Vulnerable newborn phenotypes in Peru: a population-based study of 3,841,531 births at national and subnational levels from 2012 to 2021.

Background: We aimed to examine the national and subnational prevalence of vulnerable newborn phenotypes in Peru, 2012-2021. Methods: Newborn phenotypes were defined using gestational age (preterm [PT], term [T]), birthweight for gestational age using INTERGROWTH-21st standards (small for gestational age [SGA], appropriate for gestational age [AGA] or large for gestational age [LGA]), and birthweight (low birthweight [LBW], non-LBW) using the Peruvian National Birth Registry as six (by excluding birthweight) and ten newborn phenotypes (using all three outcomes). Small phenotypes (with at least one classification of PT, SGA, or LBW) were further considered. Using individual-level data, we stratified the phenotypes by maternal educational level, maternal age, healthcare insurance, altitude of residence, and geographic region (Coast, Andes, and Amazon). Findings: The prevalence of the five vulnerable newborn phenotypes for the study period was LGA+T (15.2%), AGA+PT (5.2%), SGA+T (4.6%), LGA+PT (0.8%), and SGA+PT (0.7%). The Coast had a higher prevalence of newborns with large phenotypes (19.4%) and the Highlands a higher prevalence of newborns with small phenotypes (12.5%). Mothers with poor socioeconomic status, extreme ages and living at high altitude had a higher prevalence of newborns with small phenotypes, and mothers who were wealthier, more educated, and older had a higher prevalence of infants with large phenotypes. Interpretation: Our findings cautiously suggest that socioeconomic and geographic disparities may play a crucial role in shaping vulnerable newborn phenotypes at national and subnational level in Peru. Further studies using longitudinal data are needed to corroborate our findings and to identify individual-level risk factors. Funding: Ter Meulen Grant from the KNAW Medical Sciences Fund of the Royal Netherlands Academy of Arts and Sciences (KNAWWF/1085/TMB406, KNAWWF/1327/TMB202116), Fogarty Program (D43TW011502).

Changes in preterm birth and stillbirth during COVID-19 lockdowns in 26 countries.

Preterm birth (PTB) is the leading cause of infant mortality worldwide. Changes in PTB rates, ranging from -90% to +30%, were reported in many countries following early COVID-19 pandemic response measures ('lockdowns'). It is unclear whether this variation reflects real differences in lockdown impacts, or perhaps differences in stillbirth rates and/or study designs. Here we present interrupted time series and meta-analyses using harmonized data from 52 million births in 26 countries, 18 of which had representative population-based data, with overall PTB rates ranging from 6% to 12% and stillbirth ranging from 2.5 to 10.5 per 1,000 births. We show small reductions in PTB in the first (odds ratio 0.96, 95% confidence interval 0.95-0.98, P value <0.0001), second (0.96, 0.92-0.99, 0.03) and third (0.97, 0.94-1.00, 0.09) months of lockdown, but not in the fourth month of lockdown (0.99, 0.96-1.01, 0.34), although there were some between-country differences after the first month. For high-income countries in this study, we did not observe an association between lockdown and stillbirths in the second (1.00, 0.88-1.14, 0.98), third (0.99, 0.88-1.12, 0.89) and fourth (1.01, 0.87-1.18, 0.86) months of lockdown, although we have imprecise estimates due to stillbirths being a relatively rare event. We did, however, find evidence of increased risk of stillbirth in the first month of lockdown in high-income countries (1.14, 1.02-1.29, 0.02) and, in Brazil, we found evidence for an association between lockdown and stillbirth in the second (1.09, 1.03-1.15, 0.002), third (1.10, 1.03-1.17, 0.003) and fourth (1.12, 1.05-1.19, <0.001) months of lockdown. With an estimated 14.8 million PTB annually worldwide, the modest reductions observed during early pandemic lockdowns translate into large numbers of PTB averted globally and warrant further research into causal pathways.

A comprehensive analysis of cardiovascular mortality trends in Peru from 2017 to 2022: Insights from 183,386 deaths of the national death registry.

