Monoclonal Antibody Therapies for Infectious Diseases.

In contrast to therapy in oncology and immune-related diseases, where dozens of monoclonal antibodies (mAbs) have been introduced, often in transformative fashion, the use of mAbs for infectious diseases is generally underdeveloped, with fewer than a dozen mAbs currently licensed for the treatment of microbial diseases. This situation is paradoxical given that antibodies are major products of the immune system for protecting against infectious diseases. The underdevelopment of mAbs for infectious diseases has several causes including the availability of effective therapy against many microbial diseases, the fact that many pathogenic microbes are antigenically diverse and thus all strains are not covered by a single mAb, and the high expense of mAb therapies. Despite these hurdles the number of mAbs licensed for infectious disease indications is slowly increasing and there are numerous opportunities for the development of mAbs in the prevention and treatment of microbial diseases.

The Logic and History of Passive Immunity and Antibody Therapies.

This volume takes a broad overview of antibody-based therapies prior to and during the COVID pandemic and examines their potential use in future pandemics. Passive antibody therapy was the first effective antimicrobial treatment and its development in the early twentieth century helped catalyze immunological and microbiological research. During the era of serum therapy (1890-1940) antibody-based therapies were developed against both viral and bacterial diseases. Effective treatment required an understanding of how to quantify antibodies, how to develop serotype-specific sera and recognition of the need to treat early in disease. Thus, although the era of serum therapy essentially ended with the development of small molecule antimicrobial therapy in the 1940s, antibody-based therapies led to important new scientific understanding, while remaining in use for some toxin and venom-caused diseases and in the prevention of outbreaks of viral hepatitis. A renewed interest in antibody-based therapies was seen in the widespread deployment of convalescent plasma and monoclonal antibodies during the COVID-19 pandemic. Convalescent plasma will likely be the first specific therapy during outbreaks with new pathogens for which there is no other therapy. For all forms of antibody-based therapies, effectiveness relies on the key principles of antibody therapy, namely, treatment early in disease with preparations containing sufficient antibody specific to the microbe in question.

Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19.

BACKGROUND: Convalescent plasma has been widely used to treat coronavirus disease 2019 (Covid-19) under the presumption that such plasma contains potentially therapeutic antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that can be passively transferred to the plasma recipient. Whether convalescent plasma with high antibody levels rather than low antibody levels is associated with a lower risk of death is unknown. METHODS: In a retrospective study based on a U.S. national registry, we determined the anti-SARS-CoV-2 IgG antibody levels in convalescent plasma used to treat hospitalized adults with Covid-19. The primary outcome was death within 30 days after plasma transfusion. Patients who were enrolled through July 4, 2020, and for whom data on anti-SARS-CoV-2 antibody levels in plasma transfusions and on 30-day mortality were available were included in the analysis. RESULTS: Of the 3082 patients included in this analysis, death within 30 days after plasma transfusion occurred in 115 of 515 patients (22.3%) in the high-titer group, 549 of 2006 patients (27.4%) in the medium-titer group, and 166 of 561 patients (29.6%) in the low-titer group. The association of anti-SARS-CoV-2 antibody levels with the risk of death from Covid-19 was moderated by mechanical ventilation status. A lower risk of death within 30 days in the high-titer group than in the low-titer group was observed among patients who had not received mechanical ventilation before transfusion (relative risk, 0.66; 95% confidence interval [CI], 0.48 to 0.91), and no effect on the risk of death was observed among patients who had received mechanical ventilation (relative risk, 1.02; 95% CI, 0.78 to 1.32). CONCLUSIONS: Among patients hospitalized with Covid-19 who were not receiving mechanical ventilation, transfusion of plasma with higher anti-SARS-CoV-2 IgG antibody levels was associated with a lower risk of death than transfusion of plasma with lower antibody levels. (Funded by the Department of Health and Human Services and others; ClinicalTrials.gov number, NCT04338360.).

Corrigendum: A randomized synbiotic trial to prevent sepsis among infants in rural India.

