El embarazo y los efectos que produce en la salud de las mujeres VIH positivas / Pregnancy and the effects it produces on the health of HIV positive women

INTRODUCCIÓN: Existen 35 millones de casos de infección por el virus de la inmunodeficiencia humana (VIH) en el mundo, y de ellos, 15 millones corresponden a mujeres en edad fértil. El embarazo en las mujeres seropositivas genera efectos relevantes que afectan la condición psicosocial y física. Los cambios que genera el embarazo en una mujer VIH positiva se relacionan con resultados perinatales adversos, como hemorragia posparto, sepsis puerperal, parto prematuro y mortalidad. OBJETIVO: Conocer los efectos físicos y psicosociales que tiene el embarazo en la evolución de la mujer portadora del VIH. MÉTODO: Revisión narrativa. Se realiza un análisis de contenido de fuentes primarias obtenidas mediante búsqueda en las bases de datos CINAHL, PubMed y SciELO. La búsqueda abarcó un periodo de 10 años, en idioma español e inglés. Para la presente investigación se incluyen 22 artículos, de los que se consideraron las secciones de resultados y conclusiones. RESULTADOS: Se seleccionaron inicialmente 318 artículos y 22 fueron elegibles para su inclusión. En esta revisión se plantean tres dimensiones de análisis psicosocial, fisiopatología y características clínicas, y tratamiento farmacológico. La literatura evidencia un efecto psicológico negativo en la población de estudio, y en cuanto al tratamiento se manifiesta un escaso porcentaje de eventos adversos frente a la terapia antirretroviral, por lo que los beneficios superan los riesgos. CONCLUSIONES: Las tres dimensiones planteadas se relacionan entre sí, definiendo los efectos del embarazo en mujeres VIH positivas y lo que conlleva esta condición en la salud de la madre. Se identificaron diversos problemas que afectan la salud de las mujeres seropositiva que se embarazan. Sin embargo, estas mujeres pueden embarazarse siguiendo un tratamiento óptimo, con atenciones de salud en periodos regulares, evitando así la mayoría de los efectos que pueden afectar su salud.

INTRODUCTION: There are 35 million cases of human immunodeficiency virus (HIV) worldwide, 15 million correspond to women of childbearing age. This pregnancy condition in seropositive women generates relevant effects that affect the psychosocial and physical condition. The changes generated by pregnancy in an HIV positive woman are related to adverse perinatal results such as postpartum hemorrhage, puerperal sepsis, premature delivery and mortality. OBJECTIVE: To know the physical and psychosocial effects that pregnancy has on the evolution of women with HIV. METHOD: Narrative review. Content analysis of primary sources obtained through searches in the CINAHL, PubMed and SciELO databases is performed. The search was carried out within a 10-year range, in Spanish and English. For the present investigation 22 articles are included. The sections for the analysis were results and conclusions. RESULTS: 318 articles were initially selected, 22 articles were eligible for inclusion. In this review, three dimensions of psychosocial analysis, pathophysiology and clinical characteristics, and pharmacological treatment are proposed. The literature shows the negative psychological effect in the study population, in terms of treatment there is a low percentage of adverse events compared to ART, so the benefits outweigh the risks. CONCLUSIONS: The three dimensions raised are related to each other, defining the effects of pregnancy in HIV positive women and what the condition entails on the mothers health. Various problems were identified that affect the health of an HIV-positive woman who becomes pregnant. However, these HIV positive women can become pregnant, following optimal treatment, with regular health care, thus avoiding most of the effects that can affect her health.

Prevención de la transmisión maternoinfantil del virus de la hepatitis B. directrices sobre la profilaxis con antivirales en el embarazo / Prevention of mother-to-child transmission of hepatitis B virus. guidelines on antiviral prophylaxis in pregnancy

Según estimaciones de la Organización Mundial de la Salud (OMS), en el 2015 257 millones de personas en el mundo tenían la infección crónica por el virus de la hepatitis B (VHB) y 900 000 fallecieron a causa de ella, en la mayor parte de los casos de cirrosis o carcinoma hepatocelular. La mayoría de las defunciones asociadas con el VHB en personas adultas obedecen a infecciones contraídas al nacer o en los cinco primeros años de vida. En mayo del 2016, la Asamblea Mundial de la Salud aprobó la Estrategia mundial del sector de la salud contra las hepatitis víricas 2016-2021, en la que se hace un llamado a eliminar las hepatitis virales como amenaza de salud pública ­definida como una reducción de 90% de la incidencia de infecciones y una reducción de 65% de la mortalidad­ para el 2030. La eliminación de la infección por el VHB como amenaza de salud pública conlleva la necesidad de reducir la prevalencia del antígeno de superficie del virus de la hepatitis B (HBsAg) a menos de 0,1% en los niños de 5 años de edad. Esta meta se puede lograr mediante la vacunación de todos los recién nacidos contra la hepatitis B y otras intervenciones orientadas a prevenir la transmisión maternoinfantil del VHB

Synergistic action of estradiol and PGE2 on endometrial transcriptome in vivo resembles pregnancy effects better than estradiol alone†.

