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.

Correction to: International prospective observational cohort study of Zika in infants and pregnancy (ZIP study): study protocol.

Following publication of the original article [1], the author mentioned that two additional NIH staff were involved in the development of the protocol who did not receive recognition in the Acknowledgments section in their published article.

International prospective observational cohort study of Zika in infants and pregnancy (ZIP study): study protocol.

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.

Reduction of Arachidonate Is Associated With Increase in B-Cell Activation Marker in Infants: A Randomized Trial.

BACKGROUND: Infants who are not breast-fed benefit from formula with both docosahexaenoic acid (C22:6n3) and arachidonic acid (ARA; C20:4n6). The amount of ARA needed to support immune function is unknown. Infants who carry specific fatty acid desaturase (FADS) polymorphisms may require more dietary ARA to maintain adequate ARA status. OBJECTIVE: The aim of the study was to determine whether ARA intake or FADS polymorphisms alter ARA levels of lymphocytes, plasma, and red blood cells in term infants fed infant formula. METHODS: Infants (N = 89) were enrolled in this prospective, double-blind controlled study. Infants were randomized to consume formula containing 17 mg docosahexaenoic acid and 0, 25, or 34 mg ARA/100 kcal for 10 weeks. Fatty acid composition of plasma phosphatidylcholine and phosphatidylethanolamine, total fatty acids of lymphocytes and red blood cells, activation markers of lymphocytes, and polymorphisms in FADS1 and FADS2 were determined. RESULTS: Lymphocyte ARA was higher in the 25-ARA formula group than in the 0- or 34-ARA groups. In plasma, 16:0/20:4 and 18:0/20:4 species of phosphatidylcholine and phosphatidylethanolamine were highest and 16:0/18:2 and 18:0/18:2 were lowest in the 34-ARA formula group. In minor allele carriers of FADS1 and FADS2, plasma ARA content was elevated only at the highest level of ARA consumed. B-cell activation marker CD54 was elevated in infants who consumed formula containing no ARA. CONCLUSIONS: ARA level in plasma is reduced by low ARA consumption and by minor alleles in FADS. Dietary ARA may exert an immunoregulatory role on B-cell activation by decreasing 16:0/18:2 and 18:0/18:2 species of phospholipids. ARA intake from 25 to 34 mg/100 kcal is sufficient to maintain cell ARA level in infants across genotypes.

Formula with long-chain polyunsaturated fatty acids reduces incidence of allergy in early childhood.

BACKGROUND: Allergy has sharply increased in affluent Western countries in the last 30 years. N-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs) may protect the immune system against development of allergy. METHODS: We prospectively categorized illnesses by body system in a subset of 91 children from the Kansas City cohort of the DIAMOND (DHA Intake and Measurement of Neural Development) study who had yearly medical records through 4 years of age. As infants, they were fed either a control formula without LCPUFA (n = 19) or one of three formulas with LCPUFA from docosahexaenoic acid (DHA) and arachidonic acid (ARA) (n = 72). RESULTS: Allergic illnesses in the first year were lower in the combined LCPUFA group compared to the control. LCPUFAs significantly delayed time to first allergic illness (p = 0.04) and skin allergic illness (p = 0.03) and resulted in a trend to reduced wheeze/asthma (p = 0.1). If the mother had no allergies, LCPUFAs reduced the risk of any allergic diseases (HR = 0.24, 95% CI = 0.1, 0.56, p = 0.0.001) and skin allergic diseases (HR = 0.35, 95% CI = 0.13, 0.93, p = 0.04). In contrast, if the mother had allergies, LCPUFAs reduced wheezing/asthma (HR = 0.26, 95% CI = 0.07, 0.9, p = 0.02). CONCLUSIONS: LCPUFA supplementation during infancy reduced the risk of skin and respiratory allergic diseases in childhood with effects influenced by maternal allergies.

Infants fed formula with added long chain polyunsaturated fatty acids have reduced incidence of respiratory illnesses and diarrhea during the first year of life.

