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.

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.

Influence of Religiosity on Situational Coping Scores in Women with Malformed Fetuses.

In clinical care settings, religiosity may serve as an important source of support for coping with the prenatal diagnosis of fetal abnormalities. This study evaluated the influence of religiosity on the situational coping of 28 pregnant women with fetal abnormalities. The study was approved by the institutional research ethics committee, and the informed consent document was obtained from all participants included in this study. Validated measures of religiosity and situational coping were used to evaluate data collected. Practical religiosity but not intrinsic religiosity correlated positively and significantly with coping scores. However, the severity of the fetal malformations did not correlate significantly with the scores of maternal coping. The results showed that religious practices were associated with improved coping in women diagnosed with fetal abnormalities and should be encouraged in care settings.

Lopinavir/ritonavir treatment increases the placental transfer of bupivacaine enantiomers in human immunodeficiency virus-infected pregnant women.

AIMS: The present study evaluated the placental transfer and amniotic fluid distribution of bupivacaine enantiomers in health pregnant women and in human immunodeficiency virus (HIV)-infected pregnant women receiving epidural anaesthesia for caesarean section. METHODS: Twelve HIV-infected pregnant women (HIV group) were treated long-term (at least 8 weeks) with lopinavir/ritonavir (400/100 mg twice daily), and 12 healthy pregnant women (Control group) who submitted to epidural anaesthesia with racemic bupivacaine (75 mg) during caesarean section were investigated. At delivery, samples of maternal and fetal blood and amniotic fluid were collected (10-20 min after drug administration). RESULTS: The placental transfer ratio of bupivacaine enantiomers was significantly higher among the pregnant women from the HIV group when compared with those from the Control group (Mann-Whitney test, P ≤ 0.05). Placental transfer ratios (median and 25th - 75th percentiles) for (+)-(R)-bupivacaine were 0.58 (0.38-0.82) in the HIV group vs. 0.25 (0.18-0.33) in the Control group, and for (-)-(S)-bupivacaine, they were 0.54 (0.34-0.69) in the HIV group vs. 0.25 (0.19-0.29) in the Control group. The transplacental distribution of bupivacaine was stereoselective only in the HIV group. The umbilical artery/umbilical vein ratio and amniotic fluid/maternal vein ratio were low and nonstereoselective, and no statistically significant differences were observed between the groups. CONCLUSIONS: This study supports that the placental transfer of both bupivacaine enantiomers was 100% higher in HIV-pregnant women treated with lopinavir/ritonavir when compared with that in healthy pregnant women receiving epidural anaesthesia for caesarean section.

Effect of type 2 diabetes mellitus on the pharmacokinetics and transplacental transfer of nifedipine in hypertensive pregnant women.

AIMS: Diabetes mellitus can inhibit cytochrome P450 3A4, an enzyme responsible for the metabolism of nifedipine, used for the treatment of hypertension in pregnant women. We aimed to assess the effect of type 2 diabetes mellitus (T2DM) on the pharmacokinetics, placental transfer and distribution of nifedipine in amniotic fluid in hypertensive pregnant women. METHODS: The study was conducted in 12 hypertensive pregnant women [control group (CG)] and 10 hypertensive pregnant women with T2DM taking slow-release nifedipine (20 mg, 12/12 h). On the 34th week of gestation, serial blood samples were collected (0-12 h) after administration of the medication. At delivery, samples of maternal and fetal blood and amniotic fluid were collected for determination of nifedipine distribution in these compartments. RESULTS: The median pharmacokinetic parameters of CG were: peak plasma concentration (Cmax ) 26.41 ng ml-1 , time to reach Cmax (tmax ) 1.79 h, area under the plasma concentration vs. time curve from 0-12 h (AUC0-12 ) 235.99 ng.h ml-1 , half-life (t½) 4.34 h, volume of distribution divided by bioavailability (Vd/F) 560.96 l, and ClT /F 84.77 l h-1 . The parameters for T2DM group were: Cmax 23.52 ng ml-1 , tmax 1.48 h, AUC0-12 202.23 ng.h ml-1 , t½ 5.00 h, Vd/F 609.40 l, and apparent total clearance (ClT /F) 98.94 l h-1 . The ratios of plasma concentrations of nifedipine in the umbilical vein, intervillous space and amniotic fluid to those in the maternal vein for CG and T2DM were 0.53 and 0.44, 0.78 and 0.87, respectively, with an amniotic fluid/maternal plasma ratio of 0.05 for both groups. The ratios of plasma concentrations in the umbilical artery to those in the umbilical vein were 0.82 for CG and 0.88 for T2DM. CONCLUSIONS: There was no influence of T2DM on the pharmacokinetics or placental transfer of nifedipine in hypertensive women with controlled diabetes.

Influence of gestational diabetes on the stereoselective pharmacokinetics and placental distribution of metoprolol and its metabolites in parturients.

