuco. Departamento de Medicina Social. Recife, PE, Brazil. Funda??o Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ, Brazil. London School of Hygiene & Tropical Medicine. London, UK. Funda??o de Medicina Tropical Doutor Heitor Vieira Dourado. Manaus, AM, Brasil. Universidade Federal de Pernambuco. Centro de Ci?ncias da Sa?de. Recife, PE, Brazil. Universidade Federal do Rio de Janeiro. Departamento de Pediatria. Rio de Janeiro, RJ, Brazil. Universidade de S?o Paulo, Ribeir?o Preto. Faculdade de Medicina de Ribeir?o Preto. Ribeir?o Preto, SP, Brasil. Universidade Federal de Sergipe. Aracaju, SE, Brazil. Secretaria Municipal de Tangar? da Serra. Tangar? da Serra, MT, Brazil. Universidade Federal do Rio de Janeiro. Departamento de Pediatria. Rio de Janeiro, RJ, Brazil. Universidade Federal de Sergipe. Aracaju, SE, Brazil. Funda??o Oswaldo Cruz. Instituto Aggeu Magalh?es. Recife, PE, Brazil. Universidade Federal de Campina Grande. Campina Grande, PB, Brasil / Instituto Paraibano de Diagn?stico. Campina Grande, PB, Brazil. Universidade de Pernambuco. Faculdade de Ci?ncias M?dicas. Recife, PE, Brazil. Universidade de Pernambuco. Instituto de Ci?ncias Biol?gicas. Recife, PE, Brazil. Funda??o Oswaldo Cruz. Instituto Fernandes Figueira. Rio de Janeiro, RJ, Brasil. Universidade de S?o Paulo. Faculdade de Medicina de Ribeir?o Preto. Ribeir?o Preto, SP, Brazil. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Ananindeua, PA, Brasil Faculdade de Medicina de Jundia?. Jundia?, SP, Brasil. Instituto D?Or de Pesquisa e Ensino. Rio de Janeiro, RJ, Brazil. Universidade Federal da Bahia. Instituto Sa?de Coletiva. Salvador, BA, Brazil. Universidade Federal do Rio Grande do Sul. Porto Alegre, RS, Brazil. Universidade Federal do Maranh?o. Departamento de Sa?de P?blica. S?o Lu?s, MA, Brazil. Centro de Pesquisas Gon?alo Moniz. Salvador, BA, Brazil. Secretaria de Sa?de do Estado do Maranh?o. Assist?ncia e Reabilita??o de Crian?as. Centro de Refer?ncia em Neurodesenvolvimento. S?o Lu?s, MA, Brazil. Universidade Federal de Goi?s. Departamento de Saude Coletiva. Goi?nia, GO, Brazil. Faculdade de Medicina de S?o Jos? do Rio Preto. S?o Jos? do Rio Preto, SP, Brasil. Despite great advances in our knowledge of the consequences of Zika virus to human health, many questions remain unanswered, and results are often inconsistent. The small sample size of individual studies has limited inference about the spectrum of congenital Zika manifestations and the prognosis of affected children. The Brazilian Zika Cohorts Consortium addresses these limitations by bringing together and harmonizing epidemiological data from a series of prospective cohort studies of pregnant women with rash and of children with microcephaly and/or other manifestations of congenital Zika. The objective is to estimate the absolute risk of congenital Zika manifestations and to characterize the full spectrum and natural history of the manifestations of congenital Zika in children with and without microcephaly. This protocol describes the assembly of the Consortium and protocol for the Individual Participant Data Meta-analyses (IPD Meta-analyses). The findings will address knowledge gaps and inform public policies related to Zika virus. The large harmonized dataset and joint analyses will facilitate more precise estimates of the absolute risk of congenital Zika manifestations among Zika virus-infected pregnancies and more complete descriptions of its full spectrum, including rare manifestations. It will enable sensitivity analyses using different definitions of exposure and outcomes, and the investigation of the sources of heterogeneity between studies and regions.

