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1.
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
2.
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
3.
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
4.
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
5.
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
6.
BMC Res Notes ; 13(1): 509, 2020 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-33160408

RESUMO

OBJECTIVE: With the ongoing COVID-19 pandemic, large numbers of people will receive one of the several medications proposed to treat COVID-19, including patients of reproductive age. Given that some medications have shown adverse effects on sperm quality, there might be a transgenerational concern. We aim at examining the association between drugs proposed to treat COVID-19 when taken by the father around conception and any pre-term birth or major birth defects in offspring in a nation-wide cohort study using Danish registry data. Offspring whose father filled at least one prescription of the following medications in the 3 months preceding conception were considered exposed: chloroquine, hydroxychloroquine, losartan, azithromycin, naproxen, dexamethasone and prednisone. RESULTS: For azithromycin and naproxen, large numbers of offspring were exposed (> 1800 offspring), and we found no association with adverse birth outcomes. For chloroquine, losartan and dexamethasone, exposure was intermediate (~ 900 offspring), and there was no statistically significant association with birth defects. For hydroxychloroquine and prednisone, exposure was limited (< 300 offspring). Our evidence suggests that azithromycin and naproxen are safe with respect to pre-term birth and birth defects. For the other drugs investigated larger exposures are needed for conclusive statements.


Assuntos
Anormalidades Induzidas por Medicamentos/etiologia , Antivirais/efeitos adversos , Infecções por Coronavirus/tratamento farmacológico , Exposição Paterna , Pneumonia Viral/tratamento farmacológico , Nascimento Prematuro/induzido quimicamente , Anormalidades Induzidas por Medicamentos/epidemiologia , Adulto , Estudos de Coortes , Dinamarca , Feminino , Humanos , Masculino , Pandemias , Medição de Risco
8.
PLoS Negl Trop Dis ; 14(8): e0008329, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32760161

RESUMO

The drug thalidomide has resurged in the world market under restrictive conditions for marketing and use. In Brazil, there are still cases of pregnant women using thalidomide even after the implementation of laws that regulate the control of use (Law No. 10.651/2003 and Collegiate Board Resolution No. 11/2011). The objective of this study was to discuss the control of thalidomide use in Brazil, based on a scoping review of the scientific literature, documents, and data from the Ministry of Health. A total of 51 studies and documents related to the following subthemes were selected: (1) organization of access and use of thalidomide in the health system; (2) epidemiological and population characteristics of people affected by leprosy; and (3) occurrence of pregnancy and cases of embryopathy with the use of thalidomide. The results showed that Brazil has no unified information database about thalidomide patients. Furthermore, there is inconsistency in the accreditation of public health centers that dispense this medicine, in a country that has a high consumption of thalidomide in the Unified Health System. A large part of this amount of dispensed medicine is intended for the treatment of erythema nodosum leprosum, mainly in the North, Northeast, and Central-West regions of the country, which are endemic for leprosy. This disease is the only one among the clinical indications of the medicine approved in Brazil that does not have a Clinical Protocol and Therapeutic Guidelines. The control of thalidomide use in Brazil presents historical regulatory failures. These are currently linked to the organization and structure of primary healthcare in the country, as well as to the lack of leadership of the Ministry of Health and National Health Surveillance Agency when it comes to managing the process of control of this use.


Assuntos
Hanseníase/tratamento farmacológico , Talidomida/efeitos adversos , Talidomida/uso terapêutico , Anormalidades Induzidas por Medicamentos/epidemiologia , Brasil/epidemiologia , Eritema Nodoso/tratamento farmacológico , Feminino , Humanos , Hansenostáticos/efeitos adversos , Hansenostáticos/uso terapêutico , Hanseníase/epidemiologia , Hanseníase Virchowiana/tratamento farmacológico , Masculino , Gravidez
9.
BMJ ; 369: m1494, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32434758