This corrects the article DOI: 10.1038/nature23480.

COVID-19 Convalescent Plasma and Clinical Trials: Understanding Conflicting Outcomes.

Convalescent plasma (CP) recurs as a frontline treatment in epidemics because it is available as soon as there are survivors. The COVID-19 pandemic represented the first large-scale opportunity to shed light on the mechanisms of action, safety, and efficacy of CP using modern evidence-based medicine approaches. Studies ranging from observational case series to randomized controlled trials (RCTs) have reported highly variable efficacy results for COVID-19 CP (CCP), resulting in uncertainty. We analyzed variables associated with efficacy, such as clinical settings, disease severity, CCP SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) antibody levels and function, dose, timing of administration (variously defined as time from onset of symptoms, molecular diagnosis, diagnosis of pneumonia, or hospitalization, or by serostatus), outcomes (defined as hospitalization, requirement for ventilation, clinical improvement, or mortality), CCP provenance and time for collection, and criteria for efficacy. The conflicting trial results, along with both recent WHO guidelines discouraging CCP usage and the recent expansion of the FDA emergency use authorization (EUA) to include outpatient use of CCP, create confusion for both clinicians and patients about the appropriate use of CCP. A review of 30 available RCTs demonstrated that signals of efficacy (including reductions in mortality) were more likely if the CCP neutralizing titer was >160 and the time to randomization was less than 9 days. The emergence of the Omicron variant also reminds us of the benefits of polyclonal antibody therapies, especially as a bridge to the development and availability of more specific therapies.

Outpatient randomized controlled trials to reduce COVID-19 hospitalization: Systematic review and meta-analysis.

This COVID-19 outpatient randomized controlled trials (RCTs) systematic review compares hospitalization outcomes amongst four treatment classes over pandemic period, geography, variants, and vaccine status. Outpatient RCTs with hospitalization endpoint were identified in Pubmed searches through May 2023, excluding RCTs <30 participants (PROSPERO-CRD42022369181). Risk of bias was extracted from COVID-19-NMA, with odds ratio utilized for pooled comparison. Searches identified 281 studies with 61 published RCTs for 33 diverse interventions analyzed. RCTs were largely unvaccinated cohorts with at least one COVID-19 hospitalization risk factor. Grouping by class, monoclonal antibodies (mAbs) (OR = 0.31 [95% CI = 0.24-0.40]) had highest hospital reduction efficacy, followed by COVID-19 convalescent plasma (CCP) (OR = 0.69 [95% CI = 0.53-0.90]), small molecule antivirals (OR = 0.78 [95% CI = 0.48-1.33]), and repurposed drugs (OR = 0.82 [95% CI: 0.72-0.93]). Earlier in disease onset interventions performed better than later. This meta-analysis allows approximate head-to-head comparisons of diverse outpatient interventions. Omicron sublineages (XBB and BQ.1.1) are resistant to mAbs Despite trial heterogeneity, this pooled comparison by intervention class indicated oral antivirals are the preferred outpatient treatment where available, but intravenous interventions from convalescent plasma to remdesivir are also effective and necessary in constrained medical resource settings or for acute and chronic COVID-19 in the immunocompromised.

A randomized synbiotic trial to prevent sepsis among infants in rural India.

Sepsis in early infancy results in one million annual deaths worldwide, most of them in developing countries. No efficient means of prevention is currently available. Here we report on a randomized, double-blind, placebo-controlled trial of an oral synbiotic preparation (Lactobacillus plantarum plus fructooligosaccharide) in rural Indian newborns. We enrolled 4,556 infants that were at least 2,000 g at birth, at least 35 weeks of gestation, and with no signs of sepsis or other morbidity, and monitored them for 60 days. We show a significant reduction in the primary outcome (combination of sepsis and death) in the treatment arm (risk ratio 0.60, 95% confidence interval 0.48-0.74), with few deaths (4 placebo, 6 synbiotic). Significant reductions were also observed for culture-positive and culture-negative sepsis and lower respiratory tract infections. These findings suggest that a large proportion of neonatal sepsis in developing countries could be effectively prevented using a synbiotic containing L. plantarum ATCC-202195.

