Tabagismo materno na gestação e malformações congênitas em crianças: uma revisão sistemática com meta-análise

Dilvania Nicoletti Leilane Droppa Appel Pedro Siedersberger Neto Gabriel Waihrich Guimarães Linjie Zhang Sobre os autores

Resumos

This systematic review aimed to investigate the association between maternal smoking during pregnancy and birth defects in children. We performed an electronic search of observational studies in the databases ovid MEDLINE (1950 to April 2010), LILACS and SciELO. We included 188 studies with a total of 13,564,914 participants (192,655 cases). Significant positive associations were found between maternal smoking and birth defects in the following body systems: cardiovascular (OR: 1.11; 95%CI: 1.03-1.19), digestive (OR: 1.18; 95%CI: 1.07-1.30), musculoskeletal (OR: 1.27; 95%CI: 1.16-1.39) and face and neck (OR: 1.28; 95%CI: 1.19-1.37). The strength of association between maternal smoking and birth defects measured by the OR (95%CI) is significantly related to the amount of cigarettes smoked daily (χ2 = 12.1; df = 2; p = 0.002). In conclusion, maternal smoking during pregnancy is associated with congenital malformations in children and this association is dose-dependent.

Smoking; Pregnancy; Congenital Abnormalities


Esta revisión sistemática se encargó de investigar la asociación entre el tabaquismo materno durante el embarazo y las malformaciones congénitas en los niños. Se realizó una búsqueda electrónica de los estudios de observación en las bases de datos de ovid MEDLINE (1950 hasta abril de 2010), LILACS y SciELO. 188 estudios con 13.564.914 participantes se incluyeron en esta revisión. Se encontraron asociaciones positivas significativas entre el tabaquismo materno y malformaciones de los sistemas: cardiovascular (OR: 1,11; IC95%: 1.03-1.19), digestivo (OR: 1,18; IC95%: 1,07-1,30), musculoesqueléticos (OR: 1,27; IC95%: 1,16-1,39) y de cara y cuello (OR: 1,28; IC95%: 1,19-1,37). La fuerza de la asociación entre el tabaquismo materno y los defectos de nacimiento, medidos por el OR (IC95%) está significativamente relacionada con la cantidad de cigarrillos fumados diariamente (χ2 = 12,1; p = 0,002). Llegamos a la conclusión de que el tabaquismo materno durante el embarazo se asocia con un mayor riesgo de malformaciones congénitas en los niños y esta asociación es dosis-dependiente.

Hábito de Fumar; Embarazo; Anomalías Congénitas


Esta revisão sistemática teve como objetivo investigar a associação entre fumo materno na gestação e as malformações congênitas em crianças. Uma busca eletrônica dos estudos observacionais foi realizada nas bases de dados ovid MEDLINE (1950 até abril de 2010), SciELO e LILACS. Foram incluídos nesta revisão 188 estudos com um total de 13.564.914 participantes (192.655 casos). Foram encontradas associações positivas significativas entre fumo materno e malformações dos sistemas: cardiovascular (OR: 1,11; IC95%: 1,03-1,19), digestivo (OR: 1,18; IC95%: 1,07-1,30), musculoesquelético (OR: 1,27; IC95%: 1,16-1,39) e face e pescoço (OR: 1,28; IC95%: 1,19-1,37). A força de associação entre fumo materno e malformações medida pelo OR (IC95%) está relacionada significativamente com a quantidade diária de cigarros consumidos (χ2 = 12,1; df = 2; p = 0,002). Concluímos que fumo materno na gestação está associado com maior risco de malformações congênitas em crianças e essa associação é dose-dependente.

Hábito de Fumar; Gravidez; Anormalidades Congênitas


Introdução

As malformações congênitas apresentam elevada mortalidade e morbidade nas crianças. Estima- se que cerca de 5% dos nascidos vivos apresentem alguma anomalia do desenvolvimento 11. Horovitz DDG, Llerena Jr. JC, Mattos RA. Atenção aos defeitos congênitos no Brasil: panorama atual. Cad Saúde Pública 2005; 21:1055-64.. Nas últimas décadas, tem sido observada a crescente contribuição das malformações congênitas na mortalidade infantil22. Powell-Griner E, Woolbright A. Trends in infant deaths from congenital anomalies: results from England and Wales, Scotland, Sweden and the United States. Int J Epidemiol 1990; 19:391-8. , 33. Neto PS, Zhang L, Nicoletti D, Munchen FB. Mortalidade infantil por malformações congênitas no Brasil. Rev AMRIGS 2012; 56:129-32.. No Brasil, a proporção de óbitos infantis atribuíveis às malformações congênitas subiu de 9,7% em 1996, para 18,2% em 2008, com um aumento médio anual de 0,71%33. Neto PS, Zhang L, Nicoletti D, Munchen FB. Mortalidade infantil por malformações congênitas no Brasil. Rev AMRIGS 2012; 56:129-32.. Esse aumento pode ser por causa do melhor controle das doenças infectocontagiosas e carenciais e, consequentemente, à redução de óbitos infantis por essas doenças11. Horovitz DDG, Llerena Jr. JC, Mattos RA. Atenção aos defeitos congênitos no Brasil: panorama atual. Cad Saúde Pública 2005; 21:1055-64. , 33. Neto PS, Zhang L, Nicoletti D, Munchen FB. Mortalidade infantil por malformações congênitas no Brasil. Rev AMRIGS 2012; 56:129-32..

