Mechanistic Framework to Predict Maternal-Placental-Fetal Pharmacokinetics of Nifedipine Employing Physiologically Based Pharmacokinetic Modeling Approach.

Nifedipine is used for treating mild to severe hypertension and preventing preterm labor in pregnant women. Nevertheless, concerns about nifedipine fetal exposure and safety are always raised. The aim of this study was to develop and validate a maternal-placental-fetal nifedipine physiologically based pharmacokinetic (PBPK) model and apply the model to predict maternal, placental, and fetal exposure to nifedipine at different pregnancy stages. A nifedipine PBPK model was verified with nonpregnant data and extended to the pregnant population after the inclusion of the fetoplacental multicompartment model that accounts for the placental tissue and different fetal organs within the Simcyp Simulator version 22. Model parametrization involved scaling nifedipine transplacental clearance based on Caco-2 permeability, and fetal hepatic clearance was obtained from in vitro to in vivo extrapolation encompassing cytochrome P450 3A7 and 3A4 activities. Predicted concentration profiles were compared with in vivo observations and the transplacental transfer results were evaluated using 2-fold criteria. The PBPK model predicted a mean cord-to-maternal plasma ratio of 0.98 (range, 0.86-1.06) at term, which agrees with experimental observations of 0.78 (range, 0.59-0.93). Predicted nifedipine exposure was 1.4-, 2.0-, and 3.0-fold lower at 15, 27, and 39 weeks of gestation when compared with nonpregnant exposure, respectively. This innovative PBPK model can be applied to support maternal and fetal safety assessment for nifedipine at various stages of pregnancy.

Serum cytokines in second trimester pregnancy and their relationship with spontaneous preterm births in the Ribeirão Preto and São Luiz cohorts.

OBJECTIVE: To evaluate the association between second trimester plasma cytokine levels in asymptomatic pregnant women and preterm births (PTB) in an attempt to identify a possible predictor of preterm birth. METHODS: The study design was a nested case-control study including women with singleton a gestational age between 20-25(+ 6) weeks from two Brazilian cities. The patients were interviewed, Venous blood samples were collected. The participants were again evaluated at birth. A total of 197 women with PTB comprised the case group. The control group was selected among term births (426 patients). Forty-one cytokines were compared between groups. RESULTS: When only spontaneous PTB were analyzed, GRO, sCD40L and MCP-1 levels were lower in the case group (p < 0.05). Logarithmic transformation was performed for cytokines with discrepant results, which showed increased levels of IL-2 in the group of spontaneous PTB (p < 0.05). In both analyses, the incidence of maternal smoking and of a history of preterm delivery differed significantly between the case and control groups. In multivariate analysis, only serum GRO levels differed between the case and control groups. CONCLUSION: Lower second trimester serum levels of GRO in asymptomatic women are associated with a larger number of PTB. This finding may reflect a deficient maternal inflammatory response.

Sociodemographic and reproductive risk factors associated with obesity in a population of brazilian women from the city of Ribeirão Preto: a cross-sectional study.

BACKGROUND: Obesity is a highly prevalent chronic disease that is associated with the development of other metabolic comorbidities. Its etiology is complex and multiple risk factors have been reported. In women, weight gain during pregnancy and the effect of pregnancy on subsequent weight gain are important events in women's history. Both pregnancy and postpartum are critical periods for the development of obesity. OBJECTIVES: To identify sociodemographic and reproductive risk factors associated with obesity in women in their fourth decade of life. METHODS: Cohort study conducted on women born from June 1978 to May 1979 in Ribeirão Preto, Brazil. Sociodemographic, clinical, and obstetric data were collected by interview and clinical evaluation. Univariable and multivariable binomial logistic regression models were constructed to identify the risk factors of obesity and the adjusted relative risk (RR) was calculated. RESULTS: The cohort included 916 women and 309 (33.7%) of them were obese. Obesity was associated with low educational level (RR 1.77, 95%CI 1.33-2.35) and teenage pregnancy (RR 1.46, 95%CI 1.10-1.93). There was no association of obesity with the other covariates studied. CONCLUSION: Obesity is associated with years of schooling and teenage pregnancy.

Assessment by ABPM verified the presence of hypertension in patients with self-reported hypertension, pregnant women, as well as differences between ethnicities in women aged 38-39 years in the Ribeirão Preto cohort.

