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1.
Environ Toxicol Pharmacol ; 87: 103723, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34391906

RESUMO

Living organisms are commonly exposed to cadmium and other toxic metals. A vast body of research has shown the significant effects of these toxic metals on developmental processes. In order to study the role of toxic metals on early developmental stages of eukaryotes, we explored the effect of cadmium (Cd2+) contaminant on zebrafish. Thus, zebrafish embryos were exposed to 3 mg/L (16.7 µM) Cd2+ for 96 h and imaged every 24 h from the exposure onwards. Hatching rates of the eggs were determined at 72 h, followed by analyses at 96 h for: survival rate, morphometrical factors, and functional parameters of the cardiovascular system. Interestingly enough, significant hatching delays along with smaller cephalic region and some morphological abnormalities were observed in the treatment group. Moreover, substantial changes were noticed in the length of notochord and embryo, absorption of yolk sac with shorter extension, area of swimming bladder, as well as pericardium sac after Cd2+ treatment. Cadmium also caused significant abnormalities in heart physiology which could be the leading cause of mentioned morphological deformities. Herein, our results shine light on systematic acute embryological effects of cadmium in the early development of zebrafish for the first time.


Assuntos
Anormalidades Induzidas por Medicamentos , Anormalidades Múltiplas/induzido quimicamente , Cádmio/toxicidade , Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Teratógenos/toxicidade , Poluentes Químicos da Água/toxicidade , Anormalidades Induzidas por Medicamentos/fisiopatologia , Animais , Débito Cardíaco/efeitos dos fármacos , Embrião não Mamífero/anormalidades , Embrião não Mamífero/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Volume Sistólico/efeitos dos fármacos , Peixe-Zebra/anormalidades , Peixe-Zebra/fisiologia
2.
J Clin Psychiatry ; 82(4)2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34352165

RESUMO

Objective: Second-generation antipsychotics (SGAs) are prescribed for a wide range of indications in women of reproductive age. The National Pregnancy Registry for Atypical Antipsychotics (NPRAA) was established to determine the risk of major malformations among infants exposed to these medications during the first trimester relative to a comparison group of unexposed infants of mothers with histories of psychiatric morbidity.Methods: Women, aged 18-45 years, with histories of psychiatric illness were prospectively followed through pregnancy and during the postpartum period. Pediatric and maternal medical records were obtained and screened for evidence of major malformations. Potential cases were adjudicated by a dysmorphologist who was blinded to drug exposure.. Recruitment to the Registry, which is based at the Ammon-Pinizzotto Center for Women's Mental Health at Massachusetts General Hospital (MGH), includes nationwide provider referral, self-referral, and advertisement through the MGH Center for Women's Mental Health website.Results: As of April 9, 2020, 1,906 women had enrolled, including 889 in the exposure group and 1,017 controls. A total of 1,311 women completed the study and were eligible for inclusion in the analysis. Medical records were obtained for 81.3% of participants. Among 640 live births in the exposure group, 16 (2.50%) had confirmed major malformations reported, and among 704 live births in the control group, 14 (1.99%) had confirmed major malformations reported. The estimated odds ratio for major malformations comparing exposed and unexposed infants was 1.48 (95% CI, 0.625-3.517).Conclusions: Data from the Registry assessing SGAs as a class indicate that they are unlikely to have a major teratogenic effect. These findings provide pertinent information for women and their health care providers regarding decisions about atypical antipsychotic use during pregnancy.Trial Registration: ClinicalTrails.gov identifier: NCT01246765.


Assuntos
Anormalidades Induzidas por Medicamentos/epidemiologia , Antipsicóticos/efeitos adversos , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Lactente , Recém-Nascido , Massachusetts/epidemiologia , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/epidemiologia , Gravidez , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/epidemiologia , Estudos Prospectivos , Sistema de Registros , Método Simples-Cego
3.
Seizure ; 91: 311-315, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34273670

RESUMO

BACKGROUND: Animal data suggest teratogenic effects with zonisamide use and risk of pregnancy losses. Human data following zonisamide exposure are presently limited, but suggest low risk of malformation with elevated risk of low birth weight. OBJECTIVE: To calculate the major congenital malformation (MCM) rate of zonisamide in human pregnancy and assess for a signal of any specific malformation pattern and associations with birth weight. METHODS AND MATERIALS: Data were obtained from the UK and Ireland Epilepsy and Pregnancy register (UKIEPR) which is an observational, registration, and follow up study from December 1996 to July 2020. Eligibility criteria were use of zonisamide and to have been referred to the UKIEPR before the outcome of the pregnancy was known. Primary outcome was evidence of MCM. RESULTS: From December 1996 through July 2020 there were 112 cases of first trimester exposure to zonisamide, including 26 monotherapy cases. There were 3 MCM for monotherapy cases (MCM rate 13.0% (95% confidence interval 4.5-32.1)), and 5 MCM for polytherapy cases (MCM rate 6.9% (95% confidence interval 3.0-15.2)). While the median birth weight was on 71st and 44th centile for monotherapy and polytherapy cases respectively, there was a high rate of infants born small for gestational age (21% for both). CONCLUSION: These data raise concerns about a signal for potential teratogenicity with zonisamide in human pregnancy. Given the low numbers reported, further data will be required to adequately counsel women who use zonisamide in pregnancy.