Background/objectives: Cardiovascular diseases are the leading cause of global mortality. Systematic studies on cardiovascular-related mortality at national and subnational levels in Peru are lacking. We aimed to describe the trends in cardiovascular-related mortality between 2017 and 2022 in Peru at national and subnational levels and by socioeconomic indicators. Subjects/methods: We used data from the Peruvian death registry 2017-2022. Using ICD-10 codes, mortality was categorized into: hypertensive-, coronary-, and cerebrovascular- related deaths. We estimated age-standardized cardiovascular-related mortality rates by sex at national and regional levels, and by natural regions (Coast, Highlands, Amazon). We estimated the change in mortality rates between 2017-2019 and 2020-2022 and explored factors that contributed to such a change. We explored ecological relationships between mortality rates and socioeconomic indicators. Findings: Overall 183,386 cardiovascular-related deaths were identified. Coronary-related deaths (37.2 %) were followed by hypertensive-related (25.1 %) and cerebrovascular-related deaths (22.6 %). Peru showed a marked increasing trend in cardiovascular-related mortality in 2020-2022 (77.8 %). The increase clustered in the Coast and Highlands, with the highest change observed in Lima (132.1 %). Mortality was highest in subjects with lower education and subjects with public health insurance. Gini coefficient was associated with lower mortality rates while unemployment was associated with higher mortality rates. Interpretation: There was a notable rise in cardiovascular-related mortality in Peru, particularly during the Covid-19 pandemic with a slight decrease in 2022. Gaining a comprehensive understanding of the factors that contribute to the increase in cardiovascular deaths in Peru will facilitate the development of precise interventions at both the national and regional levels.

COVID-19 and drivers of excess death rate in Peru: A longitudinal ecological study.

Background: Peru has experienced unprecedented mortality and economic toll due to the COVID-19 (Coronavirus disease 2019) pandemic in 2020. We aimed to assess the association between socioeconomic factors and excess death rate, and to explore the relative contribution of these factors to the differences in excess death rate during January-December 2020. Methods: Different national secondary data sources were used to describe excess death rates and different determinants, from distal to proximal. A confounding-adjusted multilevel mixed-effects linear regression was used to assess the association between these variables and excess death rates. Their relative contributions to the differences in excess death rate between the periods with the highest and lowest excess death rates were analyzed through regression-based Oaxaca-Blinder decomposition methods. Findings: The excess death rate showed an increasing trend in all regions, with different slopes. The confounding-adjusted multilevel analysis showed that higher healthcare access was associated with lower excess death rates (difference (95%CI) -0.004 (-0.005, -0.002)), whereas COVID-19 incidence was associated with higher excess death rates (difference (95%CI) 0.052 (0.042, 0.063)). The decomposition analysis showed COVID-19 incidence (41.9%), per capita income (19.4%) and unemployment rate (14.6%) as the main risk factors, while the main protective factors included per capita health expenditure (44.7%), healthcare access (33.2%) and health insurance (12.1%). Interpretation: Our study suggests that the excess death rate during the COVID-19 pandemic in Peru may have been influenced by other factors besides COVID-19 incidence, from distal to proximal drivers, including socioeconomic determinants, factors outside and within the health sector, and susceptibility factors. Further studies at individual level are needed to corroborate our findings.

Fetal Exposure to Maternal Smoking and Neonatal Metabolite Profiles.

Fetal tobacco exposure has persistent effects on growth and metabolism. The underlying mechanisms of these relationships are yet unknown. We investigated the associations of fetal exposure to maternal smoking with neonatal metabolite profiles. In a population-based cohort study among 828 mother-infant pairs, we assessed maternal tobacco use by questionnaire. Metabolite concentrations of amino acids, non-esterified fatty acids, phospholipids and carnitines were determined by using LC-MS/MS in cord blood samples. Metabolite ratios reflecting metabolic pathways were computed. Compared to non-exposed neonates, those exposed to first trimester only tobacco smoking had lower neonatal mono-unsaturated acyl-alkyl-phosphatidylcholines (PC.ae) and alkyl-lysophosphatidylcholines (Lyso.PC.e) 18:0 concentrations. Neonates exposed to continued tobacco smoking during pregnancy had lower neonatal mono-unsaturated acyl-lysophosphatidylcholines (Lyso.PC.a), Lyso.PC.e.16:0 and Lyso.PC.e.18:1 concentration (False discovery rate (FDR) p-values < 0.05). Dose-response associations showed the strongest effect estimates in neonates whose mothers continued smoking ≥5 cigarettes per day (FDR p-values < 0.05). Furthermore, smoking during the first trimester only was associated with altered neonatal metabolite ratios involved in the Krebs cycle and oxidative stress, whereas continued smoking during pregnancy was associated with inflammatory, transsulfuration, and insulin resistance markers (p-value < 0.05). Thus, fetal tobacco exposure seems associated with neonatal metabolite profile adaptations. Whether these changes relate to later life metabolic health should be studied further.