A maioria das malformações congênitas tem etiologia multifatorial. Além de fator genético, sua ocorrência pode estar relacionada à exposição da criança, ainda antes do nascimento ou mesmo de seus pais, a substâncias tóxicas, entre elas o tabaco44. Stillerman KP, Mattison DR, Giudice LC, Woodruff TJ. Environmental exposures and adverse pregnancy outcomes: a review of the science. Reprod Sci 2008; 15:631-50.. Durante a realização do presente trabalho, uma revisão sistemática com 101 estudos observacionais foi publicada, demonstrando associação entre tabagismo materno na gestação e diversas anomalias congênitas em crianças 55. Hackshaw A, Rodeck C, Boniface S. Maternal smoking in pregnancy and birth defects: a systematic review based on 173687 malformed cases and 11.7 million controls. Hum Reprod Updat 2011; 17:589-604.. Esta revisão, no entanto, não incluiu um número considerável de estudos relevantes66. Bird TM, Robbins JM, Druschel C, Cleves MA, Yang S, Hobbs CA. Demographic and environmental risk factors for gastroschisis and omphalocele in the National Birth Defects Prevention Study. J Pediatr Surg 2009; 44:1546-51. , 77. Bracken MB, Holford TR, White C, Kelsey JL. Role of oral contraception in congenital malformations of offspring. Int J Epidemiol 1978; 7:309-17. , 88. Cedergren MI, Selbing AJ, Källén BAJ. Risk factors for cardiovascular malformation - a study based on prospectively collected data. Scan J Work Environ Health 2002; 28:12-7. , 99. Christensen K, Olsen J, Norgaard-Pedersen B, Basso O, Stovring H, Milhollin-Johnson L, et al. Oral clefts, transforming growth factor alpha gene variants, and maternal smoking: a population-based case-control study in Denmark, 1991-1994. Am J Epidemiol 1999; 149:248-55. , 1010. DeRoo LA, Gaudino JA, Edmonds LD. Orofacial cleft malformations: associations with maternal and infant characteristics in Washington state. Birth Defects Res A Clin Mol Teratol 2003; 67: 637-42. , 1111. Dickinson KC, Meyer RE, Kotch J. Maternal smoking and the risk for clubfoot in infants. Birth Defects Res A Clin Mol Teratol 2008; 82:86-91. , 1212. Feldkamp ML, Alder SC, Carey JC. A case control population-based study investigating smoking as a risk factor for gastroschisis in Utah, 1997-2005. Birth Defects Res A Clin Mol Teratol 2008; 82: 768-75. , 1313. Ramirez D, Lammer EJ, Iovannisci DM, Laurent C, Finnell RH, Shaw GM. Maternal smoking during early pregnancy, GSTP1 and EPHX1 variants, and risk of isolated orofacial clefts. Cleft Palate Craniofac J 2007; 44:366-73. , 1414. Williams LJ, Correa A, Rasmussen S. Maternal lifestyle factors and risk for ventricular septal defects. Birth Defects Res A Clin Mol Teratol 2004; 70:59-64.. Além disso, os defeitos da parede abdominal tais como hérnia diafragmática e inguinal, gastrosquise e onfalocele que deveriam ser considerados como anomalias do sistema musculoesquelético de acordo com a 10arevisão da Classificação Internacional de Doenças (CID-10)1515. Centro Colaborador da OMS para a Classificação de Doenças em Português. Classificação estatística internacional de doenças e problemas relacionados à saúde. 10a revisão. http://www.datasus.gov.br/cid10/V2008/cid10.htm (accessed on 20/Apr/2010).
http://www.datasus.gov.br/cid10/V2008/ci...
foram classificados como malformações gastrointestinais.

A presente revisão sistemática teve como objetivo investigar a associação entre fumo materno na gestação e as malformações congênitas em crianças, tendo sido estudada também a possível relação dose-resposta nessa associação.

Métodos

Foi realizada uma revisão sistemática com meta análise. A condução da revisão e o relato dos resultados foram baseadas nas recomendações da MOOSE (Meta-analysis of Observational Studies in Epidemiology)1616. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA 2000; 283:2008-12.. O protocolo da revisão foi avaliado e aprovado em 2010 por uma banca de qualificação composta por dois especialistas em Pediatria e um especialista em Epidemiologia.

Foram considerados elegíveis para esta revisão estudos que investigam associação entre tabagismo materno na gestação e malformações congênitas em crianças. Foram excluídos os estudos sobre associação entre fumo materno e malformações cromossômicas.

A busca eletrônica dos estudos foi realizada nas bases de dados Ovid MEDLINE (1950 até abril de 2010), SciELO e LILACS. A estratégia de busca dos estudos potencialmente relevantes para esta revisão nas bases de dados Ovid MEDLINE constitui-se de duas partes (Figura 1): a primeira (da linha #1 à linha #4) corresponde à estratégia de busca para identificar os estudos sobre tabagismo materno e a segunda parte (da linha #5 à linha #20) corresponde à estratégia para encontrar estudos relacionados com malformações congênitas. As referências bibliográficas dos artigos obtidos com texto íntegro foram revisadas para identificar os estudos adicionais. Foi utilizado Google Tradutor (https://translate.google.com.br/) para tradução de dois artigos: um em Lituano e outro em Francês.

