International variations in the gestational age distribution of births: an ecological study in 34 high-income countries.

Background: Few studies have investigated international variations in the gestational age (GA) distribution of births. While preterm births (22-36 weeks GA) and early term births (37-38 weeks) are at greater risk of adverse health outcomes compared to full term births (39-40 weeks), it is not known if countries with high preterm birth rates also have high early term birth rates. We examined rate associations between preterm and early term births and mean term GA by mode of delivery onset. Methods: We used routine aggregate data on the GA distribution of singleton live births from up to 34 high-income countries/regions in 1996, 2000, 2004, 2008 and 2010 to study preterm and early term births overall and by spontaneous or indicated onset. Pearson correlation coefficients were adjusted for clustering in time trend analyses. Results: Preterm and early term births ranged from 4.1% to 8.2% (median 5.5%) and 15.6% to 30.8% (median 22.2%) of live births in 2010, respectively. Countries with higher preterm birth rates in 2004-2010 had higher early term birth rates (r > 0.50, P < 0.01) and changes over time were strongly correlated overall (adjusted-r = 0.55, P < 0.01) and by mode of onset. Conclusion: Positive associations between preterm and early term birth rates suggest that common risk factors could underpin shifts in the GA distribution. Targeting modifiable population risk factors for delivery before 39 weeks GA may provide a useful preterm birth prevention paradigm.

Social Disparities in the Relationship Between Depression and Unintended Pregnancy During Adolescence and Young Adulthood.

PURPOSE: We investigated the influence of depression on subsequent risk of unintended pregnancy and social disparities within this relationship, during adolescence and young adulthood. METHODS: Drawing upon 15-year, nationally representative data from 8,810 young U.S. women in the National Longitudinal Study of Adolescent to Adult Health, we estimated associations between depression and time to first pregnancies reported as unintended, overall and stratified by race/ethnicity, socioeconomic status, and age with Cox proportional hazard models. RESULTS: Moderate/severe depression symptoms were associated with an increased risk of unintended first pregnancy (hazard ratio [HR], 1.21; confidence interval [CI], 1.02-1.44). In stratified models, depression increased the pregnancy risk for all minority groups (HRs, 1.36-3.25) but not white women. Depression increased the pregnancy risk for women with $0-$19,999 (HR, 1.48; CI, 1.11-1.98) and $20,000-$49,999 (HR, 1.33; CI, 1.05-1.68) income levels but not those at higher levels. Depression increased the pregnancy risk for adolescents <20 years (HR, 1.35; CI, 1.07-1.71) but decreased the risk for women >24 years (HR, .47; CI, .25-.86). CONCLUSIONS: Findings may inform more equitable, holistic public health strategies that target depression as a modifiable risk factor for adverse reproductive outcomes during adolescence and young adulthood.

Trends in Personal Belief Exemption Rates Among Alternative Private Schools: Waldorf, Montessori, and Holistic Kindergartens in California, 2000-2014.

OBJECTIVES: To evaluate trends in rates of personal belief exemptions (PBEs) to immunization requirements for private kindergartens in California that practice alternative educational methods. METHODS: We used California Department of Public Health data on kindergarten PBE rates from 2000 to 2014 to compare annual average increases in PBE rates between schools. RESULTS: Alternative schools had an average PBE rate of 8.7%, compared with 2.1% among public schools. Waldorf schools had the highest average PBE rate of 45.1%, which was 19 times higher than in public schools (incidence rate ratio = 19.1; 95% confidence interval = 16.4, 22.2). Montessori and holistic schools had the highest average annual increases in PBE rates, slightly higher than Waldorf schools (Montessori: 8.8%; holistic: 7.1%; Waldorf: 3.6%). CONCLUSIONS: Waldorf schools had exceptionally high average PBE rates, and Montessori and holistic schools had higher annual increases in PBE rates. Children in these schools may be at higher risk for spreading vaccine-preventable diseases if trends are not reversed.

Describing the Shape of the Relationship Between Gestational Age at Birth and Cognitive Development in a Nationally Representative U.S. Birth Cohort.

