Complement in breast milk modifies offspring gut microbiota to promote infant health.

Breastfeeding offers demonstrable benefits to newborns and infants by providing nourishment and immune protection and by shaping the gut commensal microbiota. Although it has been appreciated for decades that breast milk contains complement components, the physiological relevance of complement in breast milk remains undefined. Here, we demonstrate that weanling mice fostered by complement-deficient dams rapidly succumb when exposed to murine pathogen Citrobacter rodentium (CR), whereas pups fostered on complement-containing milk from wild-type dams can tolerate CR challenge. The complement components in breast milk were shown to directly lyse specific members of gram-positive gut commensal microbiota via a C1-dependent, antibody-independent mechanism, resulting in the deposition of the membrane attack complex and subsequent bacterial lysis. By selectively eliminating members of the commensal gut community, complement components from breast milk shape neonate and infant gut microbial composition to be protective against environmental pathogens such as CR.

Mobile genetic elements from the maternal microbiome shape infant gut microbial assembly and metabolism.

The perinatal period represents a critical window for cognitive and immune system development, promoted by maternal and infant gut microbiomes and their metabolites. Here, we tracked the co-development of microbiomes and metabolomes from late pregnancy to 1 year of age using longitudinal multi-omics data from a cohort of 70 mother-infant dyads. We discovered large-scale mother-to-infant interspecies transfer of mobile genetic elements, frequently involving genes associated with diet-related adaptations. Infant gut metabolomes were less diverse than maternal but featured hundreds of unique metabolites and microbe-metabolite associations not detected in mothers. Metabolomes and serum cytokine signatures of infants who received regular-but not extensively hydrolyzed-formula were distinct from those of exclusively breastfed infants. Taken together, our integrative analysis expands the concept of vertical transmission of the gut microbiome and provides original insights into the development of maternal and infant microbiomes and metabolomes during late pregnancy and early life.

A distinct clade of Bifidobacterium longum in the gut of Bangladeshi children thrives during weaning.

The gut microbiome has an important role in infant health and development. We characterized the fecal microbiome and metabolome of 222 young children in Dhaka, Bangladesh during the first two years of life. A distinct Bifidobacterium longum clade expanded with introduction of solid foods and harbored enzymes for utilizing both breast milk and solid food substrates. The clade was highly prevalent in Bangladesh, present globally (at lower prevalence), and correlated with many other gut taxa and metabolites, indicating an important role in gut ecology. We also found that the B. longum clades and associated metabolites were implicated in childhood diarrhea and early growth, including positive associations between growth measures and B. longum subsp. infantis, indolelactate and N-acetylglutamate. Our data demonstrate geographic, cultural, seasonal, and ecological heterogeneity that should be accounted for when identifying microbiome factors implicated in and potentially benefiting infant development.

Fc Characteristics Mediate Selective Placental Transfer of IgG in HIV-Infected Women.

The placental transfer of maternal IgG is critical for infant protection against infectious pathogens. However, factors that modulate the placental transfer of IgG remain largely undefined. HIV-infected women have impaired placental IgG transfer, presenting a unique "disruption model" to define factors that modulate placental IgG transfer. We measured the placental transfer efficiency of maternal HIV and pathogen-specific IgG in US and Malawian HIV-infected mothers and their HIV-exposed uninfected and infected infants. We examined the role of maternal HIV disease progression, infant factors, placental Fc receptor expression, IgG subclass, and glycan signatures and their association with placental IgG transfer efficiency. Maternal IgG characteristics, such as binding to placentally expressed Fc receptors FcγRIIa and FcγRIIIa, and Fc region glycan profiles were associated with placental IgG transfer efficiency. Our findings suggest that Fc region characteristics modulate the selective placental transfer of IgG, with implications for maternal vaccine design and infant health.

Site-specific development and progressive maturation of human tissue-resident memory T cells over infancy and childhood.

Infancy and childhood are critical life stages for generating immune memory to protect against pathogens; however, the timing, location, and pathways for memory development in humans remain elusive. Here, we investigated T cells in mucosal sites, lymphoid tissues, and blood from 96 pediatric donors aged 0-10 years using phenotypic, functional, and transcriptomic profiling. Our results revealed that memory T cells preferentially localized in the intestines and lungs during infancy and accumulated more rapidly in mucosal sites compared with blood and lymphoid organs, consistent with site-specific antigen exposure. Early life mucosal memory T cells exhibit distinct functional capacities and stem-like transcriptional profiles. In later childhood, they progressively adopt proinflammatory functions and tissue-resident signatures, coincident with increased T cell receptor (TCR) clonal expansion in mucosal and lymphoid sites. Together, our findings identify staged development of memory T cells targeted to tissues during the formative years, informing how we might promote and monitor immunity in children.