Introduction: Arterial hypertension is a global health problem and one of the main risk factors for cardiovascular diseases (CVD), and therefore for morbidity and mortality among adult men and women. Factors related to obstetric history, family history, sociodemographic characteristics, and lifestyle habits are known determinants of arterial hypertension. Methods: Case-control study of women belonging to the 1978/79 birth cohort conducted in the city of Ribeirão Preto/SP. Sociodemographic data, presence of comorbidities, maternal comorbidities, paternal comorbidities, comorbidities during pregnancy, and biometric and biophysical markers associated with blood pressure measured by 24-h ambulatory blood pressure monitoring (ABPM) were assessed in women aged 38-39 years. We want to study which variables of the previous sentence are related to the presence of hypertension measured by ABPM. Results: Data from 281 women were analyzed. Our results showed that ethnicity, a history of hypertension, and gestational hypertension reported by the women were significantly associated with the presence of hypertension measured by ABPM. Other factors such as marital status, educational level, comorbidities of the woman, paternal or maternal comorbidities, anthropometric measurements or serum levels of cardiovascular markers were not associated with the presence of hypertension measured by ABPM. Conclusion: We conclude that ethnicity, self-reported hypertension, and gestational hypertension are associated with arterial hypertension measured by ABPM.

Prediction and prevention of preeclampsia by physicians in Brazil: An original study.

Background: Considering the worldwide importance of preeclampsia, especially in Brazil, the screening of pregnant women at greater risk of developing the disease and the application of preventive measures are essential. This study aimed to assess the medical performance in this context in Brazil. Methods: A survey was developed to quantify the number of physicians who prescribe acetylsalicylic acid (ASA) and/or calcium for preeclampsia prevention. The survey was sent to all Brazilian obstetricians affiliated to the Brazilian Federation of OBGYN by email and WhatsApp. The survey remained opened for 6 months and included questions about the use of ASA and calcium, as well as about the use of a complementary test to predict preeclampsia. Results: The sample consisted of 360 responding physicians and 100% coverage of responses from physicians from the five different regions of Brazil was obtained. The vast majority of respondents (94.72%) prescribe ASA to prevent preeclampsia, with 80.3% prescribing a dose of 100 mg/day. Calcium is prescribed by 83.9% of the respondents. The majority of the interviewed sample (58.6%) requests uterine artery Doppler imaging to predict preeclampsia and 31.7% do not request any additional test. When the analysis was performed by region, only the northern region differed from the other Brazilian regions regarding the use of ASA and calcium for preeclampsia prevention. While more than 90% of physicians in the other regions prescribe ASA, 40% in the northern region do not use it (p < 0.0001). Regarding calcium, 30% of physicians in northern Brazil do not use the drug for preeclampsia prevention, a percentage that also differs from the other regions where the medication is prescribed by 80 to 90% of physicians (p = 0.021). Conclusions: The vast majority of Brazilian physicians prescribe low-dose aspirin and calcium carbonate to prevent preeclampsia in high-risk pregnant women. In addition to the identification of clinical risk factors, most doctors use Doppler of the uterine arteries as a predictive method. In the northern region of Brazil, physicians use aspirin and calcium less frequently for preventing preeclampsia compared to the rest of the country.

Association of LEPTIN and other inflammatory markers with preeclampsia: A systematic review.

Background: Preeclampsia is a serious pregnancy complication that affects 5%-10% of the obstetric population. Objective: To study inflammatory markers associated with preeclampsia. Search Strategy: Searches of articles on the topic published over a 10-year period (2009-2019) were performed in three databases (PubMed, Cochrane, and Embase) using the keywords preeclampsia and inflammatory markers. The PubMed search using 10 years and humans as filters retrieved 124 articles. Using an advanced search strategy, 0 articles were identified in Embase and 10 articles in Cochrane. After screening and eligibility assessment, 13 articles were included in the systematic review and meta-analysis. Meta-analysis and quality assessment of the studies were performed using the Review Manager 5.3 program. Results: For meta-analysis, women with preeclampsia were compared to control women, i.e., pregnancies without arterial hypertension. Leptin levels were significantly higher (p < 0.0002) in women with preeclampsia compared to controls. Total cholesterol was also significantly elevated in women with preeclampsia (p < 0.0001). There was no significant difference in HDL between groups, but women with preeclampsia had significantly increased LDL (p < 0.01). The same was observed for triglycerides, which were significantly increased in women with preeclampsia (p < 0.04) compared to controls. Analysis of TNF-alpha, an important inflammatory marker, showed higher levels in women with preeclampsia (p < 0.03) compared to controls. The same was observed for another important inflammatory marker, interleukin 6, which was significantly increased in women with preeclampsia (p < 0.0002). There was a significant increase of C-reactive protein in women with preeclampsia (p < 0.003) compared to controls. Conclusion: Women with preeclampsia have increased levels of inflammatory markers compared to control women.

Preeclampsia and Gestational Hypertension: Biochemical and Antioxidant Features in Vitro Might Help Understand Different Outcomes.