Successful pregnancy establishment in mammals depends on numerous interactions between embryos and the maternal organism. Estradiol-17ß (E2) is the primary embryonic signal in the pig, and its importance has been questioned recently. However, E2 is not the only molecule of embryonic origin. In pigs, prostaglandin E2 (PGE2) is abundantly synthesized and secreted by conceptuses and endometrium. The present study aimed to determine the role of PGE2 and its simultaneous action with E2 in changes in porcine endometrial transcriptome during pregnancy establishment. The effects of PGE2 and PGE2 acting with E2 were studied using an in vivo model of intrauterine hormone infusions, and were compared to the effects of E2 alone and conceptuses' presence on day 12 of pregnancy. The endometrial transcriptome was profiled using gene expression microarrays followed by statistical analyses. Downstream analyses were performed using bioinformatics tools. Differential expression of selected genes was verified by quantitative polymerase chain reaction. Microarray analysis revealed 2413 differentially expressed genes (DEGs) in the endometrium treated simultaneously with PGE2 and E2 (P < 0.01). No significant effect of PGE2 administered alone on endometrial transcriptome was detected. Gene ontology annotations enriched for DEGs were related to multiple processes such as: focal adhesion, vascularization, cell migration and proliferation, glucose metabolism, tissue remodeling, and activation of immune response. Simultaneous administration of E2 and PGE2 induced more changes within endometrial transcriptome characteristic to pregnancy than infusion of E2 alone. The present findings suggest that synergistic action of estradiol-17ß and PGE2 resembles the effects of pregnancy on endometrial transcriptome better than E2 alone.

Manejo anestésico de la paciente de urgencia embarazada / Pregnant patient in emergency

Laparoscopic apendicectomy posterior fossa surgery in the sitting position in a pregnant patient with cerebellopontine angle meningioma. A review is made of those anatomical and physiological changes that occur during pregnancy, that may affect anesthesia administration. Emphasis is made in upper airway, respiratory function, cardiovascular and gastrointestinal systems. Pharmacokinetic and pharmacodynamic changes that are relevant to the administration of general and regional anesthesia are described. The most suitable time for surgery is discussed and is concluded that elective surgery must not be performed during pregnancy and it should be postponed until after delivery. In some cases, immediately after, such as tubal sterilization, and others, after normalization of physiological parameters. A remark is made regarding teratogenicity: Although there is a well-known effect of anesthetic drugs on cell formation, mitosis and DNA synthesis (which participate in cell differentiation and organogenesis), any significant change in function or morphology of a child, secondary to a prenatal treatments (such as, anesthetic management) may eventually affect the outcome. Finally, recommendations are made regarding the anesthetic techniques of choice. There is not a single optimal technique for all cases but becomes clear that maintaining maternal oxygenation and uteroplacental flow are the key. Whichever technique is chosen, it is paramount to avoid hypoxemia and acidosis, maintaining normocarbia and normothermia, treating hypotension aggressively; however, in general when a regional technique is feasible, its use is preferable.

La apendicectomía laparoscópica es la cirugía más frecuente durante el embarazo. El Colegio Americano de Obstetras y Ginecólogos (ACOG), sugiere que es importante contactar a un obstetra antes de realizar la cirugía. Se hace una revisión de los cambios anatómicos y fisiológicos que ocurren durante el embarazo más relacionados con la administración de anestesia, especialmente en la vía aérea superior, en la función respiratoria, en el sistema cardiovascular y a nivel gastrointestinal. Se describen los cambios farmacológicos, farmacocinéticos y farmacodinámicos implicados con la administración de anestesia general y regional. Se discute el momento más adecuado para la realización de una cirugía: una cirugía electiva no debe realizarse durante el embarazo, sino que debe postergarse hasta después del parto; algunas inmediatamente después, como la esterilización tubaria y otras, después que los parámetros fisiológicos hayan vuelto a la normalidad. Se hace una referencia a la teratogenocidad, que no solo es el efecto de las drogas usadas en anestesia que pudieran afectar la formación celular, mitosis y síntesis de ADN, que participan en la diferenciación celular y la organogénesis, sino a cualquier cambio significativo en la función o morfología de un niño, secundario a algún tratamiento prenatal (en este caso, el manejo anestésico). Finalmente, se recomienda una técnica anestésica: no existe una única técnica óptima en la medida de que se mantenga la oxigenación materna y el flujo uteroplacentario. Cualquiera sea la técnica elegida, lo importante es evitar la hipoxemia y la acidosis, mantener la normocarbia y la normotermia, y tratar de manera agresiva la hipotensión arterial; sin embargo, en términos generales, cuando es posible, se prefiere una técnica regional.

Prenatal exposure to pesticides and risk for holoprosencephaly: a case-control study.