Flat trend of high caesarean section rates in Peru: A pooled analysis of 3,376,062 births from the national birth registry, 2012 to 2020.

Background: National and subnational C-section rates are seldom available in low- and middle-income countries to guide policies and interventions. We aimed to describe the C-section rates at the national and subnational levels in Peru (2012-2020). Methods: Based on the Peruvian national birth registry, we quantified C-section rates at the national, regional and province levels; also, by natural regions (Coast, Highlands, and Amazon). Using individual-level data from the mother, we stratified the C-section rates by educational level, healthcare insurance and provider. Ecologically, we studied the correlations between C-section rates and human development index (HDI), altitude above sea level, proportion of the population living in poverty and proportion of rural population. Findings: C-section rate in Peru decreased slightly from 2012 (39·7%) to 2020 (38·0%). A widening gap of C-section rates was observed through the study years among the Coast that showed higher rates and the other natural regions that showed lower rates. The rates in most of the 25 regions showed a flat trend, particularly in the last four years and some provinces showed a very low rate. The rates were highest in mothers with higher education and in users of private health insurance. Higher HDI, health facility located at lower altitude, lower poverty and urbanization were positively correlated with higher C-section rates. Interpretation: C-section rates in Peru are above the international recommendations. Large differences by natural region, provinces and women socioeconomic status were found. Further efforts are needed to achieve the recommended C-section rates. Funding: Academy Ter Meulen grant of the Academy Medical Sciences Fund of the Royal Netherlands Academy of Arts & Sciences (KNAWWF/1327/TMB202116), Wellcome Trust (214185/Z/18/Z), Fogarty (D43TW011502).

Maternal preconception and pregnancy tobacco and cannabis use in relation to placental developmental markers: A population-based study.

Maternal tobacco and cannabis use during pregnancy are associated with adverse perinatal outcomes. We hypothesized that maternal tobacco and cannabis use are associated with placental adaptations, which subsequently lead to adverse perinatal outcomes. In a population-based prospective cohort study of 8008 pregnant women, we assessed maternal tobacco and cannabis use by questionnaires. Placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were measured in the first and second trimester and at delivery from blood samples. Placental weight and pregnancy complications were obtained from medical records. We observed that tobacco use before and during first-trimester only was not associated with any angiogenic factors. As compared to no tobacco use, continued use during pregnancy was associated with higher PlGF, lower sFlt-1 concentrations, and lower sFlt-1/PlGF ratio in second trimester (all p-values <0.05). Also, compared to no cannabis use, use before and during pregnancy was associated with higher PlGF concentrations and lower sFlt-1/PlGF ratio in first and second trimester (all p-values <0.05). First trimester only cannabis use was associated with higher sFlt-1 concentrations and higher sFlt-1/PlGF ratio at delivery (all p-values <0.05). Compared to non-use, tobacco use before pregnancy was associated with a higher placental weight, whereas continued tobacco use during pregnancy was associated with a lower placental weight. Continued tobacco or cannabis use was related to higher placental weight to birth weight ratio and higher risk of pregnancy complications (all p-values <0.05). These results suggest that maternal tobacco and cannabis use lead to placental vascular maladaptation predisposing to adverse pregnancy outcomes.

Foetal tobacco and cannabis exposure, body fat and cardio-metabolic health in childhood.

