Sérgio Pereira da Cunha

A morphometric study of maternal smoking on apoptosis in the syncytiotrophoblast

Objectives: To study syncytiotrophoblast apoptosis in the placenta of smoking and non‐smoking pregnant women. Methods: Twelve neonates, pregnancies and placentas were available for study. Eight mothers smoked during pregnancy and the remaining four were non‐smokers used as control subjects. The main outcome measure was the apoptotic syncytiotrophoblast index for each group. Apoptosis was detected by immunohistochemistry using the TUNEL method and quantitatively measured using a Merz grid. The apoptotic syncytiotrophoblast index was calculated as the ratio of mean apoptotic labeling to percent terminal villus area using high‐power field microscopy. Results: Significant differences in apoptotic syncytiotrophoblast index were observed between the control group (15.06 ± 3.72) and the smoker group (1.66 ± 1.74) (P < 0.0001, Mann‐Whitney test), but no differences were detected in clinical or morphometric data between groups. Conclusions: The human placental syncytiotrophoblast undergoes apoptosis and this process is associated with inhibition of apoptosis by the smoking habit. The same way as the presence of trophoblast apoptosis is associated with modifications of the maternal‐fetal exchange, the inhibitory effect of the smoking habit on syncytiotrophoblast could be responsible for the poor prognosis of pregnancy in the presence of maternal smoking.

Infecção urinária na gravidez: análise dos métodos para diagnóstico e do tratamento

Objetivos: avaliar os aspectos diagnosticos, terapeuticos e as complicacoes dos casos de infeccao do trato urinario (ITU) sintomatica durante a gestacao, que necessitaram de internacao hospitalar. Metodos: foram incluidas 136 gravidas com diagnostico clinico de pielonefrite. Foram avaliados: a idade e paridade da paciente, idade gestacional em que foi feito o diagnostico, antecedentes de importância epidemiologica, propedeutica laboratorial para avaliacao da infeccao urinaria, tratamento e evolucao clinica, antimicrobianoprofilaxia e complicacoes. Resultados: pielonefrite foi diagnosticada, nas mesmas proporcoes, em todas as idades gestacionais. Houve maior incidencia de ITU entre as primigestas. Apenas 29,3% das gestantes apresentaram historia previa de ITU. Observou-se que 57,0% das pacientes apresentaram anemia e 93,0% mostraram analise urinaria alterada. A Escherichia coli foi o uropatogeno mais prevalente (75,8% dos casos), com baixos percentuais de sensibilidade a ampicilina (60,6%) e a cefalotina (63,6%) e altos percentuais de sensibilidade a cefuroxima (95,5%). A maior taxa de melhora clinica foi obtida entre as gestantes tratadas com cefuroxima (95,7%). A antimicrobianoprofilaxia foi necessaria em 11,0% das pacientes. O trabalho de parto pre-termo ocorreu em 33,3% das gestantes que deram a luz em nosso servico, e o parto pre-termo em 18,9%. Conclusoes: esses resultados reforcam a necessidade do diagnostico precoce e tratamento efetivo da ITU em gestantes, a fim de evitar a ocorrencia frequente de complicacoes perinatais, como o trabalho de parto e o parto pre-termo. Destaca-se a necessidade de avaliacao periodica do padrao de sensibilidade dos agentes etiologicos prevalentes aos antimicrobianos de uso permitido durante a gestacao, adotando-se a cefuroxima como o antimicrobiano de escolha para o tratamento das ITU na gestacao.Purpose: to assess the diagnostic and therapeutic aspects and the complications of symptomatic urinary tract infections (UTI) during pregnancy of patients who were hospitalized. Methods: a total of 136 pregnant women with a clinical diagnosis of pyelonephritis were studied. The studied parameters were: age and parity of patients, gestational age of diagnosis, epidemiologic aspects, laboratory evaluation for UTI, treatment and clinic evolution, prophylaxis and complications. Results: pyelonephritis was diagnosed at the same proportions at all gestational ages. The incidence of UTI was higher among primigravidae. Only 29.3% of the pregnant women had a previous history of UTI; 57.0% were anemic and 93.0% had altered urinalysis. Escherichia coli was the most prevalent uropathogen (75.8% of cases), with low percentages of sensitivity to ampicillin (60.6%) and high percentages of sensitivity to cefuroxime (95,5%). The highest rate of clinical improvement was obtained for the pregnant women treated with cefuroxime (95.7%). Prophylaxis was needed in 11.0% of the patients. Preterm labor occurred in 33.3% of the pregnant women who delivered in our service and preterm delivery occurred in 18.9%. Conclusions: the present results support the need for an early diagnosis and effective treatment of UTI in pregnant women in order to prevent the frequent occurrence of perinatal complications such as premature labor and delivery. We emphasize the need of a periodical evaluation of the pattern of sensitivity of the etiologic agents to the antimicrobials allowed for use during pregnancy, with cefuroxime being adopted as the antibiotic of choice for the treatment of UTI during pregnancy.