BACKGROUND: Pesticide exposure during susceptible windows and at certain doses are linked to numerous birth defects. Early experimental evidence suggests an association between active ingredients in pesticides and holoprosencephaly (HPE), the most common malformation of the forebrain in humans (1 in 250 embryos). No human studies to date have examined the association. This study investigated pesticides during multiple windows of exposure and fetal risk for HPE. It is hypothesized that pre-conception and early pregnancy, the time of brain development in utero, are the most critical windows of exposure. METHODS: A questionnaire was developed for this retrospective case-control study to estimate household, occupational, and environmental pesticide exposures. Four windows of exposure were considered: preconception, early, mid and late pregnancy. Cases were identified through the National Human Genome Research Institute's ongoing clinical studies of HPE. Similarly, controls were identified as children with Williams-Beuren syndrome, a genetic syndrome also characterized by congenital malformations, but etiologically unrelated to HPE. We assessed for differences in odds of exposures to pesticides between cases and controls. RESULTS: Findings from 91 cases and 56 controls showed an increased risk for HPE with reports of maternal exposure during pregnancy to select pesticides including personal insect repellants (adjusted odds ratio (aOR) 2.89, confidence interval (CI): 0.96-9.50) and insecticides and acaricides for pets (aOR 3.84, CI:1.04-16.32). Exposure to household pest control products during the preconception period or during pregnancy was associated with increased risk for HPE (aOR 2.60, OR: 0.84-8.68). No associations were found for occupational exposures to pesticides during pregnancy (aOR: 1.15, CI: 0.11-11.42), although exposure rates were low. Higher likelihood for HPE was also observed with residency next to an agricultural field (aOR 3.24, CI: 0.94-12.31). CONCLUSIONS: Observational findings are consistent with experimental evidence and suggest that exposure to personal, household, and agricultural pesticides during pregnancy may increase risk for HPE. Further investigations of gene by environment interactions are warranted.

Effects of maternal bisphenol A diglycidyl ether exposure during gestation and lactation on behavior and brain development of the offspring.

Bisphenol A diglycidyl ether (BADGE) is an epoxy resin used for the inner coating of canned food and beverages. BADGE can easily migrate from the containers and become a contaminant. In this study, we examined the effects of BADGE exposure to the dams on the behavioral, structural, and developmental abnormalities in the offspring. Female pregnant mice were fed with a diet containing BADGE (0.15 or 1.5 mg/kg/day) during gestation and lactation periods. In an open field test, the time spent in the corner area significantly increases in male mice of high-dose BADGE group at 5 weeks old. The histological analysis using offspring brain at postnatal day 1 delivered from BADGE (1.5 mg/kg/day)-treated dams demonstrates that positive signals of Forkhead box P2- and COUP-TF interacting protein 2 are restricted in each cortical layer, but not in the control brain. In addition, the maternal BADGE exposure reduces nestin-positive fibers of the radial glia and T-box transcription factor 2-positive intermediate progenitors in the inner subventricular zone. Furthermore, a direct BADGE exposure promotes neurite outgrowth and neuronal connection in the primary cultured cortical neurons. These data suggest that maternal BADGE exposure can accelerate neuronal differentiation in fetuses and induce anxiety-like behavior in juvenile mice.

Evaluation of Maternal, Embryo, and Placental Effects in CD-1 Mice following Gestational Exposure to Perfluorooctanoic Acid (PFOA) or Hexafluoropropylene Oxide Dimer Acid (HFPO-DA or GenX).

BACKGROUND: Perfluorooctanoic acid (PFOA) is a poly- and perfluoroalkyl substance (PFAS) associated with adverse pregnancy outcomes in mice and humans, but little is known regarding one of its replacements, hexafluoropropylene oxide dimer acid (HFPO-DA, referred to here as GenX), both of which have been reported as contaminants in drinking water. OBJECTIVES: We compared the toxicity of PFOA and GenX in pregnant mice and their developing embryo-placenta units, with a specific focus on the placenta as a hypothesized target. METHODS: Pregnant CD-1 mice were exposed daily to PFOA (0, 1, or 5mg/kg) or GenX (0, 2, or 10mg/kg) via oral gavage from embryonic day (E) 1.5 to 11.5 or 17.5 to evaluate exposure effects on the dam and embryo-placenta unit. Gestational weight gain (GWG), maternal clinical chemistry, maternal liver histopathology, placental histopathology, embryo weight, placental weight, internal chemical dosimetry, and placental thyroid hormone levels were determined. RESULTS: Exposure to GenX or PFOA resulted in increased GWG, with increase in weight most prominent and of shortest latency with 10mg/kg/d GenX exposure. Embryo weight was significantly lower after exposure to 5mg/kg/d PFOA (9.4% decrease relative to controls). Effect sizes were similar for higher doses (5mg/kg/d PFOA and 10mg/kg/d GenX) and lower doses (1mg/kg/d PFOA and 2mg/kg/d GenX), including higher maternal liver weights, changes in liver histopathology, higher placental weights and embryo-placenta weight ratios, and greater incidence of placental abnormalities relative to controls. Histopathological features in placentas suggested that PFOA and GenX may exhibit divergent mechanisms of toxicity in the embryo-placenta unit, whereas PFOA- and GenX-exposed livers shared a similar constellation of adverse pathological features. CONCLUSIONS: Gestational exposure to GenX recapitulated many documented effects of PFOA in CD-1 mice, regardless of its much shorter reported half-life; however, adverse effects toward the placenta appear to have compound-specific signatures. https://doi.org/10.1289/EHP6233.

