Introdução: Pacientes com mielomeningocele apresentam elevada mortalidade e desenvolvem déficits neurológicos que ocorrem, primariamente, pelo desenvolvimento anormal da medula e de raízes nervosas e, secundariamente, por complicações adquiridas no período pós-natal. O desafio no cuidado desses pacientes é o reconhecimento precoce dos recém-nascidos de risco para evolução desfavorável a fim de estabelecer estratégias terapêuticas individualizadas. Objetivo: Este estudo tem como objetivo identificar marcadores prognósticos de curto prazo para recém-nascidos com mielomeningocele. As características anatômicas do defeito medular e da sua correção neurocirúrgica foram analisadas para esta finalidade. Métodos: Foi realizado um estudo de coorte retrospectiva com 70 pacientes com mielomeningocele em topografia torácica, lombar ou sacral nascidos entre janeiro de 2007 a dezembro de 2013 no Centro Neonatal do Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Pacientes com infecção congênita, anomalias cromossômicas e outras malformações maiores não relacionadas à mielomeningocele foram excluídos da análise. As características anatômicas da mielomeningocele e a sua correção neurocirúrgica foram analisadas quanto aos seguintes desfechos: reanimação neonatal, tempo de internação, necessidade de derivação ventricular, deiscência da ferida operatória, infecção da ferida operatória, infecção do sistema nervoso central e sepse. Para a análise bivariada dos desfechos qualitativos com os fatores de interesse foram empregados testes do qui-quadrado e exato de Fisher. Para a análise do desfecho quantitativo, tempo de internação hospitalar, foram empregados testes de Mann-Whitney. Foram estimados os riscos relativos e os respectivos intervalos com 95% de confiança. Foram desenvolvidos modelos de regressão linear múltipla para os desfechos quantitativos e regressão de Poisson para os desfechos qualitativos. Resultados: Durante o período do estudo 12.559 recém-nascidos foram admitidos no Centro Neonatal do Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Oitenta pacientes foram diagnosticados com mielomeningocele, com incidência de 6,4 casos para cada 1.000 nascidos vivos. Dez pacientes foram excluídos da análise devido à mielomeningocele em topografia cervical (n = 1), à cardiopatia congênita (n = 4), à trissomia do cromossomo 13 (n = 1), à onfalocele (n = 3) e à encefalocele (n = 1). Ocorreram três óbitos (4,28%). Mielomeningocele extensa foi associada a infecção do sistema nervoso central, a complicação de ferida operatória e a maior tempo de internação hospitalar. Os pacientes com mielomeningocele em topografia torácica apresentaram tempo de internação, em média, 39 dias maior que aqueles com defeito em topografia lombar ou sacral. Houve maior necessidade de reanimação em sala de parto entre os pacientes com macrocrania ao nascer. A correção cirúrgica realizada após 48 horas de vida aumentou em 5,7 vezes o risco de infecção do sistema nervoso central. Entre os pacientes operados nas primeiras 48 horas de vida não foi observado benefício adicional na correção cirúrgica realizada em \"tempo zero\". A ausência de hidrocefalia antenatal foi um marcador de bom prognóstico. Nestes pacientes, a combinação dos desfechos necessidade de derivação ventricular, complicações infecciosas, complicações de ferida operatória e reanimação em sala de parto foi 70% menos frequente. Conclusão: Este estudo permitiu identificar marcadores prognósticos de curto prazo em recém-nascidos com mielomeningocele. Os defeitos medulares extensos e a correção cirúrgica após 48 horas de vida influenciaram negativamente na evolução de curto prazo. As lesões extensas foram associadas a maiores taxas de infecção do sistema nervoso central, a complicações de ferida operatória e a internação hospitalar prolongada. A correção cirúrgica realizada após 48 horas de vida aumentou significativamente a ocorrência de infecção do sistema nervoso central. Ausência de hidrocefalia antenatal foi associada a menor número de complicações nos primeiros dias de vida / Introduction: Patients with myelomeningocele have a high mortality and develop neurological disabilities that occur primarily by a defective spinal cord and nerve root development and, secondarily, by acquired post-natal complications. The challenge in the post-natal management of myelomeningocele is the early recognition of cases at risk for complications in order to establish individualized treatment strategies. Objective: This study aims to identify short-term prognostic markers for newborns with myelomeningocele. Anatomical characteristics of the spinal defect and technical aspects of the neurosurgical repair were analyzed for this purpose. Methods: A retrospective cohort study was conducted in 70 patients with thoracic, lumbar or sacral myelomeningocele born between January 2007 and December 2013 in the Centro Neonatal do Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Patients with congenital infection, chromosomal abnormalities and other major malformations unrelated to myelomeningocele were excluded from our analysis. Features of myelomeningocele anatomy and neurosurgical treatment were analyzed for the following outcomes: neonatal resuscitation, length of hospital stay, need for ventricular shunt, wound dehiscence, wound infection, central nervous system infection and sepsis. Relationships between qualitative outcomes and factors of interest were examined using chi-square or Fisher\'s exact tests. The relationships with the quantitative outcome duration of hospital stay were evaluated using the Mann-Whitney tests. Relative risks were estimated with 95% confidence intervals. Multivariate linear regression was used to evaluate the quantitative outcomes and a Poisson regression model was used for the qualitative outcomes. Results: During the study period