Maternal hypertensive disorder of pregnancy and offspring early-onset cardiovascular disease in childhood,adolescence, and young adulthood: A national population-based cohort study

BackgroundThe prevalence of cardiovascular disease (CVD) has been increasing in children, adolescents, and young adults in recent decades. Exposure to adverse intrauterine environment in fetal life may contribute to the elevated risk of early-onset CVD. Many studies have shown that maternal hypertensive disorders of pregnancy (HDP) are associated with increased risks of congenital heart disease, high blood pressure, increased BMI, and systemic vascular dysfunction in offspring. However, empirical evidence on the association between prenatal exposure to maternal HDP and early-onset CVD in childhood and adolescence remains limited.Methods and findingsWe conducted a population-based cohort study using Danish national health registers, including 2,491,340 individuals born in Denmark from 1977 to 2018. Follow-up started at birth and ended at the first diagnosis of CVD, emigration, death, or 31 December 2018, whichever came first. Exposure of maternal HDP was categorized as preeclampsia or eclampsia (n = 68,387), gestational hypertension (n = 18,603), and pregestational hypertension (n = 15,062). Outcome was the diagnosis of early-onset CVD from birth to young adulthood (up to 40 years old). We performed Cox proportional hazards regression to evaluate the associations and whether the association differed by maternal history of CVD or diabetes before childbirth. We further assessed the association by timing of onset and severity of preeclampsia. The median follow-up time was 18.37 years, and 51.3% of the participants were males. A total of 4,532 offspring in the exposed group (2.47 per 1,000 person-years) and 94,457 in the unexposed group (2.03 per 1,000 person-years) were diagnosed with CVD. We found that exposure to maternal HDP was associated with an increased risk of early-onset CVD (hazard ratio [HR]: 1.23; 95% CI = 1.19 to 1.26; P < 0.001). The HRs for preeclampsia or eclampsia, gestational hypertension, and pregestational hypertension were 1.22 (95% CI, 1.18 to 1.26; P < 0.001), 1.25 (95% CI, 1.17 to 1.34; P < 0.001), and 1.28 (95% CI, 1.15 to 1.42; P < 0.001), respectively. We also observed increased risks for type-specific CVDs, in particular for hypertensive disease (HR, 2.11; 95% CI, 1.96 to 2.27; P < 0.001) and myocardial infarction (HR, 1.49; 95% CI, 1.12 to 1.98; P = 0.007). Strong associations were found among offspring of mothers with CVD history (HR, 1.67; 95% CI, 1.41 to 1.98; P < 0.001) or comorbid diabetes (HR, 1.56; 95% CI, 1.34 to 1.83; P < 0.001). When considering timing of onset and severity of preeclampsia on offspring CVD, the strongest association was observed for early-onset and severe preeclampsia (HR, 1.48, 95% CI, 1.30 to 1.67; P < 0.001). Study limitations include the lack of information on certain potential confounders (including smoking, physical activity, and alcohol consumption) and limited generalizability in other countries with varying disparities in healthcare.ConclusionsOffspring born to mothers with HDP, especially mothers with CVD or diabetes history, were at increased risks of overall and certain type-specific early-onset CVDs in their first decades of life. Further research is warranted to better understand the mechanisms underlying the relationship between maternal HDP and early-onset CVD in offspring.

Chen Huang and co-workers study associations between maternal hypertensive disorders and cardiovascular disease in offspring.     

Hypertension and Obesity in Adults Living in a High HIV Prevalence Rural Area in South Africa

Hypertension and excess body weight are major risk factors of cardiovascular morbidity and mortality in developing countries. In countries with a high HIV prevalence, it is unknown how increased antiretroviral treatment and care (ART) coverage has affected the prevalence of overweight, obesity, and hypertension. We conducted a health survey in 2010 based on the WHO STEPwise approach in 14,198 adult resident participants of a demographic surveillance area in rural South Africa to investigate factors associated with hypertension and excess weight including HIV infection and ART status. Women had a significantly higher median body mass index (BMI) than men (26.4 vs. 21.2 kg/m², p<0.001). The prevalence of obesity (BMI≥30 kg/m²) in women (31.3%, 95% confidence interval (CI) 30.2–32.4) was 6.5 times higher than in men (4.9%, 95% CI 4.1–5.7), whereas prevalence of hypertension (systolic or diastolic blood pressure≥140 or 90 mm Hg, respectively) was 1.4 times higher in women than in men (28.5% vs 20.8%, p<0.001). In multivariable regression analysis, both hypertension and obesity were significantly associated with sex, age, HIV and ART status. The BMI of women and men on ART was on average 3.8 (95% CI 3.2–3.8) and 1.7 (95% CI 0.9–2.5) kg/m² lower than of HIV-negative women and men, respectively. The BMI of HIV-infected women and men not on ART was on average 1.2 (95% CI 0.8–1.6) and 0.4 (95% CI -0.1–0.9) kg/m² lower than of HIV-negative women and men, respectively. Obesity was a bigger risk factor for hypertension in men (adjusted odds ratio (aOR) 2.99, 95% CI 2.00–4.48) than in women (aOR 1.64, 95% CI 1.39–1.92) and overweight (25≤BMI<30) was a significant risk factor for men only (aOR 1.53 95% CI 1.14–2.06). Our study suggests that, cardiovascular risk factors of hypertension and obesity differ substantially between women and men in rural South Africa.     

Does Breastfeeding Help to Reduce the Risk of Childhood Overweight and Obesity? A Propensity Score Analysis of Data from the KiGGS Study

BackgroundCurrent studies suggest that the beneficial effect of breastfeeding on overweight and obesity may have been largely overestimated. We examined the relationship between >4 months of full breastfeeding and overweight/obesity in children living in Germany.MethodsWe analyzed retrospectively collected data on breastfeeding from children aged 3–17 years who participated in the German Health Interview and Examination Survey for Children and Adolescents (KiGGS baseline study) between 2003 and 2006 (n = 13163). To minimize confounding, we applied propensity score matching and multivariate logistic regression analyses to estimate the effect of breastfeeding on childhood overweight and obesity.ResultsAdjusted analyses of the matched dataset (n = 8034) indicated that children who were breastfed for <4 months had a significant reduction in the odds of overweight (OR 0.81 [95% CI 0.71–0.92]) and obesity (OR 0.75 [95% CI 0.61–0.92]) compared to children who were not breastfed or who were breastfed for a shorter duration. Further analyses stratified by age group showed that the association was strongest in children aged 7–10 years (OR 0.67 [95% CI 0.53–0.84] for overweight and OR 0.56 [95% CI 0.39–0.81] for obesity), while no significant effect could be seen in other age groups.DiscussionOur findings support the hypothesis that breastfeeding does have a beneficial effect on childhood overweight and obesity, although the effect seems to be strongest in children of primary school age.     