The contribution of epidemiology to the understanding of neurodevelopmental disabilities.

Epidemiological approaches have played an important role in creating better understanding of developmental disabilities by delineating their frequency in populations and changes in their frequency over time, by identifying etiological factors, and by documenting pathways to prevention. Both cerebral palsy (CP) and mild intellectual disability are declining in frequency in high-income countries. The diagnosis of autism spectrum disorder has increased in recent decades, but much of this increase is a result of changing approaches to ascertainment and recording. Epidemiological studies have found that most CP is not of birth-asphyxial origin, that most febrile seizures do not pose a major risk for epilepsy, and that folic acid deficiency may contribute to developmental disabilities apart from its effect on neural tube defects. Epidemiological research has shown that an important fraction of neural tube defects and virtually all cases of Reye syndrome are preventable, and recent trials have shown ways to prevent CP. Early psychoeducational interventions in children at risk for mild intellectual disability are an effective and valuable societal investment. Very large population-based studies starting in pregnancy have been launched in Norway, Denmark, and Japan in recent years and these and other population studies promise to continue the epidemiological contribution to a better understanding of developmental disabilities.

SPR Perspectives: scientific opportunities in the Environmental influences on Child Health Outcomes Program.

Drawing upon extant data from existing pediatric cohorts and new follow-up of a diverse set of pediatric cohorts from across the United States, the Environmental influences on Child Health Outcomes (ECHO) Program creates the opportunity for novel and innovative investigations of many previously inaccessible scientific questions in the area of child health. We describe how the large sample size, diversity of participants, emphasis on team science, and infrastructure for improving research methodology make the ECHO Program a major research resource for improving our understanding of early life determinants of childhood health and well-being. Pediatric researchers leverage the unique features of the ECHO Program to address research questions with the potential to yield far-reaching and long-term impacts on child health. IMPACT: The ECHO Program unites pediatric cohorts from across the United States, allowing for investigations of compelling research questions that were previously infeasible due to limited sample sizes or lack of participant diversity. The focus of the ECHO Program on team science, solution-oriented research, and methodological innovation propels novel scientific investigations that are responsive to the needs of a wide range of stakeholders. Features of the ECHO program's infrastructure poise its investigators to rapidly launch research endeavors that are responsive to time-sensitive and critical needs within the realm of pediatric research.

Gestational Antibodies to C. pneumoniae, H. pylori and CMV in Women with Preeclampsia and in Matched Controls.

OBJECTIVES: Some research has suggested a possible role for past infection in the development of preeclampsia. The objective of this study was to explore the role of Helicobacter pylori, cytomegalovirus, and Chlamydophila pneumoniae in the development of preeclampsia in a prospective pregnancy sample. METHODS: We conducted a nested case-control study in The Archive for Child Health (ARCH), a pregnancy cohort of 867 unselected women enrolled at the first prenatal visit with archived blood and urine in pregnancy. We matched 21 cases of preeclampsia to 52 unaffected controls on maternal age (±4 years), race, parity, and gestational age at blood draw. Using conditional logistic regression, we examined the association between preeclampsia status and immunoglobulins G (IgG) tested by indirect ELISA to each of the three microorganisms, adjusting for potential confounders. RESULTS: No significant difference was found between cases and controls. The unadjusted odds ratio was 1.5 (95%CI: 0.2-9.1), 0.6 (95%CI: 0.2-1.9), and 1.9 (95%CI: 0.6-5.6) for H. pylori, cytomegalovirus and C. pneumoniae respectively. After controlling for confounders analysis found increased odds of H. pylori IgG (AOR: 1.9; 95% CI: 0.2-15.3) and C. pneumoniae IgG (AOR: 2.3; 95% CI: 0.6-9.2) for preeclampsia, albeit being not significant. Conversely, cytomegalovirus IgG had lower odds for preeclampsia (AOR: 0.4; 95% CI: 0.1-1.7). CONCLUSIONS: Past infection with H. pylori, and C. pneumoniae in early pregnancy showed a higher risk of preeclampsia, but the findings failed to achieve statistical significance. Cytomegalovirus was not associated with preeclampsia in these data. These preliminary findings encourage future research in populations with high prevalence of these infections.

