Disease Load at Conception Predicts Survival in Later Epidemics in a Historical French-Canadian Cohort,Suggesting Functional Trans-Generational Effects in Humans

Objective

Functional trans-generational and parental effects are potentially important determinants of health in several mammals. For humans, the existing evidence is weak. We investigate whether disease exposure triggers functional trans-generational response effects among humans by analyzing siblings who were conceived under different disease loads, and comparing their mortality in later epidemics. Under functional trans-generational response mechanisms, we expect that those who were conceived under high pathogenic stress load will have relatively low mortality during a later epidemic.

Methods

We use data from the Registre de la Population du Québec Ancien, which covers the historical population living in St. Lawrence Valley, Québec, Canada. Children born in 1705–1724 were grouped according to their exposure during conception to the measles 1714–15 epidemic. The 1714–15 epidemic was followed by two mortality crises in 1729–1734. The cause of the first crises in 1729 is not exactly known. The second crisis in 1732 was caused by a smallpox epidemic. Using proportional hazard Cox regression models with multivariate adjustment and with fixed-effects approach that compare siblings, we analyze whether mortality in 1729–1734 is affected by exposure to the 1714–15 epidemic.

Results

Children who were conceived during the peak of the measles epidemic of 1714–15 exhibited significantly lower mortality during the 1729–1734 crisis than those who were born before the 1714–15 epidemic (mortality hazard ratio 0.106, p<.05 in multivariate adjusted models; 0.142 p<.1 in sibling comparison models).

Conclusions

The results are consistent with a trans-generational mechanism that functionally responds to pathogen stress and suggest that early disease exposure may be protective later in life. Alternative explanations for the mortality patterns are discussed and shown to be problematic.     

Clinical benefits, costs, and cost-effectiveness of neonatal intensive care in Mexico

Background

Neonatal intensive care improves survival, but is associated with high costs and disability amongst survivors. Recent health reform in Mexico launched a new subsidized insurance program, necessitating informed choices on the different interventions that might be covered by the program, including neonatal intensive care. The purpose of this study was to estimate the clinical outcomes, costs, and cost-effectiveness of neonatal intensive care in Mexico.

Methods and Findings

A cost-effectiveness analysis was conducted using a decision analytic model of health and economic outcomes following preterm birth. Model parameters governing health outcomes were estimated from Mexican vital registration and hospital discharge databases, supplemented with meta-analyses and systematic reviews from the published literature. Costs were estimated on the basis of data provided by the Ministry of Health in Mexico and World Health Organization price lists, supplemented with published studies from other countries as needed. The model estimated changes in clinical outcomes, life expectancy, disability-free life expectancy, lifetime costs, disability-adjusted life years (DALYs), and incremental cost-effectiveness ratios (ICERs) for neonatal intensive care compared to no intensive care. Uncertainty around the results was characterized using one-way sensitivity analyses and a multivariate probabilistic sensitivity analysis. In the base-case analysis, neonatal intensive care for infants born at 24–26, 27–29, and 30–33 weeks gestational age prolonged life expectancy by 28, 43, and 34 years and averted 9, 15, and 12 DALYs, at incremental costs per infant of US$11,400, US$9,500, and US$3,000, respectively, compared to an alternative of no intensive care. The ICERs of neonatal intensive care at 24–26, 27–29, and 30–33 weeks were US$1,200, US$650, and US$240, per DALY averted, respectively. The findings were robust to variation in parameter values over wide ranges in sensitivity analyses.

Conclusions

Incremental cost-effectiveness ratios for neonatal intensive care imply very high value for money on the basis of conventional benchmarks for cost-effectiveness analysis. Please see later in the article for the Editors'' Summary     

Developmental Exposure to Second-Hand Smoke Increases Adult Atherogenesis and Alters Mitochondrial DNA Copy Number and Deletions in apoE?/? Mice