Prevalence,Awareness, Treatment and Control of Diabetes Mellitus in a Chinese Population

ObjectiveThe purpose of this study is to evaluate the prevalence, awareness, treatment and glycemic control of diabetes mellitus (DM) in a Chinese population. The findings from this study are expected to offer scientific evidence to better prevent and control the growing number of reported and untreated cases.MethodsA cross-sectional survey was conducted in Jiangsu, China. We recruited permanent residents over 18 years of age from eight towns in Jintan (JT) and six towns in Yangzhong (YZ) using a three-stage stratified cluster sampling method. The rates of DM prevalence, awareness, treatment and control as well as their related factors were analyzed.ResultsA total number of 15404 people were entered into the analysis. The DM prevalence, awareness, treatment and control rates were 7.31%, 58.35%, 51.87% and 14.12%, respectively. Multivariable logistic regression analysis showed that being female was positively related to prevalence (OR = 1.21, 95% CI: 1.07–1.37), awareness (OR = 1.52, 95% CI: 1.19–1.93), treatment (OR = 1.48, 95% CI: 1.17–1.88) and control (OR = 1.87, 95% CI: 1.30–2.67) of DM. Having a family history of diabetes was significantly correlated with DM risk (OR = 1.86, 95% CI: 1.37–2.54) and increased awareness (OR = 3.12, 95% CI: 2.19–4.47), treatment (OR = 3.47, 95% CI: 2.45–4.90) and control (OR = 1.81, 95% CI: 1.22–2.68) of DM. Former smoking status (OR = 1.82, 95% CI: 1.23–2.71), overweight (OR = 2.11, 95% CI: 1.72–2.60) and obesity (OR = 3.46, 95% CI: 2.67–4.50) were related to the risk of DM. Additionally, we found current drinking status to be positively correlated with DM risk (OR = 1.30, 95% CI: 1.01–1.66) and negatively correlated with DM awareness (OR = 0.41, 95% CI: 0.29–0.59) and treatment (OR = 0.41, 95% CI: 0.29–0.59). Our study highlights the high prevalence and inadequate awareness, treatment and control of DM in the Chinese population.ConclusionsManagement and prevention of DM-related complications should be considered an essential strategy by governments and society. This study assessed the reasons why DM has been increasing and established the first step in determining where to start regarding preventative methods.     

High prevalence of intestinal parasite infestations among stunted and control children aged 2 to 5 years old in two neighborhoods of Antananarivo,Madagascar

BackgroundThis study aimed to compare the prevalence of intestinal parasite infestations (IPIs) in stunted children, compared to control children, in Ankasina and Andranomanalina Isotry (two disadvantaged neighborhoods of Antananarivo, Madagascar), to characterize associated risk factors and to compare IPI detection by real-time PCR and standard microscopy techniques.Methodology/Principal findingsFecal samples were collected from a total of 410 children (171 stunted and 239 control) aged 2–5 years. A single stool sample per subject was examined by simple merthiolate-iodine-formaldehyde (MIF), Kato-Katz smear and real-time PCR techniques. A total of 96.3% of the children were infested with at least one intestinal parasite. The most prevalent parasites were Giardia intestinalis (79.5%), Ascaris lumbricoides (68.3%) and Trichuris trichiura (68.0%). For all parasites studied, real-time PCR showed higher detection rates compared to microscopy (G. intestinalis [77.6% (n = 318) versus 20.9% (n = 86)], Entamoeba histolytica [15.8% (n = 65) versus 1.9% (n = 8)] and A. lumbricoides [64.1% (n = 263) versus 50.7% (n = 208)]). Among the different variables assessed in the study, age of 4 to 5 years (AOR = 4.61; 95% CI, (1.35–15.77)) and primary and secondary educational level of the mother (AOR = 12.59; 95% CI, (2.76–57.47); AOR = 9.17; 95% CI, (2.12–39.71), respectively) were significantly associated with IPIs. Children drinking untreated water was associated with infestation with G. intestinalis (AOR = 1.85; 95% CI, (1.1–3.09)) and E. histolytica (AOR = 1.9; 95% CI, (1.07–3.38)). E. histolytica was also associated with moderately stunted children (AOR = 0.37; 95% CI, 0.2–0.71). Similarly, children aged between 4 and 5 years (AOR = 3.2; 95% CI (2.04–5.01)) and living on noncemented soil types (AOR = 1.85; 95% CI, (1.18–2.09)) were associated with T. trichiura infestation.Conclusions/SignificanceThe prevalence of IPIs is substantial in the studied areas in both stunted and control children, despite the large-scale drug administration of antiparasitic drugs in the country. This high prevalence of IPIs warrants further investigation. Improved health education, environmental sanitation and quality of water sources should be provided.     

Assisted reproduction technology and long-term cardiometabolic health in the offspring

Ronald Ma and co-authors discuss Emma Norrman and colleagues’ accompanying research study on the health of children born with assisted reproductive technology.