Access to and safety of COVID-19 convalescent plasma in the United States Expanded Access Program: A national registry study.

BACKGROUND: The United States (US) Expanded Access Program (EAP) to coronavirus disease 2019 (COVID-19) convalescent plasma was initiated in response to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. While randomized clinical trials were in various stages of development and enrollment, there was an urgent need for widespread access to potential therapeutic agents. The objective of this study is to report on the demographic, geographical, and chronological characteristics of patients in the EAP, and key safety metrics following transfusion of COVID-19 convalescent plasma. METHODS AND FINDINGS: Mayo Clinic served as the central institutional review board for all participating facilities, and any US physician could participate as a local physician-principal investigator. Eligible patients were hospitalized, were aged 18 years or older, and had-or were at risk of progression to-severe or life-threatening COVID-19; eligible patients were enrolled through the EAP central website. Blood collection facilities rapidly implemented programs to collect convalescent plasma for hospitalized patients with COVID-19. Demographic and clinical characteristics of all enrolled patients in the EAP were summarized. Temporal patterns in access to COVID-19 convalescent plasma were investigated by comparing daily and weekly changes in EAP enrollment in response to changes in infection rate at the state level. Geographical analyses on access to convalescent plasma included assessing EAP enrollment in all national hospital referral regions, as well as assessing enrollment in metropolitan areas and less populated areas that did not have access to COVID-19 clinical trials. From April 3 to August 23, 2020, 105,717 hospitalized patients with severe or life-threatening COVID-19 were enrolled in the EAP. The majority of patients were 60 years of age or older (57.8%), were male (58.4%), and had overweight or obesity (83.8%). There was substantial inclusion of minorities and underserved populations: 46.4% of patients were of a race other than white, and 37.2% of patients were of Hispanic ethnicity. Chronologically and geographically, increases in the number of both enrollments and transfusions in the EAP closely followed confirmed infections across all 50 states. Nearly all national hospital referral regions enrolled and transfused patients in the EAP, including both in metropolitan and in less populated areas. The incidence of serious adverse events was objectively low (<1%), and the overall crude 30-day mortality rate was 25.2% (95% CI, 25.0% to 25.5%). This registry study was limited by the observational and pragmatic study design that did not include a control or comparator group; thus, the data should not be used to infer definitive treatment effects. CONCLUSIONS: These results suggest that the EAP provided widespread access to COVID-19 convalescent plasma in all 50 states, including for underserved racial and ethnic minority populations. The study design of the EAP may serve as a model for future efforts when broad access to a treatment is needed in response to an emerging infectious disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT#: NCT04338360.

Neonatal Cranial Ultrasound Findings among Infants Born Extremely Preterm: Associations with Neurodevelopmental Outcomes at 10 Years of Age.

OBJECTIVE: To examine the association between neonatal cranial ultrasound (CUS) abnormalities among infants born extremely preterm and neurodevelopmental outcomes at 10 years of age. STUDY DESIGN: In a multicenter birth cohort of infants born at <28 weeks of gestation, 889 of 1198 survivors were evaluated for neurologic, cognitive, and behavioral outcomes at 10 years of age. Sonographic markers of white matter damage (WMD) included echolucencies in the brain parenchyma and moderate to severe ventricular enlargement. Neonatal CUS findings were classified as intraventricular hemorrhage (IVH) without WMD, IVH with WMD, WMD without IVH, and neither IVH nor WMD. RESULTS: WMD without IVH was associated with an increased risk of cognitive impairment (OR 3.5, 95% CI 1.7, 7.4), cerebral palsy (OR 14.3, 95% CI 6.5, 31.5), and epilepsy (OR 6.9; 95% CI 2.9, 16.8). Similar associations were found for WMD accompanied by IVH. Isolated IVH was not significantly associated these outcomes. CONCLUSIONS: Among children born extremely preterm, CUS abnormalities, particularly those indicative of WMD, are predictive of neurodevelopmental impairments at 10 years of age. The strongest associations were found with cerebral palsy.