BACKGROUND: Foetal tobacco and cannabis exposure may have persistent cardio-metabolic consequences in the offspring. OBJECTIVE: We examined the associations of maternal and paternal tobacco and cannabis use during pregnancy with offspring body fat and cardio-metabolic outcomes. METHODS: In a population-based prospective cohort study among 4792 mothers, fathers, and children, we assessed parental substance use by questionnaires. Childhood outcomes included body mass index (BMI), body fat, blood pressure, and lipid, glucose and insulin concentrations at 10 years. RESULTS: Children exposed to maternal tobacco use during pregnancy had a higher android/gynoid fat mass ratio (difference 0.22 SDS, 95% confidence interval [CI]: 0.13, 0.30), fat mass index (difference 0.20 SDS, 95% CI: 0.12, 0.28), triglyceride concentrations (difference 0.15 SDS, 95% CI: 0.04, 0.26), and a higher risk of overweight (odds ratio [OR] 1.35, 95% CI: 1.07, 1.71), compared to non-exposed. Children exposed to maternal cannabis during pregnancy had a higher BMI (difference 0.26 SDS, 95% CI: 0.08, 0.44), android/gynoid fat mass ratio (difference 0.21 SDS, 95% CI: 0.04, 0.39), and fat-free mass index (difference 0.24 SDS, 95% CI: 0.06, 0.41), compared to non-exposed. The associations for paternal substance use with child cardio-metabolic health outcomes were similar as those for maternal use. CONCLUSIONS: Similar associations for maternal and paternal substance use during pregnancy suggest that these findings may be explained by shared family-based social and lifestyle factors, rather than by direct foetal programming.

National and subnational trends of birthweight in Peru: Pooled analysis of 2,927,761 births between 2012 and 2019 from the national birth registry.

BACKGROUND: National and subnational characterization of birthweight profiles lacks in low- and middle-income countries, yet these are needed for monitoring the progress of national and global nutritional targets. We aimed to describe birthweight indicators at the national and subnational levels in Peru (2012-2019), and by selected correlates. METHODS: We studied mean birthweight (g), low birthweight (<2,500 g) and small for gestational age (according to international growth curves) prevalences. We analysed the national birth registry and summarized the three birthweight indicators at the national, regional, and province level, also by geographic area (Coast, Highlands, and Amazon). With individual-level data from the mother, we described the birthweight indicators by age, educational level and healthcare provider. Following an ecological approach (province level), we described the birthweight indicators by human development index (HDI), altitude above sea level, proportion of the population living in poverty and proportion of rural population. FINDINGS: Mean birthweight was always the lowest in the Highlands (2,954 g in 2019) yet the highest in the Coast (3,516 g in 2019). The same was observed for low birthweight and small for gestational age. In regions with Coast and Highlands, the birthweight indicators worsen from the Coast to the Highlands; the largest absolute difference in mean birthweight between Coast and Highlands in the same region was 367 g. All birthweight indicators were the worst in mothers with none/initial education, while they improved with higher HDI. INTERPRETATION: This analysis suggests that interventions are needed at the province level, given the large differences observed between Coast and Highlands even in the same region. FUNDING: Wellcome Trust (214185/Z/18/Z).

Parental cannabis and tobacco use during pregnancy and childhood hair cortisol concentrations.

BACKGROUND: Fetal exposure to cannabis and tobacco during pregnancy leads to adverse fetal and childhood outcomes. We hypothesized that fetal exposure to cannabis and tobacco have persistent programming effects on hypothalamic pituitary adrenal (HPA) axis functioning in childhood. Therefore, we examined the associations of parental cannabis and tobacco use during pregnancy with childhood hair cortisol and cortisone concentrations at 6 years, as biomarkers of long-term HPA-axis functioning. METHOD: In a population-based prospective birth cohort among 2577 mothers and their children, information of parental cannabis and tobacco use was collected by questionnaires, and maternal urine samples were additionally analyzed to detect cannabis metabolite concentrations. Cortisol and cortisone were measured in hair samples at 6 years. Linear regression analysis with adjustment for several confounders was used to test our hypothesis. RESULTS: As compared to non-exposed children, offspring exposed to cannabis during pregnancy (in combination with tobacco) had higher childhood cortisol concentrations (log-10 transformed difference 0.16, 95 % Confidence Interval 0.04 to 0.28). This association was not mediated by birth weight. No differences in cortisone concentrations among cannabis-exposed children were observed. Maternal tobacco use during pregnancy was not associated with childhood cortisol or cortisone concentrations. Further, paternal cannabis or tobacco use was not associated with childhood cortisol or cortisone concentrations. CONCLUSIONS: Our findings suggest that maternal cannabis use, combined with tobacco, during pregnancy is associated with alterations in offspring HPA-axis functioning. Further studies need to replicate these findings, and assess the causality and long-term consequences of these associations.