a total of 12,559 neonates were born in Centro Neonatal do Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Eighty patients were diagnosed with myelomeningocele resulting in an incidence of 6.4 cases per 1000 live births. Ten patients were excluded from our analysis due to cervical myelomeningocele (n = 1), congenital heart disease (n = 4), trisomy 13 (n = 1), omphalocele (n = 3) and encephalocele (n = 1). Three deaths were observed in the study period (4,28%). Large myelomeningocele was associated with central nervous system infection, wound complications and longer hospital stay. Patients with thoracic myelomeningocele required longer hospital stay, on average 39 days longer when compared to patients with lumbar or sacral defects. There was a positive correlation between the need for resuscitation at the delivery room and the presence of macrocrania at birth. Late surgical repair performed after 48 hours of life increased in 5.7 times the risk of central nervous system infection. Among patients operated within the first 48 hours, no additional benefit in interventions held in \"time zero\" was observed. Absence of antenatal hydrocephalus was a favorable prognostic marker. In these cases, the combination of need for ventricular drainage, sepsis, central nervous system infection, complications of surgical site and intervention in the delivery room were 70% lower. Conclusion: This study allowed us to identify short-term prognostic markers for newborns with myelomeningocele. Extensive spinal cord defect and surgical repair after 48 hours of life negatively influenced short-term outcomes. Extensive lesions were associated with higher rates of central nervous system infections, surgical wound complications and prolonged hospital stay. Interventions performed 48 hours after birth significantly increased occurrence of central nervous system infections. Absence of antenatal hydrocephalus was associated with fewer complications in the first days of life

Introdução e objetivos: crianças e adolescente com fissuras labiopalatinas frequentemente apresentam dificuldades alimentares. O pré-operatório costuma ser um momento crítico, cheio de tensões e medos. O período pósoperatório é longo e a alimentação necessita ser alterada pelo menos por 30 dias. Este estudo avaliou o estado nutricional de crianças e adolescentes no pré-operatório de fissuras labiopalatinas, além de descrever a antropometria, o padrão alimentar e comparar o estado nutricional com a faixa etária, o tipo de fissura, o gênero e os exames laboratoriais. Métodos: estudo transversal de uma série de casos, avaliados no dia do procedimento cirúrgico. Foram avaliados 45 pacientes entre zero e 19 anos, operados no Hospital de Clínicas de Porto Alegre e no Serviço Pró-Face de Assistência Social do Círculo Operário Caxiense. Resultados: dentre os pacientes 16 (35,6%) estavam eutróficos; 13 (28,9%) desnutridos; 16 (35,6%) apresentavam sobrepeso e 9 (20%) baixa estatura. O tipo de fissura labiopalatina esteve mais relacionada com o sexo masculino 27 (60%). O VCM estava estatisticamente associado com o E/I e a dosagem de transferrina com a DCT. As crianças ≤ 5 anos consumiam diariamente mais produtos lácteos (p=0,023) e frutas (p=0,025) e as crianças > 5 anos mais leguminosas (p=0,041). Conclusão: a antropometria apresentou índices dentro da normalidade. O estado nutricional deste grupo de crianças e adolescentes que se submeteram a correção cirúrgica de fissura labiopalatina foi satisfatório, pois a maior parte dos pacientes se mostrou eutrófico. Entretando, é preocupante que quase 30% dos pacientes estivessem desnutridos em um momento crítico como o pré-operatório. As crianças com menos de 5 anos apresentaram uma alimentação mais saudável do que as maiores de 5 anos. A avaliação do estado nutricional no pré-operatório destas criancas é importante para o desfecho do procedimento. / Introduction: Children and adolescents with Cleft Lip and Palate – CL/P, often have feeding disorders. Thus, considering that preoperative period may be a critical moment, full of concerns and fears; and the postoperative period usually is longer, the diet care must be taken at least 30 days before surgery. Under these circumstances, this study have assessed the nutritional status of children and adolescents in the preoperative for clefting surgery, also describing their anthropometry, dietary patterns, and comparing all data according age, type of cleft, gender and laboratorial tests results (biochemical analysis). Methods: A cross-sectional study of a series of cases evaluated on the surgery day. We have assessed 45 patients between 0 and 19 years-old, who underwent surgical correction of CL/P at Hospital de Clínicas de Porto Alegre and Serviço Pró-Face de Assistência Social do Círculo Operário Caxiense4. Results: 16 (35.6%) of the patients were well-nourished, 13 (28.9%) were malnourished, 16 (35.6%) were overweight, and 9 (20%) have their growth stunted. 27 (60%) of the patients with cleft lip and palate was male. The Mean Corpuscular Volume-MCV was statistically associated with the H/A, and the transferrin level with the TSF. 5-year, or under, children daily consume more dairy products (p=0.023) and fruits (p=0.025) and children older than 5-year, consume more leaf vegetables (p=0.041) and sugars (p=0.065). Conclusion: Anthropometric indexes have showed normal. The nutritional status of children and adolescents who underwent surgical repair for cleft lip and palate is satisfactory. However, it is worrying that almost 30% of patients were malnourished at a critical time as the preoperative. Children under five years had a healthier diet than those older than 5 years. The assessment of nutritional status in children and adolescents on cleft lip and palate preoperative must be emphasized in order to achieve the procedure outcome.