BACKGROUND: Long chain polyunsaturated fatty acids (LCPUFAs) may influence the immune system. Our objective was to compare the frequency of common illnesses in infants who received formula with or without added LCPUFAs. METHODS: In this observational, multi-center, prospective study, infants consumed formula with 17 mg DHA and 34 mg ARA/100 kcal (n = 233) or with no added DHA or ARA (n = 92). Pediatricians recorded respiratory illnesses, otitis media, eczema, and diarrhea through 1 year of age. RESULTS: Infants who consumed formula with DHA/ARA had lower incidence of bronchitis/bronchiolitis (P = 0.004), croup (P = 0.044), nasal congestion (P = 0.001), cough (P = 0.014), and diarrhea requiring medical attention (P = 0.034). The odds ratio (OR) of having at least one episode of bronchitis/bronchiolitis (0.41, 95% CI 0.24, 0.70; P = 0.001), croup (0.23, 95% CI 0.05, 0.97; P = 0.045), nasal congestion (0.37, 95% CI 0.20, 0.66; P = 0.001), cough (0.52, 95% CI 0.32, 0.86; P = 0.011), and diarrhea requiring medical attention (0.51, 95% CI 0.28, 0.92; P = 0.026) was lower in infants fed DHA/ARA. The OR of an increased number of episodes of bronchitis/bronchiolitis, croup, nasal congestion, cough, and diarrhea, as well as the hazard ratio for shorter time to first episode of bronchitis/bronchiolitis, nasal congestion, cough, and diarrhea were also significantly lower in the DHA/ARA group. CONCLUSIONS: In healthy infants, formula with DHA/ARA was associated with lower incidence of common respiratory symptoms and illnesses, as well as diarrhea.

Extensively hydrolysed casein formula supplemented with Lactobacillus rhamnosus GG maintains hypoallergenic status: randomised double-blind, placebo-controlled crossover trial.

OBJECTIVE: To evaluate the hypoallergenicity of an extensively hydrolysed (EH) casein formula supplemented with Lactobacillus rhamnosus GG (LGG). DESIGN: A prospective, randomised, double-blind, placebo-controlled crossover trial. SETTING: Two study sites in Italy and The Netherlands. STUDY PARTICIPANTS: Children with documented cow's milk allergy were eligible for inclusion in this trial. INTERVENTIONS: After a 7-day period of strict avoidance of cow's milk protein and other suspected food allergens, participants were tested with an EH casein formula with demonstrated hypoallergenicity (control, EHF) and a formula of the same composition with LGG added at 10(8) colony-forming units per gram powder (EHF-LGG) in randomised order in a double-blind placebo-controlled food challenge (DBPCFC). After absence of adverse reactions in the DBPCFC, an open challenge was performed with EHF-LGG, followed by a 7-day home feeding period with the same formula. MAIN OUTCOME MEASURE: Clinical assessment of any adverse reactions to ingestion of study formulae during the DBPCFC. RESULTS: For all participants with confirmed cow's milk allergy (n=31), the DBPCFC and open challenge were classified as negative. CONCLUSION: The EH casein formula supplemented with LGG is hypoallergenic and can be recommended for infants and children allergic to cow's milk who require an alternative to formulae containing intact cow's milk protein. TRIAL REGISTRATION NUMBER: http://ClinicalTrials.gov Identifier: NCT01181297.

New prebiotic blend of polydextrose and galacto-oligosaccharides has a bifidogenic effect in young infants.

OBJECTIVE: The aim of the study was to evaluate the effect of infant formula with polydextrose (PDX) and galacto-oligosaccharides (GOS) on fecal microbiota and secretory IgA (sIgA). MATERIALS AND METHODS: In the present double-blind, randomized study, term infants received control (Enfamil Lipil) or the same formula with PDX/GOS (4 g/L, 1:1 ratio; PDX/GOS) for 60 days; a reference breast-fed group was included. Formula intake, tolerance, and stool characteristics were collected via electronic diary and analyzed by repeated measures analysis of variance. Anthropometric measurements and stool samples were obtained at baseline and after 30 and 60 days of feeding. Fecal sIgA was measured by enzyme-linked immunosorbent assay and fecal bacteria by fluorescent in situ hybridization and quantitative real-time polymerase chain reaction (qPCR); both were analyzed by Wilcoxon rank sum test. RESULTS: Two hundred thirty infants completed the study. Infants consuming PDX/GOS had softer stools than control at all times (P < 0.001). Using qPCR, counts in PDX/GOS were closer to the breast-fed group, tended to be higher than control for total bifidobacteria (P = 0.069) and Bifidobacterium longum (P = 0.057) at 30 days, and were significantly higher for total bifidobacteria and B longum at 60 days and B infantis at 30 days (P = 0.002). No significant differences were detected between PDX/GOS and control in changes from baseline to 30 or 60 days for sIgA or total bifidobacteria by fluorescent in situ hybridization or qPCR; however, significantly higher changes from baseline were detected between PDX/GOS and control for B infantis at 30 days and B longum at 60 days (P ≤ 0.035). CONCLUSIONS: Infant formula with PDX/GOS produces soft stools and a bifidogenic effect closer to breast milk than formula without PDX/GOS.

Stool pattern changes in toddlers consuming a follow-on formula supplemented with polydextrose and galactooligosaccharides.