Human cytomegalovirus (Human herpesvirus 5, HCMV) causes frequent asymptomatic infections in the general population. However, in immunosuppressed patients or congenitally infected infants, HCMV is related to high morbidity and mortality. In such cases, a rapid viral detection is crucial for monitoring the clinical outcome and the antiviral treatment. In this study, we optimized a sensitive biplex TaqMan® real-time PCR for the simultaneous detection and differentiation of a partial HCMV UL97 sequence and homologous extrinsic control (HEC) in the same tube. HEC was represented by a plasmid containing a modified HCMV sequence retaining the original primer binding sites, while the probe sequence was substituted by a phylogenetically divergent one (chloroplast CF0 subunit plant gene). It was estimated that the optimal HEC concentration, which did not influence the HCMV amplification is 1,000 copies/reaction. The optimized TaqMan® PCR demonstrated high analytical sensitivity (6.97 copies/reaction, CI = 95%) and specificity (100%). Moreover, the reaction showed adequate precision (repeatability, CV = 0.03; reproducibility, CV = 0.0027) and robustness (no carry-over or cross-contamination). The diagnostic sensitivity (100%) and specificity (97.8%) were adequate for the clinical application of the molecular platform. The optimized TaqMan® real-time PCR is suitable for HCMV detection and quantitation in predisposed patients and monitoring of the applied antiviral therapy. J. Med. Virol. 88:1604-1612, 2016. © 2016 Wiley Periodicals, Inc.

HIV-exposed uninfected (HEU) infants are a growing population with potentially poor health outcomes. We evaluated morbidity and mortality in HEU formula-fed infants enrolled in the NICHD HPTN 040/PACTG 1043 trial.Infectious morbidity, mortality and undernutrition were evaluated within a cohort of 1000 HEU infants enrolled between April 2004 and April 2010 in Brazil (n = 766) and South Africa (n = 234) as part of the NICHD/HPTN 040 trial of 3 different antiretroviral regimens to decrease intrapartum HIV vertical transmission.Twenty-three percent of infants had at least 1 infectious serious adverse effect. Infants born to mothers with12 years of education [adjusted odds ratio (AOR), 2.6; 95% confidence interval [CI], 1.2-5.9), with maternal viral load of1,000,000 copies/mL at delivery (AOR, 9.9; 95% CI, 1.6-63.1) were more likely to have infectious serious adverse effects. At 6 months, the infant mortality rate per 1000 live births overall was 22 ± 2.6, 9.1 ± 1.8 in Brazil and 64.1 ± 3 in South Africa. Undernutrition and stunting peaked at 1 month of age with 18% having a weight-for-age Z score ≤-2, and 22% with height for Z score ≤-2. The likelihood of infant mortality was greater among infants born in South Africa compared with Brazil (AOR, 6.2; 95% CI, 2.5-15.8), high maternal viral load (AOR, 1.7; 95% CI, 1.01-2.9) and birth weight-for-age Z score ≤-2 (AOR, 5.2; 95% CI, 1.8-14.8).There were high rates of undernutrition, stunting and infectious serious adverse effect in this study's formula-fed HEU population. Suppressing maternal HIV viral load during the peripartum period may be a modifiable risk factor to decrease infant mortality.

Congenital candidiasis is a rare condition and difficult to diagnose. We report a case of severe septic shock leading to death within six days of birth caused by disseminated candidiasis without cutaneous manifestations in a late preterm infant. We speculate that the use of drugs for treatment of gestational toxoplasmosis in a mother colonized by Candida species facilitated this occurrence.