Introdução e objetivos: crianças e adolescente com fissuras labiopalatinas frequentemente apresentam dificuldades alimentares. O pré-operatório costuma ser um momento crítico, cheio de tensões e medos. O período pósoperatório é longo e a alimentação necessita ser alterada pelo menos por 30 dias. Este estudo avaliou o estado nutricional de crianças e adolescentes no pré-operatório de fissuras labiopalatinas, além de descrever a antropometria, o padrão alimentar e comparar o estado nutricional com a faixa etária, o tipo de fissura, o gênero e os exames laboratoriais. Métodos: estudo transversal de uma série de casos, avaliados no dia do procedimento cirúrgico. Foram avaliados 45 pacientes entre zero e 19 anos, operados no Hospital de Clínicas de Porto Alegre e no Serviço Pró-Face de Assistência Social do Círculo Operário Caxiense. Resultados: dentre os pacientes 16 (35,6%) estavam eutróficos; 13 (28,9%) desnutridos; 16 (35,6%) apresentavam sobrepeso e 9 (20%) baixa estatura. O tipo de fissura labiopalatina esteve mais relacionada com o sexo masculino 27 (60%). O VCM estava estatisticamente associado com o E/I e a dosagem de transferrina com a DCT. As crianças ≤ 5 anos consumiam diariamente mais produtos lácteos (p=0,023) e frutas (p=0,025) e as crianças > 5 anos mais leguminosas (p=0,041). Conclusão: a antropometria apresentou índices dentro da normalidade. O estado nutricional deste grupo de crianças e adolescentes que se submeteram a correção cirúrgica de fissura labiopalatina foi satisfatório, pois a maior parte dos pacientes se mostrou eutrófico. Entretando, é preocupante que quase 30% dos pacientes estivessem desnutridos em um momento crítico como o pré-operatório. As crianças com menos de 5 anos apresentaram uma alimentação mais saudável do que as maiores de 5 anos. A avaliação do estado nutricional no pré-operatório destas criancas é importante para o desfecho do procedimento. / Introduction: Children and adolescents with Cleft Lip and Palate – CL/P, often have feeding disorders. Thus, considering that preoperative period may be a critical moment, full of concerns and fears; and the postoperative period usually is longer, the diet care must be taken at least 30 days before surgery. Under these circumstances, this study have assessed the nutritional status of children and adolescents in the preoperative for clefting surgery, also describing their anthropometry, dietary patterns, and comparing all data according age, type of cleft, gender and laboratorial tests results (biochemical analysis). Methods: A cross-sectional study of a series of cases evaluated on the surgery day. We have assessed 45 patients between 0 and 19 years-old, who underwent surgical correction of CL/P at Hospital de Clínicas de Porto Alegre and Serviço Pró-Face de Assistência Social do Círculo Operário Caxiense4. Results: 16 (35.6%) of the patients were well-nourished, 13 (28.9%) were malnourished, 16 (35.6%) were overweight, and 9 (20%) have their growth stunted. 27 (60%) of the patients with cleft lip and palate was male. The Mean Corpuscular Volume-MCV was statistically associated with the H/A, and the transferrin level with the TSF. 5-year, or under, children daily consume more dairy products (p=0.023) and fruits (p=0.025) and children older than 5-year, consume more leaf vegetables (p=0.041) and sugars (p=0.065). Conclusion: Anthropometric indexes have showed normal. The nutritional status of children and adolescents who underwent surgical repair for cleft lip and palate is satisfactory. However, it is worrying that almost 30% of patients were malnourished at a critical time as the preoperative. Children under five years had a healthier diet than those older than 5 years. The assessment of nutritional status in children and adolescents on cleft lip and palate preoperative must be emphasized in order to achieve the procedure outcome.

Introdução e objetivos: crianças e adolescente com fissuras labiopalatinas frequentemente apresentam dificuldades alimentares. O pré-operatório costuma ser um momento crítico, cheio de tensões e medos. O período pósoperatório é longo e a alimentação necessita ser alterada pelo menos por 30 dias. Este estudo avaliou o estado nutricional de crianças e adolescentes no pré-operatório de fissuras labiopalatinas, além de descrever a antropometria, o padrão alimentar e comparar o estado nutricional com a faixa etária, o tipo de fissura, o gênero e os exames laboratoriais. Métodos: estudo transversal de uma série de casos, avaliados no dia do procedimento cirúrgico. Foram avaliados 45 pacientes entre zero e 19 anos, operados no Hospital de Clínicas de Porto Alegre e no Serviço Pró-Face de Assistência Social do Círculo Operário Caxiense. Resultados: dentre os pacientes 16 (35,6%) estavam eutróficos; 13 (28,9%) desnutridos; 16 (35,6%) apresentavam sobrepeso e 9 (20%) baixa estatura. O tipo de fissura labiopalatina esteve mais relacionada com o sexo masculino 27 (60%). O VCM estava estatisticamente associado com o E/I e a dosagem de transferrina com a DCT. As crianças ≤ 5 anos consumiam diariamente mais produtos lácteos (p=0,023) e frutas (p=0,025) e as crianças > 5 anos mais leguminosas (p=0,041). Conclusão: a antropometria apresentou índices dentro da normalidade. O estado nutricional deste grupo de crianças e adolescentes que se submeteram a correção cirúrgica de fissura labiopalatina foi satisfatório, pois a maior parte dos pacientes se mostrou eutrófico. Entretando, é preocupante que quase 30% dos pacientes estivessem desnutridos em um momento crítico como o pré-operatório. As crianças com menos de 5 anos apresentaram uma alimentação mais saudável do que as maiores de 5 anos. A avaliação do estado nutricional no pré-operatório destas