Cardiovascular disease is a major cause of morbidity and mortality in the United States. While many studies have focused upon the effects of adult second-hand smoke exposure on cardiovascular disease development, disease development occurs over decades and is likely influenced by childhood exposure. The impacts of in utero versus neonatal second-hand smoke exposure on adult atherosclerotic disease development are not known. The objective of the current study was to determine the effects of in utero versus neonatal exposure to a low dose (1 mg/m³ total suspended particulate) of second-hand smoke on adult atherosclerotic lesion development using the apolipoprotein E null mouse model. Consequently, apolipoprotein E null mice were exposed to either filtered air or second-hand smoke: (i) in utero from gestation days 1–19, or (ii) from birth until 3 weeks of age (neonatal). Subsequently, all animals were exposed to filtered air and sacrificed at 12–14 weeks of age. Oil red-O staining of whole aortas, measures of mitochondrial damage, and oxidative stress were performed. Results show that both in utero and neonatal second-hand smoke exposure significantly increased adult atherogenesis in mice compared to filtered air controls. These changes were associated with changes in aconitase and mitochondrial superoxide dismutase activities consistent with increased oxidative stress in the aorta, changes in mitochondrial DNA copy number and deletion levels. These studies show that in utero or neonatal exposure to second-hand smoke significantly influences adult atherosclerotic lesion development and results in significant alterations to the mitochondrion and its genome that may contribute to atherogenesis.     

Maternal Overweight and Obesity and Risks of Severe Birth-Asphyxia-Related Complications in Term Infants: A Population-Based Cohort Study in Sweden

Background

Maternal overweight and obesity increase risks of pregnancy and delivery complications and neonatal mortality, but the mechanisms are unclear. The objective of the study was to investigate associations between maternal body mass index (BMI) in early pregnancy and severe asphyxia-related outcomes in infants delivered at term (≥37 weeks).

Methods and Findings

A nation-wide Swedish cohort study based on data from the Medical Birth Register included all live singleton term births in Sweden between 1992 and 2010. Logistic regression analyses were used to obtain odds ratios (ORs) with 95% CIs for Apgar scores between 0 and 3 at 5 and 10 minutes, meconium aspiration syndrome, and neonatal seizures, adjusted for maternal height, maternal age, parity, mother''s smoking habits, education, country of birth, and year of infant birth. Among 1,764,403 term births, 86% had data on early pregnancy BMI and Apgar scores. There were 1,380 infants who had Apgar score 0–3 at 5 minutes (absolute risk  = 0.8 per 1,000) and 894 had Apgar score 0–3 at 10 minutes (absolute risk  = 0.5 per 1,000). Compared with infants of mothers with normal BMI (18.5–24.9), the adjusted ORs (95% CI) for Apgar scores 0–3 at 10 minutes were as follows: BMI 25–29.9: 1.32 (1.10–1.58); BMI 30–34.9: 1.57 (1.20–2.07); BMI 35–39.9: 1.80 (1.15–2.82); and BMI ≥40: 3.41 (1.91–6.09). The ORs for Apgar scores 0–3 at 5 minutes, meconium aspiration, and neonatal seizures increased similarly with maternal BMI. A study limitation was lack of data on effects of obstetric interventions and neonatal resuscitation efforts.

Conclusion

Risks of severe asphyxia-related outcomes in term infants increase with maternal overweight and obesity. Given the high prevalence of the exposure and the severity of the outcomes studied, the results are of potential public health relevance and should be confirmed in other populations. Prevention of overweight and obesity in women of reproductive age is important to improve perinatal health. Please see later in the article for the Editors'' Summary     

Animal welfare implications of surgical castration and its alternatives in pigs

This paper constitutes a review on the welfare aspects of piglet castration that considers the scientific literature published after 2004. Castrating during the neonatal period (1 to 3 days of age) is clearly painful. In addition, inflammatory processes may take place at the sites of incision, thus adding further pain to the procedure. Surgical castration with general and local anaesthesia, in combination with long-term analgesia, has been shown to reduce pain but the additional handling and injection of the anaesthetic, the effectiveness and limited safety margins have to be thoroughly evaluated. Raising entire males during the whole fattening period or immunocastration of males towards the end of the fattening period are other alternatives with welfare benefits in young pigs compared to current surgical castration, but with some potential welfare drawbacks regarding handling stress and behaviour during fattening. Based on the current knowledge, it can be concluded that sperm sexing and raising entire males after genetic control of boar taint are potentially preferable alternatives to current practices, but need further research, as these methods are not yet available.     