Figura 1
Estratégia de busca dos estudos nas bases de dados Ovid MEDLINE.

A seleção dos estudos foi realizada independentemente por quatros investigadores (duas duplas). O processo de seleção incluiu duas etapas: na primeira, o título e o resumo dos artigos identificados na busca eletrônica foram revisados para selecionar os estudos potenciais para essa revisão. Foram obtidos os artigos com texto íntegro quando os dados contidos no título e no resumo satisfizerem os critérios de inclusão ou quando não houver dados suficientes para tomar decisão sobre sua inclusão. Na segunda etapa, foi realizada uma leitura dos artigos obtidos com texto íntegro para selecionar definitivamente os estudos, verificando-se os critérios de inclusão e exclusão. As desconcordâncias entre os investigadores foram resolvidas pelo consenso. A extração de dados foi realizada por quatros investigadores com uso de formulário-padrão. Os dados extraídos foram verificados entre os investigadores.

A meta-análise foi realizada com o programa Stata, versão 11.0 (Stata Corp., College Station, Estados Unidos). Foi aplicado o modelo de efeitos aleatórios. A associação entre fumo materno na gestação e a presença de qualquer tipo de malformações congênitas em crianças foi avaliada por odds ratios (OR) e intervalos de 95% de confiança (IC95%). Quando os estudos originais apresentaram mais de uma malformação, os resultados de cada malformação foram combinados para obter os dados de qualquer tipo de malformações. Foi utilizado OR ajustado sempre que possível.

As análises de subgrupos pré-definidas foram realizadas para investigar associação entre fumo materno na gestação e malformações congênitas em crianças de acordo com sistemas envolvidos. A classificação das malformações congênitas foi baseada na CID-10. As análises de subgrupos pré-definidas foram utilizadas também para avaliar a potencial influência dos seguintes aspectos metodológicos nos resultados da meta análise: delineamento da pesquisa (prospectivo vs. retrospectivo); tamanho da amostra (casos) (≤ 200, 200-1.000, 1.000-5.000, > 5.000); ajuste/emparelhamento dos fatores de confusão incluindo idade da mãe (sim vs. não). Foram realizadas duas análises de subgrupos post hoc para avaliar potencial impacto da definição da exposição (fumo materno) e do período da exposição durante a gestação nos resultados da meta-análise. Para investigar a possível relação dose-resposta entre fumo materno na gestação e malformações congênitas em crianças, a análise foi estratificada em três categorias conforme a quantidade de cigarros fumados por dia (1-9, 10-19 e > 20).

A heterogeneidade dos resultados entre os estudos foi avaliada pela estatística I22. Powell-Griner E, Woolbright A. Trends in infant deaths from congenital anomalies: results from England and Wales, Scotland, Sweden and the United States. Int J Epidemiol 1990; 19:391-8.; I22. Powell-Griner E, Woolbright A. Trends in infant deaths from congenital anomalies: results from England and Wales, Scotland, Sweden and the United States. Int J Epidemiol 1990; 19:391-8. > 75% indica heterogeneidade significativa1717. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analysis. BMJ 2003; 327:557-60.. Possíveis causas da heterogeneidade foram exploradas mediante análises de subgrupos citadas acima. O viés de publicação foi investigado usando o gráfico de funil e o teste de Egger1717. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analysis. BMJ 2003; 327:557-60..

Resultados

Das 1.043 citações identificadas pela busca eletrônica, 129 estudos foram selecionados. Cinquenta e nove estudos adicionais foram obtidos pela revisão dos artigos originais e pela revisão sistemática. Portanto, um total de 188 estudos (153 projetos ou bases de dados independentes)66. Bird TM, Robbins JM, Druschel C, Cleves MA, Yang S, Hobbs CA. Demographic and environmental risk factors for gastroschisis and omphalocele in the National Birth Defects Prevention Study. J Pediatr Surg 2009; 44:1546-51. , 77. Bracken MB, Holford TR, White C, Kelsey JL. Role of oral contraception in congenital malformations of offspring. Int J Epidemiol 1978; 7:309-17. , 88. Cedergren MI, Selbing AJ, Källén BAJ. Risk factors for cardiovascular malformation - a study based on prospectively collected data. Scan J Work Environ Health 2002; 28:12-7. , 99. Christensen K, Olsen J, Norgaard-Pedersen B, Basso O, Stovring H, Milhollin-Johnson L, et al. Oral clefts, transforming growth factor alpha gene variants, and maternal smoking: a population-based case-control study in Denmark, 1991-1994. Am J Epidemiol 1999; 149:248-55. , 1010. DeRoo LA, Gaudino JA, Edmonds LD. Orofacial cleft malformations: associations with maternal and infant characteristics in Washington state. Birth Defects Res A Clin Mol Teratol 2003; 67: 637-42. , 1111. Dickinson KC, Meyer RE, Kotch J. Maternal smoking and the risk for clubfoot in infants. Birth Defects Res A Clin Mol Teratol 2008; 82:86-91. , 1212. Feldkamp ML, Alder SC, Carey JC. A case control population-based study investigating smoking as a risk factor for gastroschisis in Utah, 1997-2005. Birth Defects Res A Clin Mol Teratol 2008; 82: 768-75. , 1313. Ramirez D, Lammer EJ, Iovannisci DM, Laurent C, Finnell RH, Shaw GM. Maternal smoking during early pregnancy, GSTP1 and EPHX1 variants, and risk of isolated orofacial clefts. Cleft Palate Craniofac J 2007; 44:366-73. , 1414. 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Figura 2
Fluxograma da seleção dos estudos incluídos na revisão.