Background Untreated syphilis during pregnancy is associated with spontaneous abortion, stillbirth, prematurity and infant mortality. Syphilis may facilitate HIV transmission, which is especially concerning in low- and middle-income countries where both diseases are common. Methods We performed an analysis of data available from NICHD/HPTN 040 (P1043), a study focused on the prevention of intrapartum HIV transmission to 1684 infants born to 1664 untreated HIV-infected women. This analysis evaluates risk factors and outcomes associated with a syphilis diagnosis in this cohort of HIV-infected women and their infants. Results Approximately, 10% of women (n=171) enrolled had serological evidence of syphilis without adequate treatment documented and 1.4% infants (n=24) were dually HIV and syphilis infected. Multivariate logistic analysis showed that compared with HIV-infected women, co-infected women were significantly more likely to self-identify as non-white (adjusted odds ratio [AOR] 2.5, 95% CI: 1.5-4.2), to consume alcohol during pregnancy (AOR 1.5, 95% CI: 1.1-2.1) and to transmit HIV to their infants (AOR 2.1, 95% CI: 1.3-3.4), with 88% of HIV infections being acquired in utero. As compared with HIV-infected or HIV-exposed infants, co-infected infants were significantly more likely to be born to mothers with venereal disease research laboratory titers≥1:16 (AOR 3, 95% CI: 1.1-8.2) and higher viral loads (AOR 1.5, 95% CI: 1.1-1.9). Of 6 newborns with symptomatic syphilis, 2 expired shortly after birth, and 2 were HIV-infected. Conclusion Syphilis continues to be a common co-infection in HIV-infected women and can facilitate in utero transmission of HIV to infants. Most infants are asymptomatic at birth, but those with symptoms have high mortality rates.

Objective The aim of the current study was to evaluate the safety of a new reduced protein (2.1 g/100 kcal) infant formula containing 4 g/L of 90% galacto-oligosaccharides (GOS) and 10% fructo-oligosaccharides (FOS). Methods Healthy term infants from Brazil were enrolled. Those born to human immunodeficiency virus (HIV)-positive mothers were randomized to a test ( n = 65) or control ( n = 63) formula group. Infants born to HIV-negative mothers were either exclusively breast-fed ( n = 79) or received a mixed diet (breast milk and test formula, n = 65). Between 2 weeks and 4 months of age, infants were exclusively fed according to their assigned group. Anthropometric measurements were taken at baseline, 1, 2, 3, 4, 6, 8, 10, and 12 months. Digestive tolerance was evaluated during the first 4 months. The primary outcome was mean daily weight gain between 2 weeks and 4 months in the test formula and breast-fed groups. Results Data from all infants ( N = 272) were used in the intention-to-treat (ITT) analysis and data from 230 infants were used in the per-protocol (PP) analysis. The difference in mean daily weight gain between 2 weeks and 4 months in the test formula and breast-fed groups was 1.257 g/day (onesided 95% confidence interval [CI]: -0.705 to inf, P < 0.001) in the PP analysis, showing that the lower bound of the 95% CI was above the -3.0 g/day non-inferiority margin. Results were similar in the ITT analysis. Symptoms of digestive tolerance and frequency of adverse events were similar in the two groups. Conclusions The formula containing 2.1 g/100 kcal protein and GOS and FOS was safe and tolerated well.

It is still not well known, in a population with high human cytomegalovirus (HCMV) seroprevalence, whether a child with congenital infection harbors multiple viral strains at birth, and whether the prolonged viral excretion in these children is secondary to the persistence of the same viral strain. To verify the genomic diversity of HCMV detected in congenitally infected children, the nucleotide viral sequences from urine and/or saliva obtained at birth from 14 newborns with congenital infection and breast milk obtained from mothers of 5 of these children were analyzed. Among the 14 children, 10 had sequential samples until the median age of 10 months. The viral nucleotide sequences in the breast milk were compared with those identified in the respective children at birth. The differentiation of viral strains was based on the variability of 3 regions of viral genes (UL55/gB, UL144, and UL73/gN). In 13/14 children (92.8%), a single genotype was observed at birth. Different viral genotypes were found in 1 child (7.2%). Among the sequential samples from 10 children, the same genotype obtained at birth was detected in 9/10 (90%), and in 1 of them (10%), a genotype change in the urine was found. More than 1 HCMV strain in milk was observed in 2 mothers (2/5, 40%). In a population with high seroprevalence, a single genotype was found in the majority of infected children. Reinfection did not frequently occur in the first months of life. Maternal reinfection does not seem to be a rare event in transmitter mothers.

