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1.
BMC Res Notes ; 14(1): 355, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34507611

RESUMO

OBJECTIVES: Induction of labour (IOL), or starting labour artificially, can be a lifesaving intervention for pregnant women and their babies, and rates are rising significantly globally. As rates increase, it becomes increasingly important to fully evaluate all available data, especially that from low income settings where the potential benefits and harms are greater. The goal of this paper is to describe the datasets collected as part of the Induction with Foley OR Misoprostol (INFORM) Study, a randomised trial comparing two of the recommended methods of cervical ripening for labour induction, oral misoprostol and Foley catheter, in women being induced for hypertension in pregnancy, at two sites in India during 2013-15. DATA DESCRIPTION: This dataset includes comprehensive data on 602 women who underwent IOL for hypertensive disorders in pregnancy. Women were randomly assigned to cervical ripening with oral misoprostol or a transcervical Foley catheter in two government hospitals in India. The main dataset has 367 variables including monitoring during the induction of labour, medications administered, timing and mode of delivery, measures of neonatal morbidity and mortality, maternal mortality and morbidity, maternal satisfaction and health economic data. The dataset is anonymised and available on ReShare.


Assuntos
Hipertensão , Misoprostol , Ocitócicos , Cateteres , Maturidade Cervical , Feminino , Humanos , Índia , Recém-Nascido , Trabalho de Parto Induzido , Gravidez
2.
BMC Pregnancy Childbirth ; 21(1): 537, 2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34325670

RESUMO

BACKGROUND: Every year approximately 30,000 women die from hypertensive disease in pregnancy. Magnesium sulphate and anti-hypertensives reduce morbidity, but delivery is the only cure. Low dose oral misoprostol, a prostaglandin E1 analogue, is a highly effective method for labour induction. Usually, once active labour has commenced, the misoprostol is replaced with an intravenous oxytocin infusion if ongoing stimulation is required. However, some studies have shown that oral misoprostol can be continued into active labour, a simpler and potentially more acceptable protocol for women. To date, these two protocols have never been directly compared. METHODS: This pragmatic, open-label, randomised trial will compare a misoprostol alone labour induction protocol with the standard misoprostol plus oxytocin protocol in three Indian hospitals. The study will recruit 520 pregnant women being induced for hypertensive disease in pregnancy and requiring augmentation after membrane rupture. Participants will be randomised to receive either further oral misoprostol 25mcg every 2 h, or titrated intravenous oxytocin. The primary outcome will be caesarean birth. Secondary outcomes will assess the efficacy of the induction process, maternal and fetal/neonatal complications and patient acceptability. This protocol (version 1.04) adheres to the SPIRIT checklist. A cost-effectiveness analysis, situational analysis and formal qualitative assessment of women's experience are also planned. DISCUSSION: Avoiding oxytocin and continuing low dose misoprostol into active labour may have a number of benefits for both women and the health care system. Misoprostol is heat stable, oral medication and thus easy to store, transport and administer; qualities particularly desirable in low resource settings. An oral medication protocol requires less equipment (e.g. electronic infusion pumps) and may free up health care providers to assist with other aspects of the woman's care. The simplicity of the protocol may also help to reduce human errors associated with the delivery of intravenous infusions. Finally, women may prefer to be mobile during labour and not restricted by an intravenous infusion. There is a need, therefore, to assess whether augmentation using oral misoprostol is superior clinically and economically to the standard protocol of intravenous oxytocin. TRIAL REGISTRATION: Clinical Trials.gov, NCT03749902 , registered on 21st Nov 2018.

4.
EClinicalMedicine ; 31: 100678, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33385127

RESUMO

Background: Misfolded proteins in the urine of women with preeclampsia bind to Congo Red dye (urine congophilia). We evaluated a beta prototype of a point-of-care test for the identification of urine congophilia in preeclamptic women. Methods: Prospective diagnostic case-control study conducted in 409 pregnant women (n = 204 preeclampsia; n = 205 uncomplicated pregnancies) presenting for delivery in two tertiary level hospitals located in Bangladesh and Mexico. The GV-005, a beta prototype of a point-of-care test for detecting congophilia, was performed on fresh and refrigerated urine samples. The primary outcome was the prevalence of urine congophilia in each of the two groups. Secondary outcome was the likelihood of the GV-005 (index test) to confirm and rule-out preeclampsia based on an adjudicated diagnosis (reference standard). Findings: The GV-005 was positive in 85% of clinical cases (83/98) and negative in 81% of clinical controls (79/98) in the Bangladesh cohort. In the Mexico cohort, the GV-005 test was positive in 48% of clinical cases (51/106) and negative in 77% of clinical controls (82/107). Adjudication confirmed preeclampsia in 92% of Bangladesh clinical cases (90/98) and 61% of Mexico clinical cases (65/106). The odds ratio of a urine congophilia in adjudicated cases versus controls in the Bangladesh cohort was 34.5 (14.7 - 81.1) (p<0.001) compared to 4.2 (2.1 - 8.4; p<0.001) in the Mexico cohort. Interpretation: The GV-005, a beta prototype of a point-of-care test for detection of urine congophilia, is a promising tool for rapid identification of preeclampsia. Funding: Saving Lives at Birth.