Since the birth of the first baby with the aid of in vitro fertilization (IVF) in July 1978, more than 9 million children have since been born through IVF or other assisted reproduction technology (ART). From a report covering around 2/3 of world ART activity, it was estimated that more than 4.4 million ART cycles have been initiated between 2008 and 2010, which resulted in 1.14 million births during that period [1]. From 1997 to 2016, the numbers of recorded ART treatment have increased by 5.3-fold in Europe, 4.6-fold in the United States of America, and 3.0-fold in Australia and New Zealand [1]. In an accompanying study in PLOS Medicine, Emma Norrman and colleagues address the health of babies born after ART [2].While initially met with considerable skepticism and controversy, the large number of healthy babies born over the last 4 decades is testament to the success and safety of IVF, which has transformed the lives of many couples and families. Nevertheless, given the appreciation of the Developmental Origins of Health and Disease (DOHaD) hypothesis, which posits that insults during critical times of development (including in utero or early life) may modify an individual’s phenotype and alter later risk of disease in adulthood, as well as previous demonstration of potential epigenetic changes following ART, there has been rekindled interest in the potential long-term effects of ART on offspring health [3]. In a large retrospective Nordic population-based cohort study of all children born after ART between 1982 and 2007, there was no significant increase in overall cancer rates among children born after ART, compared to children born after spontaneous conception (SC) [4]. Questions have also been raised about the long-term cardiovascular health of offspring born after ART, as several mechanisms have been postulated to potentially contribute to impaired cardiovascular health, including suboptimal culture conditions, ART-induced epigenetic changes, as well as indirect effects through low birthweight, thereby contributing to altered cardiovascular phenotype [5] (Fig 1). A systematic review and meta-analysis did not show evidence of increased cardiovascular risk or diabetes for women following ART, though there was comparatively less data to address offspring risk [6]. In line with a recent systematic review and meta-analysis [7], previous small studies have found increased adiposity, cardiometabolic risk, and blood pressure among offspring born after ART, potentially due to altered gene expression [8,9]. However, issues regarding potential selection bias have been raised for the small studies included.Open in a separate windowFig 1A DOHaD perspective on the potential relationship between ART and later risk of T2D and CVD.The putative link is highlighted by the dotted outline. ART, assisted reproduction technology; CVD, cardiovascular disease; DOHaD, Developmental Origins of Health and Disease; EDCs, endocrine-disrupting chemicals; GDM, gestational diabetes; ICSI, intracytoplasmic sperm injection; IVF, in vitro fertilization; ncRNA, noncoding RNA; PCOS, polycystic ovary syndrome; T2D, type 2 diabetes. (adapted with permission from Ma and colleagues [13]).Norrman and colleagues conducted a large population-based study from the Committee of Nordic ART and Safety (CoNARTaS) cohort, which included all individuals born in Norway, Sweden, Finland, and Denmark between 1984 and 2015, including 122,429 children born after ART, and more than 7.5 million children born after SC, to investigate the risk of cardiovascular disease (CVD), diabetes, and obesity following ART compared to SC. Offspring were followed for a mean 8.6 years in children born after ART and 14.0 years for children born following SC. Although the crude rates for CVD and type 2 diabetes (T2D) were higher among children born after ART, there were no significant difference in rates after adjustment for measured confounders. The study noted a significant increase in the risk of obesity among children born to ART, though the risk was modest, with adjusted HR 1.14 (CI 1.06 to 1.23, p = 0.001). The design of the study also meant that it could not address whether any increased risk in the offspring might be related to maternal causes of infertility (such as polycystic ovary syndrome), rather than the ART. In contrast to the previous systematic review that suggested significant increase in cardiometabolic risk factors in ART offspring, the authors concluded that the cardiometabolic outcomes in ART children are, in general, reassuring. However, further studies with longer follow-up are needed.The study provided much-needed medium-term outcome data addressing this important question of long-term cardiometabolic risk in children born after ART. By combining high-quality Nordic registers, Norrman and colleagues have been able to create a uniquely large cohort of ART children in order to compare their risk of cardiovascular health with children born after SC. Such population-based design provided high coverage rate and high validity, such that missing data and the risk of selection bias can be minimized. However, there were some notable limitations of the study, including the relatively short follow-up period, especially among children born to ART. The number of clinical outcomes of interest was limited, hence restricting statistical power to detect differences in outcome. Although the use of national registries has minimized any risk of selection bias, the definitions of outcomes were based on inpatient and outpatient attendance and may be associated with some ascertainment bias, especially in relation to capturing obesity outcomes. There is also a significant proportion with missing maternal BMI, paternal characteristics, or other covariates, which posed limitations on the analyses. Another important point to note is that the impact of different ART factors on health of offspring has not been addressed. Over the years, ART practices and technologies have continued to evolve, for example, the increasing use of oocyte freezing and embryo biopsy for genetic testing and the shift of slow freezing to vitrification method for gamete or embryo freezing. It has been shown that singleton babies conceived from fresh embryo transfers of IVF are associated with increased risks of low birthweight and preterm delivery, while ART involving frozen embryos are associated with higher incidences of large babies, macrosomia, and hypertensive disorders of pregnancy [10]. Conversely, both low birthweight, intrauterine growth restriction (IUGR), as well as macrosomia have been linked with increased risk of later T2D and CVD [11]. These differential outcomes illustrate that the different ART techniques may have different safety profiles and exert different impacts on the long-term health of offspring. Of note, the study by Norrman and colleagues included relatively few births from frozen embryos, and these have not been compared to births by SC for later risk of diabetes or CVD.This important study highlights some of the challenges in ascertaining long-term effects of ART, or other early life exposures, for that matter. The establishment of ART registries including the important exposure factors may be an important component for the way forward, especially given the long-term follow-up required. There are important challenges, including those around confidentiality, but also the increasingly diverse and complex treatment protocols, as well as innovative technologies, which may be associated with different long-term outcomes. There is currently limited understanding of the long-term outcome of some of these novel techniques. There are also new challenges given the globalization of healthcare delivery, with increasing cross-border reproductive care [12]. The increasing cryopreservation of gametes, gonadal tissues, and embryos will pose new challenges on tracking the outcomes of ART births. More population-based long-term studies are warranted, and establishing the infrastructure that would facilitate anonymous linkage of ART registers, birth records with national diabetes and other disease registers that facilitate tracking of long-term health may be one way forward. Nevertheless, given the sensitivities around the data involved, such analyses may be difficult to perform in some areas, and population-based analyses, wherever possible, will continue to contribute much-needed data to this discussion.     