Assuntos
Anormalidades Induzidas por Medicamentos , Epilepsia , Complicações na Gravidez , Anormalidades Induzidas por Medicamentos/epidemiologia , Anormalidades Induzidas por Medicamentos/etiologia , Anticonvulsivantes/efeitos adversos , Epilepsia/tratamento farmacológico , Epilepsia/epidemiologia , Feminino , Seguimentos , Humanos , Irlanda/epidemiologia , Gravidez , Complicações na Gravidez/induzido quimicamente , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/epidemiologia , Resultado da Gravidez/epidemiologia , Sistema de Registros , Reino Unido/epidemiologia , Zonisamida/uso terapêutico
4.
J Neurol Sci ; 427: 117500, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34087566

RESUMO

OBJECTIVE: Certain antiepileptic drugs are associated with an increased risk for major congenital malformations (MCM). However, little is known regarding recent patterns of antiepileptic drug (ASM) prescriptions to women of childbearing age with epilepsy (WCE) in the United States. METHODS: Data from the Medical Expenditure Panel Survey was analyzed between the years 2004-2015 to determine trends in national antiepileptic drug prescriptions for WCE. Analysis of associations between demographic covariates and prescription of ASMs with MCM rate > 5% (topiramate, valproate, or phenobarbital) was performed with logistic regression. RESULTS: There was a weighted total of 395,292 WCE. 29.1% (23.2%-35.8%) of WCE were prescribed an AED with MCM rate > 5%. The odds of a LEV prescription significantly increased in the 2010-2012 (OR 2.91, 95% CI 1.09-7.79) and 2013-2015 (OR 5.06, 95% CI 2.02-12.67) intervals compared to 2004-2006. Conversely, the odds of PB prescriptions significantly decreased in 2010-2012 (OR 0.13, 95% CI 0.02-0.83) and 2013-2015 (OR 0.13, 95% CI 0.02-0.93) compared to 2004-2006. WCE between the ages of 25-34 (OR = 2.67, 95% CI = 1.32-5.41) and 35-44 years (OR = 2.59, 95% CI = 1.23-5.45), had lower odds of being prescribed ASMs with MCM rate > 5% compared to those between the ages of 15-24 years. SIGNIFICANCE: Between 2004 and 2015, the prescriptions of ASMs given to WCE has changed. Regardless, nearly one third were prescribed potentially teratogenic medications despite available and affordable safer alternatives. Identifying factors associated with the prescription of teratogenic drugs to WCE is critical so that it may be further limited in the future.


Assuntos
Anormalidades Induzidas por Medicamentos , Epilepsia , Complicações na Gravidez , Anormalidades Induzidas por Medicamentos/tratamento farmacológico , Adulto , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Epilepsia/epidemiologia , Feminino , Humanos , Gravidez , Complicações na Gravidez/tratamento farmacológico , Topiramato/uso terapêutico , Estados Unidos/epidemiologia , Ácido Valproico/uso terapêutico
5.
Expert Opin Drug Saf ; 20(8): 965-977, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34080507

RESUMO

OBJECTIVES: To establish awareness, knowledge, use and experience in practice of a sodium valproate pregnancy prevention program (PPP) in Ireland ("prevent") among three healthcare professional (HCP) groups. METHODS: A cross-sectional study using anonymous online surveys was conducted among general practitioners (GPs), pharmacists, and specialist consultants. Descriptive analyses are presented. RESULTS: HCP response rates were 5.8% for GPs (90/1544), 10.7% for pharmacists (219/2052), and 7.6% for specialists (17/224). Across HCP groups, there was high awareness (>90%) for specialist referral when female valproate patients are planning pregnancy, or become pregnant, but less awareness to refer annually for specialist review. While awareness of a possible teratogenic effect at any stage of pregnancy was high (>80%), most GPs (62.2%, 95% CI: 51.3, 71.9%) and community pharmacists (53.1%, 95% CI: 43.2, 62.8%) were unsure of the magnitude of risk for developmental disorders, while most specialists under-estimated this risk (46.7%, 95% CI: 24.8, 69.9%). Although >70% of the respondents identified valproate to be contraindicated in any woman of childbearing potential unless the conditions of the PPP are fulfilled, experience implementing key elements in practice varied. CONCLUSIONS: Our findings suggest continued effort is needed to ensure optimal implementation of "prevent" into clinical practice in Ireland.


Assuntos
Conhecimentos, Atitudes e Prática em Saúde , Farmacêuticos/estatística & dados numéricos , Médicos/estatística & dados numéricos , Ácido Valproico/efeitos adversos , Anormalidades Induzidas por Medicamentos/prevenção & controle , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Estudos Transversais , Feminino , Clínicos Gerais/estatística & dados numéricos , Humanos , Irlanda , Gravidez , Complicações na Gravidez/prevenção & controle , Ácido Valproico/administração & dosagem
6.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071707

RESUMO

Cardiac connexins (Cxs) are proteins responsible for proper heart function. They form gap junctions that mediate electrical and chemical signalling throughout the cardiac system, and thus enable a synchronized contraction. Connexins can also individually participate in many signal transduction pathways, interacting with intracellular proteins at various cellular compartments. Altered connexin expression and localization have been described in diseased myocardium and the aim of this study is to assess the involvement of Cx43, Cx26, and some related molecules in ponatinib-induced cardiac toxicity. Ponatinib is a new multi-tyrosine kinase inhibitor that has been successfully used against human malignancies, but its cardiotoxicity remains worrisome. Therefore, understanding its signaling mechanism is important to adopt potential anti cardiac damage strategies. Our experiments were performed on hearts from male and female mice treated with ponatinib and with ponatinib plus siRNA-Notch1 by using immunofluorescence, Western blotting, and proteomic analyses. The altered cardiac function and the change in Cxs expression observed in mice after ponatinib treatment, were results dependent on the Notch1 pathway and sex. Females showed a lower susceptibility to ponatinib than males. The downmodulation of cardiac Cx43, Cx26 and miR-122, high pS368-Cx43 phosphorylation, cell viability and survival activation could represent some of the female adaptative/compensatory reactions to ponatinib cardiotoxicity.