RESUMO

OBJECTIVE: To examine the risk of congenital malformations associated with exposure to oral fluconazole at commonly used doses in the first trimester of pregnancy for the treatment of vulvovaginal candidiasis. DESIGN: Population based cohort study. SETTING: A cohort of pregnancies publicly insured in the United States, with data from the nationwide Medicaid Analytic eXtract 2000-14. PARTICIPANTS: Pregnancies of women enrolled in Medicaid from three or more months before the last menstrual period to one month after delivery, and infants enrolled for three or more months after birth. INTERVENTIONS: Use of fluconazole and topical azoles was established by requiring one or more prescriptions during the first trimester of pregnancy. MAIN OUTCOME MEASURES: Risk of musculoskeletal malformations, conotruncal malformations, and oral clefts (primary outcomes), associated with exposure to oral fluconazole, diagnosed during the first 90 days after delivery, were examined. RESULTS: The study cohort of 1 969 954 pregnancies included 37 650 (1.9%) pregnancies exposed to oral fluconazole and 82 090 (4.2%) pregnancies exposed to topical azoles during the first trimester. The risk of musculoskeletal malformations was 52.1 (95% confidence interval 44.8 to 59.3) per 10 000 pregnancies exposed to fluconazole versus 37.3 (33.1 to 41.4) per 10 000 pregnancies exposed to topical azoles. The risks of conotruncal malformations were 9.6 (6.4 to 12.7) versus 8.3 (6.3 to 10.3) per 10 000 pregnancies exposed to fluconazole and topical azoles, respectively; risks of oral clefts were 9.3 (6.2 to 12.4) versus 10.6 (8.4 to 12.8) per 10 000 pregnancies, respectively. The adjusted relative risk after fine stratification of the propensity score was 1.30 (1.09 to 1.56) for musculoskeletal malformations, 1.04 (0.70 to 1.55) for conotruncal malformations, and 0.91 (0.61 to 1.35) for oral clefts overall. Based on cumulative doses of fluconazole, the adjusted relative risks for musculoskeletal malformations, conotruncal malformations, and oral clefts overall were 1.29 (1.05 to 1.58), 1.12 (0.71 to 1.77), and 0.88 (0.55 to 1.40) for 150 mg of fluconazole; 1.24 (0.93 to 1.66), 0.61 (0.26 to 1.39), and 1.08 (0.58 to 2.04) for more than 150 mg up to 450 mg of fluconazole; and 1.98 (1.23 to 3.17), 2.30 (0.93 to 5.65), and 0.94 (0.23 to 3.82) for more than 450 mg of fluconazole, respectively. CONCLUSIONS: Oral fluconazole use in the first trimester was not associated with oral clefts or conotruncal malformations, but an association with musculoskeletal malformations was found, corresponding to a small adjusted risk difference of about 12 incidents per 10 000 exposed pregnancies overall.


Assuntos
Antifúngicos/efeitos adversos , Candidíase Vulvovaginal/tratamento farmacológico , Fluconazol/efeitos adversos , Complicações Infecciosas na Gravidez/tratamento farmacológico , Anormalidades Induzidas por Medicamentos/epidemiologia , Administração Oral , Adulto , Antifúngicos/uso terapêutico , Candidíase Vulvovaginal/etnologia , Fissura Palatina/induzido quimicamente , Fissura Palatina/epidemiologia , Anormalidades Congênitas/epidemiologia , Anormalidades Congênitas/etiologia , Síndrome de DiGeorge/induzido quimicamente , Síndrome de DiGeorge/epidemiologia , Feminino , Fluconazol/uso terapêutico , Humanos , Recém-Nascido , Anormalidades Musculoesqueléticas/induzido quimicamente , Anormalidades Musculoesqueléticas/epidemiologia , Gravidez , Complicações Infecciosas na Gravidez/epidemiologia , Primeiro Trimestre da Gravidez , Risco , Sensibilidade e Especificidade , Estados Unidos/epidemiologia
10.
Epilepsia ; 61(5): 944-950, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32314363