criancas é importante para o desfecho do procedimento. / Introduction: Children and adolescents with Cleft Lip and Palate – CL/P, often have feeding disorders. Thus, considering that preoperative period may be a critical moment, full of concerns and fears; and the postoperative period usually is longer, the diet care must be taken at least 30 days before surgery. Under these circumstances, this study have assessed the nutritional status of children and adolescents in the preoperative for clefting surgery, also describing their anthropometry, dietary patterns, and comparing all data according age, type of cleft, gender and laboratorial tests results (biochemical analysis). Methods: A cross-sectional study of a series of cases evaluated on the surgery day. We have assessed 45 patients between 0 and 19 years-old, who underwent surgical correction of CL/P at Hospital de Clínicas de Porto Alegre and Serviço Pró-Face de Assistência Social do Círculo Operário Caxiense4. Results: 16 (35.6%) of the patients were well-nourished, 13 (28.9%) were malnourished, 16 (35.6%) were overweight, and 9 (20%) have their growth stunted. 27 (60%) of the patients with cleft lip and palate was male. The Mean Corpuscular Volume-MCV was statistically associated with the H/A, and the transferrin level with the TSF. 5-year, or under, children daily consume more dairy products (p=0.023) and fruits (p=0.025) and children older than 5-year, consume more leaf vegetables (p=0.041) and sugars (p=0.065). Conclusion: Anthropometric indexes have showed normal. The nutritional status of children and adolescents who underwent surgical repair for cleft lip and palate is satisfactory. However, it is worrying that almost 30% of patients were malnourished at a critical time as the preoperative. Children under five years had a healthier diet than those older than 5 years. The assessment of nutritional status in children and adolescents on cleft lip and palate preoperative must be emphasized in order to achieve the procedure outcome.

L’asthme est l’une des maladies chroniques les plus fréquentes durant la grossesse, affectant environ 4% à 12% des femmes enceintes et ayant une prévalence qui a augmenté au cours des dernières décennies. Plusieurs études ont identifié l'asthme comme un facteur de risque pour plusieurs enjeux de santé défavorables chez le fœtus et la mère. Les lignes directrices de traitement recommandent l’utilisation de médicaments antiasthmatiques pendant la grossesse afin de contrôler l’asthme et d’éviter les problèmes de santé maternels et fœtaux. L’évaluation de la littérature sur l'utilisation maternelle de médicaments antiasthmatiques et le risque de malformations congénitales majeures a relevé plusieurs études sur l’innocuité des bêta2-agonistes inhalés à courte durée d’action (BACA) et des corticostéroïdes inhalés (CSI) pendant la grossesse, mais peu de données sur les bêta2-agonistes à longue durée d’action (BALA) ainsi que sur les thérapies combinées (BALA-CSI). Un programme de recherche en trois volets a été développé pour combler ces lacunes. Dans le premier volet, nous avons entrepris une revue systématique de la littérature sur l'impact de l'utilisation de BACA et de BALA pendant la grossesse sur le risque de différents problèmes périnataux. Vingt et une études originales ont été identifiées. Quatre études ont rapporté une augmentation significative du risque de malformations congénitales avec BACA, une étude a rapporté une augmentation significative du risque de malformations congénitales avec BALA et quatre études ont rapporté un risque significatif accru de malformations congénitales avec bêta2-agonistes (BACA et/ou BALA). Toutefois, aucun risque majeur n’a été trouvé pour les autres complications périnatales. Fait important, la plupart des études récupérées ont subi plusieurs limitations méthodologiques, y compris l'utilisation des femmes non-asthmatiques comme groupe de référence et la faible puissance statistique. De plus, les résultats qui en découlent doivent être interprétés avec prudence. Dans le deuxième volet, nous avons utilisé la base de données Québec Asthma and Pregnancy Database qui comprend toutes les grossesses de femmes asthmatiques et un échantillon aléatoire de femmes non-asthmatiques ayant accouchées entre 1990 et 2010 pour effectuer deux études. La première était une étude comparant la prévalence des malformations congénitales majeures entre les femmes enceintes asthmatiques traitées avec une combinaison de BALA-CSI et celles traitées avec une dose plus élevée de CSI en monothérapie. Dans une sous-cohorte, il y’avait 643 femmes qui utilisaient un BALA plus CSI à dose faible et 305 qui ont utilisé une dose moyenne de CSI ; l'autre sous-cohorte comprenait 198 utilisatrices de BALA plus CSI à dose moyenne et 156 utilisatrices de CSI à dose élevée. La prévalence de malformations majeures a été 6,9% et 7,2%, respectivement. Le risque de malformations congénitales majeures était similaire entre ces deux groupes de femmes avec un odds ratio ajusté (OR) de 1,1 (IC 95%: 0,6-1,9) pour les femmes souffrant d’asthme modéré et un OR ajusté de 1,2 (IC 95%: 0,5-2,7) pour les femmes souffrant d’asthme sévère. La seconde était une étude méthodologique visant à étudier l’impact de six différentes définitions opérationnelles de malformations congénitales qui varient selon la source des données et la méthode de classification sur l’estimation de la prévalence des malformations et de l'association entre l'asthme maternel et les malformations majeures. Sur 467,946 grossesses, 12,3% étaient de femmes enceintes souffrant d’asthme actif. Nous avons démontré que la source des données et la méthode de classification ont eu un impact considérable sur la prévalence