Assuntos
Cardiomiopatias , Conexina 26 , Conexina 43 , Imidazóis , Piridazinas , Fatores Sexuais , Anormalidades Induzidas por Medicamentos , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Cardiomiopatias/etiologia , Cardiomiopatias/fisiopatologia , Cardiotoxicidade , Conexina 26/efeitos dos fármacos , Conexina 26/metabolismo , Conexina 43/efeitos dos fármacos , Conexina 43/metabolismo , Modelos Animais de Doenças , Feminino , Junções Comunicantes/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Coração/efeitos dos fármacos , Coração/fisiopatologia , Imidazóis/efeitos adversos , Imidazóis/farmacologia , Masculino , Camundongos , Miocárdio/metabolismo , Miocárdio/patologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteômica , Piridazinas/efeitos adversos , Piridazinas/farmacologia , Receptor Notch1/metabolismo , Transdução de Sinais
7.
Neurol India ; 69(3): 692-697, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34169870

RESUMO

Background and Purpose: Epilepsy during pregnancy is a therapeutic challenge. Since the 1990s, the number of licensed antiepileptic drugs has substantially increased, but safety data on managing epilepsy during conception, pregnancy, and postpartum period use of newer generation antiepileptic drugs and birth defects are limited. We analyzed efficacy and safety of levetiracetam during pregnancy in northeast Indian women with active epilepsy (WWAE) which is being presented here. Design: Hospital based retrospective study. Patients and Methods: A retrospective analysis was conducted based on clinical records at a tertiary care teaching hospital and referral center in Northeast India between June 2008 through June 2018 without any personal identifying information. The Obstetric data from pregnancy register was supplemented with detailed neurologic data retrieved from medical records. Results: Of 103 women with active epilepsy, 47 (45.6%) received levetiracetam as monotherapy and 56 (54.4%) as polytherapy. During pregnancy, the seizure frequency was unchanged, or the change was better in the majority (61.1%) of the patients. With one twin pregnancy, there were 96 live births, 5 spontaneous abortions, 2 induced abortions, 1 stillbirth. However, the rate of small for gestational age was higher in WWAE, Apgar score at 5 min was lower in infants of WWAE, and the need for care in the neonatal ward and neonatal intensive care was higher. Seven of 103 exposed pregnancies had a major congenital malformation (6.79%), all 7 were exposed to other antiepileptic drugs. Generalized epilepsy accounted for 57.2%. Conclusion: Pregnancy course is uncomplicated and neonatal outcome is good in the majority of women with active epilepsy with proper antenatal and neurologic care. Levetiracetam taken in monotherapy can be considered as safer alternative for women with epilepsy of childbearing age. Long-term follow-up of neuropsychological and cognitive development of the children of WWAE is still needed.


Assuntos
Anormalidades Induzidas por Medicamentos , Epilepsia , Complicações na Gravidez , Anormalidades Induzidas por Medicamentos/tratamento farmacológico , Anticonvulsivantes/uso terapêutico , Criança , Epilepsia/tratamento farmacológico , Feminino , Humanos , Índia/epidemiologia , Lactente , Recém-Nascido , Levetiracetam/uso terapêutico , Gravidez , Complicações na Gravidez/tratamento farmacológico , Estudos Retrospectivos , Centros de Atenção Terciária
8.
BJOG ; 128(12): 1949-1957, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34036715

RESUMO

OBJECTIVE: Studies restricted to live births may underestimate severe teratogenic effects. We address the limitation by including data from both prenatal and postnatal diagnoses of cardiac malformations. DESIGN: Register-based study. SETTING: Denmark. POPULATION: 364 012 singleton pregnancies from 2007 to 2014. METHODS: We used data from five nationwide registries. Exposure to antidepressants was measured using redeemed prescriptions. MAIN OUTCOME MEASURES: Pregnancies with cardiac malformations that end in miscarriage, termination, stillbirth, postnatal death or cardiac surgery <1 year of birth were classified as severe cardiac malformations (SCM). Propensity scores with adjusted prevalence ratios (PRs) were calculated. RESULTS: SCM were reported in 972 of 364 012 pregnancies overall and in 16 of 4105 exposed. For venlafaxine, the PR for SCM was 2.13 (95% confidence interval [CI] 0.89-5.13), 1.73 (95% CI 1.08-2.77) for other cardiac malformations, and there was a cluster of hypoplastic left heart syndromes (HLHS) (crude PR 17.4 [95% CI 6.41-47.2]), none of which ended in a live birth. For HLHS, the absolute risk increase was 4.4/1000 and the number needed to harm was 225. For selective serotonin reuptake inhibitors, the PRs were 1.09 (95% CI 0.52-2.30) and 1.38 (95% CI 1.00-1.92) for SCM and other cardiac malformations, respectively. CONCLUSIONS: Pregnancy exposure to venlafaxine is associated with an increased risk of severe cardiac malformations but with a low absolute risk. Potential mechanisms include direct effects or confounding by indication. Venlafaxine exposure is a marker for risk pregnancies for which fetal echocardiography may be considered. TWEETABLE ABSTRACT: Exposure to venlafaxine is associated with an increased risk of cardiac malformations but with a low absolute risk.