RESUMO

OBJECTIVE: To assess the outcomes in women with epilepsy in relation to fetal malformation and epileptic seizure control during pregnancy when valproate (VPA) intake was ceased, or the drug's dose was reduced before pregnancy. METHODS: Statistical analysis of data collected in the Australian Pregnancy Register between 1999 and 2018 concerning 580 pregnancies previously treated with VPA, with the VPA dose reduced or the drug withdrawn prior to pregnancy in 158 cases. RESULTS: Although the available data have limitations, fetal malformation rates in the pregnancies studied were lower in the VPA changed pregnancies (4.5%) than in the VPA unchanged comparator pregnancies (10.9%, hazard ratio [HR] 0.412, 95% confidence interval [CI] 0.190-0.892), and were only 2.7% where VPA intake was ceased before pregnancy (HR 0.262, 95% CI 0.083-0.826). Seizure-affected pregnancies were more frequent in the VPA changed pregnancies than in the VPA unchanged ones (46.2% vs 30.8%, HR 1.500, 95% CI 1.203-1.870). Convulsive seizure-affected pregnancies also were increased, but the difference was not statistically significant. SIGNIFICANCE: Prepregnancy reduction in VPA dosage reduced the hazard of fetal malformations, whereas ceasing intake of the drug decreased the hazard to one similar to that which applies in the general population, but at a cost of decreased control of epileptic seizures during the pregnancies studied. Further investigations are needed to see whether such findings apply more widely in women with epilepsy.


Assuntos
Anormalidades Induzidas por Medicamentos/etiologia , Anticonvulsivantes/efeitos adversos , Epilepsia/complicações , Complicações na Gravidez/tratamento farmacológico , Ácido Valproico/efeitos adversos , Anormalidades Induzidas por Medicamentos/epidemiologia , Adulto , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/uso terapêutico , Austrália/epidemiologia , Epilepsia/tratamento farmacológico , Feminino , Humanos , Gravidez , Sistema de Registros , Convulsões/complicações , Convulsões/tratamento farmacológico , Convulsões/epidemiologia , Convulsões/prevenção & controle , Ácido Valproico/administração & dosagem , Ácido Valproico/uso terapêutico
11.
Ann Neurol ; 87(6): 897-906, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32215971

RESUMO

OBJECTIVE: The mechanisms by which antiepileptic drugs (AEDs) cause birth defects (BDs) are unknown. Data suggest that AED-induced BDs may result from a genome-wide increase of de novo variants in the embryo, a mechanism that we investigated. METHODS: Whole exome sequencing data from child-parent trios were interrogated for de novo single-nucleotide variants/indels (dnSNVs/indels) and de novo copy number variants (dnCNVs). Generalized linear models were applied to assess de novo variant burdens in children exposed prenatally to AEDs (AED-exposed children) versus children without BDs not exposed prenatally to AEDs (AED-unexposed unaffected children), and AED-exposed children with BDs versus those without BDs, adjusting for confounders. Fisher exact test was used to compare categorical data. RESULTS: Sixty-seven child-parent trios were included: 10 with AED-exposed children with BDs, 46 with AED-exposed unaffected children, and 11 with AED-unexposed unaffected children. The dnSNV/indel burden did not differ between AED-exposed children and AED-unexposed unaffected children (median dnSNV/indel number/child [range] = 3 [0-7] vs 3 [1-5], p = 0.50). Among AED-exposed children, there were no significant differences between those with BDs and those unaffected. Likely deleterious dnSNVs/indels were detected in 9 of 67 (13%) children, none of whom had BDs. The proportion of cases harboring likely deleterious dnSNVs/indels did not differ significantly between AED-unexposed and AED-exposed children. The dnCNV burden was not associated with AED exposure or birth outcome. INTERPRETATION: Our study indicates that prenatal AED exposure does not increase the burden of de novo variants, and that this mechanism is not a major contributor to AED-induced BDs. These results can be incorporated in routine patient counseling. ANN NEUROL 2020;87:897-906.