Disruption of Bone Zinc Metabolism during Postnatal Development of Rats after Early Life Exposure to Cadmium.

This current study was conducted to investigate whether bone tissue impairment induced by early life exposure to cadmium (Cd) during postnatal development could result from disruption to zinc (Zn) metabolism. For this reason, the offspring from mothers receiving either tap water, Cd, Zn or Cd + Zn during gestation and lactation periods were euthanized at PND21 and PND70. At the end of the lactation period (PND21), our results showed that exposure to Cd increased Cd accumulation and Zn depletion in the femur. Furthermore, calcium (Ca) level was reduced. At the molecular level, Cd induced an increase of MT-1 expression and caused an upregulation of ZIP2 accompanied with a down-regulation of ZnT5. Runx2, ALP, colα-1 and Oc mRNA levels were also decreased. In plasma, IGF-1 and osteocalcin concentrations were decreased. Further, Cd altered femoral growth by generating changes in the growth plate. Consequently, the toxic effect of Cd persisted at adult age (PND70) by decreasing bone volume (%BV/TV), bone mineral density (BMD) and Ca content and by increasing trabecular separation (Tb.Sp) in the distal femur. Interestingly, Zn supply provided total or partial corrections of several toxic effects of Cd. These data suggest that the increases of Zn bioavailability as well as the reduction of Cd accumulation in the femur following the changes in ZIP2 and ZnT5 expression are part of the mechanism involved in Zn protection against Cd toxicity on bone tissue.

Gestation and lactation exposure to nicotine induces transient postnatal changes in lung alveolar development.

Harmful consequences of cigarette smoke (CS) exposure during lung development can already manifest in infancy. In particular, early life exposure to nicotine, the main component of CS, was shown to affect lung development in animal models. We aimed to characterize the effect of nicotine on alveoli formation. We analyzed the kinetics of normal alveolar development during the alveolarization phase and then looked at the effect of nicotine in a mouse model of gestational and early life exposure. Immunohistochemical staining revealed that the wave of cell proliferation [i.e., vascular endothelial cells, alveolar epithelial cells (AEC) type II and mesenchymal cell] occurs at postnatal day (pnd) 8 in control and nicotine-exposed lungs. However, FACS analysis of individual epithelial alveolar cells revealed nicotine-induced transient increase of AEC type I proliferation and decrease of vascular endothelial cell proliferation at pnd8. Furthermore, nicotine increased the percentage of endothelial cells at pnd2. Transcriptomic data also showed significant changes in nicotine samples compared with the controls on cell cycle-associated genes at pnd2 but not anymore at pnd16. Accordingly, the expression of survivin, involved in cell cycle regulation, also follows a different kinetics in nicotine lung extracts. These changes resulted in an increased lung size detected by stereology at pnd16 but no longer in adult age, suggesting that nicotine can act on the pace of lung maturation. Taken together, our results indicate that early life nicotine exposure could be harmful to alveolar development independently from other toxicants contained in CS.

The hepatic effects in dams that ingested 2-aminoanthracene during gestation and lactation.

Diabetes mellitus has been on a continual rise as one of the top chronic diseases to affect individuals worldwide. The goal of this study was to determine how exposure from a well-known toxicant, a polycyclic aromatic hydrocarbon called 2-aminoanthracene (2AA), could potentially lead to diabetes, damage the liver, and have negative effects to the offspring. Humans are exposed to 2AA from foods cooked in high heat and tobacco smoke, among others. To analyze the effects of 2AA, three groups of Sprague Dawley dams consumed an adulterated 2AA diet from gestation to their postnatal period. Timed-pregnant dams ingested 0 mg/kg (control group (C)), 50 mg/kg (low dose group (LD)), and 100 mg/kg (high dose group (HD)) 2AA. Hepatic gene expressions of Adam8, Bax, Ccng1, CD68, CD93, Cdkn1c, and Ddit4 indicated a significant overexpression of Bax, Ccng1, CD68, CD93, and Cdkn1c in treated groups. Although there was no significant difference in the damage to the liver architecture by 2AA, the positively stained CD68+ cells were slightly increased in treated rats. Significant decreases in the albumin and aspartate aminotransferase levels might indicate an inflammatory response from 2AA exposure in dams. Immunoglobulin A (IgA) concentration was also decreased, in contrast to studies of liver cirrhosis that reported increased serum IgA concentration. Overexpression of genes Ddit4, Cdkn1c, Ccng1, Bax, CD93, and CD68 point to hepatic inflammation and apoptosis. Overall results suggest a link between environmental 2AA exposure and adverse liver effects, which has potential to increase susceptibility to type 2 diabetes and other diseases.