Assuntos
Anormalidades Induzidas por Medicamentos/epidemiologia , Antidepressivos/efeitos adversos , Cardiopatias Congênitas/induzido quimicamente , Complicações na Gravidez/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Adulto , Dinamarca/epidemiologia , Feminino , Cardiopatias Congênitas/epidemiologia , Humanos , Recém-Nascido , Masculino , Gravidez , Complicações na Gravidez/psicologia , Cuidado Pré-Natal/estatística & dados numéricos , Sistema de Registros , Inibidores de Captação de Serotonina/efeitos adversos , Cloridrato de Venlafaxina/efeitos adversos
9.
J Drugs Dermatol ; 20(5): s5-s11, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33938693

RESUMO

Since its approval in 1982, oral isotretinoin has revolutionized acne therapy. However, oral isotretinoin use has long been associated with challenges of variable bioavailability and food dependence. It is recommended to ingest oral isotretinoin with a high-fat meal in order to maximize absorption, but many patients fail to adhere to this recommendation. This may lead to inadequate isotretinoin absorption levels. Patients who fail to achieve isotretinoin target cumulative dose are more likely to experience symptom relapse. To address the challenge of traditional isotretinoin variable bioavailability, subsequent isotretinoin formulations have attempted to improve its absorption abilities. In 2014, an isotretinoin formulation utilizing Lidose technology, known as Absorica, showed significant improvements in absorption levels compared to traditional oral isotretinoin in the fasted state. In 2019, isotretinoin absorption levels were further advanced in a new formulation approved by the FDA known as Absorica LD. Utilizing advanced micronization technology that physically reduces the size of the drug molecule, Absorica LD exhibits twice the absorption levels of Absorica under fasting conditions. In the fed state, Absorica LD achieves similar plasma levels to Absorica with a 20 percent lower dose. Absorica LD also produces consistent serum isotretinoin levels irrespective of gastrointestinal contents. By eliminating the “food effect” seen in traditional oral isotretinoin, Absorica LD has the potential to improve patient adherence and long-term patient outcomes. J Drugs Dermatol. 20:5(Suppl):s5-11.


Assuntos
Anormalidades Induzidas por Medicamentos/prevenção & controle , Acne Vulgar/tratamento farmacológico , Fármacos Dermatológicos/farmacocinética , Composição de Medicamentos/métodos , Isotretinoína/farmacocinética , Anormalidades Induzidas por Medicamentos/etiologia , Acne Vulgar/sangue , Administração Oral , Adolescente , Adulto , Área Sob a Curva , Disponibilidade Biológica , Ensaios Clínicos como Assunto , Fármacos Dermatológicos/administração & dosagem , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/química , Dieta Hiperlipídica , Feminino , Interações Alimento-Droga , Absorção Gastrointestinal , Humanos , Isotretinoína/administração & dosagem , Isotretinoína/efeitos adversos , Isotretinoína/química , Masculino , Adesão à Medicação , Tamanho da Partícula , Adulto Jovem
10.
Yakugaku Zasshi ; 141(4): 463-471, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-33790112

RESUMO

We have been conducting research with the aim of generating evidence for the safety of perinatal drugs. As a result of reviewing the records of inquiries to the Drug Information Office of our hospital, we found a large discrepancy between the description of perinatal drugs in package inserts in Japan and the description of the Pregnancy Risk Category according to the U.S. Food and Drug Administration. In the Japan Environment and Children's Study (JECS), we determined the proportion of drug and supplement use among 97464 pregnant women. We clarified that prescriptions of antihypertensive drugs for pregnant women increased during the second half of pregnancy, while prescriptions of anti-epileptic and anti-anxiety drugs decreased after pregnancy using a claims database. A survey of pharmacists and pharmacy students revealed a lack of awareness of effective folic acid intake to reduce the risk of neural tube defects in infants. The percentage of pre-pregnancy folic acid supplementation among pregnant women participating in the Babies and their Parents' Longitudinal Observation in Suzuki Memorial Hospital on Intrauterine Period (BOSHI) study, the JECS, and the Tohoku Medical Megabank (TMM) Birth and Three-Generation (BirThree) cohort study was 6.3-18.0%. As a result of close examination of the records of inquiries to the Drug Information Office of our hospital, and of cases in which our lactation plan sheet was applied, it was found that there were discrepancies between the information on the drug package insert and the information on Medications & Mother's Milk, etc. in Japan. The results obtained have been clinically applied in daily practice and we are continuing our research while taking measures.


Assuntos
Suplementos Nutricionais , Serviços de Informação sobre Medicamentos , Medicamentos sob Prescrição , Segurança , Anormalidades Induzidas por Medicamentos/epidemiologia , Adulto , Conscientização , Aleitamento Materno , Estudos de Coortes , Bases de Dados Factuais , Rotulagem de Medicamentos , Feminino , Ácido Fólico/administração & dosagem , Humanos , Recém-Nascido , Japão , Defeitos do Tubo Neural/prevenção & controle , Farmacêuticos , Gravidez , Medicamentos sob Prescrição/efeitos adversos , Inquéritos e Questionários , Adulto Jovem
11.
Epilepsy Behav ; 118: 107941, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33852986

RESUMO

PURPOSE: To assess the possible contribution of factors in additional to intrauterine anti-seizure medication (ASM) exposure in the occurrence of fetal malformation in women with ASM-treated epilepsy. RESULTS: Logistic regression analysis showed that maternal age over 31 years, family histories of fetal malformation, and conception after assisted fertility treatment, and also dosage of valproate, carbamazepine, and topiramate, made statistically significant (P<0.05) contributions to the fetal malformation rate in 2223 pregnancies in Australian women with epilepsy. The malformation rates were lower in pregnancies where the non-ASM-associated contributory factors were not present: statistically significantly so for all ASM-exposed pregnancies, and those pregnancies exposed to the more potent teratogenic drugs. CONCLUSION: It is important to consider the possible roles of identified, and also possible non-identified, non-ASM factors in relation to the occurrence of fetal malformations in the pregnancies of women with ASM-treated epilepsy.