Use of convalescent plasma in COVID-19 patients with immunosuppression.

In the absence of effective countermeasures, human convalescent plasma has been widely used to treat severe acute respiratory syndrome coronavirus 2, the causative agent of novel coronavirus disease 19 (COVID-19), including among patients with innate or acquired immunosuppression. However, the association between COVID-19-associated mortality in patients with immunosuppression and therapeutic use of convalescent plasma is unknown. We review 75 reports, including one large matched-control registry study of 143 COVID-19 patients with hematological malignancies, and 51 case reports and 23 case series representing 238 COVID-19 patients with immunosuppression. We review clinical features and treatment protocols of COVID-19 patients with immunosuppression after treatment with human convalescent plasma. We also discuss the time course and clinical features of recovery. The available data from case reports and case series provide evidence suggesting a mortality benefit and rapid clinical improvement in patients with several forms of immunosuppression following COVID-19 convalescent plasma transfusion. The utility of convalescent plasma or other forms of antibody therapy in immune-deficient and immune-suppressed patients with COVID-19 warrants further investigation.

Prevalence of inadequate and excessive iodine intake in a US pregnancy cohort.

BACKGROUND: US iodine intake, estimated from the median urinary iodine concentration of population representative data, has declined by half since the 1970s, which is problematic because maternal iodine intake is critical for fetal neurodevelopment. Relying on median urinary concentrations to assess iodine intake of populations is standard practice but does not describe the number of individuals with insufficient intake. Prevalence estimates of inadequate and excessive intake are better for informing public health applications but require multiple urine samples per person; such estimates have been generated in pediatric populations but not yet among pregnant women. OBJECTIVE: Our aims were as follows: (1) to assess median urinary iodine concentrations across pregnancy for comparison with national data and (2) to estimate the prevalence of inadequate and excessive iodine intake among pregnant women in mid-Michigan. STUDY DESIGN: Data were collected from 2008 to 2015 as part of a prospective pregnancy cohort in which women were enrolled at their first prenatal clinic visit. Few exclusion criteria (<18 years or non-English speaking) resulted in a sample of women generally representative of the local community, unselected for any specific health conditions. Urine specimens were obtained as close as practicable to at least 1 specimen per trimester during routine prenatal care throughout pregnancy (n=1-6 specimens per woman) and stored at -80°C until urinary iodine was measured to estimate the iodine intake (n=1014 specimens from 464 women). We assessed urinary iodine across pregnancy by each gestational week of pregnancy and by trimester. We used multiple urine specimens per woman, accounted for within-person variability, performed data transformation to approximate normality, and estimated the prevalence of inadequate and excessive iodine intake using a method commonly employed for assessment of nutrient status. RESULTS: Maternal characteristics reflected the local population in racial and ethnic diversity and socioeconomic status as follows: 53% non-Hispanic white, 22% non-Hispanic black, and 16% Hispanic; 48% had less than or equal to high school education and 71% had an annual income of <$25,000. Median urinary iodine concentrations in the first, second, and third trimester-including some women contributing more than 1 specimen per trimester-were 171 µg/L (n=305 specimens), 181 µg/L (n=366 specimens), and 179 µg/L (n=343 specimens), respectively, with no significant difference by trimester (P=.50, Kruskal-Wallis test for equality of medians). The estimated prevalence of inadequate and excessive iodine intake was 23% and <1%, respectively. CONCLUSION: Median urinary iodine concentrations in each trimester were above the World Health Organization cutoff of 150 µg/L, indicating iodine sufficiency at the group level across pregnancy. However, the estimated prevalence of inadequate iodine intake was substantial at 23%, whereas prevalence of excessive intake was <1%, indicating a need for at least some women to increase consumption of iodine during pregnancy. The American Thyroid Association, the Endocrine Society, and the American Academy of Pediatrics recommend that all pregnant and lactating women receive a daily multivitamin or mineral supplement that contains 150 µg of iodine. The data presented here should encourage the collection of similar data from additional US population samples for the purpose of informing the American College of Obstetricians and Gynecologists' own potential recommendations for prenatal iodine supplementation.