Assuntos
Anormalidades Induzidas por Medicamentos/genética , Anticonvulsivantes/efeitos adversos , Carga Genética , Variação Genética/genética , Teratógenos , Anormalidades Induzidas por Medicamentos/epidemiologia , Adulto , DNA/genética , Variações do Número de Cópias de DNA/genética , Exoma/genética , Feminino , Humanos , Recém-Nascido , Masculino , Idade Paterna , Polimorfismo de Nucleotídeo Único/genética , Gravidez
12.
BMJ ; 368: m331, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32075790

RESUMO

OBJECTIVE: To assess the association between macrolide antibiotics prescribing during pregnancy and major malformations, cerebral palsy, epilepsy, attention deficit hyperactivity disorder, and autism spectrum disorder in children. DESIGN: Population based cohort study. SETTING: The UK Clinical Practice Research Datalink. PARTICIPANTS: The study cohort included 104 605 children born from 1990 to 2016 whose mothers were prescribed one macrolide monotherapy (erythromycin, clarithromycin, or azithromycin) or one penicillin monotherapy from the fourth gestational week to delivery. Two negative control cohorts consisted of 82 314 children whose mothers were prescribed macrolides or penicillins before conception, and 53 735 children who were siblings of the children in the study cohort. MAIN OUTCOME MEASURES: Risks of any major malformations and system specific major malformations (nervous, cardiovascular, gastrointestinal, genital, and urinary) after macrolide or penicillin prescribing during the first trimester (four to 13 gestational weeks), second to third trimester (14 gestational weeks to birth), or any trimester of pregnancy. Additionally, risks of cerebral palsy, epilepsy, attention deficit hyperactivity disorder, and autism spectrum disorder. RESULTS: Major malformations were recorded in 186 of 8632 children (21.55 per 1000) whose mothers were prescribed macrolides and 1666 of 95 973 children (17.36 per 1000) whose mothers were prescribed penicillins during pregnancy. Macrolide prescribing during the first trimester was associated with an increased risk of any major malformation compared with penicillin (27.65 v 17.65 per 1000, adjusted risk ratio 1.55, 95% confidence interval 1.19 to 2.03) and specifically cardiovascular malformations (10.60 v 6.61 per 1000, 1.62, 1.05 to 2.51). Macrolide prescribing in any trimester was associated with an increased risk of genital malformations (4.75 v 3.07 per 1000, 1.58, 1.14 to 2.19, mainly hypospadias). Erythromycin in the first trimester was associated with an increased risk of any major malformation (27.39 v 17.65 per 1000, 1.50, 1.13 to 1.99). No statistically significant associations were found for other system specific malformations or for neurodevelopmental disorders. Findings were robust to sensitivity analyses. CONCLUSIONS: Prescribing macrolide antibiotics during the first trimester of pregnancy was associated with an increased risk of any major malformation and specifically cardiovascular malformations compared with penicillin antibiotics. Macrolide prescribing in any trimester was associated with an increased risk of genital malformations. These findings show that macrolides should be used with caution during pregnancy and if feasible alternative antibiotics should be prescribed until further research is available. TRIAL REGISTRATION: ClinicalTrials.gov NCT03948620.