Variations in Multiple Birth Rates and Impact on Perinatal Outcomes in Europe

Objective

Infants from multiple pregnancies have higher rates of preterm birth, stillbirth and neonatal death and differences in multiple birth rates (MBR) exist between countries. We aimed to describe differences in MBR in Europe and to investigate the impact of these differences on adverse perinatal outcomes at a population level.

Methods

We used national aggregate birth data on multiple pregnancies, maternal age, gestational age (GA), stillbirth and neonatal death collected in the Euro-Peristat project (29 countries in 2010, N = 5 074 643 births). We also used European Society of Human Reproduction and Embryology (ESHRE) data on assisted conception and single embryo transfer (SET). The impact of MBR on outcomes was studied using meta-analysis techniques with random-effects models to derive pooled risk ratios (pRR) overall and for four groups of country defined by their MBR. We computed population attributable risks (PAR) for these groups.

Results

In 2010, the average MBR was 16.8 per 1000 women giving birth, ranging from 9.1 (Romania) to 26.5 (Cyprus). Compared to singletons, multiples had a nine-fold increased risk (pRR 9.4, 95% Cl 9.1–9.8) of preterm birth (<37 weeks GA), an almost 12-fold increased risk (pRR 11.7, 95% CI 11.0–12.4) of very preterm birth (<32 weeks GA). Pooled RR were 2.4 (95% Cl 1.5–3.6) for fetal mortality at or after 28 weeks GA and 7.0 (95% Cl 6.1–8.0) for neonatal mortality. PAR of neonatal death and very preterm birth were higher in countries with high MBR compared to low MBR (17.1% (95% CI 13.8–20.2) versus 9.8% (95% Cl 9.6–11.0) for neonatal death and 29.6% (96% CI 28.5–30.6) versus 17.5% (95% CI 15.7–18.3) for very preterm births, respectively).

Conclusions

Wide variations in MBR and their impact on population outcomes imply that efforts by countries to reduce MBR could improve perinatal outcomes, enabling better long-term child health.     

Arts and Ageing; Life Expectancy of Historical Artists in the Low Countries

Practising arts has been linked to lowering stress, anxiety and blood pressure. These mechanisms are all known to affect the ageing process. Therefore, we examine the relation between long-term involvement in arts and life expectancy at age 50 (LE50), in a cohort of 12,159 male acoustic, literary and visual artists, who were born between 1700 and 1899 in the Low Countries. We compared the life expectancy at age 50 of the various artists with the elite and middle class of that time. In the birth cohorts before 1850, acoustic (LE50:14.5–19.5) and literary artists (LE50:17.8–20.8) had a similar life expectancy at age 50 compared to the elite (LE50:18.0–19.0). Only visual artists (LE50:15.5–17.1) had a lower life expectancy at age 50 compared to the elite at that time. For the most recent birth cohorts from 1850 through 1899, the comparison between artists and the elite reversed and acoustic and literary artist had a lower life expectancy at age 50, while visual artists enjoyed a similar life expectancy at age 50. Although artists belonged to the middle socioeconomic class and lived predominantly in urban areas with poor living conditions, they had a life expectancy similar to the elite population. This is in line with observed favourable effects of practicing arts on health in the short-term. From our historical analysis, we hypothesize several mechanisms through which artistic creativity could influence the ageing process and life expectancy. These hypotheses, however, should be formally tested before any definite conclusions on effects of arts on ageing can be drawn.     

Intra- and Trans-Generational Costs of Reduced Female Body Size Caused by Food Limitation Early in Life in Mites

Background

Food limitation early in life may be compensated for by developmental plasticity resulting in accelerated development enhancing survival at the expense of small adult body size. However and especially for females in non-matching maternal and offspring environments, being smaller than the standard may incur considerable intra- and trans-generational costs.

Methodology/Principal Findings

Here, we evaluated the costs of small female body size induced by food limitation early in life in the sexually size-dimorphic predatory mite Phytoseiulus persimilis. Females are larger than males. These predators are adapted to exploit ephemeral spider mite prey patches. The intra- and trans-generational effects of small maternal body size manifested in lower maternal survival probabilities, decreased attractiveness for males, and a reduced number and size of eggs compared to standard-sized females. The trans-generational effects of small maternal body size were sex-specific with small mothers producing small daughters but standard-sized sons.