AIM: To investigate the influence of gestational diabetes mellitus (GDM) on the kinetic disposition and transplacental and amniotic fluid distribution of metoprolol and its metabolites O-desmethylmetoproloic acid and α-hydroxymetoprolol stereoisomers in hypertensive parturients receiving a single dose of the racemic drug. METHODS: The study was conducted on hypertensive parturients with well-controlled GDM (n = 11) and non-diabetic hypertensive parturients (n = 24), all receiving a single 100 mg oral dose of racemic metoprolol tartrate before delivery. Serial maternal blood samples (0-24 h) and umbilical blood and amniotic fluid samples were collected for the quantitation of metoprolol and its metabolite stereoisomers using LC-MS/MS or fluorescence detection. RESULTS: The kinetic disposition of metoprolol and its metabolites was stereoselective in the diabetic and control groups. Well-controlled GDM prolonged tmax for both enantiomers of metoprolol (1.5 vs. 2.5 h R-(+)-MET; 1.5 vs. 2.75 h S-(-)-MET) and O-desmethylmetoproloic acid (2.0 vs. 3.5 h R-(+)-AOMD; 2.0 vs. 3.0 h S-(-)-OAMD), and for the four stereoisomers of α-hydroxymetoprolol (2.0 vs. 3.0 h for 1'S,2R-, 1'R,2R- and 1'R,2S-OHM; 2.0 vs. 3.5 h for 1'S,2S-OHM) and reduced the transplacental distribution of 1'S,2S-, 1'R,2R-, and 1'R,2S-OHM by approximately 20%. CONCLUSIONS: The kinetic disposition of metoprolol was enantioselective, with plasma accumulation of the S-(-)-MET eutomer. Well-controlled GDM prolonged the tmax of metoprolol and O-desmethylmetoproloic acid enantiomers and the α-hydroxymetoprolol stereoisomers and reduced by about 20% the transplacental distribution of 1'S,2S-, 1'R,2R-, and 1'R,2S-OHM. Thus, well-controlled GDM did not change the activity of CYP2D6 and CYP3A involved in metoprolol metabolism.

Assessment of foetal wellbeing in pregnant women subjected to pelvic floor muscle training: a controlled randomised study.

INTRODUCTION AND HYPOTHESIS: The objective was to assess foetal wellbeing in pregnant women subjected to pelvic floor muscle training (PFMT) by evaluating the acute and chronic effects of the procedure using the Doppler method. METHODS: Ninety-six primigravidae with singleton pregnancies and at a low risk of pregnancy complications were randomised to either intervention with PFMT or no intervention. The final analysis included 26 women in the intervention group and 33 in the control group. Women from the intervention group were subjected to a daily PFMT program. Evidence of possible foetal risk was assessed by Doppler and the control group received standard care. The protocol was conducted from 20 to 36 weeks' gestation. The pulsatility indices (PI) of the uterine, umbilical and middle cerebral arteries were determined at 28, 32 and 36 weeks' gestation. The acute effects were determined by comparing the values obtained before and after exercise in the group subjected to PFMT and the chronic effects were determined by comparing the resting values of the trained group with those of the control group. RESULTS: The results obtained showed normal values for the three gestational ages in both groups, with no difference between groups. Comparison before and after exercise showed a significant decline in the PI of uterine artery at 36 weeks without changes in the flow of umbilical and middle cerebral arteries. CONCLUSION: Pelvic floor muscle training in low-risk primigravidae with singleton pregnancies was associated with a significant decline in PI of the uterine artery after exercise, while no significant changes in the flow of the middle cerebral and umbilical arteries were found. The PFMT may be recommended to women as a first-line measure to prevent of urinary incontinence during pregnancy.

A protocol to identify non-classical risk factors for preterm births: the Brazilian Ribeirão Preto and São Luís prenatal cohort (BRISA).

BACKGROUND: Preterm birth is the main cause of morbidity and mortality during the perinatal period. Classical risk factors are held responsible for only 1/3 of preterm births and no current intervention has produced an appreciable reduction of this event. It is necessary to explore new hypotheses and mechanisms of causality by using an integrated approach, collaboration among research groups and less fragmented theoretical-methodological approaches in order to detect new risk factors and to formulate more effective intervention strategies. METHODS: The study will be conducted on a convenience cohort of Brazilian pregnant women recruited at public and private prenatal health services. A total of 1500 pregnant women in São Luís, and 1500 in Ribeirão Preto, will be invited for an interview and for the collection of biological specimens from the 22nd to the 25th week of gestational age (GA). At the time of delivery they will be reinterviewed. GA will be determined using an algorithm based on two criteria: date of last menstruation (DLM) and obstetric ultrasound (OUS) performed at less than 20 weeks of GA. Illicit drug consumption during pregnancy will be determined using a self-applied questionnaire and the following instruments will be used: perceived stress scale, Beck anxiety scale, screening for depression of the Center of Epidemiological Studies (CES-D), experiences of racial discrimination, social network and social support scale of the Medical Outcomes Study and violence (Abuse Assessment Screening and violence questionnaire of the WHO). Bacterial vaginosis, urinary tract infection and periodontal disease will also be identified. Neuroendocrine, immunoinflammatory and medical intervention hypotheses will be tested. The occurrence of elective cesarean section in the absence of labor will be used as a marker of medical intervention. CONCLUSION: Psychosocial, genetic and infectious mechanisms will be selected, since there are indications that they influence preterm birth (PTB). The studies will be conducted in two Brazilian cities with discrepant socioeconomic conditions. The expectation is to identify risk factors for PTB having a greater predictive power than classically studied factors. The final objective is to propose more effective interventions for the reduction of PTB, which, after being tested, might subsidize health policies.