5.
Pregnancy Hypertens ; 23: 27-33, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33181475

RESUMO

OBJECTIVES: It is important to understand relationships of gestational weight gain with adverse pregnancy outcomes in women with chronic hypertension, given their high baseline risk of adverse outcomes. We assessed associations of gestational weight gain with adverse pregnancy outcomes in women with chronic hypertension by pre-pregnancy body mass index categories. STUDY DESIGN: We identified 14,369 women with chronic hypertension using electronic health records from 3 integrated health care delivery systems (2005-2014). Gestational weight gain-for-gestational age charts were used to calculate gestational weight gain z-scores, which account for gestational age. Modified Poisson regression models using generalized estimating equations were used to calculate relative risks and 95% confidence intervals, adjusted for sociodemographic and medical characteristics. MAIN OUTCOME MEASUREMENTS: Preeclampsia, preterm delivery, cesarean delivery, neonatal intensive care unit admission, birthweight (extracted from the electronic health record). RESULTS: In women with normal weight or overweight, low gestational weight gain (z-score < -1) was associated with 27-28% greater risk of preterm delivery and 48-82% greater risk of small-for-gestational age birthweight, while high gestational weight gain (z-score > 1) was associated with 40-90% greater risk of preeclampsia and 59-113% greater risk of large-for-gestational age birthweight. In women with obesity, low gestational weight gain was associated with 27-54% lower risk of several adverse pregnancy outcomes, including preeclampsia and cesarean delivery. CONCLUSIONS: In women with chronic hypertension and normal weight or overweight, moderate gestational weight gain may confer the lowest risk of adverse outcomes. In women with chronic hypertension and obesity, low gestational weight gain may be necessary for the lowest risk of adverse pregnancy outcomes.

6.
Pregnancy Hypertens ; 19: 112-118, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31954339

RESUMO

OBJECTIVE: To incorporate blood pressure (BP), diagnoses codes, and medication fills from electronic medical records (EMR) to identify pregnant women with hypertension. STUDY DESIGN: A retrospective cohort study of singleton pregnancies at three US integrated health delivery systems during 2005-2014. MAIN OUTCOME MEASURES: Women were considered hypertensive if they had any of the following: (1) ≥2 high BPs (≥140/90 mmHg) within 30 days during pregnancy (High BP); (2) an antihypertensive medication fill in the 120 days before pregnancy and a hypertension diagnosis from 1 year prior to pregnancy through 20 weeks gestation (Treated Chronic Hypertension); or (3) a high BP, a hypertension diagnosis, and a prescription fill within 7 days during pregnancy (Rapid Treatment). We described characteristics of these pregnancies and conducted medical record review to understand hypertension presence and severity. RESULTS: Of 566,624 pregnancies, 27,049 (4.8%) met our hypertension case definition: 24,140 (89.2%) with High BP, 5,409 (20.0%) with Treated Chronic Hypertension, and 5,363 (19.8%) with Rapid Treatment (not mutually exclusive). Of hypertensive pregnancies, 19,298 (71.3%) received a diagnosis, 9,762 (36.1%) received treatment and 11,226 (41.5%) had a BP ≥ 160/110. In a random sample (n = 55) of the 7,559 pregnancies meeting the High BP criterion with no hypertension diagnosis, clinical statements about hypertension were found in medical records for 58% of them. CONCLUSION: Incorporating EMR BP identified many pregnant women with hypertension who would have been missed by using diagnosis codes alone. Future studies should seek to incorporate BP to study treatment and outcomes of hypertension in pregnancy.


Assuntos
Registros Eletrônicos de Saúde/estatística & dados numéricos , Hipertensão Induzida pela Gravidez/epidemiologia , Hipertensão/epidemiologia , Complicações Cardiovasculares na Gravidez/epidemiologia , Adulto , Anti-Hipertensivos/uso terapêutico , Estudos de Coortes , Prestação Integrada de Cuidados de Saúde , Prescrições de Medicamentos/estatística & dados numéricos , Feminino , Humanos , Hipertensão/tratamento farmacológico , Hipertensão Induzida pela Gravidez/tratamento farmacológico , Gravidez , Complicações Cardiovasculares na Gravidez/tratamento farmacológico , Estudos Retrospectivos , Estados Unidos/epidemiologia
7.
Drug Metab Dispos ; 48(4): 264-271, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31980499

RESUMO

This study's primary objective was to fully characterize the pharmacokinetics of metformin in pregnant women with gestational diabetes mellitus (GDM) versus nonpregnant controls. Steady-state oral metformin pharmacokinetics in pregnant women with GDM receiving either metformin monotherapy (n = 24) or a combination with glyburide (n = 30) as well as in nonpregnant women with type 2 diabetes mellitus (T2DM) (n = 24) were determined utilizing noncompartmental techniques. Maternal and umbilical cord blood samples were collected at delivery from 38 women. With both 500- and 1000-mg doses, metformin bioavailability, volume of distribution beta (V ß ), clearance, and renal clearance were significantly increased during pregnancy. In addition, in the women receiving metformin 500 mg, significantly higher metformin apparent oral clearance (CL/F) (27%), weight-adjusted renal secretion clearance (64%), and apparent oral volume of distribution beta (V ß /F) (33%) were seen during pregnancy. Creatinine clearance was significantly higher during pregnancy. Increasing metformin dose from 500 to 1000 mg orally twice daily significantly increased V ß /F by 28%, weight-adjusted V ß /F by 32% and CL/F by 25%, and weight-adjusted CL/F by 28% during pregnancy. Mean metformin umbilical cord arterial-to-venous plasma concentration ratio was 1.0 ± 0.1, venous umbilical cord-to-maternal concentration ratio was 1.4 ± 0.5, and arterial umbilical cord-to-maternal concentration ratio was 1.5 ± 0.5. Systemic exposure after a 500-mg dose of metformin was lower during pregnancy compared with the nonpregnant women with T2DM. However, in patients receiving metformin 1000 mg, changes in estimated bioavailability during pregnancy offset the changes in clearance leading to no significant change in CL/F with the higher dose. SIGNIFICANCE STATEMENT: Gestational diabetes mellitus complicates 5%-13% of pregnancies and is often treated with metformin. Pregnant women undergo physiological changes that alter drug disposition. Preliminary data suggest that pregnancy lowers metformin concentrations, potentially affecting efficacy and safety. This study definitively describes pregnancy's effects on metformin pharmacokinetics and expands the mechanistic understanding of pharmacokinetic changes across the dosage range. Here we report the nonlinearity of metformin pharmacokinetics and the increase in bioavailability, clearance, renal clearance, and volume of distribution during pregnancy.