OBJECTIVE: Gestational hypertension (GH) is characterized by increased blood pressure after the 20th gestational week; the presence of proteinuria and/or signs of end-organ damage indicate preeclampsia (PE). Heme oxygenase-1 (HO-1) is an antioxidant enzyme with an important role in maintaining endothelial function, and induction of HO-1 by certain molecules shows potential in attenuating the condition's effects over endothelial tissue. HO-1 production can also be stimulated by potassium iodide (KI). Therefore, we evaluated the effects of KI over HO-1 expression in human umbilical vein endothelial cells (HUVECs) incubated with plasma from women diagnosed with GH or PE. METHODS: Human umbilical vein endothelial cells were incubated with a pool of plasma of healthy pregnant women (n = 12), pregnant women diagnosed with GH (n = 10) or preeclamptic women (n = 11) with or without the addition of KI for 24 hours to evaluate its effect on this enzyme expression. Analysis of variance was performed followed by Dunnet's test for multiple comparisons between groups only or between groups with addition of KI (p ≤ 0.05). RESULTS: KI solution (1,000 µM) reduced HO-1 in the gestational hypertension group (p = 0.0018) and cytotoxicity in the preeclamptic group (p = 0.0143); treatment with KI reduced plasma cytotoxicity but did not affect the preeclamptic group's HO-1 expression. CONCLUSION: Our findings suggest that KI alleviates oxidative stress leading to decreased HO-1 expression; plasma from preeclamptic women did not induce the enzyme's expression in HUVECs, and we hypothesize that this is possibly due to inhibitory post-transcriptional mechanisms in response to overexpression of this enzyme during early pregnancy.

OBJETIVO: A hipertensão gestacional (GH) é caracterizada pelo aumento da pressão sanguínea após a 20ª semana de gestação; a presença de proteinuria e/ou sinais de danos a órgãos como rins, fígado e cérebro indicam pré-eclâmpsia (PE). A heme oxigenase-1 (HO-1) é uma enzima antioxidante com um papel importante na manutenção da função endotelial, e a sua indução por certas moléculas se mostra potencialmente benéfica frente à característica deletéria destas condições sobre o endotélio. Já foi demonstrado anteriormente que a produção de HO-1 pode ser induzida por iodeto de potássio (KI). Portanto, nós avaliamos os efeitos do KI sobre a citotoxicidade e expressão de HO-1 por células de veia de cordão umbilical humano (HUVECs) após incubação com o plasma de mulheres diagnosticadas com GH ou PE. MéTODOS: Células de veia de cordão umbilical humano foram incubadas com pool de plasma de gestantes saudáveis (n = 12), gestantes com GH (n = 10) ou gestantes com PE (n = 11) com ou sem a adição de KI por 24 horas para avaliar a citotoxicidade através da dosagem de lactato desidrogenase e produção de HO-1 por ELISA. Foi realizada ANOVA seguida de teste de Dunnet para múltiplas comparações entre os grupos estudados, considerando significativos valores de p ≤ 0,05. RESULTADOS: A solução de KI (1.000 µM) reduziu a produção de HO-1 no grupo GH (p = 0.0018) e a citotoxicidade no grupo PE (p = 0.0143); o tratamento com KI não afetou a produção de HO-1 por HUVECs incubadas com o plasma do grupo PE. CONCLUSãO: Nossos achados sugerem que o KI atenua os efeitos do plasma de gestantes com GH ocasionando a diminuição da produção de HO-1; plasma do grupo PE não induziu a produção de HO-1 em HUVECs em comparação ao grupo saudável, e nossa hipótese é a de que tal achado pode ser devido a mecanismos pós-transcricionais em resposta a uma superestimulação da produção de HO-1 nos estágios iniciais da gravidez.

Preeclampsia and Gestational Hypertension: Biochemical and Antioxidant Features in Vitro Might Help Understand Different Outcomes / Pré-eclâmpsia e hipertensão gestacional: Fatores bioquímicos e antioxidantes in vitro podem auxiliar no entendimento de resultados clínicos distintos

Abstract Objective Gestational hypertension (GH) is characterized by increased blood pressure after the 20th gestational week; the presence of proteinuria and/or signs of end-organ damage indicate preeclampsia (PE). Heme oxygenase-1 (HO-1) is an antioxidant enzyme with an important role in maintaining endothelial function, and induction of HO-1 by certain molecules shows potential in attenuating the condition's effects over endothelial tissue. HO-1 production can also be stimulated by potassium iodide (KI). Therefore, we evaluated the effects of KI over HO-1 expression in human umbilical vein endothelial cells (HUVECs) incubated with plasma from women diagnosed with GH or PE. Methods Human umbilical vein endothelial cells were incubated with a pool of plasma of healthy pregnant women (n = 12), pregnant women diagnosed with GH (n = 10) or preeclamptic women (n = 11)with or without the addition of KI for 24 hours to evaluate its effect on this enzyme expression. Analysis of variance was performed followed by Dunnet's test for multiple comparisons between groups only or between groups with addition of KI (p ≤ 0.05). Results KI solution (1,000 µM) reduced HO-1 in the gestational hypertension group (p = 0.0018) and cytotoxicity in the preeclamptic group (p = 0.0143); treatment with KI reduced plasma cytotoxicity but did not affect the preeclamptic group's HO-1 expression. Conclusion Our findings suggest that KI alleviates oxidative stress leading to decreased HO-1 expression; plasma from preeclamptic women did not induce the enzyme's expression in HUVECs, and we hypothesize that this is possibly due to inhibitory post-transcriptional mechanisms in response to overexpression of this enzyme during early pregnancy.