Pandemic Reemergence and Four Waves of Excess Mortality Coinciding With the 1918 Influenza Pandemic in Michigan: Insights for COVID-19.

The global influenza pandemic that emerged in 1918 has become the event of reference for a broad spectrum of policymakers seeking to learn from the past. This article sheds light on multiple waves of excess mortality that occurred in the US state of Michigan at the time with insights into how epidemics might evolve and propagate across space and time. We analyzed original monthly data on all-cause deaths by county for the 83 counties of Michigan and interpreted the results in the context of what is known about the pandemic. Counties in Michigan experienced up to four waves of excess mortality over a span of two years, including a severe one in early 1920. Some counties experienced two waves in late 1918 while others had only one. The 1920 wave propagated across the state in a different manner than the fall and winter 1918 waves. The twin waves in late 1918 were likely related to the timing of the statewide imposition of a three-week social distancing order. Michigan's experience holds sobering lessons for those who wish to understand how immunologically naïve populations encounter novel viral pathogens.

Advancing human health in the decade ahead: pregnancy as a key window for discovery: A Burroughs Wellcome Fund Pregnancy Think Tank.

Recent revolutionary advances at the intersection of medicine, omics, data sciences, computing, epidemiology, and related technologies inspire us to ponder their impact on health. Their potential impact is particularly germane to the biology of pregnancy and perinatal medicine, where limited improvement in health outcomes for women and children has remained a global challenge. We assembled a group of experts to establish a Pregnancy Think Tank to discuss a broad spectrum of major gestational disorders and adverse pregnancy outcomes that affect maternal-infant lifelong health and should serve as targets for leveraging the many recent advances. This report reflects avenues for future effects that hold great potential in 3 major areas: developmental genomics, including the application of methodologies designed to bridge genotypes, physiology, and diseases, addressing vexing questions in early human development; gestational physiology, from immune tolerance to growth and the timing of parturition; and personalized and population medicine, focusing on amalgamating health record data and deep phenotypes to create broad knowledge that can be integrated into healthcare systems and drive discovery to address pregnancy-related disease and promote general health. We propose a series of questions reflecting development, systems biology, diseases, clinical approaches and tools, and population health, and a call for scientific action. Clearly, transdisciplinary science must advance and accelerate to address adverse pregnancy outcomes. Disciplines not traditionally involved in the reproductive sciences, such as computer science, engineering, mathematics, and pharmacology, should be engaged at the study design phase to optimize the information gathered and to identify and further evaluate potentially actionable therapeutic targets. Information sources should include noninvasive personalized sensors and monitors, alongside instructive "liquid biopsies" for noninvasive pregnancy assessment. Future research should also address the diversity of human cohorts in terms of geography, racial and ethnic distributions, and social and health disparities. Modern technologies, for both data-gathering and data-analyzing, make this possible at a scale that was previously unachievable. Finally, the psychosocial and economic environment in which pregnancy takes place must be considered to promote the health and wellness of communities worldwide.

The postnatal presence of human chorionic gonadotropin in preterm infants and its potential inverse association with retinopathy of prematurity.