Impaired Tumor-Necrosis-Factor-α-driven Dendritic Cell Activation Limits Lipopolysaccharide-Induced Protection from Allergic Inflammation in Infants.

Infants have a higher risk of developing allergic asthma than adults. However, the underlying mechanism remains unknown. We show here that sensitization of mice with house-dust mites (HDMs) in the presence of low-dose lipopolysaccharide (LPS) prevented T helper 2 (Th2) cell allergic responses in adult, but not infant, mice. Mechanistically, adult CD11b+ migratory dendritic cells (mDCs) upregulated the transcription factor T-bet in response to tumor necrosis factor-α (TNF-α), which was rapidly induced after HDM + LPS sensitization. Consequently, adult CD11b+ mDCs produced interleukin-12 (IL-12), which prevented Th2 cell development by promoting T-bet upregulation in responding T cells. Conversely, infants failed to induce TNF-α after HDM + LPS sensitization. Therefore, CD11b+ mDCs failed to upregulate T-bet and did not secrete IL-12 and Th2 cell responses normally developed in infant mice. Thus, the availability of TNF-α dictates the ability of CD11b+ mDCs to suppress allergic Th2-cell responses upon dose-dependent endotoxin sensitization and is a key mediator governing susceptibility to allergic airway inflammation in infant mice.

The journey toward disease modification in cow milk protein allergy.

Cow milk protein allergy (CMPA) is one of the most common food allergies in the pediatric age worldwide. Prevalence, persistence, and severity of this condition are on the rise, with a negative impact on the health-related quality of life of the patients and families and on the costs related to its management. Another relevant issue is that CMPA in early life may be the first stage of the "allergic march," leading to the occurrence of other atopic manifestations later in life, especially asthma, atopic eczema, urticaria, and rhinoconjunctivitis. Thus, "disease modification" options that are able to modulate the disease course of pediatric patients affected by CMPA would be very welcomed by affected families and healthcare systems. In this review, we report the most relevant progress on this topic.

Fibrinogen inhibits sonic hedgehog signaling and impairs neonatal cerebellar development after blood-brain barrier disruption.

Cerebellar injury in preterm infants with central nervous system (CNS) hemorrhage results in lasting neurological deficits and an increased risk of autism. The impact of blood-induced pathways on cerebellar development remains largely unknown, so no specific treatments have been developed to counteract the harmful effects of blood after neurovascular damage in preterm infants. Here, we show that fibrinogen, a blood-clotting protein, plays a central role in impairing neonatal cerebellar development. Longitudinal MRI of preterm infants revealed that cerebellar bleeds were the most critical factor associated with poor cerebellar growth. Using inflammatory and hemorrhagic mouse models of neonatal cerebellar injury, we found that fibrinogen increased innate immune activation and impeded neurogenesis in the developing cerebellum. Fibrinogen inhibited sonic hedgehog (SHH) signaling, the main mitogenic pathway in cerebellar granule neuron progenitors (CGNPs), and was sufficient to disrupt cerebellar growth. Genetic fibrinogen depletion attenuated neuroinflammation, promoted CGNP proliferation, and preserved normal cerebellar development after neurovascular damage. Our findings suggest that fibrinogen alters the balance of SHH signaling in the neurovascular niche and may serve as a therapeutic target to mitigate developmental brain injury after CNS hemorrhage.

Antiracism and positive intergenerational (infant) outcomes: A county-level examination of low birth weight and infant mortality.

Racism is associated with negative intergenerational (infant) outcomes. That is, racism, both perceived and structural, is linked to critical, immediate, and long-term health factors such as low birth weight and infant mortality. Antiracism-resistance to racism such as support for the Black Lives Matter (BLM) movement-has been linked to positive emotional, subjective, and mental health outcomes among adults and adolescents. To theoretically build on and integrate such past findings, the present research asked whether such advantageous health correlations might extend intergenerationally to infant outcomes? It examined a theoretical/correlational process model in which mental and physical health indicators might be indirectly related to associations between antiracism and infant health outcomes. Analyses assessed county-level data that measured BLM support (indexed as volume of BLM marches) and infant outcomes from 2014 to 2020. As predicted, in the tested model, BLM support was negatively correlated with 1) low birth weight (Ncounties = 1,445) and 2) mortalities (Ncounties = 409) among African American infants. Given salient, intergroup, policy debates tied to antiracism, the present research also examined associations among White Americans. In the tested model, BLM marches were not meaningfully related to rates of low birth weight among White American infants (Ncounties = 2,930). However, BLM support was negatively related to mortalities among White American infants (Ncounties = 862). Analyses controlled for structural indicators of income inequality, implicit/explicit bias, voting behavior, prior low birth weight/infant mortality rates, and demographic characteristics. Theory/applied implications of antiracism being linked to nonnegative and positive infant health associations tied to both marginalized and dominant social groups are discussed.