8.
Clin Pharmacol Ther ; 107(6): 1362-1372, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31869430

RESUMO

In gestational diabetes mellitus (GDM), women are unable to compensate for the increased insulin resistance during pregnancy. Data are limited regarding the pharmacodynamic effects of metformin and glyburide during pregnancy. This study characterized insulin sensitivity (SI), ß-cell responsivity, and disposition index (DI) in women with GDM utilizing a mixed-meal tolerance test (MMTT) before and during treatment with glyburide monotherapy (GLY, n = 38), metformin monotherapy (MET, n = 34), or GLY and MET combination therapy (COMBO; n = 36). GLY significantly decreased dynamic ß-cell responsivity (31%). MET and COMBO significantly increased SI (121% and 83%, respectively). Whereas GLY, MET, and COMBO improved DI, metformin (MET and COMBO) demonstrated a larger increase in DI (P = 0.05) and a larger decrease in MMTT peak glucose concentrations (P = 0.03) than subjects taking only GLY. Maximizing SI with MET followed by increasing ß-cell responsivity with GLY or supplementing with insulin might be a more optimal strategy for GDM management than monotherapy.


Assuntos
Diabetes Gestacional/tratamento farmacológico , Glibureto/administração & dosagem , Hipoglicemiantes/administração & dosagem , Metformina/administração & dosagem , Adolescente , Adulto , Glicemia/efeitos dos fármacos , Quimioterapia Combinada , Feminino , Glibureto/farmacologia , Humanos , Hipoglicemiantes/farmacologia , Resistência à Insulina , Células Secretoras de Insulina/metabolismo , Estudos Longitudinais , Metformina/farmacologia , Gravidez , Estudos Prospectivos , Adulto Jovem
9.
Am J Perinatol ; 37(11): 1140-1145, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-31170747

RESUMO

OBJECTIVE: We sought to evaluate associations between postpartum plasma adipokine concentrations among women with a history of preeclampsia (PE) without severe features (MPE), PE with severe features (SPE), and no PE (NPE). We also investigated relationships between adipokines and computed tomography (CT)-quantified measures of visceral fat (VF) area (VFA) and subcutaneous fat area (SCFA). STUDY DESIGN: We performed a secondary analysis of data collected as part of a previously performed cross-sectional study at our institution. Women with and without a history of PE were recruited in 10 years after delivery. VFA and SCFA measures were performed by CT scan. Anthropometric data and peripheral blood samples from subjects were collected concurrently. RESULTS: Plasma adiponectin concentrations (µg/mL) were significantly lower among MPE (18.5 ± 7.1) compared with NPE (27.3 ± 13.8) and SPE (25.7 ± 9.6). Leptin (p = 0.32) and resistin (p = 0.93) concentrations were similar among the groups. Adiponectin concentrations more closely aligned with VFA (ß = -0.001, p = 0.03), while resistin concentrations trended toward correlating with SCFA (ß = 0.02, p = 0.05). Leptin was not preferential to VFA or SCFA. CONCLUSION: VF distribution may contribute to the variation in PE phenotype. Adiponectin specifically may be a promising marker representing VFA.

10.
J Clin Pharmacol ; 60(4): 540-549, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31742716

RESUMO

Gestational diabetes mellitus is a condition similar to type 2 diabetes mellitus (T2DM) in that patients are unable to compensate for the degree of insulin resistance, and both conditions are often treated with metformin. The comparative pharmacodynamic response to metformin in these 2 populations has not been studied. This study characterized insulin sensitivity, ß-cell responsivity, and disposition index following a mixed-meal tolerance test utilizing a minimal model of glucose, insulin, and C-peptide kinetics before and during treatment with metformin. The study included women with gestational diabetes mellitus (n = 34), T2DM (n = 14), and healthy pregnant women (n = 30). Before treatment, the gestational diabetes mellitus group had significantly higher baseline (45%), dynamic (68%), static (71%), and total ß-cell responsivity (71%) than the T2DM group. Metformin significantly increased insulin sensitivity (51%) as well as disposition index (97%) and decreased mixed-meal tolerance test peak glucose concentrations (8%) in women with gestational diabetes mellitus after adjustment for gestational age-dependent effects; however, in women with T2DM metformin only significantly affected peak glucose concentrations (22%) and had no significant effect on any other parameters. Metformin had a greater effect on the change in disposition index (Δ disposition index) in women with gestational diabetes mellitus than in those with T2DM (P = .01). In conclusion, response to metformin in women with gestational diabetes mellitus is significantly different from that in women with T2DM, which is likely related to the differences in disease severity.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Diabetes Gestacional/metabolismo , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Adolescente , Adulto , Glicemia/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Gestacional/tratamento farmacológico , Feminino , Voluntários Saudáveis , Humanos , Hipoglicemiantes/sangue , Hipoglicemiantes/uso terapêutico , Resistência à Insulina , Metformina/sangue , Metformina/uso terapêutico , Pessoa de Meia-Idade , Gravidez , Gestantes , Estudos Prospectivos , Adulto Jovem
11.
Lancet ; 394(10203): 1011-1021, 2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31378394