BACKGROUND: Preterm children face higher risk of cognitive and academic deficits compared with their full-term peers. The objective of this study was to describe early childhood cognitive ability and kindergarten academic achievement across gestational age at birth in a population-based longitudinal cohort. METHODS: The study population included singletons born at 24-42 weeks gestation enrolled in the Early Childhood Longitudinal Study-Birth Cohort (n = 6150 for 2-year outcome, n = 4450 for kindergarten outcome). Home-based assessments measured cognitive ability at 2 years and reading and mathematics achievement at kindergarten age. Linear regression models estimated the association between gestational age and cognitive and academic scores using four different ways of modelling gestational age: continuous variable in linear and quadratic terms; categories for individual weeks; and clinical categories for early preterm, moderate preterm, late preterm, early term, full term, late term, and post-term. RESULTS: Children born at early preterm (24-27 weeks), moderate preterm (28-33 weeks), and late preterm (34-36 weeks) scored significantly worse than full-term (39-40 weeks) peers on 2-year and kindergarten assessments; however, no deficits were observed for early term (37-38 weeks). These categories were a clinically useful and parsimonious approach to stratifying risk of adverse cognitive and academic outcomes. CONCLUSIONS: This study estimated the relative performance of children born at 24-42 weeks in a population-based birth cohort using multiple approaches to modelling gestational age, providing a more rigorous understanding of the relationships between the full spectrum of gestational age and cognitive and academic outcomes in early childhood and at school age.

Adverse Infant Outcomes Associated with Discordant Gestational Age Estimates.

BACKGROUND: Gestational age estimation by last menstrual period (LMP) vs. ultrasound (or best obstetric estimate in the US) may result in discrepant classification of preterm vs. term birth. We investigated whether such discrepancies are associated with adverse infant outcomes. METHODS: We studied singleton livebirths in the Medical Birth Registries of Norway, Sweden and Finland and US live birth certificates from 1999 to the most recent year available. Risk ratios (RR) with 95% confidence intervals (CI) by discordant and concordant gestational age estimation for infant, neonatal and post-neonatal mortality, Apgar score <4 and <7 at 5 min, and neonatal intensive care unit (NICU) admission were estimated using generalised linear models, adjusting for maternal age, education, parity, year of birth, and infant sex. Results were presented stratified by country. RESULTS: Compared to infants born at term by both methods, infants born preterm by ultrasound/best obstetric estimate but term by LMP had higher infant mortality risks (range of adjusted RRs 3.9 to 7.2) and modestly higher risks were obtained among infants born preterm by LMP but term by ultrasound/best obstetric estimate (range of adjusted RRs 1.6 to 1.9). Risk estimates for the other outcomes showed the same pattern. These findings were consistent across all four countries. CONCLUSIONS: Infants classified as preterm by ultrasound/best estimate, but term by LMP have consistently higher risks of adverse outcomes than those classified as preterm by LMP but term by ultrasound/best estimate. Compared with ultrasound/best estimate, use of LMP overestimates the proportion of births that are preterm.

Temporal Trends in Late Preterm and Early Term Birth Rates in 6 High-Income Countries in North America and Europe and Association With Clinician-Initiated Obstetric Interventions.