Until recently, Zika virus (ZIKV) infections were considered mild and self-limiting. Since 2015, they have been associated with an increase in microcephaly and other birth defects in newborns. While this association has been observed in case reports and epidemiological studies, the nature and extent of the relationship between ZIKV and adverse pregnancy and pediatric health outcomes is not well understood. With the unique opportunity to prospectively explore the full spectrum of issues related to ZIKV exposure during pregnancy, we undertook a multi-country, prospective cohort study to evaluate the association between ZIKV and pregnancy, neonatal, and infant outcomes.At research sites in ZIKV endemic regions of Brazil (4 sites), Colombia, Guatemala, Nicaragua, Puerto Rico (2 sites), and Peru, up to 10,000 pregnant women will be recruited and consented in the first and early second trimesters of pregnancy and then followed through delivery up to 6 weeks post-partum; their infants will be followed until at least 1 year of age. Pregnant women with symptomatic ZIKV infection confirmed by presence of ZIKV RNA and/or IgM for ZIKV will also be enrolled, regardless of gestational age. Participants will be tested monthly for ZIKV infection; additional demographic, physical, laboratory and environmental data will be collected to assess the potential interaction of these variables with ZIKV infection. Delivery outcomes and detailed infant assessments, including physical and neurological outcomes, will be obtained.With the emergence of ZIKV in the Americas and its association with adverse pregnancy outcomes in this region, a much better understanding of the spectrum of clinical outcomes associated with exposure to ZIKV during pregnancy is needed. This cohort study will provide information about maternal, fetal, and infant outcomes related to ZIKV infection, including congenital ZIKV syndrome, and manifestations that are not detectable at birth but may appear during the first year of life. In addition, the flexibility of the study design has provided an opportunity to modify study parameters in real time to provide rigorous research data to answer the most critical questions about the impact of congenital ZIKV exposure.NCT02856984 . Registered August 5, 2016. Retrospectively registered.

Dear Editor, Gaur et al.1 reported HIV infection in three children in the United States from infected adults feeding them prechewed food. This practice is common among HIV-infected care providers around the world.2–6 Prechewing involves chewing food before feeding it to a child. Prewarming (or precooling) involves holding food in the mouth to adjust the temperature before offering it to a child. These practices may expose the child to blood from the mouth of an HIV-infected adult. The context of these practices and the efficiency of related HIV transmission have not been described. We previously surveyed HIV-infected pregnant women in Latin America about these practices and advised against them.3 We now follow up on this sensitized cohort, characterize the frequency and context of these practices through 18 months postpartum, and assess the risk of HIV transmission. Women were enrolled at 12 sites (Eunice Kennedy Shriver National Institute of Child Health and Human Development International Site Development Initiative [NISDI] Longitudinal Study in Latin American Countries7 [LILAC]) in Argentina, Brazil, and Peru, and followed for 18 months postpartum. At study visits (antepartum and 6, 12, and 18 months postpartum), enrolled mothers (or alternative providers) were interviewed using a standardized questionnaire about prechewing/prewarming. Information about factors influencing risk of HIV transmission, including symptoms of disrupted oral mucosal integrity in the child or the adult and the HIV/hepatitis B/hepatitis C infection status of the adult, were collected. At the end of each interview, a scripted statement was read to respondents regarding the potential risk of HIV transmission associated with these practices and advising against them. Children were tested using an HIV DNA PCR assay at birth and 6–12 weeks and 6 months. If the status of the child was indeterminate at 6 months or the child was exposed to practices that might risk transmission, testing was repeated until after the practices had ceased (ages 7–18 months). The study was approved by the ethical/institutional review board at each site, the sponsoring institution, and the data coordinating center. Adult participants provided written consent for themselves and their children. Of 398 children enrolled, 383 (96.2%), 372 (93.5%), and 360 (90.4%) had a visit at or after 6, 12, and 18 months, respectively. Fifteen (3.9%; 95% confidence interval [CI]: 2.3–6.5%) received prechewed/prewarmed food reported at or after the 6-month visit. Of these, five (33.3%) received prechewed food, seven (46.7%) prewarmed food, and three (20%) both. By country, the prevalence of these practices was: Brazil: 12/306, 3.9% (95% CI: 2.0–6.7%); Argentina: 1/35, 2.9% (95% CI: 0.1–14.9%); and Peru: 2/42, 4.8% (95% CI: 0.6–16.2%). In this cohort for whom replacement feeding was available and mothers were advised to avoid breastfeeding, only six children (6/383; 1.6% 95% CI: 0.6–3.5%) were reported as having breastfed. The median age of first offering prechewed and prewarmed food was 7 months (range: 3–12) and 6 months (range: 3–11), respectively. Details of these practices are summarized in Table 1. In most instances, parents (primarily mothers) reported these practices. “I heard about it from my friends or family” was the most common reason offered for prechewing/prewarming. Several other reasons were reported (Table 2). Table 1. Characterization of the Feeding Practices of Prechewing and Prewarming Food for HIV-Exposed Children in the NISDI-LILAC Study in Latin America Table 2. Reasons Reported for Prechewing or Prewarming Food Among Care Providers of HIV-Exposed Children in the NISDI-LILAC Study Among the 15 HIV-exposed children who received prechewed/prewarmed food, eight received feedings from HIV-infected mothers who had been advised against this practice antepartum, and two received them from other infected adults. Maternal viral load was high (>10,000 copies/mL) or CD4 count low (