RESUMO

BACKGROUND: Hypertension is the most common medical disorder in pregnancy, complicating one in ten pregnancies. Treatment of severely increased blood pressure is widely recommended to reduce the risk for maternal complications. Regimens for the acute treatment of severe hypertension typically include intravenous medications. Although effective, these drugs require venous access and careful fetal monitoring and might not be feasible in busy or low-resource environments. We therefore aimed to compare the efficacy and safety of three oral drugs, labetalol, nifedipine retard, and methyldopa for the management of severe hypertension in pregnancy. METHODS: In this multicentre, parallel-group, open-label, randomised controlled trial, we compared these oral antihypertensives in two public hospitals in Nagpur, India. Pregnant women were eligible for the trial if they were aged at least 18 years; they were pregnant with fetuses that had reached a gestational age of at least 28 weeks; they required pharmacological blood pressure control for severe hypertension (systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥110 mm Hg); and were able to swallow oral medications. Women were randomly assigned to receive 10 mg oral nifedipine, 200 mg oral labetalol (hourly, in both of which the dose could be escalated if hypertension was maintained), or 1000 mg methyldopa (a single dose, without dose escalation). Masking of participants, study investigators, and care providers to group allocation was not possible because of different escalation protocols in the study groups. The primary outcome was blood pressure control (defined as 120-150 mm Hg systolic blood pressure and 70-100 mm Hg diastolic blood pressure) within 6 h with no adverse outcomes. This study is registered with ClinicalTrials.gov, number NCT01912677, and the Clinical Trial Registry, India, number ctri/2013/08/003866. FINDINGS: Between April 1, 2015, and Aug 21, 2017, we screened 2307 women for their inclusion in the study. We excluded 1413 (61%) women who were ineligible, declined to participate, had impending eclampsia, were in active labour, or had a combination of these factors. 11 (4%) women in the nifedipine group, ten (3%) women in the labetalol group, and 11 (4%) women in the methyldopa group were ineligible for treatment (because they had only one qualifying blood pressure measurement) or had treatment stopped (because of delivery or transfer elsewhere). 894 (39%) women were randomly assigned to a treatment group and were included in the intention-to-treat analysis: 298 (33%) women were assigned to receive nifedipine, 295 (33%) women were assigned to receive labetalol, and 301 (33%) women were assigned to receive methyldopa. The primary outcome was significantly more common in women in the nifedipine group than in those in the methyldopa group (249 [84%] women vs 230 [76%] women; p=0·03). However, the primary outcome did not differ between the nifedipine and labetalol groups (249 [84%] women vs 228 [77%] women; p=0·05) or the labetalol and methyldopa groups (p=0·80). Seven serious adverse events (1% of births) were reported during the study: one (<1%) woman in the labetalol group had an intrapartum seizure and six (1%) neonates (one [<1%] neonate in the nifedipine group, two [1%] neonates in the labetalol group, and three [1%] neonates in the methyldopa group) were stillborn. No birth had more than one adverse event. INTERPRETATION: All oral antihypertensives reduced blood pressure to the reference range in most women. As single drugs, nifedipine retard use resulted in a greater frequency of primary outcome attainment than labetalol or methyldopa use. All three oral drugs-methyldopa, nifedipine, and labetalol-are viable initial options for treating severe hypertension in low-resource settings. FUNDING: PREEMPT (University of British Columbia, Vancouver, BC, Canada; grantee of Bill & Melinda Gates Foundation).


Assuntos
Anti-Hipertensivos/administração & dosagem , Hipertensão Induzida pela Gravidez/tratamento farmacológico , Labetalol/administração & dosagem , Metildopa/administração & dosagem , Nifedipino/administração & dosagem , Administração Oral , Adulto , Pressão Sanguínea/efeitos dos fármacos , Feminino , Humanos , Índia/epidemiologia , Recém-Nascido , Gravidez , Resultado da Gravidez/epidemiologia , Resultado do Tratamento , Adulto Jovem
12.
J Clin Pharmacol ; 59(12): 1678-1689, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31257615

RESUMO

Hydralazine, an antihypertensive agent used during pregnancy, undergoes N-acetylation primarily via N-acetyltransferase 2 (NAT2) to form 3-methyl-1,2,4-triazolo[3,4-a]phthalazine (MTP). To characterize the steady-state pharmacokinetics (PK) of hydralazine during pregnancy and evaluate the effects of NAT2 genotype on hydralazine and MTP PK during pregnancy, 12 pregnant subjects received oral hydralazine (5-25 mg every 6 hours) in mid- (n = 5) and/or late pregnancy (n = 8). Serial blood samples were collected over 1 dosing interval, and steady-state noncompartmental PK parameters were estimated. Subjects were classified as either (rapid acetylators, n = 6) or slow acetylators (SAs, n = 6) based on NAT2 genotype. During pregnancy, when compared with the SA group, the RA group had faster weight-adjusted hydralazine apparent oral clearance (70.0 ± 13.6 vs 20.1 ± 6.9 L/h, P < .05), lower dose-normalized area under the concentration-time curve (AUC; 1.5 ± 0.8 vs 5.9 ± 3.7 ng·h/mL, P < .05), lower dose-normalized peak concentrations (0.77 ± 0.51 vs 4.04 ± 3.18 ng/mL, P < .05), and larger weight-adjusted apparent oral volume of distribution (302 ± 112 vs 116 ± 45 L/kg, P < .05). Furthermore, the MTP/hydralazine AUC ratio was ∼10-fold higher in the RA group (78 ± 30 vs 8 ± 3, P < .05) than in the SA group. No gestational age or dose-dependent effects were observed, possibly because of the small sample size. This study describes for the first time, the PK of oral hydralazine and its metabolite, MTP, during pregnancy, and confirmed that the PK of oral hydralazine is NAT2 genotype dependent during pregnancy.