Infants' understanding of the causal power of agents and tools.

Tools are objects that are manipulated by agents with the intention to cause an effect in the world. We show that the cognitive capacity to understand tools is present in young infants, even if these tools produce arbitrary, causally opaque effects. In experiments 1-2, we used pupillometry to show that 8-mo-old infants infer an invisible causal contact to account for the-otherwise unexplained-motion of a ball. In experiments 3, we probed 8-mo-old infants' account of a state change event (flickering of a cube) that lies outside of the explanatory power of intuitive physics. Infants repeatedly watched an intentional agent launch a ball behind an occluder. After a short delay, a cube, positioned at the other end of the occluder began flickering. Rare unoccluded events served to probe infants' representation of what happened behind the occluder. Infants exhibited larger pupil dilation, signaling more surprise, when the ball stopped before touching the cube, than when it contacted the cube, suggesting that infants inferred that the cause of the state change was contact between the ball and the cube. This effect was canceled in experiment 4, when an inanimate sphere replaced the intentional agent. Altogether, results suggest that, in the infants' eyes, a ball (an inanimate object) has the power to cause an arbitrary state change, but only if it inherits this power from an intentional agent. Eight-month-olds are thus capable of representing complex event structures, involving an intentional agent causing a change with a tool.

Global biomass fires and infant mortality.

Global outdoor biomass burning is a major contributor to air pollution, especially in low- and middle-income countries. Recent years have witnessed substantial changes in the extent of biomass burning, including large declines in Africa. However, direct evidence of the contribution of biomass burning to global health outcomes remains limited. Here, we use georeferenced data on more than 2 million births matched to satellite-derived burned area exposure to estimate the burden of biomass fires on infant mortality. We find that each additional square kilometer of burning is associated with nearly 2% higher infant mortality in nearby downwind locations. The share of infant deaths attributable to biomass fires has increased over time due to the rapid decline in other important causes of infant death. Applying our model estimates across harmonized district-level data covering 98% of global infant deaths, we find that exposure to outdoor biomass burning was associated with nearly 130,000 additional infant deaths per year globally over our 2004 to 2018 study period. Despite the observed decline in biomass burning in Africa, nearly 75% of global infant deaths due to burning still occur in Africa. While fully eliminating biomass burning is unlikely, we estimate that even achievable reductions-equivalent to the lowest observed annual burning in each location during our study period-could have avoided more than 70,000 infant deaths per year globally since 2004.

Rapid infant learning of syntactic-semantic links.

In the second year of life, infants begin to rapidly acquire the lexicon of their native language. A key learning mechanism underlying this acceleration is syntactic bootstrapping: the use of hidden cues in grammar to facilitate vocabulary learning. How infants forge the syntactic-semantic links that underlie this mechanism, however, remains speculative. A hurdle for theories is identifying computationally light strategies that have high precision within the complexity of the linguistic signal. Here, we presented 20-mo-old infants with novel grammatical elements in a complex natural language environment and measured their resultant vocabulary expansion. We found that infants can learn and exploit a natural language syntactic-semantic link in less than 30 min. The rapid speed of acquisition of a new syntactic bootstrap indicates that even emergent syntactic-semantic links can accelerate language learning. The results suggest that infants employ a cognitive network of efficient learning strategies to self-supervise language development.

Vaccination, immunity, and the changing impact of COVID-19 on infant health.

