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OBJECTIVE: To describe the frequency and types of congenital anomalies and associated risk factors in Brazilian women with type 2 diabetes. METHODS: In this retrospective cohort study between 2005 and 2021, we included all pregnant participants with type 2 diabetes from the two major public hospitals in southern Brazil. We collected data from the electronic hospital records. Congenital anomalies were classified by the 10th revised International Classification of Diseases, Q chapter, enhanced by the EUROCAT registry classification, and categorized by type and gravity. We used multiple Poisson regression with robust estimates to estimate risks. RESULTS: Among 648 participants, we excluded 19, and 62 were lost to follow-up; therefore, we included 567 participants. Overt diabetes arose in 191 participants (33.7%, 95% CI 30.0% - 38.0%). Less than 20% of the participants supplemented folate. Congenital anomalies occurred in 78 neonates (13.8%, CI 11.0 - 16.9%), 73 babies (93.6%) presented major anomalies, and 20 (10.5%) cases occurred in participants with overt diabetes. Cardiac anomalies were the most frequent (43 isolated and 12 combined). Pre-eclampsia was associated with an increased risk in the analyses including all women (adjusted RR 1.87 (95% CI 1.23-2.85), p = 0.003), but not in analyses including only women with an HbA1c measured up to the 14th gestational age. HbA1c, either measured at any time in pregnancy (adjusted RR 1.21 (95% CI 1.10-1.33), p < 0.001) or up to the first 14 weeks (adjusted RR 1.22, 95% CI 1.10-1.35, p < 0.001) was the only sustained risk factor. Risk factors such as maternal age, obesity, diabetes diagnosis, or use of antidiabetic medications were not associated with congenital anomalies. CONCLUSION: We found a high frequency of congenital anomalies associated with poor maternal glycemic control and revealed an almost universal lack of preconception care. An urgent call to action is mandatory for the reversal of this gray scenario.
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BACKGROUND: Fetal alcohol syndrome (FAS) is a disorder caused by alterations in embryo-fetal development due to prenatal alcohol exposure. It is estimated that between 0.5 and 2 per 1,000 individuals are born with FAS every year. In Brazil, there are few studies addressing the extent of the problem of FAS/fetal alcohol spectrum disorders (FASD); these studies are confined to limited geographic areas. Therefore, we decided to perform a health needs assessment for FAS/FASD in Brazil. METHODS: To estimate the prevalence of FAS and FASD in Brazil, we used information from the literature, which estimates between 0.5 and 2/1,000 births per year for FAS and 10 to 50/1,000 for FASD. RESULTS: We estimated that approximately 1,500 to 6,000 children are born with FAS every year. Considering the whole population, the prevalence would be 95,377 to 380,000 affected people. However, when we consider FASD as a whole, we estimate that between 1,900,000 and 9,500,000 Brazilians might suffer the more severe consequences of alcohol exposure during pregnancy and be living with FASD. CONCLUSION: The results of the current study indicate that FAS and FASD are prevalent disorders in Brazil, and more policies targeting alcohol intake during pregnancy must be developed.
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Transtornos do Espectro Alcoólico Fetal/epidemiologia , Avaliação das Necessidades , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/legislação & jurisprudência , Bebidas Alcoólicas/legislação & jurisprudência , Brasil/epidemiologia , Atenção à Saúde , Feminino , Humanos , Gravidez , Fatores SocioeconômicosRESUMO
ABSTRACT Female patient carrier of medium-chain acyl-CoA dehydrogenase deficiency (MCADD) with recurrent clinical episodes of hypoglycemia and altered level of consciousness, presented changes in blood acylcarnitine profile by tandem mass spectrometry and in the urinary organic acid analysis by gas chromatography/mass spectrometry (GC/MS). This case demonstrates the importance of fasting prior biological sample collection (when possible) when MCADD is suspected, and emphasizes that the time/momentum of biological sample collection is crucial to diagnosis, considering the possibility that MCADD is underdiagnosed in Brazil.
RESUMEN Paciente portadora de deficiencia de acil-CoA deshidrogenasa de cadena media (MCADD) con episodios clínicos recurrentes de hipoglucemia y alteración de consciencia presentó mudanzas en el perfil de acilcarnitinas en la sangre con técnicas de espectrometría de masas en tándem y en el análisis de ácidos orgánicos urinarios mediante cromatografía de gases acoplada a espectrometría de masas. Este caso demuestra la importancia de la toma de muestras biológicas en ayunas (se posible) cuando se sospecha de MCADD y destaca que el tiempo/momento de extracción de la muestra biológica es valioso para el diagnóstico, considerando la posibilidad de que la MCADD es subdiagnosticada en Brasil.