Conclusions/Significance

Small female body size apparently intensified the well-known costs of sexual activity because mortality of small but not standard-sized females mainly occurred shortly after mating. The disadvantages of small females in mating and egg production may be generally explained by size-associated morphological and physiological constraints. Additionally, size-assortative mate preferences of standard-sized mates may have rendered small females disproportionally unattractive mating partners. We argue that the sex-specific trans-generational effects were due to sexual size dimorphism – females are the larger sex and thus more strongly affected by maternal stress than the smaller males – and to sexually selected lower plasticity of male body size.     

Risk of Early-Onset Neonatal Infection with Maternal Infection or Colonization: A Global Systematic Review and Meta-Analysis

Background

Neonatal infections cause a significant proportion of deaths in the first week of life, yet little is known about risk factors and pathways of transmission for early-onset neonatal sepsis globally. We aimed to estimate the risk of neonatal infection (excluding sexually transmitted diseases [STDs] or congenital infections) in the first seven days of life among newborns of mothers with bacterial infection or colonization during the intrapartum period.

Methods and Findings

We searched PubMed, Embase, Scopus, Web of Science, Cochrane Library, and the World Health Organization Regional Databases for studies of maternal infection, vertical transmission, and neonatal infection published from January 1, 1960 to March 30, 2013. Studies were included that reported effect measures on the risk of neonatal infection among newborns exposed to maternal infection. Random effects meta-analyses were used to pool data and calculate the odds ratio estimates of risk of infection. Eighty-three studies met the inclusion criteria. Seven studies (8.4%) were from high neonatal mortality settings. Considerable heterogeneity existed between studies given the various definitions of laboratory-confirmed and clinical signs of infection, as well as for colonization and risk factors. The odds ratio for neonatal lab-confirmed infection among newborns of mothers with lab-confirmed infection was 6.6 (95% CI 3.9–11.2). Newborns of mothers with colonization had a 9.4 (95% CI 3.1–28.5) times higher odds of lab-confirmed infection than newborns of non-colonized mothers. Newborns of mothers with risk factors for infection (defined as prelabour rupture of membranes [PROM], preterm <37 weeks PROM, and prolonged ROM) had a 2.3 (95% CI 1.0–5.4) times higher odds of infection than newborns of mothers without risk factors.

Conclusions

Neonatal infection in the first week of life is associated with maternal infection and colonization. High-quality studies, particularly from settings with high neonatal mortality, are needed to determine whether targeting treatment of maternal infections or colonization, and/or prophylactic antibiotic treatment of newborns of high risk mothers, may prevent a significant proportion of early-onset neonatal sepsis. Please see later in the article for the Editors'' Summary     

The Customer Isn't Always Right—Conservation and Animal Welfare Implications of the Increasing Demand for Wildlife Tourism

Tourism accounts for 9% of global GDP and comprises 1.1 billion tourist arrivals per annum. Visits to wildlife tourist attractions (WTAs) may account for 20–40% of global tourism, but no studies have audited the diversity of WTAs and their impacts on the conservation status and welfare of subject animals. We scored these impacts for 24 types of WTA, visited by 3.6–6 million tourists per year, and compared our scores to tourists’ feedback on TripAdvisor. Six WTA types (impacting 1,500–13,000 individual animals) had net positive conservation/welfare impacts, but 14 (120,000–340,000 individuals) had negative conservation impacts and 18 (230,000–550,000 individuals) had negative welfare impacts. Despite these figures only 7.8% of all tourist feedback on these WTAs was negative due to conservation/welfare concerns. We demonstrate that WTAs have substantial negative effects that are unrecognised by the majority of tourists, suggesting an urgent need for tourist education and regulation of WTAs worldwide.     