Given the strong selective pressures often faced by populations when colonizing a novel habitat, the level of variation present on which selection may act is an important indicator of adaptive potential. While often discussed in an ecological context, this notion is also highly relevant in our clinical understanding of viral infection, in which the novel habitat is a new host. Thus, quantifying the factors determining levels of variation is of considerable importance for the design of improved treatment strategies. Here, we focus on such a quantification of human cytomegalovirus (HCMV) - a virus which can be transmitted across the placenta, resulting in foetal infection that can potentially cause severe disease in multiple organs. Recent studies using genomewide sequencing data have demonstrated that viral populations in some congenitally infected infants diverge rapidly over time and between tissue compartments within individuals, while in other infants, the populations remain highly stable. Here, we investigate the underlying causes of these extreme differences in observed intrahost levels of variation by estimating the underlying demographic histories of infection. Importantly, reinfection (i.e. population admixture) appears to be an important, and previously unappreciated, player. We highlight illustrative examples likely to represent a single-population transmission from a mother during pregnancy and multiple-population transmissions during pregnancy and after birth.

Objectives HIV-exposed uninfected (HEU) infants have higher rates of severe and fatal infections compared with HIV-unexposed (HUU) infants, likely due to immune perturbations. We hypothesized that alterations in natural killer (NK) cell activity might occur in HEU infants and predispose them to severe infections. Design Case–control study using cryopreserved peripheral blood mononuclear cells (PBMCs) at birth and 6 months from HEU infants enrolled from 2002 to 2009 and HUU infants enrolled from 2011 to 2013. Methods NK cell phenotype and function were assessed by flow cytometry after 20-h incubation with and without K562 cells. Results The proportion of NK cells among PBMCs was lower at birth in 12 HEU vs. 22 HUU (1.68 vs. 10.30%, p

Background Low maternal vitamin D has been associated with preterm birth (PTB). Human immunodeficiency virus (HIV)-infected pregnant women are at risk for PTB, but data on maternal vitamin D and PTB in this population are scarce. Methods In a cohort of Latin American HIV-infected pregnant women from the National Institute of Child Health and Human Development International Site Development Initiative protocol, we examined the association between maternal vitamin D status and PTB. Vitamin D status was defined as the following 25-hydroxyvitamin D levels: severe deficiency ( Results Of 715 HIV-infected pregnant women, 13 (1.8%) were severely vitamin D deficient, 224 (31.3%) were deficient, and 233 were (32.6%) insufficient. Overall, 23.2% (166/715) of pregnancies resulted in PTB (median GA of PTBs = 36 weeks [interquartile range: 34–36]). In multivariate analysis, severe vitamin D deficiency was associated with PTB (odds ratio = 4.7, 95% confidence interval: 1.3–16.8]). Conclusion Severe maternal vitamin D deficiency is associated with PTB in HIV-infected Latin American pregnant women. Further studies are warranted to determine if vitamin D supplementation in HIV-infected women may impact PTB.