Tabela 1
Características gerais dos estudos incluídos.

A Table 2 mostra os resultados individuais e combinados dos 188 estudos sobre associação entre fumo materno na gestação e qualquer malformação congênita em crianças. A meta-análise dos 188 estudos demonstrou que os filhos de mães fumantes na gravidez tiveram maior risco de ter algum tipo de malformações congênitas (OR: 1,18; IC95%: 1,14-1,22; p < 0,001; I22. Powell-Griner E, Woolbright A. Trends in infant deaths from congenital anomalies: results from England and Wales, Scotland, Sweden and the United States. Int J Epidemiol 1990; 19:391-8.: 77,2%).

Tabela 2
Associação entre fumo materno na gestação e malformações congênitas em crianças: resultado dos 188 estudos com qualquer malformação congênita.

Nas análises de subgrupos de acordo com sistemas envolvidos, foram encontradas associações positivas significativas entre fumo materno e malformações dos sistemas cardiovascular (OR: 1,11; IC95%: 1,03-1,19), digestivo (OR: 1,18; IC95%: 1,07-1,30), musculoesquelético (OR: 1,27; IC95%: 1,16-1,39) e face e pescoço (OR: 1,28; IC95%: 1,19-1,37) (Figura 3). Outras análises de subgrupos mostraram que os estudos retrospectivos e aqueles com menor tamanho da amostra (≤ 1.000 casos) tiveram maiores valores de OR combinado. O uso ou não de ajuste/emparelhamento nos estudos originais para controlar fatores de confusão, especialmente idade da mãe, não afetou significativamente os resultados da meta-análise (Table 3). Duas análises de subgrupos post hoc foram realizadas para avaliar potencial impacto da definição do fumo materno e do período da gestação no qual a gestante foi exposta ao fumo nos resultados da meta-análise. Não houve diferença estatisticamente significativa entre estudos nos quais o fumo materno na gestação foi definido explicitamente como consumo diário (n = 91; OR: 1,21; IC95%: 1,16-1,26) e aqueles sem definição clara (n = 97; OR: 1,17; IC95%: 1,11-1,23) (χ2 = 1,0; p = 0,32). Também não foi observada diferença estatisticamente significativa entre estudos nos quais a exposição ao fumo foi no primeiro trimestre da gestação (n = 80; OR: 1,22; IC95%: 1,17-1,29) e aqueles sem definição clara (n = 108; OR: 1,16; IC95%: 1,10-1,21) (χ2 = 2,1; p = 0,15).

Figura 3
Fumo materno na gestação e malformações congênitas em crianças de acordo com os sistemas envolvidos. Nota: pesos são de análise de efeitos aleatórios. ES: tamanho de efeito; IC95%: intervalo de 95% de confiança; OR: odds ratio.

Tabela 3
Análises de subgrupos sobre associação entre fumo materno na gestação e malformações congênitas em crianças.