Temperature‐induced multi‐species cohort effects in sympatric snakes

In reptiles, reproductive maturity is often determined by size rather than age. Consequently, growth early in life may influence population dynamics through effects on generation time and survival to reproduction. Because reproductive phenology and pre‐ and post‐natal growth are temperature dependent, environmental conditions may induce multi‐species cohort effects on body size in sympatric reptiles. I present evidence of this using 10 years of neonatal size data for three sympatric viviparous snakes, Dekay''s Brown snakes (Storeria dekayi), Red‐bellied Snakes (S. occipitomaculata), and Common Garter snakes (Thamnophis sirtalis). End‐of‐season neonatal size varied in parallel across species such that snout–vent length was 36%–61% greater and mass was 65%–223% greater in years when gestating females could achieve higher April–May (vs. June–July or August–September) operative temperatures. Thus, temperature had a larger impact during follicular enlargement and ovulation than during gestation or post‐natal growth. Multi‐species cohort effects like these may affect population dynamics and the magnitude of these effects may increase with climate change.     

Associative Learning during Early Adulthood Enhances Later Memory Retention in Honeybees

Background

Cognitive experiences during the early stages of life play an important role in shaping the future behavior in mammals but also in insects, in which precocious learning can directly modify behaviors later in life depending on both the timing and the rearing environment. However, whether olfactory associative learning acquired early in the adult stage of insects affect memorizing of new learning events has not been studied yet.

Methodology

Groups of adult honeybee workers that experienced an odor paired with a sucrose solution 5 to 8 days or 9 to 12 days after emergence were previously exposed to (i) a rewarded experience through the offering of scented food, or (ii) a non-rewarded experience with a pure volatile compound in the rearing environment.

Principal Findings

Early rewarded experiences (either at 1–4 or 5–8 days of adult age) enhanced retention performance in 9–12-day-conditioned bees when they were tested at 17 days of age. The highest retention levels at this age, which could not be improved with prior rewarded experiences, were found for memories established at 5–8 days of adult age. Associative memories acquired at 9–12 days of age showed a weak effect on retention for some pure pre-exposed volatile compounds; whereas the sole exposure of an odor at any younger age did not promote long-term effects on learning performance.

Conclusions

The associative learning events that occurred a few days after adult emergence improved memorizing in middle-aged bees. In addition, both the timing and the nature of early sensory inputs interact to enhance retention of new learning events acquired later in life, an important matter in the social life of honeybees.     

Implications of armed conflict for maternal and child health: A regression analysis of data from 181 countries for 2000–2019

BackgroundArmed conflicts have major indirect health impacts in addition to the direct harms from violence. They create enduring political instability, destabilise health systems, and foster negative socioeconomic and environmental conditions—all of which constrain efforts to reduce maternal and child mortality. The detrimental impacts of conflict on global maternal and child health are not robustly quantified. This study assesses the association between conflict and maternal and child health globally.Methods and findingsData for 181 countries (2000–2019) from the Uppsala Conflict Data Program and World Bank were analysed using panel regression models. Primary outcomes were maternal, under-5, infant, and neonatal mortality rates. Secondary outcomes were delivery by a skilled birth attendant and diphtheria, pertussis, and tetanus (DPT) and measles vaccination coverage. Models were adjusted for 10 confounders, country and year fixed effects, and conflict lagged by 1 year. Further lagged associations up to 10 years post-conflict were tested. The number of excess deaths due to conflict was estimated. Out of 3,718 country–year observations, 522 (14.0%) had minor conflicts and 148 (4.0%) had wars. In adjusted models, conflicts classified as wars were associated with an increase in maternal mortality of 36.9 maternal deaths per 100,000 live births (95% CI 1.9–72.0; 0.3 million excess deaths [95% CI 0.2 million–0.4 million] over the study period), an increase in infant mortality of 2.8 per 1,000 live births (95% CI 0.1–5.5; 2.0 million excess deaths [95% CI 1.6 million–2.5 million]), a decrease in DPT vaccination coverage of 4.9% (95% CI 1.5%–8.3%), and a decrease in measles vaccination coverage of 7.3% (95% CI 2.7%–11.8%). The long-term impacts of war were demonstrated by associated increases in maternal mortality observed for up to 7 years, in under-5 mortality for 3–5 years, in infant mortality for up to 8 years, in DPT vaccination coverage for up to 3 years, and in measles vaccination coverage for up to 2 years. No evidence of association between armed conflict and neonatal mortality or delivery by a skilled birth attendant was found. Study limitations include the ecological study design, which may mask sub-national variation in conflict intensity, and the quality of the underlying data.ConclusionsOur analysis indicates that armed conflict is associated with substantial and persistent excess maternal and child deaths globally, and with reductions in key measures that indicate reduced availability of organised healthcare. These findings highlight the importance of protecting women and children from the indirect harms of conflict, including those relating to health system deterioration and worsening socioeconomic conditions.