To evaluate antiretroviral (ARV) drug exposure and other factors during pregnancy that may increase the risk of neurologic conditions (NCs) in HIV-exposed/uninfected (HEU) infants. A prospective cohort study was conducted at 24 clinical sites in Latin America and the Caribbean. Data on maternal demographics, health, HIV disease status, and ARV use during pregnancy were collected. Infant data included measurement of head circumference after birth and reported medical diagnoses at birth, 6-12 weeks, and 6 months. Only infants with maternal exposure to combination ARV therapy (cART) (≥3 drugs from ≥2 drug classes) during pregnancy were included. Microcephaly, defined as head circumference for age z-score less than -2, and NC were evaluated for their association with covariates, including individual ARVs, using bivariable and logistic regression analyses. From 2002 to 2009, 1,400 HEU infants met study inclusion criteria. At least one NC was reported in 134 (9.6%; 95% confidence interval [CI]: 8.1-11.2), microcephaly in 105 (7.5%; 95% CI: 6.2-9.0), and specific neurologic diagnoses in 33 (2.4%; 95% CI: 1.6-3.3) HEU infants. Microcephaly and NC were not significantly associated with any specific ARV analyzed (p > 0.05). Covariates associated with increased odds of NC included male sex (odds ratio [OR] = 1.9; 95% CI: 1.3-2.8), birth weight

Objectives To estimate, by neonatal screening, the birth prevalence of congenital toxoplasmosis among live-born infants in Sergipe state, Brazil, and to investigate the clinical features of affected infants. Methods Dried blood spot specimens obtained from 15 204 neonates were assayed for the presence of anti-T. gondii IgM antibodies. Duplicate retesting was done in infants with positive and borderline results. Confirmatory testing in peripheral blood samples consisted of testing for anti-T. gondii IgG and IgM in infants and mothers. Those with possible congenital toxoplasmosis were evaluated and followed up to a median age of 20 months. Congenital infection was confirmed in the presence of persisting anti-T. gondii IgG antibodies beyond 12 months of age. All infants with confirmed infection were treated with pyrimethamine, sulfadiazine and folinic acid for 1 year. Results Fifty-three infants had detectable IgM in dried blood spot specimens. Confirmatory testing was reactive in 39/50, of which, 38 completed follow-up. Six of 15 204 newborns were diagnosed with congenital toxoplasmosis, resulting in an estimated birth prevalence of four per 10 000 [CI 95% 1.4–8.0]. Four infants (67%) showed signs of congenital toxoplasmosis in their first year of life; three (75%) had retinochoroidal scars, and one had cerebral calcifications. Two infants remained asymptomatic until 20 months of age. Conclusions The birth prevalence of congenital toxoplasmosis is high in the Brazilian state of Sergipe, with most of the infants showing ocular lesions. Preventive measures are strongly warranted. Objectifs: Estimer par le depistage neonatal, la prevalence a la naissance de la toxoplasmose congenitale chez les enfants nes vivants dans l’etat de Sergipe, au Bresil et etudier les caracteristiques cliniques des nourrissons atteints. Methodes: Des specimens seches de goutte de sang obtenus a partir de 15.204 nouveau-nes ont ete testes pour la presence d’anticorps IgM anti T. gondii. Un second test a ete effectue chez les nourrissons ayant des resultats positifs et intermediaires. Les tests de confirmation sur les echantillons de sang peripherique ont consistea tester pour les anticorps IgG et IgM anti T. gondii chez les nourrissons et les meres. Ceux atteints d’une eventuelle toxoplasmose congenitale ont eteevalues et suivis jusqu’a un âge median de 20 mois. L’infection congenitale a ete confirmee dans la presence de la persistance d’anticorps IgG anti T. gondii au dela de l’âge de 12 mois. Tous les nourrissons atteints d’une infection confirmee ont ete traites avec la pyrimethamine, la sulfadiazine et l’acide folinique pendant un an. Resultats: 53 enfants avaient des IgM detectables dans les echantillons seches de goutte de sang. Les tests de confirmation ont ete positifs dans 39/50 cas, dont 38 ont complete le suivi. Six des 15.204 nouveaux-nes ont ete diagnostiques avec une toxoplasmose congenitale, resultant en une prevalence a la naissance estimee a 4 pour 10.000 [IC95%: 1,4 a 8,0]. Quatre nourrissons (67%) presentaient des signes de la toxoplasmose congenitale au cours de leur premiere annee de vie, trois (75%) presentaient des cicatrices retinochoroidales et un presentait des calcifications cerebrales. Deux nourrissons sont restes asymptomatiques jusqu’a l’âge de 20 mois. Conclusions: La prevalence a la naissance de la toxoplasmose congenitale est elevee dans l’etat bresilien de Sergipe, avec la plupart des nourrissons presentant des lesions oculaires. Des mesures preventives sont fortement justifiees. Objetivos: Calcular, mediante un cribado neonatal, la prevalencia de nacimientos con toxoplasmosis congenita entre ninos nacidos vivos en el estado de Sergipe, en Brasil, e investigar las caracteristicas clinicas de los neonatos afectados. Metodos: Se obtuvieron muestras de sangre seca de 15,204 neonatos y se les realizaron pruebas para evaluar la presencia de anticuerpos IgM anti-T.gondii. Se realizo una prueba confirmatoria a los neonatos con resultados positivos y dudosos. Las pruebas confirmatorias en muestras de sangre periferica consistian en detectar las IgG e IgM especificas para T.gondii en neonatos y madres. Se evaluaron aquellos con una posible toxoplasmosis congenita y se les realizo un seguimiento hasta que tenian una edad media de 20 meses. Se confirmo una infeccion congenita en presencia anticuerpos IgG anti-T.gondii persistentes mas alla de los 12 meses de edad. Todos los neonatos con una infeccion confirmada eran tratados con pirimetamina, sulfadiazina y acido folinico durante un ano. Resultados: 53 neonatos tenian IgM detectables en las muestras de sangre seca. Las pruebas confirmatorias eran reactivas en 39/50 neonatos, de los cuales 38 cumplieron con el seguimiento. A seis de 15,204 neonatos se les diagnostico una toxoplasmosis congenita, resultando en una prevalencia estimada de nacimiento de 4 por 10,000 [IC 95% 1.4-8.0]. Cuatro neonatos (67%) presentaron signos de toxoplasmosis congenita durante su primer ano de vida; tres (75%) tenian cicatrices retinocoroideas, y uno tenia calcificaciones cerebrales. Dos neonatos se mantuvieron asintomaticos hasta los 20 meses de edad. Conclusiones: La prevalencia de nacimientos con toxoplasmosis congenita es alta en el estado Brasilero de Sergipe, con la mayoria de los neonatos presentando lesiones oculares. Las medidas preventivas estan ampliamente justificadas.