Distribution of fentanyl in the placental intervillous space and in the different maternal and fetal compartments in term pregnant women

BackgroundFentanyl is used in obstetrical practice to promote analgesia and anesthesia during labor and in cesarean delivery, with rapid and short-term effects.ObjectiveTo determine fentanyl concentrations in maternal plasma, in the placental intervillous space, and in the umbilical artery and vein in term pregnant women.Patients and methodsTen healthy pregnant women underwent epidural anesthesia with fentanyl plus bupivacaine and lidocaine, and fentanyl concentrations were determined in the various maternal and fetal compartments, including the placental intervillous space, which has not been previously studied in the literature.ResultsThe ratios of fentanyl concentrations in the various maternal and fetal compartments revealed an 86% rate of placental fentanyl transfer. The highest fentanyl concentrations were detected in the placental intervillous space, being 2.19 times higher than in maternal plasma, 2.8 times higher than in the umbilical vein and 3.6 times higher than in the umbilical artery, with no significant differences between the umbilical vein and artery, demonstrating that there was no drug uptake by fetal tissues nor metabolism of the drug by the fetus despite the high rates of placental transfer.ConclusionThe present study demonstrated that the placental intervillous space acted as a site of fentanyl deposit, a fact that may be explained by two hypotheses: (1) the blood collected from the placental intervillous space is arterial and, according to some investigators, the arterial plasma concentrations of the drugs administered to patients undergoing epidural anesthesia are higher than the venous concentrations, and (2) a possible role of P-glycoprotein (P-gp).

Influence of gestational diabetes mellitus on the stereoselective kinetic disposition and metabolism of labetalol in hypertensive patients.

PurposeThis study investigated the influence of gestational diabetes mellitus on the kinetic disposition and stereoselective metabolism of labetalol administered intravenously or orally.MethodsThirty hypertensive women during the last trimester of pregnancy were divided into four groups: non-diabetic and diabetic women treated with intravenous or oral labetalol.ResultsThe pharmacokinetics of labetalol was not stereoselective in diabetic or non-diabetic pregnant women receiving the drug intravenously. However, oral administration of labetalol resulted in lower values of the area under the plasma concentration versus time curve (AUC) for the β-blocker (RR) than for the other enantiomers in both diabetic and non-diabetic women. Gestational diabetes mellitus caused changes in the kinetic disposition of the labetalol stereoisomers when administered orally. The AUC values for the less potent adrenoceptor antagonist (SS) and for the α-blocking (SR) isomers were higher in diabetic than in non-diabetic pregnant women.ConclusionsThe approximately 100% higher AUC values obtained for the (SR) isomer in diabetic pregnant women treated with oral labetalol may be of clinical relevance in terms of the α-blocking activity of this isomer.

Distribution of Bupivacaine Enantiomers and Lidocaine and Its Metabolite in the Placental Intervillous Space and in the Different Maternal and Fetal Compartments in Term Pregnant Women

The aim of this study is to determine the concentrations of lidocaine and its metabolite, monoethylglycine xylidide (MEGX), and of the enantiomers of bupivacaine in maternal and fetal compartments. Ten healthy pregnant women were submitted to epidural anesthesia. Drug concentrations were determined in the maternal vein, fetal umbilical artery and vein, and the placental intervillous space. The highest concentrations of the bupivacaine enantiomers lidocaine and of lidocaine and of its MEGX metabolite were detected in maternal plasma and in the placental intervillous space. The placental transfer was 33% for the (+)‐(R)‐bupivacaine enantiomer and 31% for the (−)‐(S)‐bupivacaine enantiomer. For lidocaine and its MEGX metabolite, respective placental transfers were 60% and 43%. Lidocaine concentration in the fetal umbilical vein was 1.46 times higher than in the fetal umbilical artery. The highest concentrations of lidocaine and its metabolite and of the enantiomers of bupivacaine were detected in the placental intervillous space. The higher lidocaine concentrations in the fetal umbilical vein than in the fetal umbilical artery suggest that there was tissue uptake of the drug or drug metabolization by the fetus.