des malformations congénitales majeures (augmentation entre 10,0% et 50,4%), alors qu’elles ont eu peu d’influence sur l’association entre l’asthme maternel et les malformations congénitales. Dans le troisième volet du programme de recherche, nous avons développé une procédure systématique pour la classification des médicaments utilisés au cours du premier trimestre de grossesse en agents tératogènes et potentiellement tératogènes dans un contexte de recherche. Nous avons développé une procédure systématique qui s’actualise facilement, avec des composantes objectives dans la plupart de ses processus. Nous avons établi une liste comprenant 91 médicaments tératogènes, et une autre liste comprenant 81 médicaments potentiellement tératogènes. Les résultats présentés dans cette thèse ont fourni des données importantes sur l’innocuité des traitements de l'asthme pendant la grossesse, aidant les cliniciens et les femmes enceintes à choisir un traitement pharmacologique sécuritaire pour maintenir l’asthme sous contrôle. De plus, les données présentées dans cette thèse sur la minimisation du biais d'indication, les définitions opérationnelles de malformations congénitales et l’identification des médicaments tératogènes pourront aisément être utilisées par les chercheurs en pharmacoépidémiologie, en tératologie et en épidémiologie périnatale. / Asthma is one of the most prevalent chronic diseases during pregnancy, affecting about 4% to 12% of pregnant women and shows an increasing prevalence over time. In the past decades, several studies have identified asthma as a risk factor for several poor fetal and maternal outcomes. A consensus exists on favoring the use of asthma medications during pregnancy to maintain asthma under control to prevent adverse maternal and fetal outcomes. An assessment of the published literature on maternal asthma medications and the risk of major congenital malformations revealed more data on the safety of short-acting beta2-agonists (SABA) and inhaled corticosteroids (ICS) during pregnancy compared to long-acting beta2-agonists (LABA), as well as a paucity of data on the fetal safety of combination therapies (e.g. LABA-ICS). A three-part research program was developed to fill this knowledge gap and answer other intriguing questions we faced, adding necessary evidence in this field. In the first part, we summarized the published evidence on the impact of maternal use of SABA and LABA during pregnancy and different perinatal outcomes in a comprehensive systematic review. Twenty-one original studies were identified. Four studies reported a significant increased risk of congenital malformations with SABA, one study reported a significant increased risk of congenital malformations with LABA and four studies reported a significant increased risk of congenital malformations with beta2-agonists (SABA and/or LABA). However, no major increased risk was found for the other perinatal outcomes. Importantly, most of the retrieved studies suffered several methodologic limitations, including using non-asthmatic women as the reference group and low statistical power. Moreover, the non-significant results reported should be interpreted with caution. In the second part, we used the Quebec Asthma and Pregnancy Database – which includes all pregnancies in asthmatic women and a random sample in nonasthmatic women between 1990 and 2010 – to conduct two studies. The first was a comparative safety study examining the prevalence of major congenital malformations in pregnant asthmatic women treated with a combination of LABA-ICS compared to those treated with a higher dose of ICS monotherapy. In one subcohort there were 643 women who used a LABA plus low-dose ICS and 305 women who used a medium-dose ICS; the other subcohort included 198 users of a LABA plus a medium dose ICS and 156 users of a high-dose ICS. The prevalence of major malformations was 6.9% and 7.2%, respectively. The risk of major malformations did not differ when a combination therapy was used among both moderate and severe asthmatic women (aOR: 1.1; 95% CI: 0.6–1.9 and aOR: 1.2; 95% CI: 0.5–2.7 respectively). The second was a methodological study aiming to compare the prevalence of major malformations using six different case ascertainment definitions that vary by the source of data and the classification method, as well as to evaluate the impact of these definitions on the association between maternal asthma and major malformations. From the 467,946 pregnancies, 12.3% were with active asthma. We demonstrated that the source of data and the classification method had a considerable impact on the prevalence of major malformations (increases between 10.0% and 50.4%), but only a small influence on the measure of association. In the third part of the research program, we aimed at constructing a systematic procedure for the classification of proven and potential teratogenic medications during the first trimester of pregnancy to be used for research. We structured a procedure that is both systematic and updatable, with objective components in most of its processes. We identified a substantial list of teratogenic medications, including 91 medications, and an extensive list of potentially teratogenic medications, including 81 medications. The results presented in the current thesis provided essential evidence on the safety of asthma treatments during pregnancy, helping clinicians and mothers to choose the optimal therapeutic regimen to keep asthma under control. The added knowledge on indication bias minimization, congenital malformations ascertainment and teratogenic medications are directly transferable to researchers in pharmacoepidemiology, teratology and other related research fields.