To evaluate cases of mother-to-child transmission of HIV-1 at multiple sites in Latin America and the Caribbean in terms of missed opportunities for prevention.Pregnant women infected with HIV-1 were eligible for inclusion if they were enrolled in either the NISDI Perinatal or LILAC protocols by October 20, 2009, and had delivered a live infant with known HIV-1 infection status after March 1, 2006.Of 711 eligible mothers, 10 delivered infants infected with HIV-1. The transmission rate was 1.4% (95% CI, 0.7-2.6). Timing of transmission was in utero or intrapartum (n=5), intrapartum (n=2), intrapartum or early postnatal (n=1), and unknown (n=2). Possible missed opportunities for prevention included poor control of maternal viral load during pregnancy; late initiation of antiretrovirals during pregnancy; lack of cesarean delivery before labor and before rupture of membranes; late diagnosis of HIV-1 infection; lack of intrapartum antiretrovirals; and incomplete avoidance of breastfeeding.Early knowledge of HIV-1 infection status (ideally before or in early pregnancy) would aid timely initiation of antiretroviral treatment and strategies designed to prevent mother-to-child transmission. Use of antiretrovirals must be appropriately monitored in terms of adherence and drug resistance. If feasible, breastfeeding should be completely avoided. Presented in part at the XIX International AIDS Conference (Washington, DC; July 22-27, 2012); abstract WEPE163.