Placental transfer of bupivacaine enantiomers in normal pregnant women receiving epidural anesthesia for cesarean section

Professor Dahlqvist, Bupivacaine [(±)-1-butyl-N-(2,6-dimethylphenyl)-2piperidine carboxamide] is probably the most frequently used drug for epidural anesthesia in obstetrics and is available as a racemic mixture of the (+)-(R) and (−)-(S) enantiomers [1, 2]. It has been that reported bupivacaine can cause adverse cardiovascular events in pregnant women, but only following its accidental injection into the intravascular space during anesthetic procedures [2]. However, other investigators have reported that the concentrations used in obstetrical procedures are so low that they do not raise concern in terms of adverse effects, even when accidentally injected into the intravascular space [3]. Bupivacaine is a chiral drug, and one of its enantiomers has been found to have a less toxic profile than that of racemic bupivacaine itself: (−)-S bupivacaine is equal to racemic bupivacaine in terms of local anesthetic potency, but it has a reduced potential for central nervous system and cardiovascular toxicity [4]. Studies on human volunteers have demonstrated differences in cardiotoxicity between (−)-S bupivacaine and racemic bupivacaine, with the reduction in myocardia mobility being 40–60% less following the infusion of the former than after racemic bupivacaine infusion, as measured by acceleration index, stroke index and ejection fraction [1]. Epidural 0.5% (−)-S bupivacaine and 0.5% racemic bupivacaine are equally efficacious anesthesia in cesarean deliveries. In addition, following the administration of (−)-S bupivacaine and racemic bupivacaine, no significant differences were observed between them in terms of maximum plasma concentration or area under the plasma drug concentration versus time curve [4]. Based on these findings, the use of racemic bupivacaine is currently being questioned, and it has been proposed that it should be definitively replaced with its enantiomers, which are considered to be safer. We report here a clinical evaluation of mothers and newborn infants that was carried out with the aim of determining maternal concentrations and the placental transfer of the enantiomers of bupivacaine in pregnant women undergoing cesarean section with epidural anesthesia. The concentrations of the enantiomers of bupivacaine and their placental transfer were determined in ten healthy pregnant women with similar anthropometric characteristics who were being given a cesarean section due to obstetrical indication. The patients were selected in an aleatory manner, without randomization. The study was approved by the Ethics Committee of the University Hospital, Faculty of Medicine of Ribeirão Preto, University of São Paulo, and all patients gave written informed consent to participate. Eur J Clin Pharmacol (2007) 63:523–526 DOI 10.1007/s00228-007-0275-7

Transferência placentária de drogas

Gravidas podem depender do uso de medicacoes para minimizar os agravos da doenca preexistente. A gravidez, por si so, pode causar situacoes que comprometem o bem-estar materno, como nauseas e vomitos, as quais necessitam de tratamento. O obstetra deve estar atento a transferencia placentaria de drogas e a exposicao do feto a agentes teratogenicos ou toxicos, que podem comprometer o seu desenvolvimento ou mesmo sua vida futura.O transporte atraves da placenta envolve o movimento de moleculas entre tres compartimentos: sangue materno, citoplasma do sinciciotrofoblasto e sangue fetal. Esse movimento pode ocorrer pelos seguintes mecanismos: difusao simples, difusao facilitada, transporte ativo, bombas classe P, V, F e grande familia ABC e endocitose. Com o uso de anticonvulsivantes a incidencia de malformacoes maiores em recem-nascidos expostos e de 4 a 6%, comparado com 2 a 4% na populacao geral. A politerapia e mais lesiva, especialmente se o acido valproico e a hidantoina fazem parte da associacao. Para as pacientes epilepticas clinicamente assintomaticas ha dois anos recomenda-se a suspensao da drogas em uso, porem se apresentam crises, torna-se prudente consultar neurologista para discussao da terapia anticonvulsivante com melhores beneficios e menores efeitos colaterais. Os anestesicos locais e os opioides sao largamente utilizados durante a resolucao da gestacao. A lidocaina utilizada como anestesico por via perineal para episiotomia, na dose fixa de 400 mg, apresenta alta concentracao plasmatica materna e alta taxa de transferencia placentaria no momento do nascimento, que vem alertar para o cuidado no uso de doses repetidas. A bupivacaina administrada por via epidural representa anestesico seguro, apresentando-se na forma racemica e com transferencia placentaria em torno de 30%. A fentanila, anestesico opioide, utilizado por via epidural na resolucao por cesariana, na dose fixa de 0,10 mg, apresenta alta taxa de transferencia placentaria, da ordem de 90%, o que vem alertar para cautela no uso de doses repetidas em analgesia durante o trabalho de parto.