In utero exposure to COVID-19 infection may lead to large intergenerational health effects. The impact of infection exposure has likely evolved since the onset of the pandemic as new variants emerge, immunity from prior infection increases, vaccines become available, and vaccine hesitancy persists, such that when infection is experienced is as important as whether it is experienced. We examine the changing impact of COVID-19 infection on preterm birth and the moderating role of vaccination. We offer the first plausibly causal estimate of the impact of maternal COVID-19 infection by using population data with no selectivity, universal information on maternal COVID-19 infection, and linked sibling data. We then assess change in this impact from 2020 to 2023 and evaluate the protective role of COVID-19 vaccination on infant health. We find a substantial adverse effect of prenatal COVID-19 infection on the probability of preterm birth. The impact was large during the first 2 y of the pandemic but had fully disappeared by 2022. The harmful impact of COVID-19 infection disappeared almost a year earlier in zip codes with high vaccination rates, suggesting that vaccines might have prevented thousands of preterm births. The findings highlight the need to monitor the changing consequences of emerging infectious diseases over time and the importance of mitigation strategies to reduce the burden of infection on vulnerable populations.

Excess risk in infant mortality among populations living in flood-prone areas in Bangladesh: A cluster-matched cohort study over three decades, 1988 to 2017.

The Ganges-Brahmaputra-Meghna river basin, running through Tibet, Nepal, Bhutan, Bangladesh, and northern India, is home to more than 618 million people. Annual monsoons bring extensive flooding to the basin, with floods predicted to be more frequent and extreme due to climate change. Yet, evidence regarding the long-term impacts of floods on children's health is lacking. In this analysis, we used high-resolution maps of recent large floods in Bangladesh to identify flood-prone areas over the country. We then used propensity score techniques to identify, among 58,945 mothers interviewed in six demographic population-based surveys throughout Bangladesh, matched cohorts of exposed and unexposed mothers and leverage data on 150,081 births to estimate that living in flood-prone areas was associated with an excess risk in infant mortality of 5.3 (95% CI 2.2 to 8.4) additional deaths per 1,000 births compared to living in non-flood-prone areas over the 30-y period between 1988 and 2017, with higher risk for children born during rainy (7.9, 95% CI: 3.3 to 12.5) vs. dry months (3.1, 95% CI: -1.1 to 7.2). Finally, drawing on national-scale, high-resolution estimates of flood risk and population distribution, we estimated an excess of 152,753 (64,120 to 241,386) infant deaths were attributable to living in flood-prone areas in Bangladesh over the past 30 y, with marked heterogeneity in attributable burden by subdistrict. Our approach demonstrates the importance of measuring longer-term health impacts from floods and provides a generalizable example for how to study climate-related exposures and long-term health effects.

Routine SARS-CoV-2 vaccination for all children.

The SARS-CoV-2 pandemic has resulted in unprecedented health and economic losses. Children generally present with less severe disease from this virus compared with adults, yet neonates and children with COVID-19 can require hospitalization, and older children can develop severe complications, such as the multisystem inflammatory syndrome, resulting in >1500 deaths in children from COVID-19 since the onset of the pandemic. The introduction of effective SARS-CoV-2 vaccines in school-age children and adult populations combined with the emergence of new, more highly transmissible SARS-CoV-2 variants has resulted in a proportional increase of infections in young children. Here, we discuss (1) the current knowledge on pediatric SARS-CoV-2 infection and pathogenesis in comparison with adults, (2) the data on vaccine immunogenicity and efficacy in children, and (3) the benefits of early life SARS-CoV-2 vaccination.

Neuronal Coupling Modes Show Differential Development in the Early Cortical Activity Networks of Human Newborns.

The third trimester is a critical period for the development of functional networks that support the lifelong neurocognitive performance, yet the emergence of neuronal coupling in these networks is poorly understood. Here, we used longitudinal high-density electroencephalographic recordings from preterm infants during the period from 33 to 45 weeks of conceptional age (CA) to characterize early spatiotemporal patterns in the development of local cortical function and the intrinsic coupling modes [ICMs; phase-phase (PPCs), amplitude-amplitude (AACs), and phase-amplitude correlations (PACs)]. Absolute local power showed a robust increase with CA across the full frequency spectrum, while local PACs showed sleep state-specific, biphasic development that peaked a few weeks before normal birth. AACs and distant PACs decreased globally at nearly all frequencies. In contrast, the PPCs showed frequency- and region-selective development, with an increase of coupling strength with CA between frontal, central, and occipital regions at low-delta and alpha frequencies together with a wider-spread decrease at other frequencies. Our findings together present the spectrally and spatially differential development of the distinct ICMs during the neonatal period and provide their developmental templates for future basic and clinical research.

Mapping Early Brain-Body Interactions: Associations of Fetal Heart Rate Variation with Newborn Brainstem, Hypothalamic, and Dorsal Anterior Cingulate Cortex Functional Connectivity.