OBJECTIVE: HIV transmission has been associated with offering a child food prechewed by an HIV-infected caregiver. We assessed awareness of prechewing and oral prewarming of food by an adult before offering it to a child among HIV-infected pregnant women and clinical investigators in 3 Latin American countries. METHODS: HIV-infected pregnant women at 12 sites (Eunice Kennedy Shriver National Institute of Child Health and Human Development International Site Development Initiative Perinatal Longitudinal Study in Latin American Countries, a prospective cohort trial) in Argentina, Brazil, and Peru were administered a screening survey about prechewing/prewarming of infant foods and cautioned against these feeding practices. Survey responses were analyzed, overall, and stratified according to country. RESULTS: Of the 401 HIV-infected pregnant women interviewed, 34% had heard about prechewing (50% from Argentina, 32% from Brazil, and 36% from Peru), 23% knew someone who prechewed food for infants, and 4% had prechewed food in the past. Seventeen percent had heard about oral prewarming of food, 13% knew someone who prewarmed food for infants, and 3% had prewarmed food for an infant in the past. Women who reported knowing someone who prechewed were more likely to also know someone who prewarmed food (P < .0001). Few site investigators anticipated that their patients would be aware of these practices. CONCLUSIONS: Prechewing food, a potential risk factor for HIV transmission, and orally prewarming food, which has not been associated with HIV transmission but might expose a child to blood from an HIV-infected adult, are not uncommon practices in Latin America. Both practices should be further investigated. Site investigator responses underscore that health care providers could be missing information about cultural practices that patients may not report unless specifically asked.

Our objective was to describe the prevalence of low concentrations of retinol, β-carotene, and vitamin E in a group of human immunodeficiency virus (HIV)-infected Latin American children and a comparison group of HIV-exposed, uninfected children. Our hypothesis was that the rates of low concentrations of these micronutrients would be higher in the HIV-infected group than those in the HIV-exposed, uninfected group. This was a cross-sectional substudy of a larger cohort study at clinical pediatric HIV centers in Latin America. Serum levels of micronutrients were measured in the first stored sample obtained after each child's first birthday by high-performance liquid chromatography. Low concentrations of retinol, β-carotene, and vitamin E were defined as serum levels below 0.70, 0.35, and 18.0 μmol/L, respectively. The population for this analysis was 336 children (124 HIV-infected, 212 HIV-exposed, uninfected) aged 1 year or older to younger than 4 years. Rates of low concentrations were 74% for retinol, 27% for β-carotene, and 89% for vitamin E. These rates were not affected by HIV status. Among the HIV-infected children, those treated with antiretrovirals were less likely to have retinol deficiency, but no other HIV-related factors correlated with micronutrient low serum levels. Low concentrations of retinol, β-carotene, and vitamin E are very common in children exposed to HIV living in Brazil, Argentina, and Mexico, regardless of HIV-infection status.

Background The natural history of congenital cytomegalovirus (CMV) infection is scarcely known in populations with high maternal CMV seroprevalence. This study evaluated the birth prevalence, clinical findings at birth, and hearing outcome in CMV-infected children from such a population. Methods Consecutively born infants were screened for the presence of CMV in urine and/or saliva specimens during the first 2 weeks after birth. Neonatal clinical findings were recorded, and CMV-infected children were tested to document hearing function during follow-up. A subset of mothers of CMV-infected infants were prenatally tested for the presence of anti-CMV immunoglobulin G antibodies. Results Congenital CMV infection was confirmed in 87 (1.08%; 95% confidence interval [CI], 0.86%-1.33%) of 8047 infants. Seven infants (8.1%; 95% CI, 3.3%-15.9%) had at least 1 clinical finding suggestive of CMV infection, and 4 (4.6%; 95% CI, 1.3%-11.3%) had >3 findings of systemic disease. Sensorineural hearing loss was found in 5 (8.6%; 95% CI, 2.9%-19.0%) of 58 children tested at a median age of 21 months. Bilateral profound hearing loss was observed in 2 children, and the hearing threshold was >60 decibels in all 5 children with hearing loss, including 2 children born to mothers with probable nonprimary CMV infection. Conclusions The results of this large newborn screening study in a population with high CMV seroimmunity provide additional evidence that congenital CMV disease occurs in populations with high seroprevalence rates, with a similar incidence of CMV-related hearing loss to that reported in the offspring of women from populations in developed countries with lower rates of seroimmunity to CMV.