Resistance exercise,alone and in combination with aerobic exercise,and obesity in Dallas,Texas, US: A prospective cohort study

BackgroundObesity is a significant and growing public health problem in high-income countries. Little is known about the relationship between resistance exercise (RE), alone and in combination with aerobic exercise (AE), and the risk of developing obesity. The purpose of this prospective cohort study was to examine the associations between different amounts and frequencies of RE, independent of AE, and incident obesity.Methods and findingsParticipants were 11,938 healthy adults ages 18–89 years with a BMI < 30 kg/m² at baseline who completed at least 2 clinical examinations during 1987–2005 as part of the Aerobics Center Longitudinal Study. Self-reported RE participation in minutes/week and days/week was collected from a standardized questionnaire. Incident obesity was defined as a BMI ≥ 30 kg/m² at follow-up. Incident obesity was also defined by waist circumference (WC) > 102/88 cm for men/women and percent body fat (PBF) ≥ 25%/30% for men/women at follow-up in participants who were not obese by WC (n = 9,490) or PBF (n = 8,733) at baseline. During the average 6-year follow-up, 874 (7%), 726 (8%), and 1,683 (19%) developed obesity defined by BMI, WC, or PBF, respectively. Compared with no RE, 60–119 min/wk of RE was associated with 30%, 41%, and 31% reduced risk of obesity defined by BMI (hazard ratio [95% CI], 0.70 [0.54–0.92], p = 0.008), WC (0.59 [0.44–0.81], p < 0.001), and PBF (0.69 [0.57–0.83], p < 0.001), respectively, after adjusting for confounders including age, sex, examination year, smoking status, heavy alcohol consumption, hypertension, hypercholesterolemia, diabetes, and AE. Compared with not meeting the RE guidelines of ≥2 d/wk, meeting the RE guidelines was associated with 18%, 30%, and 30% reduced risk of obesity defined by BMI (hazard ratio [95% CI], 0.82 [0.69–0.97], p = 0.02), WC (0.70 [0.57–0.85], p < 0.001), and PBF (0.70 [0.62–0.79], p < 0.001), respectively. Compared with meeting neither guideline, meeting both the AE and RE guidelines was associated with the smallest hazard ratios for obesity. Limitations of this study include limited generalizability as participants were predominantly white men from middle to upper socioeconomic strata, use of self-reported RE, and lack of detailed diet data for the majority of participants.ConclusionsIn this study, we observed that RE was associated with a significantly reduced risk of obesity even after considering AE. However, meeting both the RE and AE guidelines was associated with the lowest risk of obesity.

In a prospective cohort study, Angelique G. Brellenthin and colleagues investigate associations between resistance and aerobic exercise, and incident obesity in the United States.     

Comparison of CT-Determined Pulmonary Artery Diameter,Aortic Diameter,and Their Ratio in Healthy and Diverse Clinical Conditions

BackgroundThe main pulmonary artery diameter (mPA), aortic diameter (Ao), and the mPA/Ao ratio, easily measured using chest computed tomography (CT), provide information that enables the diagnosis and evaluation of cardiopulmonary diseases. Here, we used CT to determine the sex- and age-specific distribution of normal reference values for mPA, Ao, and mPA/Ao ratio in an adult Korean population.MethodsData from non-contrast, ECG-gated, coronary-calcium-scoring CT images of 2,547 individuals who visited the Health Screening Center of the Severance Hospital were analyzed. Healthy individuals (n = 813) included those who do not have hypertension, diabetes, asthma, obstructive lung disease, ischemic heart disease, stroke, smoking, obesity, and abnormal CT findings. Both mPA and Ao were measured at the level of bifurcation of the main pulmonary artery.ResultsThe mean mPA and Ao were 25.9 mm and 30.0 mm in healthy participants, respectively, while the mean mPA/Ao ratio was 0.87. Medical conditions associated with a larger mPA were male, obesity, smoking history, hypertension, and diabetes. A larger mPA/Ao ratio was associated with female, the obese, non-smoker, normotensive, and normal serum level of lipids, while a smaller mPA/Ao ratio was associated with older age. In healthy individuals, the 90th percentile sex-specific mPA, Ao, and mPA/Ao ratio were, 31.3 mm (95% CI 29.9–32.2), 36.8 mm (95% CI 35.7–37.5), and 1.05 (95% CI 0.99–1.07) in males, and 29.6 mm (95% CI 29.1–30.2), 34.5 mm (95% CI 34.1–34.9), and 1.03 (95% CI 1.02–1.06) in females, respectively.ConclusionIn the Korean population, the mean mPA reference values in male and female were 26.5 mm and 25.8 mm, respectively, while the mean mPA/Ao ratio was 0.87. These values were influenced by a variety of underlying medical conditions.     

Separating parental and treatment contributions to perinatal health after fresh and frozen embryo transfer in assisted reproduction: A cohort study with within-sibship analysis

BackgroundCompared to naturally conceived children, adverse perinatal outcomes are more common among children born after assisted reproductive technology with fresh embryo transfer (fresh-ET) or frozen embryo transfer (frozen-ET). However, most previous studies could not adequately control for family confounding factors such as subfertility. We compared birth size and duration of pregnancy among infants born after fresh-ET or frozen-ET versus natural conception, using a within-sibship design to account for confounding by maternal factors.Methods and findingsThis registry-based cohort study with nationwide data from Denmark (1994–2014), Norway (1988–2015), and Sweden (1988–2015) consisted of 4,510,790 live-born singletons, 4,414,703 from natural conception, 78,095 from fresh-ET, and 17,990 from frozen-ET. We identified 33,056 offspring sibling groups with the same mother, conceived by at least 2 different conception methods. Outcomes were mean birthweight, small and large for gestational age, mean gestational age, preterm (<37 weeks, versus ≥37), and very preterm birth (<32 weeks, versus ≥32). Singletons born after fresh-ET had lower mean birthweight (−51 g, 95% CI −58 to −45, p < 0.001) and increased odds of small for gestational age (odds ratio [OR] 1.20, 95% CI 1.08 to 1.34, p < 0.001), while those born after frozen-ET had higher mean birthweight (82 g, 95% CI 70 to 94, p < 0.001) and increased odds of large for gestational age (OR 1.84, 95% CI 1.56 to 2.17, p < 0.001), compared to naturally conceived siblings. Conventional population analyses gave similar results. Compared to naturally conceived siblings, mean gestational age was lower after fresh-ET (−1.0 days, 95% CI −1.2 to −0.8, p < 0.001), but not after frozen-ET (0.3 days, 95% CI 0.0 to 0.6, p = 0.028). There were increased odds of preterm birth after fresh-ET (OR 1.27, 95% CI 1.17 to 1.37, p < 0.001), and in most models after frozen-ET, versus naturally conceived siblings, with somewhat stronger associations in population analyses. For very preterm birth, population analyses showed increased odds for both fresh-ET (OR 2.03, 95% CI 1.90 to 2.12, p < 0.001) and frozen-ET (OR 1.66, 95% CI 1.42 to 1.94, p < 0.001) compared with natural conception, but results were notably attenuated within siblings (OR 1.18, 95% CI 1.0 to 1.41, p = 0.059, and OR 0.92, 95% CI 0.67 to 1.27, p = 0.6, for fresh-ET and frozen-ET, respectively). Sensitivity analyses in full siblings, in siblings born within 3-year interval, by birth order, and restricting to single embryo transfers and blastocyst transfers were consistent with the main analyses. Main limitations were high proportions of missing data on maternal body mass index and smoking.ConclusionsWe found that infants conceived by fresh-ET had lower birthweight and increased odds of small for gestational age, and those conceived by frozen-ET had higher birthweight and increased odds of large for gestational age. Conception by either fresh-ET or frozen-ET was associated with increased odds of preterm birth. That these findings were observed within siblings, as well as in conventional multivariable population analyses, reduces the likelihood that they are explained by confounding or selection bias.Trial registrationClinicalTrials.gov ISRCTN11780826.