A Figura 4 mostra a relação dose-resposta entre fumo materno na gestação e malformações congênitas em crianças. Sessenta estudos66. Bird TM, Robbins JM, Druschel C, Cleves MA, Yang S, Hobbs CA. Demographic and environmental risk factors for gastroschisis and omphalocele in the National Birth Defects Prevention Study. J Pediatr Surg 2009; 44:1546-51. , 77. Bracken MB, Holford TR, White C, Kelsey JL. Role of oral contraception in congenital malformations of offspring. Int J Epidemiol 1978; 7:309-17. , 88. Cedergren MI, Selbing AJ, Källén BAJ. Risk factors for cardiovascular malformation - a study based on prospectively collected data. Scan J Work Environ Health 2002; 28:12-7. , 99. Christensen K, Olsen J, Norgaard-Pedersen B, Basso O, Stovring H, Milhollin-Johnson L, et al. Oral clefts, transforming growth factor alpha gene variants, and maternal smoking: a population-based case-control study in Denmark, 1991-1994. Am J Epidemiol 1999; 149:248-55. , 1111. Dickinson KC, Meyer RE, Kotch J. Maternal smoking and the risk for clubfoot in infants. Birth Defects Res A Clin Mol Teratol 2008; 82:86-91. , 1212. Feldkamp ML, Alder SC, Carey JC. A case control population-based study investigating smoking as a risk factor for gastroschisis in Utah, 1997-2005. Birth Defects Res A Clin Mol Teratol 2008; 82: 768-75. , 1616. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA 2000; 283:2008-12. , 2121. Alderman BW, Bradley CM, Greene C, Fernbach SK, Baron AE. Increased risk of craniosynostosis with maternal cigarette smoking during pregnancy. Teratology 1994; 50:13-8. , 2424. Bailey RR. The effect of maternal smoking on the infant birth weight. N Z Med J 1970; 71:293-4. , 3232. Bille C, Olsen J, Vach W, Knudsen VK, Olsen SF, Rasmussen K, et al. Oral clefts and life style factors: a case-cohort study based on prospective Danish data. 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Does maternal cigarette smoking during pregnancy cause cleft lip and palate in offspring? Am J Dis Child 1989; 143:333-7. , 9292. Krapels IP, Zielhuis GA, Vroom F, de Jong-van den Berg LT, Kuijpers-Jagtman AM, van der Molen AB, et al. Periconceptional health and lifestyle factors of both parents affect the risk of live-born children with orofacial clefts. Birth Defects Res A Clin Mol Teratol 2006; 76:613-20. , 9999. Lam PK, Torfs CP. Interaction between maternal smoking and malnutrition in infant risk of gastroschisis. Birth Defects Res A Clin Mol Teratol 2006; 76:182-6. , 100100. Leite IC, Koifman S. Oral clefts, consanguinity, parental tobacco and alcohol use: a case-control study in Rio de Janeiro, Brazil. Pesqui Odontol Bras 2009; 23:31-7. , 101101. Li DK, Mueller BA, Hickok DE, Daling JR, Fantel AG, Checkoway H, et al. Maternal smoking during pregnancy and the risk of congenital urinary tract anomalies. Am J Public Health 1996; 86: 249-53. , 103103. 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Maternal cigarette smoking during pregnancy increases the risk of having a child with a congenital digital anomaly. Plast Reconst Surg 2006; 117:301-8. , 119119. McDonald AD, Armstrong BG, Sloan M. Cigarette, alcohol, and coffee consumption and congenital defects. Am J Public Health 1992; 82:91-3. , 121121. Miller EA, Manning SE, Rasmussen SA, Reefhuis J, Honein MA; National Birth Defects Prevention Study. Maternal exposure to tobacco smoke, alcohol and caffeine, and risk of anorectal atresia: National Birth Defects Prevention Study 1997-2003. Paediatr Perinat Epidemiol 2009; 23:9-17. , 122122. Miller EA, Rasmussen SA, Siega-Riz AM, Frías JL, Honein MA. Risk factors for non-syndromic holoprosencephaly in the national birth defects prevention study. Am J Med Genet C Semin Med Genet 2010; 154C:62-72. , 123123. Mitchell LE, Murray JC, O'Brien S, Christensen K. Evaluation of two putative susceptibility loci for oral clefts in the Danish population. 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Use of US birth certificate data to estimate the risk of maternal cigarette smoking for oral clefting. Cleft Palate Craniofac J 2002; 39:188-92. com um total de 12.137.944 participantes (103.107 casos) contribuíram os dados para a análise, dos quais 11 foram estudos prospectivos. A força de associação entre fumo materno e malformações medida pelo OR (IC95%) está relacionada significativamente com a quantidade diária de cigarros consumidos (χ² = 12,1; p = 0,002). Foram realizadas análises de subgrupos post hocde acordo com delineamento da pesquisa, controle de feitos de confundidores e tamanho da amostra (casos). A relação dose-resposta estatisticamente significativa foi observada nos subgrupos de estudos com fatores de confusão controlados e naqueles com o número de casos entre 200 e 5.000 (Table 4). O delineamento da pesquisa não afetou substancialmente os resultados da relação dose-resposta.

Figura 4
Relação dose-resposta entre fumo materno e malformações congênitas em crianças. Nota: pesos são de análise de efeitos aleatórios. Teste para diferenças entre subgrupos (χ(2) = 12; df = 2; p = 0,002). ES: tamanho de efeito; IC95%: intervalo de 95% de confiança; OR: odds ratio.

Tabela 4
Análises de subgrupos post hoc sobre relação dose-resposta entre fumo materno na gestação e malformações congênitas em crianças.

A meta-análise cumulativa mostrou uma associação estatisticamente significativa entre fumo materno na gestação e malformações congênitas em crianças quando 40 estudos publicados até 1990 com um número total de 26.827 casos foram incluídos na análise (OR: 1,09; IC95%: 1,001-1,19; p = 0,035). O OR (IC95%) e os valores de p foram de 1,16 (1,10-1,23) e de < 0,001, respectivamente, quando 87 estudos publicados até 2000 com um total de 95.556 casos foram incluídos na meta-análise. O resultado da meta-análise manteve-se quase inalterado com inclusão de 101 estudos (97.099 casos) publicados entre 2001 e 2010 (Figura 5).

Figura 5
Meta-análise cumulativa sobre associação entre fumo materno na gestação e malformações congênitas em crianças. Nota: pesos são de análise de efeitos aleatórios. ES: tamanho de efeito; IC95%: intervalo de 95% de confiança; OR: odds ratio.