Assuntos
Anormalidades Induzidas por Medicamentos/etiologia , Antibacterianos/efeitos adversos , Macrolídeos/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Anormalidades Induzidas por Medicamentos/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/induzido quimicamente , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/epidemiologia , Anormalidades Cardiovasculares/induzido quimicamente , Anormalidades Cardiovasculares/epidemiologia , Paralisia Cerebral/induzido quimicamente , Paralisia Cerebral/epidemiologia , Estudos de Coortes , Bases de Dados Factuais , Prescrições de Medicamentos/estatística & dados numéricos , Epilepsia/induzido quimicamente , Epilepsia/epidemiologia , Feminino , Humanos , Recém-Nascido , Gravidez , Primeiro Trimestre da Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Estudos Retrospectivos , Sensibilidade e Especificidade , Reino Unido/epidemiologia
13.
BMJ ; 368: m237, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32075794

RESUMO

OBJECTIVE: To evaluate the risk of adverse maternal and infant outcomes following in utero exposure to duloxetine. DESIGN: Cohort study nested in the Medicaid Analytic eXtract for 2004-13. SETTING: Publicly insured pregnancies in the United States. PARTICIPANTS: Pregnant women 18 to 55 years of age and their liveborn infants. INTERVENTIONS: Duloxetine exposure during the etiologically relevant time window, compared with no exposure to duloxetine, exposure to selective serotonin reuptake inhibitors, exposure to venlafaxine, and exposure to duloxetine before but not during pregnancy. MAIN OUTCOME MEASURES: Congenital malformations overall, cardiac malformations, preterm birth, small for gestational age infant, pre-eclampsia, and postpartum hemorrhage. RESULTS: Cohort sizes ranged from 1.3 to 4.1 million, depending on the outcome. The number of women exposed to duloxetine varied by cohort and exposure contrast and was around 2500-3000 for early pregnancy exposure and 900-950 for late pregnancy exposure. The base risk per 1000 unexposed women was 36.6 (95% confidence interval 36.3 to 36.9) for congenital malformations overall, 13.7 (13.5 to 13.9) for cardiovascular malformations, 107.8 (107.3 to 108.3) for preterm birth, 20.4 (20.1 to 20.6) for small for gestational age infant, 33.6 (33.3 to 33.9) for pre-eclampsia, and 23.3 (23.1 to 23.4) for postpartum hemorrhage. After adjustment for measured potential confounding variables, all baseline characteristics were well balanced for all exposure contrasts. In propensity score adjusted analyses versus unexposed pregnancies, the relative risk was 1.11 (95% confidence interval 0.93 to 1.33) for congenital malformations overall and 1.29 (0.99 to 1.68) for cardiovascular malformations. For preterm birth, the relative risk was 1.01 (0.92 to 1.10) for early exposure and 1.19 (1.04 to 1.37) for late exposure. For small for gestational age infants the relative risks were 1.14 (0.92 to 1.41) and 1.20 (0.83 to 1.72) for early and late pregnancy exposure, respectively, and for pre-eclampsia they were 1.12 (0.96 to 1.31) and 1.04 (0.80 to 1.35). The relative risk for postpartum hemorrhage was 1.53 (1.08 to 2.18). Results from sensitivity analyses were generally consistent with the findings from the main analyses. CONCLUSIONS: On the basis of the evidence available to date, duloxetine is unlikely to be a major teratogen but may be associated with an increased risk of postpartum hemorrhage and a small increased risk of cardiac malformations. While continuing to monitor the safety of duloxetine as data accumulate over time, these potential small increases in risk of relatively uncommon outcomes must be weighed against the benefits of treating depression and pain during pregnancy in a given patient. TRIAL REGISTRATION: EUPAS 15946.