Effect of chronic administration of a gonadotropin-releasing agonist on luteal function and pregnancy rates in dairy cattle.

Increased embryonic losses may be associated with inadequate progesterone (P4) concentrations in high-producing lactating dairy cattle. The objectives of the present studies were to determine if chronic administration of a gonadotropin-releasing hormone (GnRH) agonist, Deslorelin, would increase circulating P4 concentrations and subsequently increase pregnancy rates in dairy cattle. Administration of Deslorelin for 12 days increased (p < .05) luteal volume and circulating P4 concentrations in primiparous lactating dairy cows, but increased only luteal volumes in multiparous cows. Treatment with Deslorelin increased Day 45 pregnancy rates in cows as compared to untreated controls. Chronic treatment with Deslorelin in dairy cattle; (a) increased luteal volume of the primary CL, (b) induced accessory CL, (c) increased circulating P4 concentration in primiparous cows only, (d) did not lengthen the estrous cycle upon removal of treatment, and (e) increased pregnancy rates. Although luteal volume was increased in multiparous cows and circulating P4 concentrations were not with Deslorelin treatment, there was an apparent effect on pregnancy rates. This hormonal strategy may represent a suitable model to address local effects of P4 and GnRH/luteinizing hormone on uterine environment and subsequent embryonic survival.

Navigating monoclonal antibody use in breastfeeding women: Do no harm or do little good?

Many neurologic diseases disproportionately affect women, particularly during their reproductive years. For many of these diseases, monoclonal antibodies (mAbs) are becoming widely available as a treatment option, for example, in migraine, multiple sclerosis, and myasthenia gravis. Yet, despite how common pregnancy is (latest estimates suggest that 86% of US women ages 40-44 have given birth), there is a paucity of research on the safety of prescription medications, including mAbs, during the peripartum period. In this article, we focus on the safety of mAbs during breastfeeding. We summarize how pregnancy affects the trajectory of these diseases and explore the benefit derived from mAb therapies. We posit that as neurologists, we are uniquely poised to lead the study of peripartum safety for the mAbs now on the market and provide a framework for their future study.

Perfil de pacientes em idade reprodutiva tratadas por epilepsia / Profile of patients in reproductive age treated by epilepsy

Objetivo: Descrever o perfil de pacientes em idade reprodutiva internadas por epilepsia nas regiões brasileiras em 5 anos, elucidando os riscos promovidos por ela durante a gravidez e abordando o gerenciamento do quadro. Métodos: Pesquisa e análise de dados disponibilizados pelo Departamento de Informática do Sistema Único de Saúde (DATASUS), acerca das internações em mulheres em idade reprodutiva (10 a 49 anos) por epilepsia, avaliando a ocorrência, de acordo com faixa etária, etnia e região do Brasil, no período de janeiro de 2012 a dezembro de 2016. Resultados: No total, foram notificadas 42.204 internações de mulheres em idade reprodutiva associadas à epilepsia, estando a maior parte delas (22,66%) na faixa de 20 a 29 anos e na de 40 a 49 anos (22,59%). O Sudeste correspondeu a 43,01% do total de casos (18.152), seguido pela Região Sul, com 9.456 registros (22,4%), e pelo Nordeste (8.245; 19,53%). A etnia mais atingida foi a de brancas (15.804; 37,44% dos atendimentos) e pardas (12.200; 28,9%). Conclusão: O planejamento da gravidez em mulheres epilépticas contribui para redução dos riscos tanto maternos quanto fetais, pois permite ao prescritor e à gestante pesar quais os benefícios e os malefícios de cada terapia anticonvulsivante disponível. Vale lembrar que uma abordagem individualizada da paciente epiléptica grávida por equipe multidisciplinar se faz necessária para melhorar os desfechos e prevenir internações por crises convulsivas. (AU)

Objective: To describe the profile of female patients in childbearing age hospitalized due to epilepsy in the Brazilian regions in 5 years, elucidating the risks it causes during pregnancy, and addressing the management of the condition. Methods: Research and analysis of data provided by the Informatics Department of the Unified Health System (DATASUS), concerning hospitalizations of women of childbearing age (10-49 years) due to epilepsy, evaluating the occurrence according to age, ethnicity and the region in Brazil, from January 2012 to December 2016. Results: A total of 42,204 admissions of women of childbearing age due to epilepsy were reported, with most of them in the age group from 20 to 29 years old (22,66%), and in the 40-49 age group (22.59%). The Southeast Region accounted for 43.01% of the total number of cases (18,152), followed by the South Region, with 9,456 records (22.4%), and the Northeast (8,245 - 19.53%). The most affected ethnic group was the white one (15,804; 37,44% of the admissions) and brown one (12,200; 28,9%). Conclusion: Pregnancy planning in epileptic women contributes to both maternal and fetal risk reduction, since it allows the prescriber and the pregnant woman to weigh the benefits and harms of each available anticonvulsant therapy. It is worth remembering that an individualized, multidisciplinary approach of the epileptic pregnant patient is necessary to improve the outcomes, and to prevent hospitalizations due to seizures. (AU)

Is There a Safety Signal for Dolutegravir and Integrase Inhibitors During Pregnancy?