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.

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

Objective: To identify sociodemographic and reproductive risk factors associated with MetS 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 metabolic syndrome and the adjusted relative risk (RR) was calculated. Results: The cohort included 916 women, and 286 (31.2%) of them have metabolic syndrome. MetS was associated with lack of paid work (RR 1.49; 95% CI 1.14-1.95), marital status of without a partner (RR 1.33; 95% CI 1.03-1.72), low educational level (less than 8 years of schooling [RR 1.72; 95% CI 1.23-2.41], 8 to 12 years of schooling [RR 1.37; 95% CI 1.06-1.76], when compared with more than 12 years of schooling), and teenage pregnancy (RR 2.00; 95% CI 1.45-2.77). There was no association between MetS, and the other covariates studied. Conclusion: Metabolic syndrome in a population of women in the fourth decade of life was associated with lack of employment, lack of a partner, low educational level, and teenage pregnancy.

Stereoselective determination of metoprolol and its metabolite α-hydroxymetoprolol in plasma by LC-MS/MS: application to pharmacokinetics during pregnancy.

Metoprolol is available for clinical use as a racemic mixture. The S-(-)-metoprolol enantiomer is the one expressing higher activity in the blockade of the ß(1)-adrenergic receptor. The α-hydroxymetoprolol metabolite also has activity in the blockade of the ß(1)-adrenergic receptor. The present study describes the development and validation of a stereoselective method for sequential analysis of metoprolol and of α-hydroxymetoprolol in plasma using high-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS). 1-ml aliquots of plasma were extracted with dichloromethane : diisopropyl ether (1:1, v/v). Metoprolol enantiomers and α-hydroxymetoprolol isomers were separated on a Chiralpak AD column (Daicel Chemical Industries, New York, NY, USA) and quantitated by LC-MS/MS. The limit of quantitation obtained was 0.2 ng of each metoprolol enantiomer/ml plasma and 0.1 ng/ml of each α-hydroxymetoprolol isomer/ml plasma. The method was applied to the study of kinetic disposition of metoprolol in plasma samples collected up to 24 h after the administration of a single oral dose of 100-mg metoprolol tartrate to a hypertensive parturient with a gestational age of 42 weeks. The clinical study showed that the metoprolol pharmakokinetics is enantioselective, with the observation of higher area under the curve (AUC)(0-∞) values for S-(-)-metoprolol (AUC(S-(-)) /AUC(R-(+)) = 1.81) and the favoring of the formation of the new chiral center 1'R of α-hydroxymetoprolol (AUC(0-∞) (1'R/1'S) = 2.78).

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.

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.

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.

Metformin pharmacokinetics in nondiabetic pregnant women with polycystic ovary syndrome.

BACKGROUND: The use of metformin throughout gestation by pregnant women with polycystic ovary syndrome (PCOS) significantly reduces the number of first trimester spontaneous abortions and the rate of occurrence of gestational diabetes. OBJECTIVE: The objective of this study was to investigate the pharmacokinetics and the placental transfer of metformin in pregnant women with PCOS. PATIENTS AND METHODS: Eight pregnant women with PCOS taking 850 mg metformin every 12 h during the third trimester of pregnancy were evaluated. Maternal blood samples were collected at steady state during the dose interval (0-12 h). Maternal and umbilical cord blood samples were also obtained at delivery. Metformin plasma concentrations were analyzed by high-performance liquid chromatography, and pharmacokinetic parameters were determined using a non-compartmental model. Data are reported as median and minimum and maximum values. RESULTS: Metformin pharmacokinetic parameters were: t(½), 3.8 (2.8-5.4) h; t(max), 2.0 (0.5-3.0) h; C(max), 1.4 (0.5-2.1) mg/L; C(mean), 0.5 (0.2-0.9) mg/L; AUC(0-12), 6.4 (1.1-9.2) mg h/L; Cl/f, 105 (60-274) L/h; Vd/f, 551 (385-1173) L; median fluctuation, 89 (79-95)%. Umbilical/maternal metformin plasma concentration ratios were 0.7 (0.4-1.3). CONCLUSION: Metformin oral clearance (Cl/f) had increased in our patients relative to nonpregnant healthy volunteers or diabetic patients. Therefore, lower plasma metformin concentrations were observed for nondiabetic pregnant women with PCOS. Future studies should be conducted to demonstrate the therapeutic efficacy of metformin during pregnancy. Caution is warranted as umbilical/maternal metformin plasma concentrations ratios of around 0.7 require metformin dosage adjustment.

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.

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.

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.