Assuntos
Cloridrato de Duloxetina/efeitos adversos , Complicações na Gravidez/tratamento farmacológico , Resultado da Gravidez/epidemiologia , Inibidores da Recaptação de Serotonina e Norepinefrina/efeitos adversos , Anormalidades Induzidas por Medicamentos/epidemiologia , Anormalidades Induzidas por Medicamentos/etiologia , Adolescente , Adulto , Estudos de Coortes , Cloridrato de Duloxetina/uso terapêutico , Feminino , Cardiopatias Congênitas/induzido quimicamente , Cardiopatias Congênitas/epidemiologia , Humanos , Recém-Nascido Pequeno para a Idade Gestacional , Pessoa de Meia-Idade , Hemorragia Pós-Parto/induzido quimicamente , Hemorragia Pós-Parto/epidemiologia , Pré-Eclâmpsia/induzido quimicamente , Gravidez , Complicações na Gravidez/epidemiologia , Nascimento Prematuro/induzido quimicamente , Nascimento Prematuro/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Inibidores da Recaptação de Serotonina e Norepinefrina/uso terapêutico , Estados Unidos/epidemiologia , Adulto Jovem
14.
Eur J Obstet Gynecol Reprod Biol ; 247: 42-48, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32058188

RESUMO

OBJECTIVE: We aimed to characterize drug exposures during pregnancy where the outcome was known that had benefited from counselling through our Teratology Information Service (TIS) between 1994-2016. STUDY DESIGN: This observational study analysed data collected through the drug exposures during pregnancy counselling. Data was analysed descriptively. RESULTS: Data from a total of 1'374 pregnant women were collected. Mean age was of 32 years. These women were exposed to more than ten drugs in 1.4 % (N = 19) of cases, with a mean drug intake of two. Analysis of the drugs altogether (N = 3'129) showed that FDA Pregnancy Category C drugs represented 42.9 % (N = 1'342) of drugs and ATC code N (nervous system) represented 36.4 % (N = 1'138). The onset of drug exposure was during the first trimester of pregnancy in 95.1 % (N = 2'982) of patients. Regarding outcomes, the rate of induced abortion was 10.8 % (N = 151), of pregnancy complications was 11.2 % (N = 157) and of malformations was 4.5 % (N = 49). CONCLUSION: Pregnant women counselled by our TIS take a mean of two drugs, ranging from one to 17. Drugs are from FDA Pregnancy Category C and ATC N drugs in most cases, 42.9 % and 36.4 % respectively. The rate of malformation of our cohort was of 4.5 %, close to the estimated spontaneous rate of malformation. This data gives a reassuring aspect of drug exposure in pregnancy but takes into account the outcome at birth only.


Assuntos
Anormalidades Induzidas por Medicamentos/epidemiologia , Resultado da Gravidez/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Aborto Induzido/estatística & dados numéricos , Adulto , Aconselhamento , Serviços de Informação sobre Medicamentos , Feminino , Humanos , Gravidez , Estudos Prospectivos , Teratologia/estatística & dados numéricos , Adulto Jovem
15.
Aliment Pharmacol Ther ; 51(4): 410-420, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31909512

RESUMO

BACKGROUND: There have been safety concerns considering long-term proton pump inhibitor (PPI) use, also during pregnancy. AIMS: To assess the risk of adverse neonatal outcomes associated with maternal intake of PPIs by means of systematic review and meta-analysis. METHODS: The systematic search included PubMed, Web of Science, Cochrane Database and Embase (inception until June 2019). All studies reporting ≥1 adverse pregnancy outcome comparing PPI users to non-users. Histamine-2 receptor antagonists (H2RA) were also compared to both non-users and PPI users. Outcomes included congenital malformations, abortion, stillbirth, neonatal death, preterm birth, small for gestational age and low birth weight. Pooled odds ratios (OR) and 95% confidence intervals (CI) were obtained by random-effects modelling. PROSPERO study-protocol: CRD42018103320. RESULTS: In total, 26 observational studies (20 cohort, 6 case-control studies) were identified, of which 19 assessed PPIs and 12 H2RA. PPI use was associated with an increased risk of congenital malformations (OR 1.28, 95% CI 1.09-1.52), especially in case-control studies (OR 2.04, 1.46-2.86). No associations were found between H2RA and congenital malformations. No significant associations were found between PPI use and abortions, stillbirth, neonatal death, preterm birth and low-birth weight, although H2RA use may be associated with an increased risk of preterm birth (OR 1.25, 95% CI 1.02-1.56). Although statistical heterogeneity and the risk of bias were overall low, clinical heterogeneity, information and selection bias may be present in the individual studies. CONCLUSIONS: This meta-analysis suggests an association between maternal PPI use and congenital malformations in humans, yet power was insufficient to assess specific malformations and drugs.