RESUMO Paciente portadora de deficiência de acil-CoA desidrogenase de cadeia média (MCADD), com episódios clínicos recorrentes de hipoglicemia e alteração de consciência, apresentou alterações no perfil de acilcarnitinas em sangue por espectrometria de massas em tandem e na análise de ácidos orgânicos urinários por cromatografia gasosa acoplada à espectrometria de massa. Este caso demonstra a importância da coleta de amostra biológica em jejum (se possível) quando há suspeita de MCADD e ressalta que o tempo/momento de coleta da amostra biológica é importante para o diagnóstico, considerando a possibilidade de a MCADD ser subdiagnosticada no Brasil.
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Abstract Objective: The aim of this study was to identify the causes of congenital microcephaly in Rio Grande do Sul, a state in southern Brazil, where no ZIKV outbreak was detected, from December 2015 to December 2016, which was the period when ZIKV infection was at its peak in northeast Brazil. Methods: This was a cross-sectional study where all notifications of congenital microcephaly in the state of Rio Grande do Sul were included for analysis. Evaluation of cases followed the guidelines of the Brazilian Ministry of Health. Dysmorphological and neurological evaluations were performed by a specialized team, and genetic tests and neuroimaging were performed when clinically indicated. STORCH infections were diagnosed using standard tests. ZIKV infection was diagnosed through maternal serum RT-PCR and/or neuroimaging associated with clinical/epidemiological criteria. Results: From 153 744 registered live births in the study period, 148 cases were notified, but 90 (60.8%) of those were later excluded as "non-confirmed" microcephaly. In the 58 confirmed cases of microcephaly (prevalence = 3.8/10 000 live births), congenital infections (syphilis, toxoplasmosis, cytomegalovirus, and ZIKV) constituted the predominant etiology (50.0%), followed by isolated CNS (15.5%), and genetic syndromes (10.3%). Congenital ZIKV syndrome (CZS) with typical phenotype was diagnosed in three cases (5.2% of all confirmed microcephaly cases or 10.4% of all congenital infections). Conclusion: In Rio Grande do Sul, where no outbreak of ZIKV infection was recorded, congenital infections were the leading cause of congenital microcephaly, and the attributable risk for CZS in the etiology of microcephaly was 5.2%.
Resumo: Objetivo: Identificar as causas da microcefalia congênita no Rio Grande do Sul, Região Sul do Brasil, onde não foi detectado surto de ZIKV, de dezembro de 2015 a dezembro de 2016. Esse foi o período em que a infecção por ZIKV estava em seu auge no Nordeste do Brasil. Métodos: Este é um estudo transversal no qual todas as notificações de microcefalia congênita no estado do Rio Grande do Sul foram incluídas para análise. A avaliação dos casos seguiu as orientações do Ministério da Saúde. A avaliação dismorfológica e neurológica foi feita por uma equipe especializada e os testes genéticos e as neuroimagens foram feitos quando indicado clinicamente. As infecções STORCH (Sífilis, Toxoplasmose, Rubéola, Citomegalovírus e Herpes simples) foram diagnosticadas utilizando testes padrão. A infecção por ZIKV foi diagnosticada por meio da transcriptase reversa seguida de reação em cadeia da polimerase (RT-PCR) no soro materno e/ou neuroimagem associada a critérios clínicos/epidemiológicos. Resultados: De 153.744 nascidos vivos registrados no período do estudo, 148 bebês foram casos notificados, porém 90 (60,8%) casos foram excluídos posteriormente como microcefalia "não confirmada". Nos 58 casos confirmados de microcefalia (prevalência = 3,8/10.000 nascidos vivos), as infecções congênitas (sífilis, toxoplasmose, citomegalovírus e ZIKV) constituíram a etiologia predominante (50,0%), seguidas de doenças ligadas ao SNC isolado (15,5%) e síndromes genéticas (10,3%). A síndrome congênita do ZIKV (SCZ) com fenótipo típico foi diagnosticada em três casos (5,2% de todos os casos confirmados de microcefalia ou 10,4% de todas as infecções congênitas). Conclusão: No Rio Grande do Sul, Brasil, onde não foi registrado surto de infecção por ZIKV, a principal causa de microcefalia congênita foram infecções congênitas e o risco atribuível para SCZ na etiologia de microcefalia foi de 5,2%.