Assuntos
Anti-Hipertensivos/farmacocinética , Arilamina N-Acetiltransferase/genética , Hidralazina/farmacocinética , Acetilação , Adulto , Área Sob a Curva , Feminino , Genótipo , Humanos , Fenótipo , Gravidez
13.
Am J Obstet Gynecol ; 219(4): 405.e1-405.e7, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30012335

RESUMO

BACKGROUND: Maternal mortality and severe maternal morbidity are growing public health concerns in the United States. The Centers for Disease Control and Prevention Severe Maternal Morbidity measure provides insight into processes underlying maternal mortality and may highlight modifiable risk factors for adverse maternal health outcomes. OBJECTIVE: The primary objective of this study was to evaluate the association between hypertensive disorders and severe maternal morbidity at a regional perinatal referral center. We hypothesized that women with preeclampsia with severe features would have a higher rate of severe maternal morbidity compared to normotensive women. We also assessed the proportion of severe maternal morbidity diagnoses that were present on admission, in contrast to those arising during the delivery hospitalization. STUDY DESIGN: In this retrospective cross-sectional analysis, we assessed rates of severe maternal morbidity diagnoses (eg, renal insufficiency, shock, and sepsis) and procedures (eg, transfusion and hysterectomy) for all 7025 women who delivered at the University of Washington Medical Center from Oct. 1, 2013, through May 31, 2017. Severe maternal morbidity was determined from prespecified International Classification of Diseases diagnosis and procedure codes; all diagnoses were confirmed by chart review. Present-on-admission rates were calculated for each diagnosis through hospital administrative data provided by the Vizient University Health System Consortium. Maternal demographic and clinical characteristics were compared for women with and without severe maternal morbidity. The χ2 and Fisher exact tests were used to determine statistical significance. Odds ratios and 95% confidence intervals were calculated for the associations between maternal demographic and clinical characteristics and severe maternal morbidity. RESULTS: Of 7025 deliveries, 284 (4%) had severe maternal morbidity; 154 had transfusion only, 27 had other procedures, and 103 women had 149 severe maternal morbidity diagnoses (26 women had multiple diagnoses). Severe preeclampsia occurred in 438 deliveries (6.2%). Notably, hypertension was associated with severe maternal morbidity in a dose-dependent fashion, with the strongest association observed for preeclampsia with severe features (odds ratio, 5.4; 95% confidence interval, 3.9-7.3). Severe maternal morbidity was also significantly associated with preeclampsia without severe features, chronic hypertension, preterm delivery, pregestational diabetes, and multiple gestation. Among women with severe maternal morbidity, over one third of preterm births were associated with maternal hypertension. American Indian/Alaskan Native women had significantly higher severe maternal morbidity rates compared to other racial/ethnic groups (11.7% vs 3.9% for Whites, P < .01). Overall, 39.6% of severe maternal morbidity diagnoses were present on admission. CONCLUSION: Hypertensive disorders in pregnancy are strongly associated with severe maternal morbidity in a dose-dependent relationship, suggesting that strategies to address rising maternal morbidity rates should include early recognition and management of hypertension. Prevention strategies focused on hypertension might also impact medically indicated preterm deliveries. The finding of increased severe maternal morbidity among American Indian/Alaskan Native women, a disadvantaged population in Washington State, underscores the role that socioeconomic factors may play in adverse maternal health outcomes. As 39% of severe maternal morbidity diagnoses were present on admission, this measure should be risk-adjusted if used as a quality metric for comparison between hospitals.


Assuntos
Hipertensão/epidemiologia , Complicações Cardiovasculares na Gravidez/epidemiologia , Adulto , Estudos Transversais , Feminino , Humanos , Hipertensão/mortalidade , Mortalidade Materna , Noroeste dos Estados Unidos/epidemiologia , Pré-Eclâmpsia/epidemiologia , Pré-Eclâmpsia/mortalidade , Gravidez , Complicações Cardiovasculares na Gravidez/mortalidade , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/mortalidade , Estudos Retrospectivos
14.
Mol Pharmacol ; 94(4): 1125-1131, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30012584