Kjersti Westvik-Johari and co-workers report on perinatal outcomes following fresh and frozen embryo transfer.     

Dose-dependent oral glucocorticoid cardiovascular risks in people with immune-mediated inflammatory diseases: A population-based cohort study

BackgroundGlucocorticoids are widely used to reduce disease activity and inflammation in patients with a range of immune-mediated inflammatory diseases. It is uncertain whether or not low to moderate glucocorticoid dose increases cardiovascular risk. We aimed to quantify glucocorticoid dose-dependent cardiovascular risk in people with 6 immune-mediated inflammatory diseases.Methods and findingsWe conducted a population-based cohort analysis of medical records from 389 primary care practices contributing data to the United Kingdom Clinical Practice Research Datalink (CPRD), linked to hospital admissions and deaths in 1998–2017. We estimated time-variant daily and cumulative glucocorticoid prednisolone-equivalent dose-related risks and hazard ratios (HRs) of first all-cause and type-specific cardiovascular diseases (CVDs). There were 87,794 patients with giant cell arteritis and/or polymyalgia rheumatica (n = 25,581), inflammatory bowel disease (n = 27,739), rheumatoid arthritis (n = 25,324), systemic lupus erythematosus (n = 3,951), and/or vasculitis (n = 5,199), and no prior CVD. Mean age was 56 years and 34.1% were men. The median follow-up time was 5.0 years, and the proportions of person–years spent at each level of glucocorticoid daily exposure were 80% for non-use, 6.0% for <5 mg, 11.2% for 5.0–14.9 mg, 1.6% for 15.0–24.9 mg, and 1.2% for ≥25.0 mg.Incident CVD occurred in 13,426 (15.3%) people, including 6,013 atrial fibrillation, 7,727 heart failure, and 2,809 acute myocardial infarction events. One-year cumulative risks of all-cause CVD increased from 1.4% in periods of non-use to 8.9% for a daily prednisolone-equivalent dose of ≥25.0 mg. Five-year cumulative risks increased from 7.1% to 28.0%, respectively. Compared to periods of non-glucocorticoid use, those with <5.0 mg daily prednisolone-equivalent dose had increased all-cause CVD risk (HR = 1.74; 95% confidence interval [CI] 1.64–1.84; range 1.52 for polymyalgia rheumatica and/or giant cell arteritis to 2.82 for systemic lupus erythematosus). Increased dose-dependent risk ratios were found regardless of disease activity level and for all type-specific CVDs. HRs for type-specific CVDs and <5.0-mg daily dose use were: 1.69 (95% CI 1.54–1.85) for atrial fibrillation, 1.75 (95% CI 1.56–1.97) for heart failure, 1.76 (95% CI 1.51–2.05) for acute myocardial infarction, 1.78 (95% CI 1.53–2.07) for peripheral arterial disease, 1.32 (95% CI 1.15–1.50) for cerebrovascular disease, and 1.93 (95% CI 1.47–2.53) for abdominal aortic aneurysm.The lack of hospital medication records and drug adherence data might have led to underestimation of the dose prescribed when specialists provided care and overestimation of the dose taken during periods of low disease activity. The resulting dose misclassification in some patients is likely to have reduced the size of dose–response estimates.ConclusionsIn this study, we observed an increased risk of CVDs associated with glucocorticoid dose intake even at lower doses (<5 mg) in 6 immune-mediated diseases. These results highlight the importance of prompt and regular monitoring of cardiovascular risk and use of primary prevention treatment at all glucocorticoid doses.

Mar Pujades-Rodriguez and colleagues investigate whether low dose steroids are associated with increased risks of cardiovascular diseases.     

Serology,infection, and clinical trachoma as tools in prevalence surveys for re-emergence of trachoma in a formerly hyperendemic district

BackgroundTo eliminate trachoma as a public health problem, countries must achieve a district-level prevalence of trachomatous inflammation—follicular (TF) <5% in children ages 1–9 years. Re-emergence of TF could trigger additional rounds of mass drug/antibiotic administration (MDA), so accurate tools for use in surveys assessing trachoma prevalence are essential.Methodology & principal findingsWe surveyed 2401 children ages 1–9 years from 50 villages in Kongwa, Tanzania, 2 years post-MDA and 1.5 years after an impact survey found TF <5% in the same villages. Our survey included multiple tools: clinical determination of TF, Cepheid testing for Chlamydia trachomatis infection, and testing for anti-pgp3 antibodies via multiplex bead array. Photographs of the upper tarsal conjunctiva were taken in a subset of children to corroborate the field grades.Overall TF prevalence in 1–9 year olds was 7.1% (95% CI: 5.6%-8.9%), which decreased with age (p = <0.0001). TF prevalence by village was heterogeneous, with 19 villages having TF <5% and 16 villages having TF >10%. There was a strong correlation between field and photo grading of TF (kappa = 0.69; 95% CI: 0.60–0.78) and between TF and infection, with 21.5% of TF-positive children also testing positive for infection, as compared to only 1.6% of TF-negative children (p = 0.0010). Overall seroprevalence was 18.2% (95% CI: 14.8%-22.1%), which increased with age (p = <0.0001). Notably, 1–2 year olds, who were born after the cessation of MDA and theoretically should not have had exposure to C. trachomatis in the absence of transmission, had an average seroprevalence of 6.7%.Conclusions & significanceField TF prevalence, supported by photographic review and infection data, suggested re-emergence of trachoma in Kongwa. Moreover, seropositivity in the children born after cessation of MDA indicated exposure to C. trachomatis despite a previous survey finding of TF <5%. Examining seropositivity in specific age groups expected to have limited exposure to C. trachomatis can be used to detect re-emergence.     