BACKGROUND: Dolutegravir, an integrase strand transfer inhibitor (InSTI), is a major antiretroviral agent for HIV infection. Its use is promising, especially in low- and middle-income countries, because of a high resistance barrier and a good safety profile. Very recently, a World Health Organization safety signal has been raised regarding neural tube defects after the first-trimester exposure. Furthermore, to date, the experience is limited regarding the use of the other InSTI drugs (raltegravir and elvitegravir) during pregnancy. Our objective is to analyze the safety of InSTI drugs in pregnant women. SETTING: Nation-wide database cohort analysis. METHODS: We evaluated the risk of major birth defects according to EUROCAT classification in pregnant women, which had had a first-trimester exposure to dolutegravir, raltegravir, or elvitegravir. RESULTS: We found a major birth defect rate of 1.9% in the general population between 2012 and 2016. As InSTI drugs are not used as first-line therapy in pregnant women, we found a very low exposure in this population. Among 49, 240, and 70 pregnancy outcomes exposed to dolutegravir, raltegravir, and elvitegravir, respectively, during the first trimester, there were 2, 3, and 1 major birth defects, respectively. There was no case of neural tube defect. CONCLUSIONS: Drug exposure to InSTI is limited in our nation-wide database. Nevertheless, our data do not support a pharmacovigilance signal on neural tube defects in women exposed to dolutegravir, raltegravir or elvitegravir during pregnancy. Owing to a small number of pregnancy outcomes, these results need to be confirmed with further studies.

Ácido fólico y embarazo, ¿beneficio o riesgo? / Folic acid and pregnancy, benefit or risk?

RESUMEN El consumo de ácido fólico se ha relacionado con la disminución en la incidencia de malformaciones congénitas y deficiencias obstétricas, pero existen criterios de que no siempre su uso tiene los efectos favorables esperados para la madre y su descendencia. Con el objetivo de estructurar los presupuestos teóricos que sustentan el beneficio y el riesgo del consumo de ácido fólico para el embarazo, se realizó una búsqueda sobre el tema consultándose 37 referencias bibliográficas actualizadas. El ácido fólico ostenta dos grandes funciones en el organismo: la síntesis y reparación de los ácidos nucleicos, así como la síntesis del aminoácido metionina a partir de la homocisteina, esta última, al acumularse en el organismo se asocia a defectos congénitos y enfermedades crónicas del adulto. A partir de estos aspectos se corrobora que su consumo antes y durante el embarazo es beneficioso pues previene defectos del tubo neural, algunas cardiopatías congénitas, hendiduras bucofaciales, síndrome de Down, desórdenes del espectro autista, infecciones obstétricas, preeclampsia, hemorragia uterina, desprendimiento abrupto de la placenta, retardo del crecimiento intrauterino y prematuridad. El consumo excesivo de más de 5 mg/día se ha asociado a anemia por deficiencia de vitamina B12, déficit de zinc, crecimiento intrauterino retardado y prematuridad; en modelos animales acelera la transformación maligna de tumores existentes. Se concluye que el ácido fólico contribuye a preservar una embriogénesis y placentación normal y no se han demostrado efectos adversos por su uso, pero debe ser consumido en la dosis adecuada y por prescripción médica.

ABSTRACT Acid folic intake has been related to the decrease in the incidence of congenital malformations and obstetric deficiencies but there are criteria about folic acid not always achieving the expected favorable results for mothers and their descendants. A search on the theme was carried out with the objective of structuring the theoretical assumptions upholding the benefit and risk of folic acid intake for pregnancy. 37 updated bibliographic references were consulted. The folic acid has two main functions in the organism: nucleic acids´ synthesis and repair, and also the synthesis of the methionine amino acid from homocystein; when the last one accumulates in the organism, it is associated to congenital defects and adults´ chronic diseases. Beginning from these aspects, it is stated that the intake before and after pregnancy is beneficial because it prevents defects of the neural tube, some congenital deficiencies, oral facial clefts, Down syndrome, autism spectrum disorders, obstetric infections, preeclampsia, uterine hemorrhage, sudden placental abruption, intrauterine grow retardation and prematurity. The excessive intake of more than 5 mg/d has been associate to anemia due vitamin B12 deficiency, zinc deficiency, intrauterine retarded grow and prematurity; in animal models it speeds up the malignant transformation of existent tumors. The authors arrived to the conclusion that folic acid contributes to preserving a normal embryogenesis and placentation, and that no adverse effects have been demonstrated, nevertheless it should be taken in adequate doses and for medical prescription.

Effect of dietary phosphorus deprivation on leukocyte function in transition cows.