Assuntos
Anormalidades Induzidas por Medicamentos , Epilepsia , Complicações na Gravidez , Anormalidades Induzidas por Medicamentos/epidemiologia , Anormalidades Induzidas por Medicamentos/etiologia , Adulto , Anticonvulsivantes/efeitos adversos , Austrália/epidemiologia , Epilepsia/tratamento farmacológico , Feminino , Humanos , Gravidez , Complicações na Gravidez/tratamento farmacológico , Ácido Valproico/efeitos adversos
12.
Epilepsia ; 62(5): 1141-1147, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33782943

RESUMO

OBJECTIVE: This is an audit of the use of valproate (VPA) during pregnancy in women with epilepsy (WWE). METHODS: We identified all pregnancies exposed to VPA in the Kerala Registry of Epilepsy and Pregnancy between January 2010 and December 2019. Subjects' past usage of antiepileptic drugs (AEDs), seizure count before and during pregnancy, fetal outcome, and major congenital malformations (MCMs) were abstracted from the registry records. The presumed reason for usage of VPA was deducted from the clinical records. RESULTS: There were 221 pregnancies (17.75%) exposed to VPA (monotherapy, n = 149) during the audit period. The MCM rate for the completed pregnancies exposed to VPA was higher (n = 20, 10.36%) than that of VPA-unexposed pregnancies (n = 39, 4.96%). The relative risk for MCM with VPA exposure was 2.1 (95% confidence interval = 1.24-3.48, number needed to treat with VPA to result in MCM = 19). Reasons for using VPA during pregnancy (some women had more than one reason) were (1) VPA was the first AED prescribed and was effective (68, 29.06%), (2) other AEDs were ineffective (128, 54.70%), and (3) other AEDs were discontinued due to adverse effects (17, 7.28%). Other reasons (21, 8.97%) were (1) VPA was selected after the epilepsy classification was revised (3, 1.28%), (2) other AEDs were expensive (2, .85%), and (3) patient switched to VPA from other AEDs for unspecified reason (16, 6.83%). VPA was discontinued during pregnancy for 6 (2.71%) persons. Less than 10% of women were tried on lamotrigine or levetiracetam before switching to VPA. SIGNIFICANCE: Nine MCMs per thousand pregnancies can be avoided if VPA is not used in WWE. Safe and effective AEDs as alternatives to VPA are the need of the hour. Professional bodies and regulatory authorities need to implement updated guidelines on AED usage in girls and women.


Assuntos
Anormalidades Induzidas por Medicamentos/epidemiologia , Anormalidades Induzidas por Medicamentos/etiologia , Anticonvulsivantes/efeitos adversos , Epilepsia/tratamento farmacológico , Complicações na Gravidez/tratamento farmacológico , Ácido Valproico/efeitos adversos , Adulto , Feminino , Humanos , Índia/epidemiologia , Gravidez , Sistema de Registros
13.
Br J Clin Pharmacol ; 87(10): 3890-3900, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33783857

RESUMO

AIMS: Maternal antithyroid drug (ATD) use during pregnancy has been associated with an increased risk of birth defects in offspring. Uncertainty remains on the size of this risk and how it compares to untreated hyperthyroidism due to methodological limitations of previous studies. METHODS: Systematic review of MEDLINE and EMBASE identifying observational studies examining ATD use during pregnancy and risk of birth defects by 28 August 2020. Data were extracted on study characteristics, effect estimates and comparator groups. Adjusted effect estimates were pooled using a random-effects generic inverse variance method and absolute risk calculated. RESULTS: Seven cohort studies and 1 case-control study involving 6 212 322 pregnancies and 388 976 birth defects were identified reporting regression effect estimates. Compared to an unexposed population comparison, the association between ATD use during pregnancy and birth defects in offspring was: adjusted risk ratio (aRR) 1.16 95% confidence interval (CI) 1.08-1.25 for propylthiouracil (PTU); aRR 1.28 95%CI 1.06-1.54 for methimazole/carbimazole (MMI/CMZ); aRR 1.51, 95%CI 1.16-1.97 for both MMI/CMZ and PTU; and aRR 1.15 95%CI 1.02-1.29 for untreated hyperthyroidism. The excess risk of any and major birth defects per 1000, respectively, was: 10.2 and 1.3 for PTU; 17.8 and 2.3 for MMI/CMZ; 32.5 and 4.1 for both MMI/CMZ and PTU; and 9.6 and 1.2 for untreated hyperthyroidism. CONCLUSIONS: When appropriately analysed the risk of birth defects associated with ATD use in pregnancy is attenuated. Although still elevated, the risk of birth defects is smallest with PTU compared to MMI/CMZ and may be similar to that of untreated hyperthyroidism.