Mohammed Jawad and co-workers report on a global analysis of maternal and child health outcomes in situations of armed conflict.     

My pigs are ok,why change? – animal welfare accounts of pig farmers

Intensive pig production systems are a source of stress, which is linked to reduced animal welfare and increased antimicrobial use. As the gatekeepers of the welfare of the animals under their care, farmers are seen as the stakeholder responsible for improving animal welfare. The aim of this study was to explore the knowledge and attitudes of pig farmers towards pig welfare and the impact of such attitudes on farmers' selection of management strategies on the farm. We conducted in-depth semi-structured interviews with 44 pig farmers in one of the main pig producing regions of Brazil. Interviews covered knowledge and attitudes towards pig sentience and behaviour and welfare-related issues commonly observed in intensive pig farms (belly-nosing, fights, tail-biting, diarrhoea and castration without pain control) and farmers' conception and attitudes towards pig welfare. We identified many management and animal-based indicators of poor welfare, such as the use of painful and stressful management practices and use of environments that limit the expression of natural behaviours. However, most farmers were satisfied with animal welfare standards at their farms. Farmers' perceptions are aligned with their understanding of animal welfare. Although they identified all the dimensions that impact the welfare of a pig on a farm (affect, biological functioning and naturalness), their social reality, industry demands and available advice pushed them to perceive their range of action limited to biological and environmental aspects of the animals that do not necessarily benefit affective state. This precluded farmers from making associations between good health and the animal's ability to express a full behavioural repertoire, as well as from viewing abnormal behaviours as problems. The negative consequences for the welfare of the animals were commonly alleviated by routines that relied on constant use of medication, including high dependence on antibiotics. Expressions of estrangement from the production chain were common voices among the participants. This suggests that farmers may not be sufficiently informed or engaged in responding to consumers' expectations and commitments made by companies, which can pose a severe economic risk for farmers. The findings of this study indicate that economic, technical and social factors restrict farmers' autonomy and their ability to perform their role as stewards of animal welfare. (Re)connecting different human, animal and environmental interests may be a step to changing this scenario.     

Helicobacter sp. MIT 01-6451 infection during fetal and neonatal life in laboratory mice

Helicobacter sp. MIT 01-6451 has been detected in SPF mice kept in Japan. To characterize strain MIT 01-6451, its infection route during fetal and neonatal life and effects on pregnancy were investigated using immunocompetent and immunodeficient mouse strains (BALB/c, C57BL/6, and SCID). MIT 01-6451 was detected in the uterus, vagina, and mammary glands of 50% of infected SCID mice, whereas these tissues were all negative in immunocompetent mice. No fetal infections with MIT 01-6451 were detected at 16–18 days after pregnancy in any mouse strain. In newborn mice, MIT 01-6451 was detected in intestinal tissue of C57BL/6 and SCID mice at 9–11 days after birth, but not in BALB/c mice. The IgA and IgG titers to MIT 01-6451 in sera of C57BL/6 female mice were significantly lower than those of BALB/c mice. Although no significant differences in the number of newborns per litter were observed between MIT 01-6451-infected and MIT 01-6451-free dams, the birth rate was lower in infected SCID mice than in control SCID mice. The present results indicated that MIT 01-6451 infects newborn mice after birth rather than by vertical transmission to the fetus via the placenta and that MIT 01-6451 infection shows opportunistically negative effects on the birth rate. In addition, the maternal immune response may affect infection of newborn mice with MIT 01-6451 through breast milk.     