Selon les lignes directrices de traitement de l'asthme pendant la grossesse, les beta2-agonistes inhalés à courte durée d’action (SABA) sont les médicaments de choix pour tous les types d’asthme [intermittent, persistant, léger, modéré et sévère] comme médicaments de secours rapide et dans la gestion des exacerbations aiguës. D’autre part, les beta2-agonistes inhalés à longue durée d’action (LABA) sont utilisés pour les patients atteints d'asthme persistant, modéré à sévère, qui ne sont pas entièrement contrôlés par des corticostéroïdes inhalés seuls. Malgré que plusieurs études aient examinées l’association entre les LABA, les SABA et les malformations congénitales chez les nouveau-nés, les risques réels restent controversés en raison de résultats contradictoires et des difficultés inhérentes à la réalisation d'études épidémiologiques chez les femmes enceintes. L'objectif de cette étude était d'évaluer l'association entre l'exposition maternelle aux SABA et LABA pendant le premier trimestre de grossesse et le risque de malformations congénitales chez les nouveau-nés de femmes asthmatiques. Une cohorte de grossesses de femmes asthmatiques ayant accouchées entre le 1er janvier 1990 et le 31 décembre 2002 a été formée en croisant trois banques de données administratives de la province de Québec (Canada). Les issues principales de cette étude étaient les malformations congénitales majeures de touts types. Comme issues secondaires, nous avons considéré des malformations congénitales spécifiques. L'exposition principale était la prise de SABA et/ou de LABA au cours du premier trimestre de grossesse. L'exposition secondaire étudiée était le nombre moyen de doses de SABA par semaine au cours du premier trimestre. L'association entre les malformations congénitales et la prise de SABA et de LABA a été évaluée en utilisant des modèles d’équations généralisées (GEE) en ajustant pour plusieurs variables confondantes reliées à la grossesse, l’asthme de la mère et la santé de la mère et du foetus. Dans la cohorte formée de 13 117 grossesses de femmes asthmatiques, nous avons identifié 1 242 enfants avec une malformation congénitale (9,5%), dont 762 avaient une malformation majeure (5,8%). Cinquante-cinq pour cent des femmes ont utilisé des SABA et 1,3% ont utilisé des LABA pendant le premier trimestre. Les rapports de cotes ajustées (IC à 95%) pour une malformation congénitale associée à l'utilisation des SABA et des LABA étaient de 1,0 (0,9-1,2) et 1,3 (0,9-2,1), respectivement. Les résultats correspondants étaient de 0,9 (0,8-1,1) et 1,3 (0,8-2,4) pour les malformations majeures. Concernant le nombre moyen de doses de SABA par semaine, les rapports de cotes ajustées (IC à 95%) pour une malformation congénitale était de 1.1 (1.0-1.3), 1.1 (0.9-1.3), et 0.9 (0.7-1.1) pour les doses >0-3, >3-10, and >10 respectivement. Les résultats correspondants étaient de 1.0 (0.8-1.2), 0.8 (0.7-1.1), et 0.7 (0.5-1.0) pour les malformations majeures. D'autre part, des rapports de cotes (IC à 95%) statistiquement significatifs ont été observés pour les malformations cardiaques (2.4 (1.1-5.1)), les malformations d'organes génitaux (6.8 (2.6-18.1)), et d'autres malformations congénitales (3.4 (1.4 à 8.5)), en association avec les LABA pris pendant le premier trimestre. Notre étude procure des données rassurantes pour l’utilisation des SABA pendant la grossesse, ce qui est en accord avec les lignes directrices de traitement de l’asthme. Toutefois, d'autres études sont nécessaires avant de pouvoir se prononcer sur l’innocuité des LABA pendant la grossesse. / According to asthma management guidelines during pregnancy, short-acting β2-agonists (SABA) are the drug of choice in all types of asthma [intermittent or persistent, mild, moderate and severe] as a quick reliever medication and in the management of acute exacerbations or emergency hospitalizations. On the other hand, long-acting β2-agonists (LABA) are used for patients with moderate and severe persistent asthma not fully controlled with inhaled corticosteroids alone. While many studies examined their associations with congenital malformations in newborns, the actual risks remain controversial due to the discordance between different risk reports and the difficulties in performing epidemiological studies on pregnant women. The objective of this study is to investigate the association between maternal exposure to SABA and LABA during the first trimester of pregnancy and the risk of congenital malformations in the newborns among asthmatic women. Through the linkage of three administrative databases from Québec, a cohort of pregnancies from asthmatic women insured by the RAMQ drug insurance plan was formed between January 1, 1990 and December 31, 2002. The primary outcomes were major and any congenital malformations and the secondary outcomes were specific malformations. The primary exposure was the separate exposure to SABA and LABA during the first trimester, while the secondary exposure was the average number of doses of SABA per week taken during the first trimester. The association between congenital malformations and SABA and LABA exposure was assessed using generalized estimating equation models while adjusting for sociodemographic, asthma, maternal and fetal variables. We identified 1242 infants with a congenital malformation (9.5%), 762 of which had a major malformation (5.8%) within the cohort formed of 13117 pregnancies. Fifty-five percent of the women used SABA during the first trimester, and 1.3% used LABA. The adjusted odds ratio (95% CI) for any malformation associated with the use of SABA and LABA were 1.0 (0.9-1.2) and 1.3 (0.9-2.1), respectively. The corresponding figures were 0.9 (0.8-1.1) and 1.3 (0.8-2.4) for major malformations. Regarding the average number of doses of SABA per week, the adjusted odds ratio (95% CI) for any malformation were 1.1 (1.0-1.3), 1.1 (0.9-1.3), and 0.9 (0.7-1.1) for doses >0-3, >3-10, and >10 respectively. The corresponding figures were 1.0 (0.8-1.2), 0.8 (0.7-1.1), and 0.7 (0.5-1.0) for major malformations. On the other hand, significant increased risks, odds ratio (95% CI), of cardiac malformations 2.4 (1.1-5.1), genital organ malformations 6.8 (2.6-18.1), and other congenital malformations 3.4 (1.4-8.5) were observed with LABA use in the 1st trimester. Our study adds evidence, in concordance with asthma management guidelines, to the safety of SABA during pregnancy. However, more research is needed before we can decide on the safety of LABA during pregnancy.