Hypertension awareness,treatment, and control and their association with healthcare access in the middle-aged and older Indian population: A nationwide cohort study

BackgroundHypertension is the most important cardiovascular risk factor in India, and representative studies of middle-aged and older Indian adults have been lacking. Our objectives were to estimate the proportions of hypertensive adults who had been diagnosed, took antihypertensive medication, and achieved control in the middle-aged and older Indian population and to investigate the association between access to healthcare and hypertension management.Methods and findingsWe designed a nationally representative cohort study of the middle-aged and older Indian population, the Longitudinal Aging Study in India (LASI), and analyzed data from the 2017–2019 baseline wave (N = 72,262) and the 2010 pilot wave (N = 1,683). Hypertension was defined as self-reported physician diagnosis or elevated blood pressure (BP) on measurement, defined as systolic BP ≥ 140 mm Hg or diastolic BP ≥ 90 mm Hg. Among hypertensive individuals, awareness, treatment, and control were defined based on self-reports of having been diagnosed, taking antihypertensive medication, and not having elevated BP, respectively. The estimated prevalence of hypertension for the Indian population aged 45 years and older was 45.9% (95% CI 45.4%–46.5%). Among hypertensive individuals, 55.7% (95% CI 54.9%–56.5%) had been diagnosed, 38.9% (95% CI 38.1%–39.6%) took antihypertensive medication, and 31.7% (95% CI 31.0%–32.4%) achieved BP control. In multivariable logistic regression models, access to public healthcare was a key predictor of hypertension treatment (odds ratio [OR] = 1.35, 95% CI 1.14–1.60, p = 0.001), especially in the most economically disadvantaged group (OR of the interaction for middle economic status = 0.76, 95% CI 0.61–0.94, p = 0.013; OR of the interaction for high economic status = 0.84, 95% CI 0.68–1.05, p = 0.124). Having health insurance was not associated with improved hypertension awareness among those with low economic status (OR = 0.96, 95% CI 0.86–1.07, p = 0.437) and those with middle economic status (OR of the interaction = 1.15, 95% CI 1.00–1.33, p = 0.051), but it was among those with high economic status (OR of the interaction = 1.28, 95% CI 1.10–1.48, p = 0.001). Comparing hypertension awareness, treatment, and control rates in the 4 pilot states, we found statistically significant (p < 0.001) improvement in hypertension management from 2010 to 2017–2019. The limitations of this study include the pilot sample being relatively small and that it recruited from only 4 states.ConclusionsAlthough considerable variations in hypertension diagnosis, treatment, and control exist across different sociodemographic groups and geographic areas, reducing uncontrolled hypertension remains a public health priority in India. Access to healthcare is closely tied to both hypertension diagnosis and treatment.

Jinkook Lee and colleagues investigate hypertension management and its association with healthcare access in middle-aged and older adults in India.     

Risk of developing active tuberculosis following tuberculosis screening and preventive therapy for Tibetan refugee children and adolescents in India: An impact assessment

BackgroundTuberculosis (TB) rates among Tibetan refugee children and adolescents attending boarding schools in India are extremely high. We undertook a comprehensive case finding and TB preventive treatment (TPT) program in 7 schools in the Zero TB Kids project. We aimed to measure the TB infection and disease burden and investigate the risk of TB disease in children and adults who did and did not receive TPT in the schools.Methods and findingsA mobile team annually screened children and staff for TB at the 7 boarding schools in Himachal Pradesh, India, using symptom criteria, radiography, molecular diagnostics, and tuberculin skin tests. TB infection (TBI) was treated with short-course regimens of isoniazid and rifampin or rifampin. TB disease was treated according to Tibetan and Indian guidelines. Between April 2017 and December 2019, 6,582 schoolchildren (median age 14 [IQR 11–16] years) and 807 staff (median age 40 [IQR 33–48] years) were enrolled. Fifty-one percent of the students and 58% of the staff were females. Over 13,161 person-years of follow-up in schoolchildren (median follow-up 2.3 years) and 1,800 person-years of follow-up in staff (median follow-up 2.5 years), 69 TB episodes occurred in schoolchildren and 4 TB episodes occurred in staff, yielding annual incidence rates of 524/100,000 (95% CI 414–663/100,000) person-years and 256/100,000 (95% CI 96–683/100,000) person-years, respectively. Of 1,412 schoolchildren diagnosed with TBI, 1,192 received TPT. Schoolchildren who received TPT had 79% lower risk of TB disease (adjusted hazard ratio [aHR] 0.21; 95% CI 0.07–0.69; p = 0.010) compared to non-recipients, the primary study outcome. Protection was greater in recent contacts (aHR 0.07; 95% CI 0.01–0.42; p = 0.004), the secondary study outcome. The prevalence of recent contacts was 28% (1,843/6,582). Two different TPT regimens were used (3HR and 4R), and both were apparently effective. No staff receiving TPT developed TB. Overall, between 2017 and 2019, TB disease incidence decreased by 87%, from 837/100,000 (95% CI 604–1,129/100,000) person-years to 110/100,000 (95% CI 36–255/100,000) person-years (p < 0.001), and TBI prevalence decreased by 42% from 19% (95% CI 18%–20%) to 11% (95% CI 10%–12%) (p < 0.001). A limitation of our study is that TB incidence could be influenced by secular trends during the study period.ConclusionsIn this study, following implementation of a school-wide TB screening and preventive treatment program, we observed a significant reduction in the burden of TB disease and TBI in children and adolescents. The benefit of TPT was particularly marked for recent TB contacts. This initiative may serve as a model for TB detection and prevention in children and adolescents in other communities affected by TB.