IMPORTANCE: Clinicians have been urged to delay the use of obstetric interventions (eg, labor induction, cesarean delivery) until 39 weeks or later in the absence of maternal or fetal indications for intervention. OBJECTIVE: To describe recent trends in late preterm and early term birth rates in 6 high-income countries and assess association with use of clinician-initiated obstetric interventions. DESIGN: Retrospective analysis of singleton live births from 2006 to the latest available year (ranging from 2010 to 2015) in Canada, Denmark, Finland, Norway, Sweden, and the United States. EXPOSURES: Use of clinician-initiated obstetric intervention (either labor induction or prelabor cesarean delivery) during delivery. MAIN OUTCOMES AND MEASURES: Annual country-specific late preterm (34-36 weeks) and early term (37-38 weeks) birth rates. RESULTS: The study population included 2,415,432 Canadian births in 2006-2014 (4.8% late preterm; 25.3% early term); 305,947 Danish births in 2006-2010 (3.6% late preterm; 18.8% early term); 571,937 Finnish births in 2006-2015 (3.3% late preterm; 16.8% early term); 468,954 Norwegian births in 2006-2013 (3.8% late preterm; 17.2% early term); 737,754 Swedish births in 2006-2012 (3.6% late preterm; 18.7% early term); and 25,788,558 US births in 2006-2014 (6.0% late preterm; 26.9% early term). Late preterm birth rates decreased in Norway (3.9% to 3.5%) and the United States (6.8% to 5.7%). Early term birth rates decreased in Norway (17.6% to 16.8%), Sweden (19.4% to 18.5%), and the United States (30.2% to 24.4%). In the United States, early term birth rates decreased from 33.0% in 2006 to 21.1% in 2014 among births with clinician-initiated obstetric intervention, and from 29.7% in 2006 to 27.1% in 2014 among births without clinician-initiated obstetric intervention. Rates of clinician-initiated obstetric intervention increased among late preterm births in Canada (28.0% to 37.9%), Denmark (22.2% to 25.0%), and Finland (25.1% to 38.5%), and among early term births in Denmark (38.4% to 43.8%) and Finland (29.8% to 40.1%). CONCLUSIONS AND RELEVANCE: Between 2006 and 2014, late preterm and early term birth rates decreased in the United States, and an association was observed between early term birth rates and decreasing clinician-initiated obstetric interventions. Late preterm births also decreased in Norway, and early term births decreased in Norway and Sweden. Clinician-initiated obstetric interventions increased in some countries but no association was found with rates of late preterm or early term birth.

Selectivity in the Use of Gi/o Proteins Is Determined by the DRF Motif in CXCR6 and Is Cell-Type Specific.

CXCR6, the receptor for CXCL16, is expressed on multiple cell types and can be a coreceptor for human immunodeficiency virus 1. Except for CXCR6, all human chemokine receptors contain the D(3.49)R(3.50)Y(3.51) sequence, and all but two contain A(3.53) at the cytoplasmic terminus of the third transmembrane helix (H3C), a region within class A G protein-coupled receptors that contacts G proteins. In CXCR6, H3C contains D(3.49)R(3.50)F(3.51)I(3.52)V(3.53) at positions 126-130. We investigated the importance and interdependence of the canonical D126 and the noncanonical F128 and V130 in CXCR6 by mutating D126 to Y, F128 to Y, and V130 to A singly and in combination. For comparison, we mutated the analogous positions D142, Y144, and A146 to Y, F, and V, respectively, in CCR6, a related receptor containing the canonical sequences. Mutants were analyzed in both human embryonic kidney 293T and Jurkat E6-1 cells. Our data show that for CXCR6 and/or CCR6, mutations in H3C can affect both receptor signaling and chemokine binding; noncanonical H3C sequences are functionally linked, with dual changes mitigating the effects of single mutations; mutations in H3C that compromise receptor activity show selective defects in the use of individual Gi/o proteins; and the effects of mutations in H3C on receptor function and selectivity in Gi/o protein use can be cell-type specific. Our findings indicate that the ability of CXCR6 to make promiscuous use of the available Gi/o proteins is exquisitely dependent on sequences within the H3C and suggest that the native sequence allows for preservation of this function across different cellular environments.

Three randomized trials of maternal influenza immunization in Mali, Nepal, and South Africa: Methods and expectations.

Influenza infection in pregnancy can have adverse impacts on maternal, fetal, and infant outcomes. Influenza vaccination in pregnancy is an appealing strategy to protect pregnant women and their infants. The Bill & Melinda Gates Foundation is supporting three large, randomized trials in Nepal, Mali, and South Africa evaluating the efficacy and safety of maternal immunization to prevent influenza disease in pregnant women and their infants <6 months of age. Results from these individual studies are expected in 2014 and 2015. While the results from the three maternal immunization trials are likely to strengthen the evidence base regarding the impact of influenza immunization in pregnancy, expectations for these results should be realistic. For example, evidence from previous influenza vaccine studies - conducted in general, non-pregnant populations - suggests substantial geographic and year-to-year variability in influenza incidence and vaccine efficacy/effectiveness. Since the evidence generated from the three maternal influenza immunization trials will be complementary, in this paper we present a side-by-side description of the three studies as well as the similarities and differences between these trials in terms of study location, design, outcome evaluation, and laboratory and epidemiological methods. We also describe the likely remaining knowledge gap after the results from these trials become available along with a description of the analyses that will be conducted when the results from these individual data are pooled. Moreover, we highlight that additional research on logistics of seasonal influenza vaccine supply, surveillance and strain matching, and optimal delivery strategies for pregnant women will be important for informing global policy related to maternal influenza immunization.