Assuntos
Anormalidades Induzidas por Medicamentos , Hipertireoidismo , Complicações na Gravidez , Anormalidades Induzidas por Medicamentos/epidemiologia , Anormalidades Induzidas por Medicamentos/etiologia , Antitireóideos/efeitos adversos , Estudos de Casos e Controles , Feminino , Humanos , Hipertireoidismo/induzido quimicamente , Hipertireoidismo/epidemiologia , Metimazol , Estudos Observacionais como Assunto , Gravidez , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/epidemiologia , Propiltiouracila/efeitos adversos
14.
Gastroenterology ; 161(1): 107-115.e3, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33744307

RESUMO

BACKGROUND & AIMS: We conducted a retrospective cohort study to inform the safety of exposure to immunosuppressive and/or biologic agents around conception in expectant fathers with immune-mediated inflammatory diseases (IMIDs) on birth outcomes. METHODS: Using a deidentified administrative claims database (OptumLabs Data Warehouse), we identified 7453 expectant fathers with IMIDs (inflammatory bowel diseases, rheumatoid arthritis, psoriasis/psoriatic arthritis, and ankylosing spondylitis) linked to newborns with periconception medication exposure between 38 and 60 weeks before the newborn birth date (34-58 weeks prior for preterm newborns) and neonatal follow-up for 3 months after the birth date. Through logistic regression adjusting for paternal age and race (and, in a subset, for maternal age, race, presence of IMIDs, and nonsingleton births), we compared the risk of major congenital malformations (primary outcome) and preterm birth and low birth weight in fathers exposed to thiopurines (n = 461), methotrexate (n = 171), tumor necrosis factor (TNF) α antagonists (n = 1082), or non-TNF-targeting biologic agents (n = 132) vs fathers not exposed to any of these medications (n = 5607). RESULTS: As compared to unexposed fathers (3.4% prevalence of major congenital malformations), exposure to thiopurines (relative risk [RR], 1.12; 95% confidence interval [CI], 0.66-1.76), methotrexate (RR, 0.67; 95% CI, 0.21-1.55), TNF-α antagonists (RR, 1.14; 95% CI, 0.81-1.57), and non-TNF-targeting biologic agents (RR, 1.75; 95% CI, 0.80-3.24) was not associated with increased risk of major congenital malformations. No association was observed between paternal medication exposure and risk of preterm birth or low birth weight. Results were stable on subanalyses of linked father-mother-newborn triads. CONCLUSIONS: In a large cohort study of 7453 expectant fathers with IMIDs, exposure to immunosuppressive or biologic agents around conception was not associated with increased risk of adverse birth outcomes.


Assuntos
Anormalidades Induzidas por Medicamentos/etiologia , Fatores Biológicos/efeitos adversos , Doenças do Sistema Imunitário/tratamento farmacológico , Imunossupressores/efeitos adversos , Exposição Paterna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Adulto , Fatores Biológicos/uso terapêutico , Anormalidades Congênitas/etiologia , Feminino , Humanos , Imunossupressores/uso terapêutico , Recém-Nascido de Baixo Peso , Recém-Nascido , Inflamação/tratamento farmacológico , Masculino , Gravidez , Nascimento Prematuro/induzido quimicamente , Nascimento Prematuro/etiologia , Efeitos Tardios da Exposição Pré-Natal/etiologia , Estudos Retrospectivos
15.
Toxicol Appl Pharmacol ; 414: 115424, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33524444

RESUMO

For the determination of acute toxicity of chemicals in zebrafish (Danio rerio) embryos, the OECD test guideline 236, relative to the Fish Embryo Toxicity Test (FET), stipulates a dose-response analysis of four lethal core endpoints and a quantitative characterization of abnormalities including their time-dependency. Routinely, the data are analyzed at the different observation times separately. However, observations at a given time strongly depend on the previous effects and should be analyzed jointly with them. To solve this problem, we developed multistate models for occurrence of developmental malformations and live events in zebrafish embryos exposed to eight concentrations of valproic acid (VPA) the first five days of life. Observations were recorded daily per embryo. We statistically infer on model structure and parameters using a numerical Bayesian framework. Hatching probability rate changed with time and we compared five forms of its time-dependence; a constant rate, a piecewise constant rate with a fixed hatching time at 48 h post fertilization, a piecewise constant rate with a variable hatching time, as well as a Hill and Gaussian form. A piecewise constant function of time adequately described the hatching data. The other transition rates were conditioned on the embryo body concentration of VPA, obtained using a physiologically-based pharmacokinetic model. VPA impacted mostly the malformation probability rate in hatched and non-hatched embryos. Malformation reversion probability rates were lowered by VPA. Direct mortality was low at the concentrations tested, but increased linearly with internal concentration. The model makes full use of data and gives a finer grain analysis of the teratogenic effects of VPA in zebrafish than the OECD-prescribed approach. We discuss the use of the model for obtaining toxicological reference values suitable for inter-species extrapolation. A general result is that complex multistate models can be efficiently evaluated numerically.