Resumo Objetivo A hipertensão gestacional (GH) é caracterizada pelo aumento da pressão sanguínea após a 20ª semana de gestação; a presença de proteinuria e/ou sinais de danos a órgãos como rins, fígado e cérebro indicam pré-eclâmpsia (PE). A heme oxigenase-1 (HO-1) é uma enzima antioxidante com um papel importante na manutenção da função endotelial, e a sua indução por certas moléculas se mostra potencialmente benéfica frente à característica deletéria destas condições sobre o endotélio. Já foi demonstrado anteriormente que a produção de HO-1 pode ser induzida por iodeto de potássio (KI). Portanto, nós avaliamos os efeitos do KI sobre a citotoxicidade e expressão de HO-1 por células de veia de cordão umbilical humano (HUVECs) após incubação com o plasma de mulheres diagnosticadas com GH ou PE. Métodos Células de veia de cordão umbilical humano foram incubadas com pool de plasma de gestantes saudáveis (n = 12), gestantes com GH (n = 10) ou gestantes com PE (n = 11) com ou sem a adição de KI por 24 horas para avaliar a citotoxicidade através da dosagem de lactato desidrogenase e produção de HO-1 por ELISA. Foi realizada ANOVA seguida de teste de Dunnet para múltiplas comparações entre os grupos estudados, considerando significativos valores de p ≤ 0,05. Resultados A solução de KI (1.000 µM) reduziu a produção de HO-1 no grupo GH (p = 0.0018) e a citotoxicidade no grupo PE (p = 0.0143); o tratamento com KI não afetou a produção de HO-1 por HUVECs incubadas com o plasma do grupo PE. Conclusão Nossos achados sugerem que o KI atenua os efeitos do plasma de gestantes com GH ocasionando a diminuição da produção de HO-1; plasma do grupo PE não induziu a produção de HO-1 em HUVECs em comparação ao grupo saudável, e nossa hipótese é a de que tal achado pode ser devido a mecanismos pós-transcricionais em resposta a uma superestimulação da produção de HO-1 nos estágios iniciais da gravidez.

Melatonin and the cardiovascular system in animals: systematic review and meta-analysis.

Melatonin, a hormone released by the pineal gland, demonstrates several effects on the cardiovascular system. Herein, we performed a systematic review and meta-analysis to verify the effects of melatonin in an experimental model of myocardial infarction. We performed a systematic review according to PRISMA recommendations and reviewed MEDLINE, Embase, and Cochrane databases. Only articles in English were considered. A systematic review of the literature published between November 2008 and June 2019 was performed. The meta-analysis was conducted using the RevMan 5.3 program provided by the Cochrane Collaboration. In total, 858 articles were identified, of which 13 were included in this review. The main results of this study revealed that melatonin benefits the cardiovascular system by reducing infarct size, improving cardiac function according to echocardiographic and hemodynamic analyses, affords antioxidant effects, improves the rate of apoptosis, decreases lactate dehydrogenase activity, enhances biometric analyses, and improves protein levels, as analyzed by western blotting and quantitative PCR. In the meta-analysis, we observed a statistically significant decrease in infarct size (mean difference [MD], -20.37 [-23.56, -17.18]), no statistical difference in systolic pressure (MD, -1.75 [-5.47, 1.97]), a statistically significant decrease in lactate dehydrogenase in animals in the melatonin group (MD, -4.61 [-6.83, -2.40]), and a statistically significant improvement in the cardiac ejection fraction (MD, -8.12 [-9.56, -6.69]). On analyzing potential bias, we observed that most studies presented a low risk of bias; two parameters were not included in the analysis, and one parameter had a high risk of bias. Melatonin exerts several effects on the cardiovascular system and could be a useful therapeutic target to combat various cardiovascular diseases.

Determination of misoprostol acid in plasma samples by UPLC-MS/MS with application in a maternal-fetal pharmacokinetic study following a low misoprostol dose vaginally to induce labor.

Misoprostol is a prostaglandin E1 synthetic analogous used for elective interruptions of early pregnancy, treatment of incomplete abortion, postpartum hemorrhage and induction of full-term labor. Its a lipophilic drug, passing by extensive and rapid pre-systemic metabolism into the active metabolite, misoprostol acid (MA). The objective of this study was to develop and validate a highly sensitive method for MA determination in plasma using UPLC-MSMS, with application in a study of maternal-fetal pharmacokinetics in healthy parturients women (n = 10) after administration of 25 µg misoprostol vaginally. The method presented linearity of 2-10 pg/mL and acceptable precision, accuracy, plasma and solution stability. The parturients women presented median (interquartile range) values of AUC0-6 of 68.0 (40.8-84.7) pg.h/mL, Cmax of 21.9 (11.9-30.1) pg/mL and Tmax of 2.25 (0.69-5.00) h. The placental transfer of MA was assessed from the umbilical vein/maternal blood ratios of 1.40 (0.91-2.13) and intervillous space/maternal blood ratios of 0.49 (0.15-3.41). In conclusion, this method presented high sensitivity, being able to quantify MA in plasma samples following a low 25 µg misoprostol administered vaginally aimed to induce labor in parturients women. Additionally, this is the first description of the placental transfer of MA after a vaginal administration of misoprostol.