Does neighborhood deprivation modify the effect of preterm birth on children's first grade academic performance?

Children's cognitive development and academic performance are linked to both fetal and early childhood factors, including preterm birth and family socioeconomic status. We evaluated whether the relationship between preterm birth (PTB) and first grade standardized test performance among Georgia public school students was modified by neighborhood deprivation in early childhood. The Georgia Birth to School cohort followed 327,698 children born in Georgia from 1998 to 2002 through to end-of-year first grade standardized tests. Binomial and log-binomial generalized estimating equations were used to estimate risk differences and risk ratios for the associations of both PTB and the Neighborhood Deprivation Index for the census tract in which each child's mother resided at the time of birth with test failure (versus passing). The presence of additive and multiplicative interaction was assessed. PTB was strongly associated with test failure, with increasing risk for earlier gestational ages. There was positive additive interaction between PTB and neighborhood deprivation. The main effect of PTB versus term birth increased risk of mathematics failure: 15.9% (95%CI: 13.3-18.5%) for early, 5.0% (95% CI: 4.1-5.9%) for moderate, and 1.3% (95%CI: 0.9-1.7%) for late preterm. Each 1 standard deviation increase in neighborhood deprivation was associated with 0.6% increased risk of mathematics failure. For children exposed to both PTB and higher neighborhood deprivation, test failure was 4.8%, 1.5%, and 0.8% greater than the sum of two main effects for early, moderate, and late PTB, respectively. Results were similar, but slightly attenuated, for reading and English/language arts. Our results suggest that PTB and neighborhood deprivation additively interact to produce greater risk among doubly exposed children than would be predicted from the sum of the effects of the two exposures. Understanding socioeconomic disparities in the effect of PTB on academic outcomes at school entry is important for targeting of early childhood interventions.

The ketogenic diet for the treatment of pediatric status epilepticus.

BACKGROUND: Refractory status epilepticus carries a high risk of morbidity and mortality for children. Traditional treatment of status epilepticus consists of multiple anticonvulsant drugs and, if needed, induction of a medical coma. The ketogenic diet has been used for intractable epilepsy for many years. The purpose of this article is to report a case series of five patients with refractory status epilepticus successfully managed with the ketogenic diet. METHODS: A summary of pediatric patients with refractory status epilepticus treated with diet was performed. CONCLUSIONS: Ketogenic diet therapy should be considered as a treatment option in pediatric patients with refractory status epilepticus.

A systematic review of interventions for reducing parental vaccine refusal and vaccine hesitancy.

Unvaccinated individuals pose a public health threat to communities. Research has identified many factors associated with parental vaccine refusal and hesitancy toward childhood and adolescent immunizations. However, data on the effectiveness of interventions to address parental refusal are limited. We conducted a systematic review of four online databases to identify interventional studies. We used criteria recommended by the WHO's Strategic Advisory Group of Experts on immunization (SAGE) for the quality assessment of studies. Intervention categories and outcomes were evaluated for each body of evidence and confidence in overall estimates of effect was determined. There is limited evidence to guide implementation of effective strategies to deal with the emerging threat of parental vaccine refusal. There is a need for appropriately designed, executed and evaluated intervention studies to address this gap in knowledge.

Regional susceptibility to stress-induced intestinal injury in the mouse.