No gráfico de funil (Figura 6) foi encontrada uma leve assimetria devido à ausência dos estudos no canto inferior esquerdo, sugerindo a não publicação dos estudos com pequenas amostras que demonstram efeito protetor do fumo materno contra malformações em crianças. O teste de Egger também mostrou evidência do efeito de "pequenos estudos" sugerindo a presença de viés de publicação (p < 0,001).

Figura 6
Gráfico de funil.

Discussão

A presente revisão sistemática com meta-análise demonstrou que filhos de mães fumantes durante a gestação apresentam maior risco de ter algum tipo de malformação congênita. Foram evidenciadas associações significativas entre fumo materno na gestação e malformações congênitas dos sistemas cardiovascular, digestivo, musculoesquelético e da face e do pescoço. Foram observadas também associações positivas entre fumo materno e malformações congênitas dos sistemas respiratório, nervoso e urogenital, porém essas associações não foram estatisticamente significativas.

Foi encontrada, nesta revisão sistemática, uma relação dose-resposta estatisticamente significativa entre fumo materno na gestação e risco de malformações congênitas em crianças, isto é, quanto maior o número de cigarros fumados por dia pelas mães, maior o risco de ter filhos com algum tipo de malformação congênita. Verificou- se ainda que, todas as três doses de consumo diário de cigarros estavam associadas significativamente com maior risco de malformações congênitas comparadas com não fumantes, sugerindo que o consumo regular de cigarros pela gestante, mesmo em pequena quantidade, pode causar impacto adverso no desenvolvimento do feto.

Os mecanismos de ação do tabaco no aumento do surgimento de anomalias em bebês não são precisamente compreendidos. Acredita-se que a ação vasoconstritora da nicotina possa causar a redução do fluxo sanguíneo uteroplacentário 197197. Leopércio W, Gigliotti A. Tabagismo e suas peculiaridades durante a gestação: uma revisão crítica. J Bras Pneumol 2004; 30:176-85.. O monóxido de carbono liga-se à hemoglobina de modo que menos oxigênio estaria disponível para a placenta. Também a injúria endotelial causada pelo tabaco aumenta o rompimento de neovasos da placenta levando à redução do aporte sanguíneo fetal resultando em hipoxia, o que provavelmente resulta em morfogênese anormal fetal198198. Quinton AE, Cook CM, Peek MJ. The relationship between cigarette smoking, endothelial function and intrauterine growth restriction in human pregnancy. BJQG 2008; 115:780-4.. Portanto, o somatório de exposição a toxinas, hipoxia e isquemia celular resulta em proliferação celular anormal.

Aproximadamente um terço dos adultos brasileiros era fumante no final da década 1990; houve, contudo, uma redução de aproximadamente 50% (de 34% para 18,2%) na prevalência de fumo nessa população no período entre 1989 e 2008199199. Szklo AS, de Almeida LM, Figueiredo VC, Autran M, Malta D, Caixeta R, et al. Snapshot of the striking decrease in cigarette smoking prevalence in Brazil between 1989 and 2008. Prev Med 2012; 54:162-7.. Vários fatores têm sido atribuídos para tal redução, incluindo políticas antitabaco e disponibilidade de tratamento para cessação de fumar. Há uma preocupação especial com relação ao fumo na gestação por conta de sua associação com diversos desfechos materno-fetais com baixo peso ao nascer, partos prematuros, mortes perinatais e malformações congênitas200200. Salihu HM, Wilson RE. Epidemiology of parental smoking and perinatal outcomes. Early Hum Dev 2007; 83:713-20. , 201201. Zhang L, González-Chica DA, Cesar JA, Mendoza-Sassi RA, Beskow B, Larentis N, et al. Tabagismo materno durante a gestação e medidas antropométricas do recém-nascido: um estudo de base populacional no extremo sul do Brasil. Cad Saúde Pública 2011; 27:1768-76.. Em países como os Estados Unidos e o Canadá, onde políticas governamentais antitabágicas são agressivas e são empregados investimentos maciços para se controlar o fumo durante a gravidez, a prevalência do fumo materno durante a gestação está atualmente em torno de 10 a 12% 202202. Tong VT, Dietz PM, Morrow B, D'Angelo DV, Farr SL, Rockhill KM, et al. Trends in smoking before, during, and after pregnancy: Pregnancy Risk Assessment Monitoring System, United States, 40 sites, 2000-2010. MMWR Surveill Summ 2013; 62:1-19. , 203203. Ontario Tobacco Research Unit. Indicators of smoke-free Ontario progress. Toronto: Ontario Tobacco Research Unit; 2010.. Um estudo recente realizado em nove países na América Latina (Argentina, Brasil, Equador, Guatemala e Uruguai), Ásia (Índia e Paquistão) e África (República Democrática de Congo e Zâmbia) demonstra a maior prevalência do fumo materno durante a gestação no Uruguai (18,3%), seguido pela Argentina (10,3%) e Brasil (6,1%) 204204. Bloch M, Althabe F, Onyamboko M, Kaseba-Sata C, Castilla EE, Freire S, et al. Tobacco use and secondhand smoke exposure during pregnancy: an investigative survey of women in 9 developing nations. Am J Public Health 2008; 98:1833-40. . Entretanto, alguns estudos locais no Brasil têm mostrado uma prevalência de fumo ativo em torno de 20% entre as gestantes 201201. Zhang L, González-Chica DA, Cesar JA, Mendoza-Sassi RA, Beskow B, Larentis N, et al. Tabagismo materno durante a gestação e medidas antropométricas do recém-nascido: um estudo de base populacional no extremo sul do Brasil. Cad Saúde Pública 2011; 27:1768-76. , 205205. Reis LG, da Silva CF, Trindade A, Abrahão M, da Silva VA. Quem são as mulheres tabagistas que param de fumar na gestação? Rev Bras Saúde Matern Infant 2008; 8:217-21. , muito maior do que a relatada nesse estudo multicêntrico internacional. Esses dados corroboram para ainda mais ações contra o uso do tabaco durante a gestação na América Latina, inclusive o Brasil.