Phosphorus depletion and hypophosphatemia have been described to hamper immune function in different species, an effect barely studied in dairy cows commonly developing hypophosphatemia in early lactation. Dietary P deprivation in mid lactating dairy cows was associated with a decline of the number of granulocytes and impaired granulocyte survival, whereas the phagocytic activity remained unaffected. The objective of the study reported here was to determine the effect of P deprivation on the leukocyte function of periparturient dairy cows. Eighteen multiparous and late pregnant dairy cows were randomly assigned to either a treatment group that was offered a markedly P-deficient diet or a control group receiving the same ration with adequate P content. The study consisted of a 2-wk acclimation period that was followed by a P deprivation period extending from 4 wk before to 4 wk after parturition and a P repletion period of 2 wk thereafter. Blood samples for leukocyte counts and leukocyte function analysis were obtained at the end of the acclimation period, after 2 wk of P deprivation, within the first week of lactation, at the end of the P depletion period and after 2 wk of dietary P supplementation. Blood samples for biochemical analysis were obtained weekly. Immune function was assessed by means of a phagocytosis assay and a lymphocyte stimulation test. Dietary P deprivation resulted in pronounced and sustained hypophosphatemia. Time effects were observed on the counts of different leukocyte fractions, the relative number of phagocytic granulocytes, the degree of phagocytosis, and the lymphocyte proliferation. Differences between P-deprived and control cows were only identified for the degree of phagocytosis that was lower in P-deprived cows compared with control cows. The correlation and regression analyses, however, revealed positive associations of the plasma phosphate concentration and the granulocyte count, the relative number of phagocytic granulocytes, and the degree of phagocytosis at the end of the dietary P deprivation when P depletion was most severe. The results of the study reported here indicate a mild negative effect of pronounced and sustained hypophosphatemia on the granulocyte count and the phagocytic activity of granulocytes in transition dairy cows. The clinical relevance of this effect for health and productivity of dairy cows remains to be determined.

Avaliação toxicológica da exposição à Cannabis e cocaína na gravidez em cordão umbilical humano: validação de método analítico e prospecção de biomarcadores proteicos de toxicidade / Toxicological assessment of Cannabis and cocaine exposure during pregnancy in human umbilical cord tissue: analytical method validation and prospection of protein biomarkers related to fetotoxicity

O abuso de drogas atinge aproximadamente 35 milhões de pessoas em todo planeta, sendo um problema alarmante em decorrência de graves danos à saúde, como a dependência química e intoxicações fatais. No Brasil, o número de usuários tem crescido principalmente para o consumo de produtos da Cannabis e cocaína, drogas amplamente consumidas, inclusive entre mulheres em período gestacional, trazendo à tona um novo grupo de risco. A exposição gestacional a drogas de abuso está diretamente relacionada a malformações fetais e complicações de saúde para mãe e bebê nos períodos pré- e pós-natal. Tradicionalmente, a avaliação toxicológica da exposição é realizada pela detecção da droga parental e de seus produtos de biotransformação em matrizes materno-fetais por meio de métodos bioanalíticos. Entretanto, estes ensaios não fornecem informações acerca dos impactos fisiológicos ocasionados pela exposição, deixando uma lacuna no que tange às informações sobre os mecanismos e moléculas subjacentes envolvidos em processos de toxicidade. Desse modo, o desenvolvimento de análises toxicológicas mais robustas utilizando tecnologia de ponta, que possam comprovar o uso drogas e também elucidar aspectos de toxicidade é de suma importância, pois auxiliam na compreensão do impacto biológico relativo à exposição humana a xenobióticos. Neste trabalho foram desenvolvidos ensaios bioanalíticos, utilizando o tecido do cordão umbilical para a avaliação da exposição in utero à canabinoides. Foi desenvolvido e validado método QuECheRS adaptado como preparo de amostra, no qual etapas simultâneas de extração e hidrólise alcalina de canabinoides são alcançadas, utilizando cromatografia em fase gasosa acoplada a espectrômetro de massas para detecção de delta-9-tetraidrocanabinol (THC), canabinol (CBN), 11-hidroxi-delta-9-tetraidrocanabinol (11-OHTHC) e 11-nor-9-carboxi-tetrahidrocanabinol (THC-COOH). Também foram desenvolvidas metodologias utilizando LC-MS/MS e Trapped Ion Mobility Mass Spectrometry para análise de proteoma de cordão umbilical humano em diferentes regiões, no intuito de identificar biomarcadores proteicos relativos à fetotoxicidade do uso de drogas na gravidez. Até o presente momento, QuECheRS é utilizado pela primeira vez como abordagem bioanalítica para avaliação de drogas ilícitas em matrizes teciduais materno-fetais e mostrou-se satisfatório para detecção de produtos da Cannabis. Nos ensaios proteômicos, foram identificados potenciais biomarcadores de fetotoxicidade, como as moléculas ACTA 2, Collagen alpha-1 (XVIII), SMC1A, KNL1, KMT2A, em tecidos expostos à Cannabis e/ou cocaína. Tais macromoléculas estão correlacionadas a malformações embriogênicas e complicações de saúde na vida intra-uterina. As metodologias desenvolvidas neste trabalho podem ser úteis para uma melhor avaliação da toxicidade do uso de drogas na gravidez, fornecendo novas pistas sobre a exposição e/ou efeitos tóxicos significativos considerados na avaliação de risco