Injury to the intestinal mucosa is a life-threatening problem in a variety of clinical disorders, including hemorrhagic shock, trauma, burn, pancreatitis, and heat stroke. The susceptibility to injury of different regions of intestine in these disorders is not well understood. We compared histological injury across the small intestine in two in vivo mouse models of injury, hemorrhagic shock (30% loss of blood volume) and heat stroke (peak core temperature 42.4°C). In both injury models, areas near the duodenum showed significantly greater mucosal injury and reductions in villus height. To determine if these effects were dependent on circulating factors, experiments were performed on isolated intestinal segments to test for permeability to 4-kDa FITC-dextran. The segments were exposed to hyperthermia (42°C for 90 min), moderate simulated ischemia (Po2 ∼30 Torr, Pco2 ∼60 Torr, pH 7.1), severe ischemia (Po2 ∼20 Torr, Pco2 ∼80 Torr, pH 6.9), or severe hypoxia (Po2 ∼0 Torr, Pco2 ∼35 Torr) for 90 min, and each group was compared with sham controls. All treatments resulted in marked elevations in permeability within segments near the duodenum. In severe hypoxia or hyperthermia, permeability was also moderately elevated in the jejunum and ileum; in moderate or severe ischemia, permeability was unaffected in these regions. The results demonstrate increased susceptibility of proximal regions of the small intestine to acute stress-induced damage, irrespective of circulating factors. The predominant injury in the duodenum may impact the pattern of acute inflammatory responses arising from breach of the intestinal barrier, and such knowledge may be useful for designing therapeutic strategies.

Partners in immunization: 2010 survey examining differences among H1N1 vaccine providers in Washington state.

OBJECTIVES: Emergency response involving mass vaccination requires the involvement of traditional vaccine providers as well as other health-care providers, including pharmacists, obstetricians, and health-care providers at correctional facilities. We explored differences in provider experiences administering pandemic vaccine during a public health emergency. METHODS: We conducted a cross-sectional survey of H1N1 vaccine providers in Washington State, examining topics regarding pandemic vaccine administration, participation in preparedness activities, and communication with public health agencies. We also examined differences among provider types in responses received (n=619, 80.9% response rate). RESULTS: Compared with other types of vaccine providers (e.g., family practitioners, obstetricians, and specialists), pharmacists reported higher patient volumes as well as higher patient-to-practitioner ratios, indicating a broad capacity for community reach. Pharmacists and correctional health-care providers reported lower staff coverage with seasonal and H1N1 vaccines. Compared with other vaccine providers, pharmacists were also more likely to report relying on public health information from federal sources. They were less likely to report relying on local health departments (LHDs) for pandemic-related information, but indicated a desire to be included in LHD communications and plans. While all provider types indicated a high willingness to respond to a public health emergency, pharmacists were less likely to have participated in training, actual emergency response, or surge capacity initiatives. No obstetricians reported participating in surge capacity initiatives. CONCLUSIONS: Results from this survey suggest that efforts to increase communication and interaction between public health agencies and pharmacy, obstetric, and correctional health-care vaccine providers may improve future preparedness and emergency response capability and reach.

Nonmedical exemptions to immunization requirements in California: a 16-year longitudinal analysis of trends and associated community factors.

BACKGROUND: Rates of nonmedical exemptions to kindergarten-entry immunization requirements have increased over the past 2 decades, especially in states that permit philosophical exemptions and/or have easier administrative policies for obtaining nonmedical exemptions. We evaluated trends in school personal belief exemption rates over the period 1994-2009 in California, and associated school and community characteristics. METHODS: We used data on personal belief exemptions from 6392 public and private elementary schools from the California Department of Public Health, as well as census tract and school demographic data. Generalized estimating equations were used to model annual mean increases in personal belief exemption rates, and to identify school and community characteristics associated with personal belief exemption rates. RESULTS: Over the study period, the average school personal belief exemption rate increased from 0.6% in 1994 to 2.3% in 2009, an average of 9.2% (95% CI: 8.8-9.6%) per year. The average personal belief exemption rate among private schools over the entire study period was 1.77 (95% CI: 1.55-2.01) times that among public schools. The annual rate of increase was slightly higher among private schools (10.1%, 95% CI: 9.1-11.1%) than among public schools (8.8%, 95% CI: 8.4-9.2%). Schools located within census tracts classified as rural had 1.66 (95% CI: 1.26-2.08) times higher personal belief exemption rates than schools located within urban census tracts. Exemption rates were also associated with race, population density, education, and income. CONCLUSIONS: This study confirms concerns about increasing rates of nonmedical exemptions to kindergarten vaccine requirements within the state of California, using data collected over a 16-year period.