RPS Brazilian Birth Cohorts Consortium (Ribeirão Preto, Pelotas and São Luís): history, objectives and methods.

This paper describes the history, objectives and methods used by the nine Brazilian cohorts of the RPS Brazilian Birth Cohorts Consortium (Ribeirão Preto, Pelotas and São Luís) Common thematic axes are identified and the objectives, baseline periods, follow-up stages and representativity of the population studied are presented. The Consortium includes three birth cohorts from Ribeirão Preto, São Paulo State (1978/1979, 1994 and 2010), four from Pelotas, Rio Grande do Sul State (1982, 1993, 2004 and 2015), and two from São Luís, Maranhão State (1997 and 2010). The cohorts cover three regions of Brazil, from three distinct states, with marked socioeconomic, cultural and infrastructure differences. The cohorts were started at birth, except for the most recent one in each municipality, where mothers were recruited during pregnancy. The instruments for data collection have been refined in order to approach different exposures during the early phases of life and their long-term influence on the health-disease process. The investigators of the nine cohorts carried out perinatal studies and later studied human capital, mental health, nutrition and precursor signs of noncommunicable diseases. A total of 17,636 liveborns were recruited in Ribeirão Preto, 19,669 in Pelotas, and 7,659 in São Luís. In the studies starting during pregnancy, 1,400 pregnant women were interviewed in Ribeirão Preto, 3,199 in Pelotas, and 1,447 in São Luís. Different strategies were employed to reduce losses to follow-up. This research network allows the analysis of the incidence of diseases and the establishment of possible causal relations that might explain the health outcomes of these populations in order to contribute to the development of governmental actions and health policies more consistent with reality.

Previous preeclampsia and its association with the future development of cardiovascular diseases: a systematic review and meta-analysis.

Preeclampsia is a multifactorial disease. Among these factors, untreated hypertension during pregnancy can result in high morbidity and mortality rates and may also be related to the future development of cardiovascular diseases.Therefore, this systematic review aimed to determine the association of previous preeclampsia with the future development of cardiovascular diseases. Studies on the association between preeclampsia and future cardiovascular diseases published in the last 10 years (2009-2019) were identified from the PubMed/Medline (207 articles), Embase (nine articles), and Cochrane (three articles) databases using the keywords "preeclampsia" and "future cardiovascular diseases", "preeclampsia" and "future heart attack", and "preeclampsia" and "future cardiac disease". After applying the inclusion and exclusion criteria, 15 articles were analyzed by systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The meta-analysis and the determination of the quality of the articles were conducted using RevMan software, version 5.3. Statistically significant differences were observed between the control and previous preeclampsia groups with respect to systolic blood pressure (mean difference [MD] 4.32; 95% confidence interval [95%CI] 3.65, 4.99; p<0.001), diastolic blood pressure (MD): 2.11; 95%CI: 1.68, 2.55; p<0.0001), and insulin level (MD: 2.80; 95% CI: 0.50, 5.11; p<0.001). Body mass index (MD: 2.57, 95%CI: 2.06, 3.07; p=0.0001), total cholesterol (MD: 10.39; 95%CI: 8.91, 11.87; p=0.0001), HDL (MD: 2.83; 95%CI: 2.20, 3.46; p=0.0001), and LDL (MD: 1.77; 95%CI: 0.42, 3.13; p=0.0001) also differed significantly between groups. Thus, the results of the present study showed that women with a history of preeclampsia were more likely to develop cardiovascular disease.

RPS Brazilian Birth Cohorts Consortium (Ribeirão Preto, Pelotas and São Luís): history, objectives and methods / Consórcio RPS (Ribeirão Preto, Pelotas e São Luís) de coortes de nascimento brasileiras: história, objetivos e métodos / Consorcio RPS (Ribeirão Preto, Pelotas y São Luís) cohortes brasileñas de nacimiento: historia, objetivos y métodos