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Humanos , Masculino , Feminino , Gravidez , Recém-Nascido , Complicações Infecciosas na Gravidez/epidemiologia , Infecção por Zika virus/complicações , Infecção por Zika virus/epidemiologia , Microcefalia/epidemiologia , Microcefalia/virologia , Complicações Infecciosas na Gravidez/virologia , Brasil/epidemiologia , Prevalência , Surtos de Doenças , Estudos Transversais , Fatores de Risco , Idade Gestacional , Distribuição por SexoRESUMO
OBJECTIVE: The aim of this study was to identify the causes of congenital microcephaly in Rio Grande do Sul, a state in southern Brazil, where no ZIKV outbreak was detected, from December 2015 to December 2016, which was the period when ZIKV infection was at its peak in northeast Brazil. METHODS: This was a cross-sectional study where all notifications of congenital microcephaly in the state of Rio Grande do Sul were included for analysis. Evaluation of cases followed the guidelines of the Brazilian Ministry of Health. Dysmorphological and neurological evaluations were performed by a specialized team, and genetic tests and neuroimaging were performed when clinically indicated. STORCH infections were diagnosed using standard tests. ZIKV infection was diagnosed through maternal serum RT-PCR and/or neuroimaging associated with clinical/epidemiological criteria. RESULTS: From 153744 registered live births in the study period, 148 cases were notified, but 90 (60.8%) of those were later excluded as "non-confirmed" microcephaly. In the 58 confirmed cases of microcephaly (prevalence = 3.8/10000 live births), congenital infections (syphilis, toxoplasmosis, cytomegalovirus, and ZIKV) constituted the predominant etiology (50.0%), followed by isolated CNS (15.5%), and genetic syndromes (10.3%). Congenital ZIKV syndrome (CZS) with typical phenotype was diagnosed in three cases (5.2% of all confirmed microcephaly cases or 10.4% of all congenital infections). CONCLUSION: In Rio Grande do Sul, where no outbreak of ZIKV infection was recorded, congenital infections were the leading cause of congenital microcephaly, and the attributable risk for CZS in the etiology of microcephaly was 5.2%.
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Microcefalia/epidemiologia , Microcefalia/virologia , Complicações Infecciosas na Gravidez/epidemiologia , Infecção por Zika virus/complicações , Infecção por Zika virus/epidemiologia , Brasil/epidemiologia , Estudos Transversais , Surtos de Doenças , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Gravidez , Complicações Infecciosas na Gravidez/virologia , Prevalência , Fatores de Risco , Distribuição por SexoRESUMO
Abstract Introduction: Newborn Screening Program (NBS) in Uruguay includes congenital hypothyroidism (CHT), phenylketonuria (PKU), congenital adrenal hyperplasia (CAH), cystic fibrosis (CF), medium chain acyl-CoA dehydrogenase deficiency (MCADD), and Congenital Hearing Loss (CHL). Objetives: This study describe the epidemiological characteristics of newborns with abnormal neonatal screening tests diagnosed by blood drop and otoacoustic emissions in Uruguay. Results: Cases with abnormal NBS tests (399 newborns; 0.17%) were compared to the newborns with normal tests in the same period (239,240). Prevalence rates (per 10,000 livebirths) were 10.00 for CHL; 3.70 for CH; 1.20 for CF; 0.59 for CAH; 0.54 for PKU; 0.13 for MCADD. The Department of Artigas had the highest rate of abnormal tests. Lower maternal education, less prenatal care, increased prematurity rate and neonatal depression were more frequent in in mothers whose children had CHL. Conclusions: This is the first study evaluating the characteristics of newborns with abnormal screening in Uruguay. Because these results may impact the planning of health services, data transmission between clinical care and public health systems is needed to improve both follow-up and management.
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In early 2015, an outbreak of Zika virus, a flavivirus transmitted by Aedes mosquitoes, was identified in northeast Brazil, an area where dengue virus was also circulating. By September, reports of an increase in the number of infants born with microcephaly in Zika virus-affected areas began to emerge, and Zika virus RNA was identified in the amniotic fluid of two women whose fetuses had been found to have microcephaly by prenatal ultrasound. The Brazil Ministry of Health (MoH) established a task force to investigate the possible association of microcephaly with Zika virus infection during pregnancy and a registry for incident microcephaly cases (head circumference ≥2 standard deviations [SD] below the mean for sex and gestational age at birth) and pregnancy outcomes among women suspected to have had Zika virus infection during pregnancy. Among a cohort of 35 infants with microcephaly born during August-October 2015 in eight of Brazil's 26 states and reported to the registry, the mothers of all 35 had lived in or visited Zika virus-affected areas during pregnancy, 25 (71%) infants had severe microcephaly (head circumference >3 SD below the mean for sex and gestational age), 17 (49%) had at least one neurologic abnormality, and among 27 infants who had neuroimaging studies, all had abnormalities. Tests for other congenital infections were negative. All infants had a lumbar puncture as part of the evaluation and cerebrospinal fluid (CSF) samples were sent to a reference laboratory in Brazil for Zika virus testing; results are not yet available. Further studies are needed to confirm the association of microcephaly with Zika virus infection during pregnancy and to understand any other adverse pregnancy outcomes associated with Zika virus infection. Pregnant women in Zika virus-affected areas should protect themselves from mosquito bites by using air conditioning, screens, or nets when indoors, wearing long sleeves and pants, using permethrin-treated clothing and gear, and using insect repellents when outdoors. Pregnant and lactating women can use all U.S. Environmental Protection Agency (EPA)-registered insect repellents according to the product label.