RESUMO

Metformin, an oral antihyperglycemic, is increasingly being prescribed to pregnant women with gestational diabetes. Metformin is a hydrophilic cation and relies on organic cation transporters to move across cell membranes. We previously demonstrated that human and mouse placentas predominantly express organic cation transporter 3 (OCT3), but the impact of this transporter on maternal and fetal disposition of metformin is unknown. Using immunofluorescence colocalization studies in term human placenta, we showed that OCT3 is localized to the basal (fetal-facing) membrane of syncytiotrophoblast cells with no expression on the apical (maternal-facing) membrane. OCT3 positive staining was also observed in fetal capillaries. To determine the in vivo role of OCT3 in maternal and fetal disposition of metformin, we determined metformin maternal pharmacokinetics and overall fetal exposure in wild-type and Oct3-null pregnant mice. After oral dosing of [14C]metformin at gestational day 19, the systemic drug exposure (AUC0-∞) in maternal plasma was slightly reduced by ∼16% in the Oct3-/- pregnant mice. In contrast, overall fetal AUC0-∞ was reduced by 47% in the Oct3-/- pregnant mice. Consistent with our previous findings in nonpregnant mice, metformin tissue distribution was respectively reduced by 70% and 52% in the salivary glands and heart in Oct3-/- pregnant mice. Our in vivo data in mice clearly demonstrated a significant role of Oct3 in facilitating metformin fetal distribution and exposure during pregnancy. Modulation of placental OCT3 expression or activity by gestational age, genetic polymorphism, or pharmacological inhibitors may alter fetal exposure to metformin or other drugs transported by OCT3.


Assuntos
Feto/efeitos dos fármacos , Feto/metabolismo , Metformina/farmacologia , Fator 3 de Transcrição de Octâmero/metabolismo , Placenta/efeitos dos fármacos , Animais , Transporte Biológico/efeitos dos fármacos , Linhagem Celular , Feminino , Células HEK293 , Humanos , Hipoglicemiantes/farmacologia , Camundongos , Camundongos Knockout , Placenta/metabolismo , Gravidez , Distribuição Tecidual/efeitos dos fármacos
15.
BMC Pregnancy Childbirth ; 18(1): 290, 2018 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-29976161

RESUMO

BACKGROUND: Magnesium sulfate is the preferred pharmacological intervention for the prevention and treatment of eclamptic seizures in pregnancy. Pain associated with intramuscular injections and the need for an electronic infusion pump for use intravenously represent significant barriers to broader utilization. We hypothesize that an alternative regimen based on serial intravenous (IV) boluses can produce serum concentrations comparable to those produced by a continuous infusion. METHODS: An open-label randomized trial was performed at two hospitals in Egypt. Women with severe preeclampsia were eligible and enrolled between January 2015 and February 2016. Two hundred subjects were randomized by random numbers generated centrally in distinct blocks and stratified by study site. They were assigned to a continuous infusion arm, (4 g loading dose with 1 g/hr. continuous infusion) or a serial IV bolus arm, (6 g loading dose with 2 g bolus every 2 h using a Springfusor® pump). Sparsely sampled magnesium serum concentrations were collected, nonlinear mixed effect modeling was conducted and Monte Carlo simulations were used to generate 200 simulated subjects in each treatment arm. The simulated populations were used to determine area under the concentration-time curve (AUC) as a measure of total drug exposure and compared. RESULTS: Simulated area under the magnesium serum concentration-time curve was significantly higher in the serial IV bolus arm than in the continuous infusion arm (1107 ± 461 mmol•min /L vs. 1010 ± 398 mmol•min /L, (P = 0.02)). Four percent of women in the serial bolus arm considered the treatment unacceptable or very unacceptable compared to 2% in the continuous infusion arm, (P = 0.68). CONCLUSIONS: Serial IV boluses achieve serum magnesium concentrations statistically significantly higher but clinically comparable to those achieved with a continuous infusion and offer a third option for the administration of MgSO4 to women with preeclampsia that may reduce barriers to utilization. TRIAL REGISTRATION: Trial no. NCT02091401, March 17, 2014.


Assuntos
Sulfato de Magnésio , Pré-Eclâmpsia , Convulsões , Adulto , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Área Sob a Curva , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Infusões Intravenosas , Injeções Intravenosas , Sulfato de Magnésio/administração & dosagem , Sulfato de Magnésio/efeitos adversos , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/tratamento farmacológico , Gravidez , Resultado da Gravidez , Convulsões/tratamento farmacológico , Convulsões/etiologia , Índice de Gravidade de Doença , Resultado do Tratamento
16.
J Clin Pharmacol ; 58(9): 1223-1232, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29733485

RESUMO

To evaluate the steady-state pharmacokinetics of prednisone and its metabolite prednisolone in pregnant and lactating female subjects, 19 subjects received prednisone (4-40 mg/day orally) in early (n = 3), mid (n = 9), and late (n = 13) pregnancy as well as postpartum with (n = 2) and without (n = 5) lactation. Serial blood and urine samples were collected over 1 dosing interval. Prednisone and its metabolite, prednisolone, steady-state noncompartmental pharmacokinetic parameters were estimated. During pregnancy, prednisone apparent oral clearance increased with dose (35.1 ± 11.4 L/h with 5 mg, 52.6 ± 5.2 L/h with 10 mg, and 64.3 ± 6.9 L/h with 20 mg, P = .001). Similarly, unbound prednisone apparent oral clearance increased with dose. In addition, prednisolone renal clearance increased with dose (0.3 ± 0.3 L/h with 5 mg, 0.5 ± 0.4 L/h with 10 mg, and 1.3 ± 1.1 L/h with 20 mg, P = .002). Higher prednisone (r = 0.57, P ≤ .05) and prednisolone (r = 0.75, P ≤ .05) concentrations led to a higher percentage of unbound drug. Breast-milk/plasma area under the concentration-time curve ratios were 0.5-0.6 for prednisone and 0.02-0.03 for prednisolone. Relative infant doses were 0.35% to 0.53% and 0.09% to 0.18%, for prednisone and prednisolone, respectively. Prednisone and prednisolone exhibit dose- and concentration-dependent pharmacokinetics during pregnancy, and infant exposure to these agents via breast milk is minimal.