Sex differences in aging,life span and spontaneous tumorigenesis in 129/Sv mice neonatally exposed to metformin

The perinatal (prenatal and early neonatal) period is a critical stage for hypothalamic programming of sexual differentiation as well as for the development of energy and metabolic homeostasis. We hypothesized that neonatal treatment with antidiabetic drug biguanide metformin would positively modify regulation of growth hormone – IGF-1 – insulin signaling pathway slowing down aging and improving cancer preventive patterns in rodents. To test this hypothesis male and female 129/Sv mice were s.c. injected with metformin (100 mg/kg) at the 3rd, 5th and 7th days after birth. Metformin-treated males consumed less food and water and their body weight was decreased as compared with control mice practically over their entire lifespan. There were no significant differences in age-related dynamics of food and water consumption in females and they were heavier than controls. The fraction of mice with regular estrous cycles decreased with age and demonstrated a tendency to decrease in the females neonatally treated with metformin. Neonatal exposure to metformin practically failed to change the extent of hormonal and metabolic parameters in blood serum of male and female mice. In males, neonatal metformin treatment significantly increased the mean life span (+20%, P < 0.05) and slightly increased the maximum life span (+3.5%). In females, the mean life span and median in metformin-treated groups were slightly decreased (−9.1% and −13.8% respectively, P > 0.05) in comparison to controls, whereas mean life span of last 10% survivors and maximum life span were the same as in controls. Almost half (45%) of control male mice and 71.8% male mice neonatally exposed to metformin survived up to 800 d of age, the same age was achieved by 54.3% of mice in control female group and 30% of metformin-treated females (P < 0.03). Thus, neonatal metformin exposure slows down aging and prolongs lifespan in male but not in female mice.     

Intergenerational effects of maternal birth season on offspring size in rural Gambia

Environmental conditions experienced in early life can influence an individual's growth and long-term health, and potentially also that of their offspring. However, such developmental effects on intergenerational outcomes have rarely been studied. Here we investigate intergenerational effects of early environment in humans using survey- and clinic-based data from rural Gambia, a population experiencing substantial seasonal stress that influences foetal growth and has long-term effects on first-generation survival. Using Fourier regression to model seasonality, we test whether (i) parental birth season has intergenerational consequences for offspring in utero growth (1982 neonates, born 1976-2009) and (ii) whether such effects have been reduced by improvements to population health in recent decades. Contrary to our predictions, we show effects of maternal birth season on offspring birth weight and head circumference only in recent maternal cohorts born after 1975. Offspring birth weight varied according to maternal birth season from 2.85 to 3.03 kg among women born during 1975-1984 and from 2.84 to 3.41 kg among those born after 1984, but the seasonality effect reversed between these cohorts. These results were not mediated by differences in maternal age or parity. Equivalent patterns were observed for offspring head circumference (statistically significant) and length (not significant), but not for ponderal index. No relationships were found between paternal birth season and offspring neonatal anthropometrics. Our results indicate that even in rural populations living under conditions of relative affluence, brief variation in environmental conditions during maternal early life may exert long-term intergenerational effects on offspring.     

Risk of Childhood Overweight after Exposure to Tobacco Smoking in Prenatal and Early Postnatal Life

Objective

To investigate the association between exposure to mothers smoking during prenatal and early postnatal life and risk of overweight at age 7 years, while taking birth weight into account.

Methods

From the Danish National Birth Cohort a total of 32,747 families were identified with available information on maternal smoking status in child''s pre- and postnatal life and child''s birth weight, and weight and height at age 7 years. Outcome was overweight according to the International Obesity Task Force gender and age specific body mass index. Smoking exposure was categorized into four groups: no exposure (n = 25,076); exposure only during pregnancy (n = 3,343); exposure only postnatally (n = 140); and exposure during pregnancy and postnatally (n = 4,188). Risk of overweight according to smoking status as well as dose-response relationships were estimated by crude and adjusted odds ratios using logistic regression models.

Results

Exposure to smoking only during pregnancy, or both during pregnancy and postnatally were both significantly associated with overweight at 7 years of age (OR: 1.31, 95% CI: 1.15–1.48, and OR: 1.76, 95% CI: 1.58–1.97, respectively). Analyses excluding children with low birth weight (<2,500 gram) revealed similar results. A significant prenatal dose-response relationship was found. Per one additional cigarette smoked per day an increase in risk of overweight was observed (OR: 1.02, 95% CI: 1.01–1.03). When adjusting for quantity of smoking during pregnancy, prolonged exposure after birth further increased the risk of later overweight in the children (OR 1.28, 95% CI:1.09–1.50) compared with exposure only in the prenatal period.

Conclusions

Mother''s perinatal smoking increased child''s OR of overweight at age 7 years irrespective of birth weight, and with higher OR if exposed both during pregnancy and in early postnatal life. Clear dose-response relationships were observed, which emphasizes the need for prevention of any tobacco exposure of infants.     