The autonomic nervous system (ANS) regulates the body's physiology, including cardiovascular function. As the ANS develops during the second to third trimester, fetal heart rate variability (HRV) increases while fetal heart rate (HR) decreases. In this way, fetal HR and HRV provide an index of fetal ANS development and future neurobehavioral regulation. Fetal HR and HRV have been associated with child language ability and psychomotor development behavior in toddlerhood. However, their associations with postbirth autonomic brain systems, such as the brainstem, hypothalamus, and dorsal anterior cingulate cortex (dACC), have yet to be investigated even though brain pathways involved in autonomic regulation are well established in older individuals. We assessed whether fetal HR and HRV were associated with the brainstem, hypothalamic, and dACC functional connectivity in newborns. Data were obtained from 60 pregnant individuals (ages 14-42) at 24-27 and 34-37 weeks of gestation using a fetal actocardiograph to generate fetal HR and HRV. During natural sleep, their infants (38 males and 22 females) underwent a fMRI scan between 40 and 46 weeks of postmenstrual age. Our findings relate fetal heart indices to brainstem, hypothalamic, and dACC connectivity and reveal connections with widespread brain regions that may support behavioral and emotional regulation. We demonstrated the basic physiologic association between fetal HR indices and lower- and higher-order brain regions involved in regulatory processes. This work provides the foundation for future behavioral or physiological regulation research in fetuses and infants.

2023 American Heart Association and American Academy of Pediatrics Focused Update on Neonatal Resuscitation: An Update to the American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care.

This 2023 focused update to the neonatal resuscitation guidelines is based on 4 systematic reviews recently completed under the direction of the International Liaison Committee on Resuscitation Neonatal Life Support Task Force. Systematic reviewers and content experts from this task force performed comprehensive reviews of the scientific literature on umbilical cord management in preterm, late preterm, and term newborn infants, and the optimal devices and interfaces used for administering positive-pressure ventilation during resuscitation of newborn infants. These recommendations provide new guidance on the use of intact umbilical cord milking, device selection for administering positive-pressure ventilation, and an additional primary interface for administering positive-pressure ventilation.

Pharmacological Management of Cardiac Arrhythmias in the Fetal and Neonatal Periods: A Scientific Statement From the American Heart Association: Endorsed by the Pediatric & Congenital Electrophysiology Society (PACES).

Disorders of the cardiac rhythm may occur in both the fetus and neonate. Because of the immature myocardium, the hemodynamic consequences of either bradyarrhythmias or tachyarrhythmias may be far more significant than in mature physiological states. Treatment options are limited in the fetus and neonate because of limited vascular access, patient size, and the significant risk/benefit ratio of any intervention. In addition, exposure of the fetus or neonate to either persistent arrhythmias or antiarrhythmic medications may have yet-to-be-determined long-term developmental consequences. This scientific statement discusses the mechanism of arrhythmias, pharmacological treatment options, and distinct aspects of pharmacokinetics for the fetus and neonate. From the available current data, subjects of apparent consistency/consensus are presented, as well as future directions for research in terms of aspects of care for which evidence has not been established.

The genetic architecture of pediatric cardiomyopathy.

To understand the genetic contribution to primary pediatric cardiomyopathy, we performed exome sequencing in a large cohort of 528 children with cardiomyopathy. Using clinical interpretation guidelines and targeting genes implicated in cardiomyopathy, we identified a genetic cause in 32% of affected individuals. Cardiomyopathy sub-phenotypes differed by ancestry, age at diagnosis, and family history. Infants < 1 year were less likely to have a molecular diagnosis (p < 0.001). Using a discovery set of 1,703 candidate genes and informatic tools, we identified rare and damaging variants in 56% of affected individuals. We see an excess burden of damaging variants in affected individuals as compared to two independent control sets, 1000 Genomes Project (p < 0.001) and SPARK parental controls (p < 1 × 10-16). Cardiomyopathy variant burden remained enriched when stratified by ancestry, variant type, and sub-phenotype, emphasizing the importance of understanding the contribution of these factors to genetic architecture. Enrichment in this discovery candidate gene set suggests multigenic mechanisms underlie sub-phenotype-specific causes and presentations of cardiomyopathy. These results identify important information about the genetic architecture of pediatric cardiomyopathy and support recommendations for clinical genetic testing in children while illustrating differences in genetic architecture by age, ancestry, and sub-phenotype and providing rationale for larger studies to investigate multigenic contributions.