Kunchok Dorjee and colleagues investigate infection and disease burden following mass tuberculosis preventive treatment for Tibetan refugee children at schools in India.     

Cancer risk in individuals with intellectual disability in Sweden: A population-based cohort study

BackgroundA knowledge gap exists about the risk of cancer in individuals with intellectual disability (ID). The primary aim of this study was to estimate the cancer risk among individuals with ID compared to individuals without ID.Methods and findingsWe conducted a population-based cohort study of all children live-born in Sweden between 1974 and 2013 and whose mothers were born in a Nordic country. All individuals were followed from birth until cancer diagnosis, emigration, death, or 31 December 2016 (up to age 43 years), whichever came first. Incident cancers were identified from the Swedish Cancer Register. We fitted Cox regression models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) as measures of cancer risk in relation to ID after adjusting for several potential confounders. We analyzed ID by severity, as well as idiopathic ID and syndromic ID separately. We performed a sibling comparison to investigate familial confounding. The study cohort included a total of 3,531,305 individuals, including 27,956 (0.8%) individuals diagnosed with ID. Compared with the reference group (individuals without ID and without a full sibling with ID), individuals with ID were in general more likely to be male. The median follow-up time was 8.9 and 23.0 years for individuals with ID and individuals without ID, respectively. A total of 188 cancer cases were identified among individuals with ID (incidence rate [IR], 62 per 1,000 person-years), and 24,960 among individuals in the reference group (IR, 31 per 1,000 person-years). A statistically significantly increased risk was observed for any cancer (HR 1.57, 95% CI 1.35–1.82; P < 0.001), as well as for several cancer types, including cancers of the esophagus (HR 28.4, 95% CI 6.2–130.6; P < 0.001), stomach (HR 6.1, 95% CI 1.5–24.9; P = 0.013), small intestine (HR 12.0, 95% CI 2.9–50.1; P < 0.001), colon (HR 2.0, 95% CI 1.0–4.1; P = 0.045), pancreas (HR 6.0, 95% CI 1.5–24.8; P = 0.013), uterus (HR 11.7, 95% CI 1.5–90.7; P = 0.019), kidney (HR 4.4, 95% CI 2.0–9.8; P < 0.001), central nervous system (HR 2.7, 95% CI 2.0–3.7; P < 0.001), and other or unspecified sites (HR 4.8, 95% CI 1.8–12.9; P = 0.002), as well as acute lymphoid leukemia (HR 2.4, 95% CI 1.3–4.4; P = 0.003) and acute myeloid leukemia (HR 3.0, 95% CI 1.4–6.4; P = 0.004). Cancer risk was not modified by ID severity or sex but was higher for syndromic ID. The sibling comparison showed little support for familial confounding. The main study limitations were the limited statistical power for the analyses of specific cancer types, and the potential for underestimation of the studied associations (e.g., due to potential underdetection or delayed diagnosis of cancer among individuals with ID).ConclusionsIn this study, we found that individuals with ID showed an increased risk of any cancer, as well as of several specific cancer types. These findings suggest that extended surveillance and early intervention for cancer among individuals with ID are warranted.

In a nationwide cohort study in Sweden, Qianwei Liu and co-workers report on cancer risk in people with intellectual disability.     

Serum cobalamin in children with moderate acute malnutrition in Burkina Faso: Secondary analysis of a randomized trial

BackgroundAmong children with moderate acute malnutrition (MAM) the level of serum cobalamin (SC) and effect of food supplements are unknown. We aimed to assess prevalence and correlates of low SC in children with MAM, associations with hemoglobin and development, and effects of food supplements on SC.Methods and findingsA randomized 2 × 2 × 3 factorial trial was conducted in Burkina Faso. Children aged 6 to 23 months with MAM received 500 kcal/d as lipid-based nutrient supplement (LNS) or corn–soy blend (CSB), containing dehulled soy (DS) or soy isolate (SI) and 0%, 20%, or 50% of total protein from milk for 3 months. Randomization resulted in baseline equivalence between intervention groups. Data on hemoglobin and development were available at baseline. SC was available at baseline and after 3 and 6 months. SC was available from 1,192 (74.1%) of 1,609 children at baseline. The mean (±SD) age was 12.6 (±5.0) months, and 54% were females. Low mid-upper arm circumference (MUAC; <125 mm) was found in 80.4% (958) of the children and low weight-for-length z-score (WLZ; <−2) in 70.6% (841). Stunting was seen in 38.2% (456). Only 5.9% were not breastfed. Median (IQR) SC was 188 (137; 259) pmol/L. Two-thirds had SC ≤222 pmol/L, which was associated with lower hemoglobin. After age and sex adjustments, very low SC (<112 pmol/L) was associated with 0.21 (95% CI: 0.01; 0.41, p = 0.04) and 0.24 (95% CI: 0.06; 0.42, p = 0.01) z-score lower fine and gross motor development, respectively.SC data were available from 1,330 (85.9%) of 1,548 children followed up after 3 months and 398 (26.5%) of the 1,503 children after 6 months. Based on tobit regression, accounting for left censored data, and adjustments for correlates of missing data, the mean (95% CI) increments in SC from baseline to the 3- and 6-month follow-up were 72 (65; 79, p < 0.001) and 26 (16; 37, p < 0.001) pmol/L, respectively. The changes were similar among the 310 children with SC data at all 3 time points. Yet, the increase was 39 (20; 57, p < 0.001) pmol/L larger in children given LNS compared to CSB if based on SI (interaction, p < 0.001). No effect of milk was found. Four children died, and no child developed an allergic reaction to supplements. The main limitation of this study was that only SC was available as a marker of status and was missing from a quarter of the children.ConclusionsLow SC is prevalent among children with MAM and may contribute to impaired erythropoiesis and child development. The SC increase during supplementation was inadequate. The bioavailability and adequacy of cobalamin in food supplements should be reconsidered.Trial registrationISRCTN Registry ISRCTN42569496.

Henrik Friis and colleagues, investigate the prevalence and correlates of low serum cobalamin, associations with hemoglobin and child development, and associations of serum cobalamin levels with food supplementation in children moderate acute malnutrition in Burkina Faso.     