Neonatal outcomes after antenatal influenza immunization during the 2009 H1N1 influenza pandemic: impact on preterm birth, birth weight, and small for gestational age birth.

BACKGROUND: Influenza infection during pregnancy is associated with adverse fetal outcomes such as preterm birth and small for gestational age (SGA). Maternal influenza immunization may prevent these adverse infant outcomes during periods of influenza circulation. METHODS: We conducted a retrospective cohort study of live births within Kaiser Permanente (KP) Georgia and Mid-Atlantic States (n = 3327) during the period of 2009 influenza A (H1N1) virus circulation. Primary outcomes were third-trimester preterm birth (27-36 weeks), birth weight, low birth weight (LBW, <2500 g), and SGA. RESULTS: There were 327 (9.8%) preterm, 236 (7.4%) LBW, and 267 (8.4%) SGA births. Among H1N1-vaccinated mothers (n = 1125), there were 86 (7.6%) preterm, 68 (6.4%) LBW, and 99 (9.3%) SGA births, and the mean birth weight was 3308.5 g (95% confidence interval [CI], 3276.6-3340.4). Among unvaccinated mothers (n = 1581), there were 191 (12.1%) preterm, 132 (8.8%) LBW, and 123 (8.2%) SGA births, and the mean birth weight was 3245.3 g (95% CI, 3216.5-3274.2). Infants of H1N1-vaccinated mothers had 37% lower odds of being born preterm than infants of unvaccinated mothers (adjusted odds ratio, 0.63 [95% CI, .47-.84]). The mean birth weight difference between infants of H1N1-vaccinated mothers and infants of unvaccinated mothers was 45.1 g (95% CI, 1.8-88.3). There was no significant association between maternal H1N1 influenza immunization and LBW or SGA. CONCLUSIONS: Pregnant women who received H1N1 influenza vaccine were less likely to give birth preterm, and gave birth to heavier infants. The findings support US vaccine policy choices to prioritize pregnant women during the 2009 influenza A (H1N1) pandemic.

Gift card incentives and non-response bias in a survey of vaccine providers: the role of geographic and demographic factors.

This study investigates the effects of non-response bias in a 2010 postal survey assessing experiences with H1N1 influenza vaccine administration among a diverse sample of providers (N = 765) in Washington state. Though we garnered a high response rate (80.9%) by using evidence-based survey design elements, including intensive follow-up and a gift card incentive from Target, non-response bias could exist if there were differences between respondents and non-respondents. We investigated differences between the two groups for seven variables: road distance to the nearest Target store, practice type, previous administration of vaccines, region, urbanicity, size of practice, and Vaccines for Children (VFC) program enrollment. We also examined the effect of non-response bias on survey estimates. Statistically significant differences between respondents and non-respondents were found for four variables: miles to the nearest Target store, type of medical practice, whether the practice routinely administered additional vaccines besides H1N1, and urbanicity. Practices were more likely to respond if they were from a small town or rural area (OR = 7.68, 95% CI = 1.44-40.88), were a non-traditional vaccine provider type (OR = 2.08, 95% CI = 1.06-4.08) or a pediatric provider type (OR = 4.03, 95% CI = 1.36-11.96), or administered additional vaccines besides H1N1 (OR = 1.80, 95% CI = 1.03-3.15). Of particular interest, for each ten mile increase in road distance from the nearest Target store, the likelihood of provider response decreased (OR = 0.73, 95% CI = 0.60-0.89). Of those variables associated with response, only small town or rural practice location was associated with a survey estimate of interest, suggesting that non-response bias had a minimal effect on survey estimates. These findings show that gift card incentives alongside survey design elements and follow-up can achieve high response rates. However, there is evidence that practices farther from the nearest place to redeem gift cards may be less likely to respond to the survey.