Drug abuse affects approximately 35 million people worldwide and can be considered a significant burden on society due to severe health problems, e.g. drug addiction and fatal poisonings. In Brazil, the number of users has been growing related to Cannabis and cocaine products, drugs widely used, including among women in gestational period, bringing up a new risk group. Gestational exposure to drugs of abuse is directly related to fetal malformations and health complications for mother and babies in the pre- and postnatal periods. Traditionally, toxicological assessment of exposure is performed by detecting the parent drug and its biotransformation products in maternal-fetal matrices using bioanalytical methods. However, these assays do not provide information about the physiological impacts caused by exposure, leaving a lack of information about the pathways and molecules involved in toxicity processes. Thus, the development of robust toxicological analyzes using cutting-edge technologies in order to prove drug use and also elucidate aspects of toxicity is very important, as they help in understanding the biological impact of human exposure to xenobiotics. Herein, bioanalytical methods using umbilical cord tissue to assess in utero exposure to cannabinoids were developed. A QuECheRS method was developed fully validated as a sample preparation technique for simultaneous extraction and alkaline hydrolysis of cannabinoids, using gas chromatography coupled to mass spectrometry to detect the analytes delta-9-tetrahydrocannabinol (THC), cannabinol (CBN), 11-hydroxydelta-9-tetrahydrocannabinol (11-OH-THC) and 11-nor-9-carboxy-tetrahydrocannabinol (THC-COOH). LC-MS/MS based proteomics and Trapped Ion Mobility Mass Spectrometry were also developed in order to identify protein biomarkers related to fetotoxicity of drug use in pregnancy. Our works represents the first use of QuECheRS for evaluation of illicit drugs in maternal-fetal tissue and was suitable for detection of Cannabis products. In the proteomic assays, potential biomarkers of fetotoxicity were identified in the exposed tissues, such as ACTA 2, Collagen alpha-1 (XVIII), SMC1A, KNL1, KMT2A. These proteins are related to embryogenic malformations and health complications in intrauterine life. The methodologies developed in this project may be useful for a better assessment of the toxicity of drug use in pregnancy, providing new clues about exposure and/or significant toxic effects that should be considered in the risk assessment

Drug interactions in maternal intensive care: prevalence, risk factors, and potential risk medications / Interações medicamentosas em terapia intensiva materna: prevalência, fatores e medicamentos de risco

ABSTRACT Objective: To characterize severe potential drug interactions in maternal intensive care, and to determine their frequency, risk factors and potential risk medications. Methods: An observational and longitudinal study conducted between December 2014 and December 2015 in a maternal intensive care unit. Clinical data were collected and severe potential drug interactions were identified on pregnant inpatients. The drug interactions were classified by type, prevalence and exposure rate. A multivariate logistic regression model was used to identify the severe potential drug interactions and the related drugs (p<0.05). Results: A total of 95.1% of patients were exposed to, at least, one potential drug interaction; in that, 91.7% 33.9% were related to, respectively, moderate and severe potential drug interactions. The patients were exposed, on average, on 69.2% of days they were in the intensive care unit. The main drugs involved in more severe drug interactions were magnesium sulfate, metoclopramide, propranolol and diazepam. Conclusion: The severe potential drug interactions were observed in almost all patients of the study, and, approximately one third of those interactions were related to greater severity and resulted in exposure during long hospital stay. The higher number of prescribed drugs and its previous use of medications at home increase the occurrence of severe potential drug interactions.

RESUMO Objetivo: Caracterizar as interações medicamentosas potenciais graves em terapia intensiva materna, e determinar sua frequência, os fatores e os medicamentos de risco associados à ocorrência dessas interações. Métodos: Estudo observacional e longitudinal executado entre dezembro de 2014 a dezembro de 2015, conduzido em uma unidade de terapia intensiva materna. Foram coletados dados clínicos e identificadas interações medicamentosas potenciais graves de gestantes admitidas. As interações medicamentosas foram caracterizadas quanto ao tipo, à prevalência e à taxa de exposição. Um modelo multivariado de regressão logística foi utilizado para identificação de fatores associados à ocorrência de interações medicamentosas potenciais graves e os medicamentos implicados (p<0,05). Resultados: Um total de 95,1% das pacientes foi exposto a, no mínimo, uma interação medicamentosa potencial, com 91,7% delas envolvidas com interações medicamentosas potenciais moderadas e 33,9% com as interações graves. As pacientes ficaram expostas, em média, em 69,2% dos dias que estiveram sob terapia intensiva. Os principais medicamentos implicados em interações medicamentosas de maior gravidade foram sulfato de magnésio, metoclopramida, propranolol e diazepam. Conclusão: As interações medicamentosas potenciais graves ocorreram na maioria das pacientes avaliadas. Aproximadamente um terço das interações foram graves e levaram à maior exposição por um longo período de internação. Maior número de fármacos prescritos e uso prévio domiciliar de medicamentos elevam a ocorrência de interações medicamentosas potenciais graves.