Assuntos
Glucocorticoides/farmacocinética , Lactação , Prednisona/farmacocinética , Área Sob a Curva , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/sangue , Meia-Vida , Humanos , Período Pós-Parto , Prednisona/administração & dosagem , Prednisona/sangue , Gravidez
17.
Cancer Chemother Pharmacol ; 81(3): 455-460, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29305638

RESUMO

PURPOSE: The purpose of this report is to describe, for the first time, the pharmacokinetics of dacarbazine (DTIC) and its metabolites [5-[3-methyl-triazen-1-yl]-imidazole-4-carboxamide (MTIC), 5-[3-hydroxymethyl-3-methyl-triazen-1-yl]-imidazole-4-carboxamide (HMMTIC) and 5-aminoimidazole-4-carboxamide (AIC)] during pregnancy (n = 2) and postpartum (n = 1). METHODS: Non-compartmental DTIC, MTIC, HMMTIC, and AIC pharmacokinetics (PK) were estimated in one case at 29 week gestation and 18 day postpartum and a second case at 32 week gestation, in women receiving DTIC in combination with doxorubicin, bleomycin, and vinblastine for treatment of Hodgkin's lymphoma. Drug concentrations were measured by HPLC. RESULTS: In the subject who completed both pregnancy and postpartum study days, DTIC area under the concentration-time curve (AUC) was 27% higher and metabolite AUCs were lower by 27% for HMMTIC, 38% for MTIC, and 83% of AIC during pregnancy compared to postpartum. At 7 and 9 year follow-up, both subjects were in remission of their Hodgkin's lymphoma. CONCLUSIONS: Based on these two case reports, pregnancy appears to decrease the metabolism of the pro-drug dacarbazine, likely through inhibition of CYP1A2 activity. Lower concentrations of active metabolites and decreased efficacy may result, although both these subjects experienced long-term remission of their Hodgkin's lymphoma.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Dacarbazina , Doença de Hodgkin , Complicações Neoplásicas na Gravidez , Administração Intravenosa , Adulto , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/sangue , Antineoplásicos Alquilantes/farmacocinética , Área Sob a Curva , Bleomicina/farmacologia , Dacarbazina/administração & dosagem , Dacarbazina/efeitos adversos , Dacarbazina/análogos & derivados , Dacarbazina/sangue , Dacarbazina/farmacocinética , Dacarbazina/farmacologia , Doxorrubicina/farmacologia , Monitoramento de Medicamentos/métodos , Feminino , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Humanos , Recém-Nascido , Estadiamento de Neoplasias , Gravidez , Complicações Neoplásicas na Gravidez/tratamento farmacológico , Complicações Neoplásicas na Gravidez/patologia , Resultado da Gravidez , Resultado do Tratamento , Vimblastina/farmacologia
18.
Lancet ; 390(10095): 669-680, 2017 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-28668289

RESUMO

BACKGROUND: Between 62 000 and 77 000 women die annually from pre-eclampsia and eclampsia. Prompt delivery, preferably by the vaginal route, is vital for good maternal and neonatal outcomes. Two low-cost interventions-low-dose oral misoprostol tablets and transcervical Foley catheterisation-are already used in low-resource settings. We aimed to compare the relative risks and benefits of these interventions. METHODS: We undertook this multicentre, open-label, randomised controlled trial in two public hospitals in Nagpur, India. Women (aged ≥18 years) who were at 20 weeks' gestation or later with a live fetus and required delivery as a result of pre-eclampsia or hypertension were randomly assigned (1:1), via computer-generated block randomisation (block sizes of four, six, and eight) with concealment by use of opaque, sequentially numbered, sealed envelopes, to receive labour induction with either oral misoprostol 25 µg every 2 h (maximum of 12 doses) or a transcervical Foley catheter (silicone, size 18 F with 30 mL balloon). Randomisation was stratified by study centre. The catheter remained in place until active labour started, the catheter fell out, or 12 h had elapsed. If the catheter did not fall out within 12 h, induction continued with artificial membrane rupture and oxytocin, administered through a micro-drip gravity infusion set. Fetal monitoring was by intermittent auscultation. The primary outcome was vaginal birth within 24 h. Due to the nature of the interventions, masking of participants, study investigators, and care providers to group allocation was not possible. We analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01801410. FINDINGS: Between Dec 20, 2013, and June 29, 2015, we randomly assigned 602 women to induction with misoprostol (n=302) or the Foley catheter (n=300; intention-to-treat population). Vaginal birth within 24 h was more common in women in the misoprostol group than in the Foley catheter group (172 [57·0%] vs 141 [47·0%] women; absolute risk difference 10·0%, 95% CI 2·0-17·9; p=0·0136). Rates of uterine hyperstimulation were low in both the misoprostol and Foley catheter groups (two [0·7%] vs one [0·3%] cases; absolute risk difference 0·3%, 95% CI -0·8 to 1·5; p=0·566) and neonatal deaths did not differ significantly between groups (six [2·0%] vs three [1·0%] neonatal deaths; 1·0, -1·04 to 2·97; p=0·322). 17 serious adverse events (3%) were reported during the study: one case of intrapartum convulsion and one case of disseminated intravascular coagulation (both in the Foley group); ten perinatal deaths, including two stillbirths (both in the Foley catheter group) and eight neonatal deaths (n=5 in the misoprostol group and n=3 in the Foley catheter group); and five of neonatal morbidity, comprising birth asphyxia (n=3), septicaemia (n=1), and neonatal convulsion (n=1). INTERPRETATION: Oral misoprostol was more effective than transcervical Foley catheterisation for induction of labour in women with pre-eclampsia or hypertension. Future studies are required to assess whether oxytocin augmentation following misoprostol can be replaced by regular doses of oral misoprostol tablets. FUNDING: Medical Research Council, Department for International Development, and Wellcome Trust Joint Global Health Trials Scheme.