Healthy 9- to 48-month-old children (n = 133) were randomized to receive a cow's-milk-based follow-on formula (control) or the same formula with polydextrose and galactooligosaccharides (PDX/GOS) for 108 days. Pediatricians assessed diarrheal disease, stool pattern, acute respiratory infection, systemic antibiotic use, and growth. The 2 groups had similar weight-for-length/height z score and similar odds of having diarrheal disease, acute respiratory infection, and systemic antibiotic use; however, PDX/GOS had greater odds of increased defecation than control (P ≤ 0.01). Addition of PDX and GOS to a follow-on formula was well tolerated and induced a pattern of more frequent and softer stools in toddlers.

Hypoallergenicity and effects on growth and tolerance of a new amino acid-based formula with docosahexaenoic acid and arachidonic acid.

OBJECTIVE: In study 1, to compare the effect on growth in healthy infants of a new amino acid-based formula (AAF) and a control extensively hydrolyzed formula (EHF), with both docosahexaenoic acid (DHA) and arachidonic acid (ARA) at levels similar to those in human milk worldwide. In study 2, to evaluate the hypoallergenicity of this new AAF in infants and children with confirmed cow's milk allergy (CMA). STUDY DESIGN: In study 1, a total of 165 healthy, full-term, formula-fed infants randomly received the new AAF or control formula. Anthropometric measurements, tolerance, and adverse events were recorded throughout the study. Plasma amino acid profiles were evaluated in a subset of the infants. In study 2, the hypoallergenicity of the new AAF was evaluated in 32 infants and children using a double-blind, placebo-controlled food challenge; an open challenge; and a 7-day feeding. RESULTS: In study 1, overall growth, tolerance, and safety outcomes were similar in both groups. In study 2, 29 of the 32 subjects completed both challenges; no allergic reaction was seen in any of the 32 subjects. CONCLUSIONS: The new AAF with DHA and ARA at levels similar to those in human milk worldwide is hypoallergenic. It also is safe and supports growth in healthy, term infants.

Maximum bronchodilator effect of pirbuterol and procaterol administered as sprays with and without an aerochamber

Objective of the study: To determine the maximal bronchodilator dose of procaterol and pirbuterol administered by inhalation with an without an aerochamber (Aerocâmera) to children with acute brinchial asthma attacks. Type of study: Prospective. 18 children (6-15 years of age) with acute bronchial asthma attacks (FEV1 < 80 per cents of the predicted value) received pirbuterol (N = 10) or procaterol (N = 8) by metered-dose inhaler, one puff every 5 minutes, for a total of five doses. During another acute attack, the same patient received the same medication with the aid of a spacer (Aerocâmera). Clinical evaluation and pulmonary function tests were performed 5 minutes after each inhaled dose. Results: For both drugs, maximal bronchodilation was obtained after the second dose. No significant side effects were observed even after procaterol doses of 50 µg or pirbuterol doses of 1000 µg. The results were unaffected by the use of the spacer. Conclusions: The doses that induced maximal bronchodilation were 400 µg pirbuterol and 20 µg procaterol Although the spacer did not change the results, it is a valuable aid for patients who have difficulty in using the metered-dose inhaler (M.D.I.)

Doenca alergica e sua repercussao sobre o crescimento / Alergic disease and its repercussion above the growth

A incidencia de baixa estatura (<2,5 percentil) entre pacientes com doenca atopica varia de 2 a 10%. Observamos entre 393 criancas com doenca atopica (asma e/ou rinite e/ou dermatite atopica e/ou urticaria) 12,7%, valor esse significantmente maior ao observado entre criancas atendidas no setor detriagem pediatrica do mesmo servico (8,87%) e criancas atendidas em clinica privada de Pediatria (1,89%) e de Alergia (3,21%). Nao observamos relacao entre tempo de doenca atopica, gravidade da asma bronquica, uso de corticosteroide sistemico (tempo igual ou superior a 7 dias) e maior frequencia de baixa estatura. Entre os pacientes portadores de asma grave, o uso de corticosteroide sistemico foi significantemente maior quando comparado aos demais grupos. O acompanhamento de 43 desses pacientes com baixa estatura, por prazo superior a 6 meses mostrou aceleracao do crescimento em 41,3% (19/46) com mudanca para percentil superior em 28% principalmente entre meninos com idade superior a 10 anos. Atraso na idade ossea superior a 18 meses em relacao a cronologica foi observada em 87,5% (14,/16), havendo correspondencia daquela com a idade-estatura. Os niveis de hormonio decrescimento apos exercicio padronizado foram identicos para criancas asmaticas com baixa estatura ou nao. O mesmo foi observado quanto aos niveis de triodotironina. Diante desses dados concluimos que a doenca atopica, aliada a condicao socio-economica desfavoravel, proporciona maior frequencia de baixa estatura. O atraso na maturacao ossea corresponde a idade-estatura, revela para esses pacientes potencial para crescimento normal .