L’objectif général de ce travail était d’étudier la relation entre exposition professionnelle maternelle aux solvants organiques et malformations congénitales.Ce projet s’est appuyé sur les données de la cohorte PELAGIE. Il s’agit d’une cohorte mère enfant avec inclusion de 3 421 femmes en début de grossesse en population générale en Bretagne. L’exposition aux solvants était définie par différentes méthodes (expositions déclarées, matrices emplois-expositions, dosages urinaires de métabolites de solvants chlorés et d’éthers de glycol).Nous avons mis en évidence une relation entre l’exposition aux solvants mesurée par des méthodes indirectes et les malformations congénitales. Puis, pour un échantillon aléatoire de451 femmes, nous avons étudié les déterminants de la détection urinaire des métabolites de solvants. Enfin, dans le cadre d’une étude cas-témoins dans la cohorte, la relation entre métabolites urinaires de solvants et malformations congénitales a été étudiée. / The aim of this project was to study the relation between maternal occupational exposure to solvents and congenital malformations.This project used data from the PELAGIE study. This is a mother child cohort which had included 3 421 women from the general population at the beginning of their pregnancy in Britany. Occupational exposure to solvents was assessed by different methods (self-report, job exposure matrix, and urinary determination of glycol ethers and chlorinated solvents metabolites).We have shown an association between solvent exposure using indirect method of assessment and congenital malformations. Using a randomized sample of 451 women, we have studied the occupational and non occupational determinants of urinary detection of glycol ethers and chlorinated solvents metabolites. Finally, we have studied in a nested case-control study, the relation between urinary solvent metabolites and congenital malformations.

<p>To assess the impact of congenital malformations in Down syndrome (DS) on morbidity, mortality and outcome at birth, information on all children with DS born in the northern part of Sweden in 1973-80 (n=211) and 1995-98 (n=88) was collected. Most common were congenital heart defects (CHD), dominated by atrioventricular septal defects (AVSD). Up to age 10 years, morbidity and mortality were more than 10 times higher in DS children with CHD than in healthy DS children. The DS children seemed more vulnerable at birth than Swedish children in general: they had increased frequencies of Cesarean sections, premature birth, asphyxia, and low birthweight, and higher proportions of children small for gestational age, regardless of the presence of CHD. Infant mortality decreased from 14.2% to 2.3% between the two periods.</p><p>All children with AVSD with and without DS born in Sweden 1973-1997 (n=801) were followed up retrospectively to 2001. Children with isolated AVSD without complex additional CHDs were studied more closely (n=502). A reduction in age at operation and postoperative mortality (from 28 to 1%) was observed. No significant difference in 5-year postoperative mortality between genders or between DS and non-DS children was found. The 5-year postoperative mortality in DS decreased from 35% in 1973-77 to about 10% in 1993-97. </p><p>CHD had a major influence on morbidity, infectionrate and mortality in DS, but not on DS birth variables. The formerly high mortality in CHD is now reduced. In isolated AVSD measures seem equally successful in DS and non-DS children. Mortality is still 3 times higher in DS children with isolated AVSD than in healthy DS children. </p>

To assess the impact of congenital malformations in Down syndrome (DS) on morbidity, mortality and outcome at birth, information on all children with DS born in the northern part of Sweden in 1973-80 (n=211) and 1995-98 (n=88) was collected. Most common were congenital heart defects (CHD), dominated by atrioventricular septal defects (AVSD). Up to age 10 years, morbidity and mortality were more than 10 times higher in DS children with CHD than in healthy DS children. The DS children seemed more vulnerable at birth than Swedish children in general: they had increased frequencies of Cesarean sections, premature birth, asphyxia, and low birthweight, and higher proportions of children small for gestational age, regardless of the presence of CHD. Infant mortality decreased from 14.2% to 2.3% between the two periods. All children with AVSD with and without DS born in Sweden 1973-1997 (n=801) were followed up retrospectively to 2001. Children with isolated AVSD without complex additional CHDs were studied more closely (n=502). A reduction in age at operation and postoperative mortality (from 28 to 1%) was observed. No significant difference in 5-year postoperative mortality between genders or between DS and non-DS children was found. The 5-year postoperative mortality in DS decreased from 35% in 1973-77 to about 10% in 1993-97. CHD had a major influence on morbidity, infectionrate and mortality in DS, but not on DS birth variables. The formerly high mortality in CHD is now reduced. In isolated AVSD measures seem equally successful in DS and non-DS children. Mortality is still 3 times higher in DS children with isolated AVSD than in healthy DS children.