Assuntos
Anormalidades Induzidas por Medicamentos/etiologia , Modelos Biológicos , Teratógenos/toxicidade , Testes de Toxicidade Aguda , Ácido Valproico/toxicidade , Anormalidades Induzidas por Medicamentos/embriologia , Animais , Teorema de Bayes , Simulação por Computador , Relação Dose-Resposta a Droga , Embrião não Mamífero/anormalidades , Embrião não Mamífero/efeitos dos fármacos , Análise Numérica Assistida por Computador , Teratógenos/farmacocinética , Toxicocinética , Ácido Valproico/farmacocinética , Peixe-Zebra/embriologia
16.
BMJ ; 372: n107, 2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33568349

RESUMO

OBJECTIVE: To examine the association between the use of macrolide antibiotics in pregnancy and the risk of major birth defects. DESIGN: Nationwide, register based cohort study. SETTING: Denmark, 1997-2016. PARTICIPANTS: Of 1 192 539 live birth pregnancies, pregnancies during which macrolides had been used (13 019) were compared with those during which penicillin (that is, phenoxymethylpenicillin) had been used (matched in a 1:1 ratio on propensity scores). Other comparative groups were pregnancies when macrolides had been used recently but before pregnancy (matched 1:1) and pregnancies where no antibiotics had been used (matched 1:4). MAIN OUTCOME MEASURES: Association with an outcome of any major birth defect and specific subgroups of birth defects were assessed by relative risk ratios and absolute risk differences. RESULTS: In matched comparisons, 457 infants were born with major birth defects to women who had used macrolides during pregnancy (35.1 per 1000 pregnancies) compared with 481 infants (37.0 per 1000 pregnancies) to women who had used penicillin (relative risk ratio 0.95; 95% confidence interval 0.84 to 1.08), corresponding to an absolute risk difference of -1.8 (95% confidence interval -6.4 to 2.7) per 1000 pregnancies. The risk of major birth defects was not significantly increased for women who had used macrolides during pregnancy compared with those who had used macrolides recently but before becoming pregnant (relative risk ratio 1.00 (95% confidence interval 0.88 to 1.14); absolute risk difference -0.1 (95% confidence interval -4.8 to 4.7) per 1000 pregnancies) or compared with women who did not use any antibiotics (1.05 (0.95 to 1.17); 1.8 (-1.7 to 5.3) per 1000 pregnancies). For all three comparative group analyses and in the analyses of use of individual macrolides, no significant increased risk of specific subgroups of birth defects associated with the use of macrolides was found. CONCLUSIONS: In this nationwide cohort study, the use of macrolide antibiotics in pregnancy was not associated with an increased risk of major birth defects. Analyses of the associated risk of 12 specific subgroups of birth defects with the use of macrolides in pregnancy were not significant.


Assuntos
Anormalidades Induzidas por Medicamentos/epidemiologia , Antibacterianos/uso terapêutico , Macrolídeos/uso terapêutico , Penicilina V/uso terapêutico , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Padrões de Prática Médica/estatística & dados numéricos , Gravidez , Pontuação de Propensão , Sistema de Registros
17.
BMJ ; 372: n102, 2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33568363

RESUMO

OBJECTIVE: To evaluate the risk of first trimester exposure to prescription opioids for major congenital malformations, previously reported to be associated with such exposure. DESIGN: Population based cohort study. SETTING: Nationwide sample of publicly and commercially insured pregnant women linked to their liveborn infants, nested in the Medicaid Analytic eXtract (MAX, 2000-14) and the MarketScan Research Database (MarketScan, 2003-15). PARTICIPANTS: 1 602 580 publicly insured (MAX) and 1 177 676 commercially insured (MarketScan) pregnant women with eligibility from at least three months before pregnancy to one month after delivery; infants with eligibility for at least three months after birth. INTERVENTIONS: Use of prescription opioids was ascertained by requiring two or more dispensations of any opioid during the first trimester. MAIN OUTCOMES MEASURES: Major malformations overall, cardiac malformations overall, ventricular septal defect, secundum atrial septal defect/patent foramen ovale, neural tube defect, clubfoot, and oral cleft, defined based on validated algorithms. Propensity score stratification was used to adjust for potential confounders and/or proxies for confounders. Estimates from each database were combined using meta-analysis. RESULTS: 70 447 (4.4%) of 1 602 580 publicly insured and 12 454 (1.1%) of 1 177 676 commercially insured pregnant women had two or more dispensations of an opioid during the first trimester. Absolute risk of malformations overall was 41.0 (95% confidence interval 39.5 to 42.5) per 1000 pregnancies exposed to opioids versus 32.0 (31.7 to 32.3) per 1000 unexposed pregnancies in the MAX cohort, and 42.6 (39.0 to 46.1) and 37.3 (37.0 to 37.7) per 1000, respectively, in the MarketScan cohort. Pooled unadjusted relative risk estimates were raised for all outcomes but shifted substantially toward the null after adjustment; for malformations overall (relative risk 1.06, 95% confidence interval 1.02 to 1.10), cardiovascular malformations (1.09, 1.00 to 1.18), ventricular septal defect (1.07, 0.95 to 1.21), atrial septal defect/patent foramen ovale (1.04, 0.88 to 1.24), neural tube defect (0.82, 0.53 to 1.27), and clubfoot (1.06, 0.88 to 1.28). The relative risk for oral clefts remained raised after adjustment (1.21, 0.98 to 1.50), with a higher risk of cleft palate (1.62, 1.23 to 2.14). CONCLUSIONS: Prescription opioids used in early pregnancy are not associated with a substantial increase in risk for most of the malformation types considered, although a small increase in the risk of oral clefts associated with their use is possible.