Assuntos
Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/epidemiologia , Resultado da Gravidez/epidemiologia , Inibidores da Bomba de Prótons/efeitos adversos , Anormalidades Induzidas por Medicamentos/epidemiologia , Estudos de Casos e Controles , Estudos de Coortes , Anormalidades Congênitas/epidemiologia , Feminino , Azia/tratamento farmacológico , Azia/epidemiologia , Antagonistas dos Receptores H2 da Histamina/efeitos adversos , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Masculino , Gravidez , Nascimento Prematuro/epidemiologia , Fatores de Risco , Natimorto/epidemiologia
17.
Neurosciences (Riyadh) ; 25(1): 32-37, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31982897

RESUMO

OBJECTIVE: To determine the prevalence of epilepsy in Saudi pregnant women and estimate the frequency of seizure types in suffering individuals using different anti-epileptic drug modalities. It also aimed to report the teratogenic effects of anti-epileptic drugs as observed in neonates. METHODS: This prospective study was conducted at King Fahd University Hospital from June 2018 to July 2019. Sixty-eight pregnant women diagnosed with epilepsy were included in this study. Seizure types and their frequencies were recorded along with anti-epileptic drug therapies and their association with fetal/neonatal malformations RESULTS: Out of 68 epileptic pregnant females, 30 (44.1%) experienced focal seizures and 38 (55.9%) experienced generalized seizures. Thirty-nine (57.3%) received monotherapy, 21 (30.9%) received polytherapy and 8 (11.8%) did not take antiepileptic drugs during pregnancy. Thirty-six (52.9%) patients experienced no change in seizure frequency during pregnancy, 19 (27.9%) experienced increase in seizure frequency and 13 (19.1%) showed decreased seizure frequency. The pregnancy outcomes analysis showed 2 (2.9%) intrauterine fetal deaths, whereas 4 (4.9%) neonates showed facial and/or organ malformations. CONCLUSION: The frequency of seizures was found to increase in only 27.9% of the pregnant women in the sample. Malformation and mortality rates were higher in fetuses/neonates of patients with generalized seizures. It was observed that for the patient group using monotherapy, the rate of healthy babies was higher than that of the group using polytherapy.


Assuntos
Anormalidades Induzidas por Medicamentos/epidemiologia , Anticonvulsivantes/efeitos adversos , Anormalidades Congênitas/epidemiologia , Epilepsia/epidemiologia , Complicações na Gravidez/epidemiologia , Resultado da Gravidez/epidemiologia , Anormalidades Induzidas por Medicamentos/diagnóstico , Adolescente , Adulto , Anormalidades Congênitas/diagnóstico , Epilepsia/tratamento farmacológico , Feminino , Humanos , Recém-Nascido , Gravidez , Complicações na Gravidez/tratamento farmacológico , Adulto Jovem
18.
Neurology ; 94(14): e1502-e1511, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-31806691