Selon les lignes directrices de traitement de l'asthme pendant la grossesse, les beta2-agonistes inhalés à courte durée d’action (SABA) sont les médicaments de choix pour tous les types d’asthme [intermittent, persistant, léger, modéré et sévère] comme médicaments de secours rapide et dans la gestion des exacerbations aiguës. D’autre part, les beta2-agonistes inhalés à longue durée d’action (LABA) sont utilisés pour les patients atteints d'asthme persistant, modéré à sévère, qui ne sont pas entièrement contrôlés par des corticostéroïdes inhalés seuls. Malgré que plusieurs études aient examinées l’association entre les LABA, les SABA et les malformations congénitales chez les nouveau-nés, les risques réels restent controversés en raison de résultats contradictoires et des difficultés inhérentes à la réalisation d'études épidémiologiques chez les femmes enceintes. L'objectif de cette étude était d'évaluer l'association entre l'exposition maternelle aux SABA et LABA pendant le premier trimestre de grossesse et le risque de malformations congénitales chez les nouveau-nés de femmes asthmatiques. Une cohorte de grossesses de femmes asthmatiques ayant accouchées entre le 1er janvier 1990 et le 31 décembre 2002 a été formée en croisant trois banques de données administratives de la province de Québec (Canada). Les issues principales de cette étude étaient les malformations congénitales majeures de touts types. Comme issues secondaires, nous avons considéré des malformations congénitales spécifiques. L'exposition principale était la prise de SABA et/ou de LABA au cours du premier trimestre de grossesse. L'exposition secondaire étudiée était le nombre moyen de doses de SABA par semaine au cours du premier trimestre. L'association entre les malformations congénitales et la prise de SABA et de LABA a été évaluée en utilisant des modèles d’équations généralisées (GEE) en ajustant pour plusieurs variables confondantes reliées à la grossesse, l’asthme de la mère et la santé de la mère et du foetus. Dans la cohorte formée de 13 117 grossesses de femmes asthmatiques, nous avons identifié 1 242 enfants avec une malformation congénitale (9,5%), dont 762 avaient une malformation majeure (5,8%). Cinquante-cinq pour cent des femmes ont utilisé des SABA et 1,3% ont utilisé des LABA pendant le premier trimestre. Les rapports de cotes ajustées (IC à 95%) pour une malformation congénitale associée à l'utilisation des SABA et des LABA étaient de 1,0 (0,9-1,2) et 1,3 (0,9-2,1), respectivement. Les résultats correspondants étaient de 0,9 (0,8-1,1) et 1,3 (0,8-2,4) pour les malformations majeures. Concernant le nombre moyen de doses de SABA par semaine, les rapports de cotes ajustées (IC à 95%) pour une malformation congénitale était de 1.1 (1.0-1.3), 1.1 (0.9-1.3), et 0.9 (0.7-1.1) pour les doses >0-3, >3-10, and >10 respectivement. Les résultats correspondants étaient de 1.0 (0.8-1.2), 0.8 (0.7-1.1), et 0.7 (0.5-1.0) pour les malformations majeures. D'autre part, des rapports de cotes (IC à 95%) statistiquement significatifs ont été observés pour les malformations cardiaques (2.4 (1.1-5.1)), les malformations d'organes génitaux (6.8 (2.6-18.1)), et d'autres malformations congénitales (3.4 (1.4 à 8.5)), en association avec les LABA pris pendant le premier trimestre. Notre étude procure des données rassurantes pour l’utilisation des SABA pendant la grossesse, ce qui est en accord avec les lignes directrices de traitement de l’asthme. Toutefois, d'autres études sont nécessaires avant de pouvoir se prononcer sur l’innocuité des LABA pendant la grossesse. / According to asthma management guidelines during pregnancy, short-acting β2-agonists (SABA) are the drug of choice in all types of asthma [intermittent or persistent, mild, moderate and severe] as a quick reliever medication and in the management of acute exacerbations or emergency hospitalizations. On the other hand, long-acting β2-agonists (LABA) are used for patients with moderate and severe persistent asthma not fully controlled with inhaled corticosteroids alone. While many studies examined their associations with congenital malformations in newborns, the actual risks remain controversial due to the discordance between different risk reports and the difficulties in performing epidemiological studies on pregnant women. The objective of this study is to investigate the association between maternal exposure to SABA and LABA during the first trimester of pregnancy and the risk of congenital malformations in the newborns among asthmatic women. Through the linkage of three administrative databases from Québec, a cohort of pregnancies from asthmatic women insured by the RAMQ drug insurance plan was formed between January 1, 1990 and December 31, 2002. The primary outcomes were major and any congenital malformations and the secondary outcomes were specific malformations. The primary exposure was the separate exposure to SABA and LABA during the first trimester, while the secondary exposure was the average number of doses of SABA per week taken during the first trimester. The association between congenital malformations and SABA and LABA exposure was assessed using generalized estimating equation models while adjusting for sociodemographic, asthma, maternal and fetal variables. We identified 1242 infants with a congenital malformation (9.5%), 762 of which had a major malformation (5.8%) within the cohort formed of 13117 pregnancies. Fifty-five percent of the women used SABA during the first trimester, and 1.3% used LABA. The adjusted odds ratio (95% CI) for any malformation associated with the use of SABA and LABA were 1.0 (0.9-1.2) and 1.3 (0.9-2.1), respectively. The corresponding figures were 0.9 (0.8-1.1) and 1.3 (0.8-2.4) for major malformations. Regarding the average number of doses of SABA per week, the adjusted odds ratio (95% CI) for any malformation were 1.1 (1.0-1.3), 1.1 (0.9-1.3), and 0.9 (0.7-1.1) for doses >0-3, >3-10, and >10 respectively. The corresponding figures were 1.0 (0.8-1.2), 0.8 (0.7-1.1), and 0.7 (0.5-1.0) for major malformations. On the other hand, significant increased risks, odds ratio (95% CI), of cardiac malformations 2.4 (1.1-5.1), genital organ malformations 6.8 (2.6-18.1), and other congenital malformations 3.4 (1.4-8.5) were observed with LABA use in the 1st trimester. Our study adds evidence, in concordance with asthma management guidelines, to the safety of SABA during pregnancy. However, more research is needed before we can decide on the safety of LABA during pregnancy.