Vários recursos estão disponíveis para facilitar o abandono do tabagismo pela paciente como adesivos antitabaco e ansiolíticos como a bupropiona197197. Leopércio W, Gigliotti A. Tabagismo e suas peculiaridades durante a gestação: uma revisão crítica. J Bras Pneumol 2004; 30:176-85.. Eles podem ser usados antes de a paciente engravidar. Por esse motivo, destaca-se a importância do aconselhamento pré-concepcional.

Uma revisão sistemática prévia também mostrou associação entre fumo materno na gestação e malformações congênitas em crianças55. Hackshaw A, Rodeck C, Boniface S. Maternal smoking in pregnancy and birth defects: a systematic review based on 173687 malformed cases and 11.7 million controls. Hum Reprod Updat 2011; 17:589-604.. Comparado com aquela revisão, a presente revisão incluiu 20 estudos adicionais66. Bird TM, Robbins JM, Druschel C, Cleves MA, Yang S, Hobbs CA. Demographic and environmental risk factors for gastroschisis and omphalocele in the National Birth Defects Prevention Study. J Pediatr Surg 2009; 44:1546-51. , 77. Bracken MB, Holford TR, White C, Kelsey JL. Role of oral contraception in congenital malformations of offspring. Int J Epidemiol 1978; 7:309-17. , 88. Cedergren MI, Selbing AJ, Källén BAJ. Risk factors for cardiovascular malformation - a study based on prospectively collected data. Scan J Work Environ Health 2002; 28:12-7. , 99. Christensen K, Olsen J, Norgaard-Pedersen B, Basso O, Stovring H, Milhollin-Johnson L, et al. Oral clefts, transforming growth factor alpha gene variants, and maternal smoking: a population-based case-control study in Denmark, 1991-1994. Am J Epidemiol 1999; 149:248-55. , 1010. DeRoo LA, Gaudino JA, Edmonds LD. Orofacial cleft malformations: associations with maternal and infant characteristics in Washington state. Birth Defects Res A Clin Mol Teratol 2003; 67: 637-42. , 1111. Dickinson KC, Meyer RE, Kotch J. Maternal smoking and the risk for clubfoot in infants. Birth Defects Res A Clin Mol Teratol 2008; 82:86-91. , 1212. Feldkamp ML, Alder SC, Carey JC. A case control population-based study investigating smoking as a risk factor for gastroschisis in Utah, 1997-2005. Birth Defects Res A Clin Mol Teratol 2008; 82: 768-75. , 1313. Ramirez D, Lammer EJ, Iovannisci DM, Laurent C, Finnell RH, Shaw GM. Maternal smoking during early pregnancy, GSTP1 and EPHX1 variants, and risk of isolated orofacial clefts. Cleft Palate Craniofac J 2007; 44:366-73. , 1414. Williams LJ, Correa A, Rasmussen S. Maternal lifestyle factors and risk for ventricular septal defects. Birth Defects Res A Clin Mol Teratol 2004; 70:59-64. , 2424. Bailey RR. The effect of maternal smoking on the infant birth weight. N Z Med J 1970; 71:293-4. , 4343. Carmichael SL, Shaw GM, Laurent C, Lammer EJ, Olney RS. Hypospadias and maternal exposures to cigarette smoke. Pediatr Perinat Epidemiol 2005; 19:406-12. , 7979. Hobbs CA, James SJ, Jernigan S, Melnyk S, Lu Y, Malik S, et al. Congenital heart defects, maternal homocysteine smoking, and the 677 C>T polymorphism in the methylenetetrahydroflate reductase gene: evaluating gene-environment interactions. Am J Obstet Gynecol 2006; 194:218-24. , 8383. Honein MA, Rasmussen SA, Reefhuis J, Romitti PA, Lammer EJ, Sun L, et al. Maternal smoking and environmental tobacco smoke exposure and the risk of orofacial clefts. Epidemiology 2007; 18:226-33. , 9595. Kuciene R, Dulskiene V. Maternal socioeconomic and lifestyle factors during pregnancy and the risk of congenital heart defects. Medicina (Kaunas) 2009; 45:904-9. , 9999. Lam PK, Torfs CP. Interaction between maternal smoking and malnutrition in infant risk of gastroschisis. Birth Defects Res A Clin Mol Teratol 2006; 76:182-6. , 102102. Li Z, Ren A, Zhang L, Guo Z, Li Z. A population-based case-control study of risk factors for neural tube defects in four high-prevalence areas of Shanxi province, China. Paediatr Perinat Epidemiol 2006; 20:43-53. , 103103. Lie RT, Wilcox AJ, Taylor J, Gjessing HK, Saugstad OD, Aabyholm F, et al. Maternal smoking and oral clefts. Epidemiology 2008; 19:606-15. , 122122. Miller EA, Rasmussen SA, Siega-Riz AM, Frías JL, Honein MA. Risk factors for non-syndromic holoprosencephaly in the national birth defects prevention study. Am J Med Genet C Semin Med Genet 2010; 154C:62-72. , 125125. Morgana LM, Cohn BA, Cohen RD, Christianson RE. Maternal smoking, alcohol consumption, and caffeine consumption during pregnancy in relation to a son's risk of persistent cryptorchidism: a prospective study in the Child Health and Development Studies Cohort, 1959-1967. Am J Epidemiol 2008; 167:257-61. , 188188. Werler MM, Bosco JLF, Shapira SK. Maternal vasoactive exposures, amniotic bands, and terminal transverse limb defects. Birth Defects Res A Clin Mol Teratol 2009; 85:52-7. com um acréscimo aproximadamente de 10 mil casos de malformações e 800 mil de controles. Outra diferença entre duas revisões foi que 19 estudos sobre defeitos da parede abdominal foram incluídos na meta-análise do sistema gastrointestinal na revisão prévia, enquanto esses defeitos foram classificados como malformações do sistema musculoesquelético pela presente revisão. Apesar dessas diferenças metodológicas, as duas revisões apresentaram resultados semelhantes quanto à associação entre fumo materno na gestação e malformações dos sistemas cardiovascular, respiratório, digestivo, nervoso, urogenital e musculoesquelético. A revisão prévia realizou uma meta-análise com 38 estudos nos quais todas as malformações foram combinadas e não mostrou associação significativa entre fumo materno e malformações congênitas (OR: 1,01; IC95%: 0,96-1,07). A meta-análise da presente revisão incluiu todos os 188 estudos, tanto com malformações combinadas juntos quanto com um determinado tipo de malformação, demonstrando uma associação estatisticamente significativa entre fumo materno na gestação e risco de ter algum tipo de malformação congênita em crianças (OR: 1,18; IC95%: 1,14-1,22).