Abstract: This paper describes the history, objectives and methods used by the nine Brazilian cohorts of the RPS Brazilian Birth Cohorts Consortium (Ribeirão Preto, Pelotas and São Luís) Common thematic axes are identified and the objectives, baseline periods, follow-up stages and representativity of the population studied are presented. The Consortium includes three birth cohorts from Ribeirão Preto, São Paulo State (1978/1979, 1994 and 2010), four from Pelotas, Rio Grande do Sul State (1982, 1993, 2004 and 2015), and two from São Luís, Maranhão State (1997 and 2010). The cohorts cover three regions of Brazil, from three distinct states, with marked socioeconomic, cultural and infrastructure differences. The cohorts were started at birth, except for the most recent one in each municipality, where mothers were recruited during pregnancy. The instruments for data collection have been refined in order to approach different exposures during the early phases of life and their long-term influence on the health-disease process. The investigators of the nine cohorts carried out perinatal studies and later studied human capital, mental health, nutrition and precursor signs of noncommunicable diseases. A total of 17,636 liveborns were recruited in Ribeirão Preto, 19,669 in Pelotas, and 7,659 in São Luís. In the studies starting during pregnancy, 1,400 pregnant women were interviewed in Ribeirão Preto, 3,199 in Pelotas, and 1,447 in São Luís. Different strategies were employed to reduce losses to follow-up. This research network allows the analysis of the incidence of diseases and the establishment of possible causal relations that might explain the health outcomes of these populations in order to contribute to the development of governmental actions and health policies more consistent with reality.

Resumo: O artigo descreve a história, objetivos e métodos utilizados pelas nove coortes do Consórcio RPS de Coortes de Nascimento. São identificados eixos temáticos comuns, com apresentação dos objetivos, anos de linha de base, fases de seguimento e representatividade das populações de estudo. O Consórcio inclui três coortes de nascimento de Ribeirão Preto, Estado de São Paulo (1978/1979, 1994 e 2010), quatro de Pelotas, Estado do Rio Grande do Sul (1982, 1993, 2004 e 2015) e duas de São Luís, Estado do Maranhão (1997 e 2010). As coortes provêm de três regiões do Brasil, de três estados diferentes, com importantes diferenças socioeconômicas, culturais e de infraestrutura. As coortes foram iniciadas ao nascer dos participantes, exceto a mais recente em cada município, onde as mães foram recrutadas durante a gestação. Os instrumentos para a coleta de dados foram refinados para aproximar diferentes exposições na primeira infância e a influência, a longo prazo, no processo saúde-doença. Os investigadores das nove coortes realizaram estudos perinatais e depois examinaram o capital humano, saúde mental, nutrição e sinais percursores de doenças crônicas. Um total de 17.636 nascidos vivos foram recrutados em Ribeirão Preto, 19.669 em Pelotas e 7.659 em São Luís. Nas coortes que foram iniciadas durante a gestação, foram entrevistadas 1.400 gestantes em Ribeirão Preto, 3.199 em Pelotas e 1.447 em São Luís. Foram utilizadas diferentes estratégias para reduzir as perdas de seguimento. A rede de pesquisa do Consórcio permite analisar a incidência de doenças e identificar possíveis relações causais que podem explicar os desfechos de saúde nessas populações e contribuir para o desenvolvimento de medidas públicas e políticas de saúde que estejam mais de acordo com as respectivas realidades.

Resumen: El trabajo describe la historia, objetivos y métodos usados por nueve cohortes brasileñas del RPS Consorcio de Cohortes de Nacimiento. Se identificaron los ejes temáticos comunes y los objetivos, así como los periodos de referencia, la presentación del estadio de seguimiento y representatividad de la población estudiada. El consorcio incluye tres cohortes de nacimiento de Ribeirão Preto, Estado de São Paulo (1978/1979, 1994 y 2010), cuatro de Pelotas, Estado del Rio Grande do Sul (1982, 1993, 2004 y 2015), y dos de São Luís, Estado del Maranhão (1997 y 2010). Las cohortes cubren tres regiones de Brasil, de tres estados distintos, con marcadas diferencias socioeconómicas, culturales y de infraestructura. Las cohortes comenzaron con el nacimiento, excepto para la más reciente en cada municipio, donde las madres fueron reclutadas durante la gestación. Los instrumentos para la recogida de datos han sido depurados, con el fin de realizar una aproximación a diferentes exposiciones durante las fases tempranas de la vida y su influencia a largo plazo en el proceso de salud-enfermedad. Se incluyeron a los investigadores de las nueve cohortes, donde se llevaron a cabo estudios perinatales, así como los recursos humanos analizados posteriormente, al igual que la salud mental, nutrición y signos precursores de enfermedades no comunicables. Un total de 17.636 nacidos vivos fueron reclutados en Ribeirão Preto, 19.669 en Pelotas, y 7.659 en São Luís. En los estudios que comenzaron durante el embarazo, 1.400 mujeres embarazadas fueron entrevistadas en Ribeirão Preto, 3.199 en Pelotas, y 1.447 en São Luís. Se usaron diferentes estrategias para reducir pérdidas, con el fin de realizar el seguimiento. Esta red de investigación permite el análisis de la incidencia de enfermedades y el establecimiento de posibles relaciones causales que podrían explicar los resultados de salud de estas poblaciones, con el fin de contribuir al desarrollo de acciones gubernamentales y políticas de salud más consistentes con la realidad.