Assuntos
Hipertensão Induzida pela Gravidez/terapia , Trabalho de Parto Induzido/métodos , Misoprostol , Ocitócicos , Pré-Eclâmpsia/terapia , Administração Oral , Adolescente , Adulto , Análise Custo-Benefício , Feminino , Humanos , Hipertensão Induzida pela Gravidez/economia , Índia , Trabalho de Parto Induzido/economia , Pré-Eclâmpsia/economia , Gravidez , Resultado da Gravidez , Comprimidos , Cateterismo Urinário/economia , Cateterismo Urinário/estatística & dados numéricos , Vagina , Adulto Jovem
19.
Kidney Int ; 91(6): 1464-1472, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28233609

RESUMO

In the absence of uncontrolled hypertension or renal insufficiency, many consider the perinatal outcomes in pregnant women with nephrotic syndrome to be good. To further investigate this we performed a retrospective chart review of women with biopsy-proven nephrotic syndrome due to primary glomerular disease during pregnancy at a single tertiary center. Our review determined characteristics, presentation, management, pathologic diagnoses, and associated renal and maternal-fetal outcomes of 19 individuals with 26 pregnancies and 26 offspring. The mean age was 27.6 years, the mean gestational age at the presentation of nephrotic syndrome was 18.6 weeks, the mean creatinine was 0.85 mg/dL, mean serum albumin was 1.98 g/dL, and the mean proteinuria was 8.33 g/24 hours. The mean cardiac output was 8.6 L/minute, which was elevated compared to normal pregnancy. A kidney biopsy was performed during pregnancy in 8 individuals (median gestational age at time of biopsy was 21 weeks), changing management in six. Of the 26 pregnancies, maternal complications included preeclampsia in seven, acute kidney injury in six, premature rupture of membranes in two, and cellulitis in three. The mean age of gestation at delivery was 35.5 weeks. Fetal complications included low birth weight (under 2,500 g) in 14, intra-uterine growth restriction in three, and neonatal intensive care unit admission in eight. Thus, pregnant women with nephrotic syndrome are at high risk for developing both maternal and fetal complications, even in the absence of significant renal impairment or uncontrolled hypertension at the time of presentation of nephrotic syndrome.


Assuntos
Rim/fisiopatologia , Síndrome Nefrótica/complicações , Complicações na Gravidez/etiologia , Adulto , Biomarcadores/sangue , Biópsia , Pressão Sanguínea , Creatinina/sangue , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Rim/patologia , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/fisiopatologia , Síndrome Nefrótica/terapia , Gravidez , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/fisiopatologia , Complicações na Gravidez/terapia , Resultado da Gravidez , Estudos Retrospectivos , Fatores de Risco , Centros de Atenção Terciária , Resultado do Tratamento , Washington , Adulto Jovem
20.
Drug Metab Dispos ; 45(3): 325-329, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28069720

RESUMO

N1-methylnicotinamide (1-NMN) has been investigated as an endogenous probe for the renal transporter activity of organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins 1 and 2-K (MATE1 and MATE2-K). As pregnancy increased the renal secretion of metformin, a substrate for OCT2, MATE1, and MATE2-K, we hypothesized that the renal secretion of 1-NMN would be similarly affected. Blood and urine samples collected from women prescribed metformin for type 2 diabetes, gestational diabetes, and polycystic ovarian syndrome during early, mid, and late pregnancy (n = 34 visits) and postpartum (n = 14 visits) were analyzed for 1-NMN using liquid chromatography-mass spectrometry. The renal clearance and secretion clearance, using creatinine clearance to correct for glomerular filtration, were estimated for 1-NMN and correlated with metformin renal clearance. 1-NMN renal clearance was higher in both mid (504 ± 293 ml/min, P < 0.01) and late pregnancy (557 ± 305 ml/min, P < 0.01) compared with postpartum (240 ± 106 ml/min). The renal secretion of 1-NMN was 3.5-fold higher in mid pregnancy (269± 267, P < 0.05) and 4.5-fold higher in late pregnancy compared with postpartum (342 ± 283 versus 76 ± 92 ml/min, P < 0.01). Because creatinine is also a substrate of OCT2, MATE1, and MATE2-K, creatinine clearance likely overestimates filtration clearance, whereas the calculated 1-NMN secretion clearance is likely underestimated. Metformin renal clearance and 1-NMN renal clearance were positively correlated (rs = 0.68, P < 0.0001). 1-NMN renal clearance increases during pregnancy due to increased glomerular filtration and net secretion by renal transporters.


Assuntos
Hipoglicemiantes/farmacocinética , Rim/metabolismo , Metformina/farmacocinética , Niacinamida/análogos & derivados , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Gravidez/metabolismo , Adulto , Feminino , Idade Gestacional , Humanos , Hipoglicemiantes/sangue , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/urina , Taxa de Depuração Metabólica , Metformina/sangue , Metformina/uso terapêutico , Metformina/urina , Niacinamida/sangue , Niacinamida/metabolismo , Niacinamida/urina , Transportador 2 de Cátion Orgânico/metabolismo , Gravidez/sangue , Gravidez/urina
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