A meta-análise cumulativa da presente revisão mostra que já havia evidência da associação entre fumo materno na gestação e malformações congênitas em crianças, analisando os resultados de 40 estudos publicados até 1990 com um total de 26.827 casos de malformações (OR = 1,09; p = 0,035). A evidência da associação se tornou mais robusta com resultados de 87 estudos publicados até 2000 com um total de 95.556 casos (OR = 1,16; p < 0,0001). Entre 2000 e 2010, mais de 100 estudos foram realizados envolvendo aproximadamente 100 mil casos de malformações; no entanto a inclusão desses estudos não alterou substancialmente os resultados da meta-análise. Esses dados indicam que as evidências sobre associação entre fumo materno na gestação e malformações congênitas em crianças são convincentes e não haja necessidade de mais estudos epidemiológicos para investigar a associação.

Alguns aspectos metodológicos devem ser considerados na interpretação dos resultados desta revisão sistemática. A heterogeneidade entre os resultados dos estudos incluídos nesta revisão é esperada, tendo em vista as diferenças em relação ao delineamento da pesquisa, ao tipo de malformação e método utilizado para o diagnóstico, à definição do fumo materno e ao controle de efeito dos fatores de confusão. Alguns desses fatores foram investigados mediante análises de subgrupos, cujos resultados sugerem que o tipo de malformação, o delineamento da pesquisa e o tamanho da amostra atuam como possíveis causas da heterogeneidade. A qualidade dos estudos incluídos não foi avaliada individualmente por causa das limitações dos instrumentos atualmente disponíveis 206206. Sanderson S, Iain D, Tatt ID, Higgins JPT. Tools for assessing quality and susceptibility to bias in observational studies in epidemiology: a systematic review and annotated bibliography. Int J Epidemiol 2007; 36:666-76., porém as potenciais influências dos aspectos metodológicos dos estudos (delineamento da pesquisa, tamanho da amostra, controle de efeito dos fatores de confusão e definição da exposição) nos resultados da meta-análise foram investigadas pela análise de subgrupos. A influência do fumo passivo na associação entre fumo materno na gestação e malformações congênitas em crianças não foi investigada devido à falta de informações na maioria dos estudos originais. Estudos futuros devem abordar essa questão. O gráfico de funil e o teste de Egger sugerem a presença do viés de publicação em razão da não publicação dos estudos pequenos que demonstram efeito protetor do fumo materno contra malformações em crianças. Acreditamos que o número desse tipo de estudos é limitado e a ausência de dados desses estudos não afeta significativamente os resultados da meta-análise.

Com esta revisão sistemática com meta-análise, evidencia-se que fumo materno na gestação está associado com maior risco de malformações congênitas em crianças e essa associação é dose-dependente.

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Datas de Publicação

  • Publicação nesta coleção
    Dez 2014

Histórico

  • Recebido
    15 Jun 2013
  • Revisado
    30 Jun 2014
  • Aceito
    18 Ago 2014
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