Melatonin and the cardiovascular system in animals: systematic review and meta-analysis

Melatonin, a hormone released by the pineal gland, demonstrates several effects on the cardiovascular system. Herein, we performed a systematic review and meta-analysis to verify the effects of melatonin in an experimental model of myocardial infarction. We performed a systematic review according to PRISMA recommendations and reviewed MEDLINE, Embase, and Cochrane databases. Only articles in English were considered. A systematic review of the literature published between November 2008 and June 2019 was performed. The meta-analysis was conducted using the RevMan 5.3 program provided by the Cochrane Collaboration. In total, 858 articles were identified, of which 13 were included in this review. The main results of this study revealed that melatonin benefits the cardiovascular system by reducing infarct size, improving cardiac function according to echocardiographic and hemodynamic analyses, affords antioxidant effects, improves the rate of apoptosis, decreases lactate dehydrogenase activity, enhances biometric analyses, and improves protein levels, as analyzed by western blotting and quantitative PCR. In the meta-analysis, we observed a statistically significant decrease in infarct size (mean difference [MD], -20.37 [-23.56, -17.18]), no statistical difference in systolic pressure (MD, -1.75 [-5.47, 1.97]), a statistically significant decrease in lactate dehydrogenase in animals in the melatonin group (MD, -4.61 [-6.83, -2.40]), and a statistically significant improvement in the cardiac ejection fraction (MD, -8.12 [-9.56, -6.69]). On analyzing potential bias, we observed that most studies presented a low risk of bias; two parameters were not included in the analysis, and one parameter had a high risk of bias. Melatonin exerts several effects on the cardiovascular system and could be a useful therapeutic target to combat various cardiovascular diseases.

Previous preeclampsia and its association with the future development of cardiovascular diseases: a systematic review and meta-analysis

Preeclampsia is a multifactorial disease. Among these factors, untreated hypertension during pregnancy can result in high morbidity and mortality rates and may also be related to the future development of cardiovascular diseases.Therefore, this systematic review aimed to determine the association of previous preeclampsia with the future development of cardiovascular diseases. Studies on the association between preeclampsia and future cardiovascular diseases published in the last 10 years (2009-2019) were identified from the PubMed/Medline (207 articles), Embase (nine articles), and Cochrane (three articles) databases using the keywords "preeclampsia" and "future cardiovascular diseases", "preeclampsia" and "future heart attack", and "preeclampsia" and "future cardiac disease". After applying the inclusion and exclusion criteria, 15 articles were analyzed by systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The meta-analysis and the determination of the quality of the articles were conducted using RevMan software, version 5.3. Statistically significant differences were observed between the control and previous preeclampsia groups with respect to systolic blood pressure (mean difference [MD] 4.32; 95% confidence interval [95%CI] 3.65, 4.99; p<0.001), diastolic blood pressure (MD): 2.11; 95%CI: 1.68, 2.55; p<0.0001), and insulin level (MD: 2.80; 95% CI: 0.50, 5.11; p<0.001). Body mass index (MD: 2.57, 95%CI: 2.06, 3.07; p=0.0001), total cholesterol (MD: 10.39; 95%CI: 8.91, 11.87; p=0.0001), HDL (MD: 2.83; 95%CI: 2.20, 3.46; p=0.0001), and LDL (MD: 1.77; 95%CI: 0.42, 3.13; p=0.0001) also differed significantly between groups. Thus, the results of the present study showed that women with a history of preeclampsia were more likely to develop cardiovascular disease.

SIRT1-dependent effects of resveratrol and grape juice in an in vitro model of preeclampsia.

Preeclampsia (PE) is a multifactorial hypertensive disorder of pregnancy that is partly responsible for both maternal and fetal morbidity and mortality levels worldwide. It has been recently discovered that sirtuin-1 (SIRT1) is reduced in the circulation and in an in vitro model of PE. Therefore, in this study, we investigated the effects of trans-resveratrol, a potent antioxidant and activator of SIRT1, on oxidative stress and nitric oxide (NO) production in an in vitro model of PE compared to gestational hypertensive (GH) and healthy pregnant (HP) women. Furthermore, we also evaluated the effects of an acute intake of grape juice on women with PE to assess whether it could mimic in vitro trans-resveratrol supplementation. (1) In the GH group, resveratrol decreased intracellular reactive oxygen species (ROS) and increased their antioxidant capacity, while inhibiting SIRT1 reestablished previous levels. (2) In PE, inhibition of SIRT1 increased antioxidant activity. (3) Intracellular NO and supernatant nitrite levels were increased by inhibiting SIRT1 in the PE group. (4) Grape juice intake increased intracellular NO levels versus before grape juice intake control; however, the inhibition of SIRT1 before grape juice intake initially increased NO, but decreased it 1 h after grape juice intake. In conclusion, activating SIRT1 by using resveratrol alone may not be beneficial to women with PE, and GH and PE seem to have different responsive mechanisms to this molecule. Furthermore, grape juice intake seems to have different effects compared to resveratrol supplementation alone in this in vitro model of PE, demonstrating the potential of the combination of other biologically active molecules from grape juice over the SIRT1-eNOS-NO in PE treatment.