The Promise of Prevention: The Effects of Four Preventable Risk Factors on National Life Expectancy and Life Expectancy Disparities by Race and County in the United States

Background

There has been substantial research on psychosocial and health care determinants of health disparities in the United States (US) but less on the role of modifiable risk factors. We estimated the effects of smoking, high blood pressure, elevated blood glucose, and adiposity on national life expectancy and on disparities in life expectancy and disease-specific mortality among eight subgroups of the US population (the “Eight Americas”) defined on the basis of race and the location and socioeconomic characteristics of county of residence, in 2005.

Methods and Findings

We combined data from the National Health and Nutrition Examination Survey and the Behavioral Risk Factor Surveillance System to estimate unbiased risk factor levels for the Eight Americas. We used data from the National Center for Health Statistics to estimate age–sex–disease-specific number of deaths in 2005. We used systematic reviews and meta-analyses of epidemiologic studies to obtain risk factor effect sizes for disease-specific mortality. We used epidemiologic methods for multiple risk factors to estimate the effects of current exposure to these risk factors on death rates, and life table methods to estimate effects on life expectancy. Asians had the lowest mean body mass index, fasting plasma glucose, and smoking; whites had the lowest systolic blood pressure (SBP). SBP was highest in blacks, especially in the rural South—5–7 mmHg higher than whites. The other three risk factors were highest in Western Native Americans, Southern low-income rural blacks, and/or low-income whites in Appalachia and the Mississippi Valley. Nationally, these four risk factors reduced life expectancy at birth in 2005 by an estimated 4.9 y in men and 4.1 y in women. Life expectancy effects were smallest in Asians (M, 4.1 y; F, 3.6 y) and largest in Southern rural blacks (M, 6.7 y; F, 5.7 y). Standard deviation of life expectancies in the Eight Americas would decline by 0.50 y (18%) in men and 0.45 y (21%) in women if these risks had been reduced to optimal levels. Disparities in the probabilities of dying from cardiovascular diseases and diabetes at different ages would decline by 69%–80%; the corresponding reduction for probabilities of dying from cancers would be 29%–50%. Individually, smoking and high blood pressure had the largest effect on life expectancy disparities.

Conclusions

Disparities in smoking, blood pressure, blood glucose, and adiposity explain a significant proportion of disparities in mortality from cardiovascular diseases and cancers, and some of the life expectancy disparities in the US. Please see later in the article for the Editors'' Summary     

Reducing Neonatal Mortality in India: Critical Role of Access to Emergency Obstetric Care

Background

Neonatal mortality currently accounts for 41% of all global deaths among children below five years. Despite recording a 33% decline in neonatal deaths between 2000 and 2009, about 900,000 neonates died in India in 2009. The decline in neonatal mortality is slower than in the post-neonatal period, and neonatal mortality rates have increased as a proportion of under-five mortality rates. Neonatal mortality rates are higher among rural dwellers of India, who make up at least two-thirds of India''s population. Identifying the factors influencing neonatal mortality will significantly improve child survival outcomes in India.

Methods

Our analysis is based on household data from the nationally representative 2008 Indian District Level Household Survey (DLHS-3). We use probit regression techniques to analyse the links between neonatal mortality at the household level and households'' access to health facilities. The probability of the child dying in the first month of birth is our dependent variable.

Results

We found that 80% of neonatal deaths occurred within the first week of birth, and that the probability of neonatal mortality is significantly lower when the child''s village is closer to the district hospital (DH), suggesting the critical importance of specialist hospital care in the prevention of newborn deaths. Neonatal deaths were lower in regions where emergency obstetric care was available at the District Hospitals. We also found that parental schooling and household wealth status improved neonatal survival outcomes.

Conclusions

Addressing the main causes of neonatal deaths in India – preterm deliveries, asphyxia, and sepsis – requires adequacy of specialised workforce and facilities for delivery and neonatal intensive care and easy access by mothers and neonates. The slow decline in neonatal death rates reflects a limited attention to factors which contribute to neonatal deaths. The suboptimal quality and coverage of Emergency Obstetric Care facilities in India require urgent attention.