Gastrointestinal Infections and Diarrheal Disease in Ghanaian Infants and Children: An Outpatient Case-Control Study

IntroductionDiarrheal diseases are among the most frequent causes of morbidity and mortality in children worldwide, especially in resource-poor areas. This case-control study assessed the associations between gastrointestinal infections and diarrhea in children from rural Ghana.MethodsStool samples were collected from 548 children with diarrhea and from 686 without gastrointestinal symptoms visiting a hospital from 2007–2008. Samples were analyzed by microscopy and molecular methods.ResultsThe organisms most frequently detected in symptomatic cases were Giardia lamblia, Shigella spp./ enteroinvasive Escherichia coli (EIEC), and Campylobacter jejuni. Infections with rotavirus (adjusted odds ratio [aOR] = 8.4; 95% confidence interval [CI]: 4.3–16.6), C. parvum/hominis (aOR = 2.7; 95% CI: 1.4–5.2) and norovirus (aOR = 2.0; 95%CI: 1.3–3.0) showed the strongest association with diarrhea. The highest attributable fractions (AF) for diarrhea were estimated for rotavirus (AF = 14.3%; 95% CI: 10.9–17.5%), Shigella spp./EIEC (AF = 10.5%; 95% CI: 3.5–17.1%), and norovirus (AF = 8.2%; 95% CI 3.2–12.9%). Co-infections occurred frequently and most infections presented themselves independently of other infections. However, infections with E. dispar, C. jejuni, and norovirus were observed more often in the presence of G. lamblia.ConclusionsDiarrheal diseases in children from a rural area in sub-Saharan Africa are mainly due to infections with rotavirus, Shigella spp./EIEC, and norovirus. These associations are strongly age-dependent, which should be considered when diagnosing causes of diarrhea. The presented results are informative for both clinicians treating gastrointestinal infections as well as public health experts designing control programs against diarrheal diseases.     

Host Factors and Biomarkers Associated with Poor Outcomes in Adults with Invasive Pneumococcal Disease

BackgroundInvasive pneumococcal disease (IPD) causes considerable morbidity and mortality. We aimed to identify host factors and biomarkers associated with poor outcomes in adult patients with IPD in Japan, which has a rapidly-aging population.MethodsIn a large-scale surveillance study of 506 Japanese adults with IPD, we investigated the role of host factors, disease severity, biomarkers based on clinical laboratory data, treatment regimens, and bacterial factors on 28-day mortality.ResultsOverall mortality was 24.1%, and the mortality rate increased from 10.0% in patients aged ˂50 years to 33.1% in patients aged ≥80 years. Disease severity also increased 28-day mortality, from 12.5% among patients with bacteraemia without sepsis to 35.0% in patients with severe sepsis and 56.9% with septic shock. The death rate within 48 hours after admission was high at 54.9%. Risk factors for mortality identified by multivariate analysis were as follows: white blood cell (WBC) count <4000 cells/μL (odds ratio [OR], 6.9; 95% confidence interval [CI], 3.7–12.8, p < .001); age ≥80 years (OR, 6.5; 95% CI, 2.0–21.6, p = .002); serum creatinine ≥2.0 mg/dL (OR, 4.5; 95% CI, 2.5–8.1, p < .001); underlying liver disease (OR, 3.5; 95% CI, 1.6–7.8, p = .002); mechanical ventilation (OR, 3.0; 95% CI, 1.7–5.6, p < .001); and lactate dehydrogenase ≥300 IU/L (OR, 2.4; 95% CI, 1.4–4.0, p = .001). Pneumococcal serotype and drug resistance were not associated with poor outcomes.ConclusionsHost factors, disease severity, and biomarkers, especially WBC counts and serum creatinine, were more important determinants of mortality than bacterial factors.     

Pre- and Postnatal Risk Factors in Relation to Allergic Rhinitis in School-Aged Children in China

ObjectiveThe objective of this study was to investigate the relationship between prenatal and postnatal risk factors and the prevalence of allergic rhinitis (AR) in Chinese children of specific ages.ResultsThe overall prevalence of AR was found in this study to be 9.8%. After adjusting for several likely confounders, there was a higher likelihood of AR in school-aged children who were not exclusively breastfed in the first 4 months of their lives (odds ratio [OR]: 1.28; 95% confidence interval [CI]: 1.16–1.41), children who were born post-term (OR: 1.34; 95% CI: 1.12–1.60), children delivered by cesarean section (OR: 1.07; 95% CI: 1.00–1.19), or children born to mothers who experienced depressive symptoms during the pre- and postnatal periods (OR: 1.28; 95% CI: 1.15–1.42).ConclusionsAR in school-aged children was found to be associated with pre- and postnatal events. These findings indicate that strategies to reduce exposure to risk factors during pre- and postnatal periods for childhood allergies might be warranted.     

Seroprevalence of Strongyloides stercoralis infection in a South Indian adult population

BackgroundThe prevalence of Strongyloides stercoralis infection is estimated to be 30–100 million worldwide, although this an underestimate. Most cases remain undiagnosed due to the asymptomatic nature of the infection. We wanted to estimate the seroprevalence of S. stercoralis infection in a South Indian adult population.MethodsTo this end, we performed community-based screening of 2351 individuals (aged 18–65) in Kanchipuram District of Tamil Nadu between 2013 and 2020. Serological testing for S. stercoralis was performed using the NIE ELISA.ResultsOur data shows a seroprevalence of 33% (768/2351) for S. stercoralis infection which had a higher prevalence among males 36% (386/1069) than among females 29.8% (382/1282). Adults aged ≥55 (aOR = 1.65, 95% CI: 1.25–2.18) showed higher adjusted odds of association compared with other age groups. Eosinophil levels (39%) (aOR = 1.43, 95% CI: 1.19–1.74) and hemoglobin levels (24%) (aOR = 1.25, 95% CI: 1.11–1.53) were significantly associated with S. stercoralis infection. In contrast, low BMI (aOR = 1.15, 95% CI: 0.82–1.61) or the presence of diabetes mellitus (OR = 1.18, 95% CI: 0.83–1.69) was not associated with S. stercoralis seropositivity.ConclusionsOur study provides evidence for a very high baseline prevalence of S. stercoralis infection in South Indian communities and this information could provide realistic and concrete planning of control measures.