Author Correction: Changes in Infant and Neonatal Mortality and Associated Factors in Eight Cohorts from Three Brazilian Cities.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Interaction Between NOS3 and HMOX1 on Antihypertensive Drug Responsiveness in Preeclampsia.

OBJECTIVE: We examined the interaction of polymorphisms in the genes heme oxygenase-1 (HMOX1) and nitric oxide synthase (NOS3) in patients with preeclampsia (PE) as well as the responsiveness to methyldopa and to total antihypertensive therapy. METHODS: The genes HMOX1 (rs2071746, A/T) and NOS3 (rs1799983, G/T) were genotyped using TaqMan allele discrimination assays (Applied Biosystems, Foster City, CA, USA ), and the levels of enzyme heme oxygenase-1 (HO-1) were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: We found interactions between genotypes of the HMOX-1 and NOS3 genes and responsiveness to methyldopa and that PE genotyped as AT presents lower levels of protein HO-1 compared with AA. CONCLUSION: We found interactions between the HMOX-1 and NOS3 genes and responsiveness to methyldopa and that the HMOX1 polymorphism affects the levels of enzyme HO-1 in responsiveness to methyldopa and to total antihypertensive therapy. These data suggest impact of the combination of these two polymorphisms on antihypertensive responsiveness in PE.

OBJETIVO: Examinamos a interação dos polimorfismos nos genes heme oxigenase-1 (HMOX1) eóxido nítrico sintase (NOS3) em pacientes com pré-eclâmpsia (PE)bem como as capacidades de resposta à metildopa e à terapia anti-hipertensiva. MéTODOS: Os polimorfismos nos genes HMOX1 (rs2071746, A/T) e NOS3 (rs1799983, G/T) foram genotipados usando TaqMan allele discrimination assays (Applied Biosystems, Foster City, CA, EUA), e os níveis da enzima heme oxigenase-1 (HO-1) foram medidos por enzyme-linked immunosorbent assay (ELISA). RESULTADOS: Foram encontradas interações entre os genótipos da HMOX-1 e NOS3 e responsividade à metildopa, e que pacientes genotipados como AT apresentam níveis mais baixos de proteína HO-1 em comparação com o genótipo AA. CONCLUSãO: Foram encontradas interações entre os genes HMOX-1 e NOS3 e responsividade à metildopa e que o polimorfismo localizado no gene HMOX1 afeta os níveis de enzima HO-1 na resposta à metildopa e à terapia anti-hipertensiva. Esses dados sugerem o impacto da combinação desses dois polimorfismos na resposta anti-hipertensiva na PE.

Chiral Discrimination of P-glycoprotein in Parturient Women: Effect of Fluoxetine on Maternal-Fetal Fexofenadine Pharmacokinetics.

BACKGROUND AND OBJECTIVE: Fluoxetine, antidepressant widely-used during pregnancy, is a selective inhibitor for P-glycoprotein (P-gp). Fexofenadine, an in vivo P-gp probe, is an antihistamine drug for seasonal allergic rhinitis and chronic urticaria treatment during pregnancy and it is available as a racemic mixture. This study evaluated the chiral discrimination of P-gp investigating the effect of fluoxetine on maternal-fetal pharmacokinetics of fexofenadine. METHODS: Healthy parturient women received either a single oral dose of 60 mg racemic fexofenadine (Control group; n = 8) or a single oral dose of 40 mg racemic fluoxetine 3 h before a single oral dose of 60 mg racemic fexofenadine (Interaction group; n = 8). Maternal blood and urine samples were collected up to 48 h after fexofenadine administration. At delivery, maternal-placental-fetal blood samples were collected. RESULTS: The maternal pharmacokinetics of fexofenadine was enantioselective (AUC0-∞R-(+)/S-(-) ~ 1.5) in both control and interaction groups. Fluoxetine increased AUC0-∞ (267.7 vs 376.1 ng.h/mL) and decreased oral total clearance (105.1 vs 74.4 L/h) only of S-(-)-fexofenadine, whereas the renal clearance were reduced for both enantiomers, suggesting that the intestinal P-gp-mediated transport of S-(-)-fexofenadine is influenced by fluoxetine to a greater extent that the R-(+)-fexofenadine. However, the transplacental transfer of fexofenadine is low (~16%), non-enantioselective and non-influenced by fluoxetine. CONCLUSIONS: A single oral dose of 40 mg fluoxetine inhibited the intestinal P-gp mediated transport of S-(-)-fexofenadine to a greater extent than R-(+)-fexofenadine in parturient women. However, the placental P-gp did not discriminate fexofenadine enantiomers and was not inhibited by fluoxetine.