Stereoselective analysis of labetalol in human plasma by LC-MS/MS: Application to pharmacokinetics

Labetalol is clinically available as a mixture of two racemates (four stereoisomers). The stereoisomer (R,R) has as main activity the beta1-antagonism and the stereoisomer (S,R) is highly selective for the alpha1 adrenoceptor and is responsible for most of the alpha-blocker activity. In the present investigation, a method for the analysis of labetalol stereoisomers in human plasma was developed and applied to pharmacokinetic studies. Plasma samples (0.5 ml) were extracted with methyl tert-butyl ether at pH 9.5. The four labetalol stereoisomers were analyzed by LC-MS/MS on a Chirobiotic V column using a mobile phase consisting of methanol, acetic acid, and diethylamine, with a recovery of more than 90% for all four. The quantitation limit was 0.5 ng/ml and linearity was observed at 250 ng/ml plasma for each stereoisomer. Studies of precision and accuracy presented coefficients of variation and percentage inaccuracy of less than 15%, indicating that the method is precise and accurate. The method was applied to the study of the kinetic disposition of labetalol over a period of 12 h after oral administration of a single 100 mg dose to a hypertensive pregnant woman. The clinical study revealed stereoselectivity in the pharmacokinetics of labetalol, with a lower plasma proportion for the active stereoisomers (R,R)-labetalol and (S,R)-labetalol. The stereoselectivity observed after oral administration is due to the hepatic metabolism and the first pass effect, with an AUC(R,R)/AUC(S,S) ratio of 0.5.

Dopplervelocimetria das artérias uterinas na predição de complicações em gestações de baixo risco

OBJETIVO: determinar a validade da dopplervelocimetria das arterias uterinas na predicao de complicacoes da gestacao em populacao de nuliparas de baixo risco. METODOS: foi conduzido estudo prospectivo que incluiu 45 pacientes primigestas, sem historia de doencas cronicas. A dopplervelocimetria das arterias uterinas foi realizada entre 24 e 26 semanas, com determinacao do indice de resistencia (IR), indice de pulsatilidade (IP), relacao S/D e a presenca ou ausencia de incisura na onda de velocidade de fluxo. Na analise estatistica foi utilizado o teste de Mann-Whitney para amostras nao parametricas e o teste exato de Fisher foi utilizado na avaliacao dos parâmentros qualitativos. RESULTADOS: complicacoes da gravidez foram observadas em 12 pacientes, com quatro casos de pre-eclâmpsia, um caso de recem-nascido pequeno para a idade gestacional (PIG), um caso de PIG e parto pre-termo (PPT), tres casos de PPT, um caso de centralizacao fetal e dois casos de meconio espesso no liquido amniotico no momento da resolucao da gestacao. Notamos que o IR (mediana 0,56 x 0,68), IP (mediana 0,98 x 1,29) e a relacao S/D (mediana 2,2 x 2,9) estavam mais elevados no exame realizado entre a 24 e a 26a semana nas pacientes que apresentaram qualquer complicacao da gestacao e nao mostrou diferenca nos casos de pre-eclâmpsia ou PIG. A presenca de incisura bilateral apresentou sensibilidade de 100 e 90%, especificidade de 60,6 e 62,5%, valor preditivo positivo (VPP) de 29,4 e 42,9%, valor preditivo negativo (VPN) de 100 e 95,2% para a deteccao de pre-eclâmpsia ou PIG e qualquer complicacao da gestacao, respectivamente. A dopplervelocimetria alterada apresentou sensibilidade de 83,3 e 83,3%, especificidade de 69,7 e 69,7%, VPP de 33,3 e 50,0%, VPN de 95,8 e 92,0% para a deteccao de pre-eclâmpsia ou PIG e qualquer complicacao da gestacao, respectivamente. CONCLUSAO: indices de alta impedância e a presenca de incisura bilateral nas arterias uterinas entre a 24a e a 26a semana de gestacao podem ser bons indicadores de complicacoes gestacionais e perinatais.

Avaliação prospectiva do índice de líquido amniótico em gestações normais e complicadas

OBJECTIVE: To prospectively analyze the amniotic fluid index of low-risk pregnant women who presented or not complications during pregnancy and perinatal period. MATERIALS AND METHODS: The amniotic fluid index was prospectively studied in 45 first pregnancy women with no diseases at study entry. The amniotic fluid index was determined at four time points during pregnancy - 18-20, 24-26, 28-30 and 34-36 weeks - and the values were correlated with the appearance of pregnancy and perinatal complications, uterine artery Doppler findings, gestational age at delivery, route of delivery, and newborn weight. RESULTS: Amniotic fluid index was not significantly different among patients with normal and high risk pregnancies at any of the four time points studied. Likewise, there was no association with gestational age at delivery, route of delivery or newborn weight. The mean amniotic fluid index at 28-30 weeks was higher (p = 0.004) in patients with bilateral incisure than in patients with normal Doppler. CONCLUSION: Prospective evaluation of amniotic fluid index in low-risk pregnancies does not seem to be a good predictor of complications during pregnancy or perinatal period.