RESUMO

OBJECTIVE: To examine occurrence of severe adverse fetal outcomes (SAO), including fetal loss and major congenital malformations (MCMs), in pregnant women with epilepsy (PWWE) vs healthy pregnant women (HPW). METHODS: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is an NIH-funded, prospective, observational, multicenter investigation of pregnancy outcomes for both mother and child, which enrolled women December 2012 through January 2016. RESULTS: The 351 PWWE had 365 conceptions, and 105 HPW had 109 conceptions. SAOs occurred more often in PWWE (7.9%) vs HPW (1.9%) (p = 0.025) with odds ratio (OR) 4.45 (95% confidence intervals [CI] 1.04-19.01). There were no significant differences for fetal loss (2.8% vs 0%, p = 0.126) or MCMs (5.2% vs 1.9%, p = 0.185; OR 2.86, 95% CI 0.65-12.53) individually. No fetal losses in PWWE appeared to be related to acute seizures. Outcomes were not affected by periconceptional folate, unplanned/unwanted pregnancies, prior maternal pregnancy history, or antiepileptic drug (AED) blood levels, except for an AED level effect for fetal loss that appeared to be due to polytherapy. Combined maternal or paternal family history of MCM was marginally associated with increased SAOs (p = 0.046). CONCLUSIONS: The findings provide additional information on risks of SAOs in PWWE, assessing effects of both AED levels and periconceptional folate. Group differences in average enrollment gestational age could have affected fetal loss results. Analyses are limited by small sample sizes as the MONEAD study was not powered for these secondary outcomes. The large majority of pregnancies in women with epilepsy do not have SOAs.


Assuntos
Anormalidades Induzidas por Medicamentos/epidemiologia , Aborto Espontâneo/epidemiologia , Aborto Espontâneo/etiologia , Anticonvulsivantes/efeitos adversos , Epilepsia/complicações , Adulto , Quimioterapia Combinada/efeitos adversos , Feminino , Ácido Fólico/sangue , Humanos , Recém-Nascido , Estado Nutricional , Gravidez , Complicações na Gravidez , Resultado da Gravidez , Gravidez não Planejada , Estudos Prospectivos , Fatores Socioeconômicos , Adulto Jovem
20.
Epilepsy Behav ; 103(Pt A): 106481, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31711866

RESUMO

Data from 2182 pregnancies in the Australian Register of antiepileptic drugs in pregnancy that were followed to term, with 1965 followed for another year, were analyzed to ascertain whether preexisting illness influenced i. the hazard of fetal malformations, and ii. seizure control during pregnancy. Fetal malformation occurred in 74 of the 842 pregnancies associated with preexisting illness (8.8%) and in 84 of the 1340 comparator pregnancies (6.27%), Relative Risk (R.R.) = 1.402 (95% Confidence Interval (C.I.) = 1.038, 1.893). Logistic regression showed statistically significant effects of preexisting maternal drug-treated psychiatric illness, untreated psychiatric illness, and use of citalopram, carbamazepine, valproate, and topiramate in increasing hazard of fetal malformation. Preexisting nonpsychiatric illness and other antiepileptic drugs and drugs prescribed for psychiatric illness, mainly antidepressants, had no such effect. Seizures occurred during 405 of the 842 pregnancies associated with preexisting illness, and during 593 of 1340 comparison pregnancies (48.1% v 44.3%; R.R. = 1.087; 95% C.I. = 0.991, 1.192). There were no statistically significant relationships between preexisting nonpsychiatric and psychiatric illnesses separately and seizure control during pregnancy. Thus, apart from consequences of antiepileptic drug exposure, preexisting maternal psychiatric illness, in its own right, or when treated with citalopram, appears to be associated with increased hazards of fetal malformation.


Assuntos
Anticonvulsivantes/efeitos adversos , Antidepressivos/efeitos adversos , Anormalidades Congênitas , Epilepsia , Transtornos Mentais , Complicações na Gravidez , Sistema de Registros , Convulsões , Anormalidades Induzidas por Medicamentos/epidemiologia , Anormalidades Induzidas por Medicamentos/etiologia , Adulto , Austrália/epidemiologia , Anormalidades Congênitas/epidemiologia , Anormalidades Congênitas/etiologia , Epilepsia/complicações , Epilepsia/tratamento farmacológico , Epilepsia/epidemiologia , Feminino , Humanos , Transtornos Mentais/complicações , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/epidemiologia , Gravidez , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/epidemiologia , Convulsões/tratamento farmacológico , Convulsões/epidemiologia
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