Assuntos
Anormalidades Induzidas por Medicamentos/epidemiologia , Analgésicos Opioides/efeitos adversos , Complicações na Gravidez/tratamento farmacológico , Anormalidades Induzidas por Medicamentos/etiologia , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Estudos Transversais , Bases de Dados Factuais , Feminino , Humanos , Recém-Nascido , Manejo da Dor/métodos , Manejo da Dor/estatística & dados numéricos , Padrões de Prática Médica/estatística & dados numéricos , Gravidez , Complicações na Gravidez/epidemiologia , Primeiro Trimestre da Gravidez , Risco
18.
Epidemiol Health ; 43: e2021008, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33541012

RESUMO

OBJECTIVES: This meta-analysis investigated the risk of congenital anomalies among infants of human immunodeficiency virus-infected pregnant women who were exposed to antiretroviral therapy (ART). METHODS: Cohort studies, case-control studies, randomized controlled trials, and controlled clinical trials were reviewed by searching MEDLINE/PubMed, Embase, Web of Science, Scopus, AIDSLINE, CINAHL, Cochrane Library, and Google/Google Scholar. Methodological quality was assessed using the GRADE evaluation. A DerSimonian and Laird random-effects model was used. Subgroup analyses and meta-regression were used to investigate heterogeneity. RESULTS: The electronic searches yielded 765 items. After quality assessment and grading, 30 studies were suitable for metaanalysis. In total, 1,461 congenital anomalies were found among 53,186 births. Children born to women receiving combined antiretroviral therapy (cART) had an approximately 10% higher risk of developing congenital anomalies (relative risk [RR], 1.09; 95% confidence interval [CI], 1.04 to 1.14). A subgroup analysis found no significant difference in the risk of congenital anomalies between cART and efavirenz users. However, zidovudine and protease inhibitor (RR, 1.09; 95% CI, 1.00 to 1.19) users were found to have a 10% increased risk of congenital anomalies, and integrase inhibitor users had a 60% increase in risk (RR, 1.61; 95% CI, 1.60 to 2.43). The subgroup results should be interpreted cautiously because of the moderate heterogeneity (I2 =58%). CONCLUSIONS: The use of protease inhibitors, integrase inhibitors, zidovudine, and newer drugs should be carefully considered in pregnant women. Further studies are needed to address environmental, nutrition, and adherence factors related to ART. Establishing a congenital anomalies surveillance system is recommended.


Assuntos
Anormalidades Induzidas por Medicamentos/epidemiologia , Antirretrovirais/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Lactente , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco
19.
Cardiol Young ; 31(5): 853-855, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33455599

RESUMO

Interestingly, our case presenting with coronary AV fistula firstly reported in the literature with fetal valproate syndrome. Although differential diagnosis is sometimes difficult, it can be diagnosed with detailed history, physical examination and appropriate laboratory tests. Fetal valproate syndrome can be prevented by discontinue of the valproic acid especially during first trimester of pregnancy.


Assuntos
Anormalidades Induzidas por Medicamentos , Fístula Arteriovenosa , Feminino , Humanos , Gravidez , Primeiro Trimestre da Gravidez , Ácido Valproico/efeitos adversos
20.
J Clin Psychiatry ; 82(1)2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33406323

RESUMO

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) medications are increasingly used in pregnancy. Studies on the pregnancy safety of these medications that are restricted to live births may underestimate severe teratogenic effects that cause fetal demise or termination of pregnancy. The present study addresses this limitation by including data from both prenatal and postnatal diagnoses of major malformations. METHODS: A nationwide registry-based study was conducted of 364,012 singleton pregnancies in Denmark from November 1, 2007, to February 1, 2014. Exposures to ADHD medication were obtained from redeemed prescriptions from the Danish Health Services Prescription Database. Outcome data included prenatally diagnosed malformations from the Danish Fetal Medicine Database and postnatally diagnosed malformations from the Danish National Patient Registry. The primary outcome was major malformations overall, and secondary outcomes were malformations of the central nervous system and cardiac malformations. The comparison group was pregnancies with no redeemed prescriptions for ADHD medication. We defined severe cardiac malformations (SCM) as concurrent diagnoses of a cardiac malformation with miscarriage, termination, stillbirth, postnatal death, or cardiac surgery within 1 year of birth. RESULTS: The prevalence of first-trimester exposure to ADHD medication increased during the study period from 0.05% in 2008 to 0.27% in 2013, with the majority (473/569) of the exposures being to methylphenidate. There were 5.1% malformations overall and 2.1% cardiac malformations among the exposed compared to 4.6% and 1.0%, respectively, among the unexposed. For methylphenidate, the adjusted prevalence ratios (PRs) were 1.04 (95% confidence interval [CI], 0.70-1.55) for malformations overall and 1.65 (95% CI, 0.89-3.05) for any cardiac malformations (number needed to harm [NNH] = 92), with septum defects in 10 out of 12 cases. The PR for ventricular septal defect was 2.74 (95% CI, 1.03-7.28) and for SCM, 2.59 (95% CI, 0.98-6.90). CONCLUSIONS: Exposure to methylphenidate was not associated with an increased risk of malformations overall in data that included information from both prenatal and postnatal diagnoses of major malformations. There was an increased risk of cardiac malformations with NNH of 92 based on 12 cases among the exposed. More data are needed on other types of ADHD medication.


Assuntos
Anormalidades Induzidas por Medicamentos/etiologia , Aborto Espontâneo/induzido quimicamente , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/efeitos adversos , Mortalidade Perinatal , Complicações na Gravidez/tratamento farmacológico , Natimorto , Anormalidades Induzidas por Medicamentos/epidemiologia , Aborto Espontâneo/epidemiologia , Adulto , Estimulantes do Sistema Nervoso Central/uso terapêutico , Dinamarca/epidemiologia , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez , Prevalência , Sistema de Registros , Fatores de Risco , Natimorto/epidemiologia
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