BACKGROUND: Human chorionic gonadotropin (hCG) and luteinizing hormone (LH) are pro-angiogenic gonadotropic hormones, which classically target the reproductive organs. However, hCG, LH, and their shared CG/LH receptor are also present in the human eye. The possibility that a deficiency of these hormones may be involved in the pathogenesis of retinopathy of prematurity (ROP) during its early non-proliferative phase has not been explored. METHODS: We conducted a cross-sectional study of Michigan-born preterm infants utilizing dried blood spots. We analyzed hCG and LH blood levels at 1 week and 4 weeks of age from 113 study participants (60 without ROP; 53 with non-proliferative ROP). We utilized electrochemiluminescence assays on the Mesoscale Discovery platform. RESULTS: Similar levels of hCG are found in preterm infants at both 1 week and 4 weeks after birth. Preterm infants with non-proliferative ROP, after adjusting for sex and gestational age, have 2.42 [95% CI: 1.08-5.40] times the odds of having low hCG at fourth week of age. CONCLUSIONS: We found that hCG is present postnatally in preterm infants and that a deficiency of hCG at 4 weeks of age is potentially associated with non-proliferative ROP. This provides novel evidence to suggest that hCG may participate in human retinal angiogenesis.

Association of Circulating Proinflammatory and Anti-inflammatory Protein Biomarkers in Extremely Preterm Born Children with Subsequent Brain Magnetic Resonance Imaging Volumes and Cognitive Function at Age 10 Years.

OBJECTIVES: To examine elevated neonatal inflammatory and neurotrophic proteins from children born extremely preterm in relation to later childhood brain Magnetic Resonance Imaging volumes and cognition. STUDY DESIGN: We measured circulating inflammation-related proteins and neurotrophic proteins on postnatal days 1, 7, and 14 in 166 children at 10 years of age (73 males; 93 females). Top quartile levels on ≥2 days for ≥3 inflammation-related proteins and for ≥4 neurotrophic proteins defined exposure. We examined associations among protein levels, brain Magnetic Resonance Imaging volumes, and cognition with multiple linear and logistic regressions. RESULTS: Analyses were adjusted for gestational age at birth and sex. Children with ≥3 elevated inflammation-related proteins had smaller grey matter, brain stem/cerebellar, and total brain volumes than those without elevated inflammation-related proteins, adjusted for neurotrophic proteins. When adjusted for inflammation-related proteins, children with ≥4 neurotrophic proteins, compared with children with no neurotrophic proteins, had larger grey matter and total brain volumes. Higher grey matter, white matter, and cerebellum and brainstem volumes were significantly correlated with higher IQ. Grey and white matter volumes were correlated with each other (r = -0.18; P = .021), and cerebellum and brainstem was highly correlated with grey matter (r = 0.55; P < .001) and white matter (r = 0.29; P < .001). Adjusting for other brain compartments, cerebellum and brainstem was associated with IQ (P = .016), but the association with white matter was marginally significant (P = .051). Grey matter was not associated with IQ. After adjusting for brain volumes, elevated inflammation-related proteins remained significantly associated with a lower IQ, and elevated neurotrophic proteins remained associated with a higher IQ. CONCLUSIONS: Newborn inflammatory and neurotrophin protein levels are associated with later brain volumes and cognition, but their effects on cognition are not entirely explained by altered brain volumes.

Short-Term Birth Sequelae of the 1918-1920 Influenza Pandemic in the United States: State-Level Analysis.

This paper examines short-term birth sequelae of the influenza pandemic of 1918-1920 in the United States using monthly data on births and all-cause deaths for 19 US states in conjunction with data on maternal deaths, stillbirths, and premature births. The data on births and all-cause deaths are adjusted for seasonal and trend effects, and the residual components of the 2 time series coinciding with the timing of peak influenza mortality are examined for these sequelae. Notable findings include: 1) a drop in births in the 3 months following peak mortality; 2) a reversion in births to normal levels occurring 5-7 months after peak mortality; and 3) a steep drop in births occurring 9-10 months after peak mortality. Interpreted in the context of parallel data showing elevated premature births, stillbirths, and maternal mortality during times of peak influenza mortality, these findings suggest that the main impacts of the 1918-1920 influenza on reproduction occurred through: 1) impaired conceptions, possibly due to effects on fertility and behavioral changes; 2) an increase in the preterm delivery rate during the peak of the pandemic; and 3) elevated maternal and fetal mortality, resulting in late-term losses in pregnancy.