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Microcefalia/epidemiologia , Microcefalia/virologia , Complicações Infecciosas na Gravidez/epidemiologia , Infecção por Zika virus/epidemiologia , Brasil/epidemiologia , Feminino , Humanos , Recém-Nascido , GravidezRESUMO
Uruguay is a middle-income country and the smallest in South America. Its population is under 3.3 million. The demographic and epidemiological characteristics are similar to those of developed countries, with a high burden associated with congenital anomalies. Infant mortality rate (IMR) decreased from 37/1000 live births, in 1980, to 8.8/1000, in 2013. This is largely explained by medical and social policies. IMR related to congenital anomalies, however, remained unchanged for the last 30 years. Therefore, programmes for prevention of congenital disorders were developed, such as the National Newborn Screening Programme. Mandatory, universal, free infant screening was implemented two decades ago. The Ministry of Public Health created the Comprehensive Plan on Birth Defects and Rare Diseases (PIDCER), to develop a strategic public policy tool enabling comprehensive, universal, quality care during their entire lifetime. Recent national legislation created provisions for newborn and infant screening, including for congenital hypothyroidism, phenylketonuria, congenital adrenal hyperplasia, cystic fibrosis and medium-chain acyl-CoA dehydrogenase, via blood spot test, otoacoustic emissions, systematic physical examination and hip ultrasound. We discuss how this programme was implemented, the current situation of rare diseases, the institution managing disability in Uruguay and the development of new laws based on the MPH's PIDCER. It illustrates how Uruguay is developing public policies in the genomic era, based both on science and bioethics.
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Campomelic dysplasia (CD) is an autosomal, dominantly inherited, skeletal abnormality belonging to the subgroup of bent bone dysplasias. In addition to bowed lower limbs, CD typically includes the following: disproportionate short stature, flat face, micrognathia, cleft palate, bell-shaped thorax, and club feet. Up to three quarters of 46, XY individuals may be sex-reversed. Radiological signs include scapular and pubic hypoplasia, narrow iliac wings, spaced ischia, and bowed femora and tibiae. Lethal CD is usually due to heterozygous mutations in SOX9, a major regulator of chondrocytic development. We present a detailed clinical and molecular characterization of nine Brazilian CD patients. Infants were either stillborn (n = 2) or died shortly after birth and presented similar phenotypes. Sex-reversal was observed in one of three chromosomally male patients. Sequencing of SOX9 revealed new heterozygous mutations in seven individuals. Six patients had mutations that resulted in premature transcriptional termination, while one infant had a single-nucleotide substitution at the conserved splice-site acceptor of intron 1. No clear genotype-phenotype correlations were observed. This study highlights the diversity of SOX9 mutations leading to lethal CD, and expands the group of known genetic alterations associated with this skeletal dysplasia.
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In some cases Neu-Laxova syndrome (NLS) is linked to serine deficiency due to mutations in the phosphoglycerate dehydrogenase (PHGDH) gene. We describe the prenatal and postnatal findings in a fetus with one of the most severe NLS phenotypes described so far, caused by a homozygous nonsense mutation of PHGDH. Serial ultrasound (US) and pre- and postnatal magnetic resonance imaging (MRI) evaluations were performed. Prenatally, serial US evaluations suggested symmetric growth restriction, microcephaly, hypoplasia of the cerebellar vermis, micrognathia, hydrops, shortened limbs, arthrogryposis, and talipes equinovarus. The prenatal MRI confirmed these findings prompting a diagnosis of NLS. After birth, radiological imaging did not detect any gross bone abnormalities. DNA was extracted from fetal and parental peripheral blood, all coding exons of PHGDH were PCR-amplified and subjected to Sanger sequencing. Sequencing of PHGDH identified a homozygous premature stop codon mutation (c.1297C>T; p.Gln433*) in fetal DNA, both parents (first-cousins) being heterozygotes. Based on previous associations of mutations in this gene with a milder NLS phenotype, as well as cases of serine deficiency, these observations lend further support to a genotype-phenotype correlation between the degree of PHGDH inactivation and disease severity.