INTRODUCTION Congenital anomalies (CAs) represent one of the main cause of foetal death, infant mortality and morbidity, and long-term disability. CAs have been object of systematic registration activity for a long-time in many geographical areas in Europe and worldwide. CAs are often associated with disabilities of different types and severity, including the developed Countries worldwide. According to the World Health Organization (WHO), each year approximately 3,2 million of children worldwide are born with a CA and approximately 300,000 newborns with a diagnosis of birth defect die within the first 28 days of life. In Europe, CAs are the leading cause of perinatal mortality: the European Surveillance of Congenital Anomalies (EUROCAT) network estimated a perinatal mortality associated with CAs of 9.2 per 10,000 births in 2008-2012. In Italy, the Ministry of Health estimates that, on the average of 500,000 births each year, about 25,000 present at least one CA. Moreover, approximately 25% of infant mortality is due to CAs and about 50% of infant mortality is attributable to perinatal morbidity, almost always of prenatal origin. Regarding long-term survival, a recent population study conducted between 1985 and 2003 in the UK estimated a 20.5-year survival of 85.5% of children born with at least one CA. According to the Centre for Disease Control and Prevention, approximately 3.3% of live births in the United States have a severe birth defect. Since CAs represent a significant public health issue, an effective primary prevention strategy should be a priority for public policies and healthcare system. Regarding aetiology, although in many cases the cause is still unknown, it has been hypothesized that CAs may be developed during the first trimester of pregnancy as a result of hereditary polygenic defects or of a gene-environment interaction. The aetiology is predominantly multifactorial, caused by complex interactions between genes and environment, which modify the normal embryo-foetal development, especially during the organogenesis phase. In particular, environmental factors (e.g., chemical toxicants, infection agents, maternal disease, and exogenous factors) can have preconceptional mutagenic action, postconceptional teratogenic effects, periconceptional endocrine disruption or epigenetic action. Regarding genetic causes, there are geneticchromosomal aberrations or dysgeneses. Furthermore, socioeconomic factors affect reproductive health by differentiating the exposure to the other risk factors as well as the access to prevention measures. In recent years, the importance of the environment as a major factor of reproductive risk has been highlighted. An individual may be exposed to pollutants present in the workplace and the population may be exposed to multiple sources of environmental contamination of water, soil, and air matrices. Pregnant women and the developing foetus are particularly sensitive to the effects of environmental exposure. OBJECTIVE The aim of the present working paper is to produce an updated review of the epidemiological evidence on the risk of CAs associated with environmental exposures, socioeconomic, and main individual risk factors, such as cigarette smoking and alcohol consumption, according to the approach proposed by Pirastu et al. 2010 in the framework of the SENTIERI Project (the Italian Epidemiological Study of Residents in National Priority Contaminated Sites). DESIGN AND METHODS Literature search was carried out in PubMed, following the SENTIERI project criteria to evaluate evidence, by selecting articles in English or Italian language published from 2011 to 2016 regarding human studies. For this review, descriptive and analytical epidemiological studies (cohort, case-control, cross-sectional, and ecological), systematic reviews, and metanalyses reporting association estimates between the outcome and at least one of the risk factors were selected. As in Pirastu et al., the sources of environmental exposure have been classified into four macrocategories: industries, mines, landfills, and incinerators. The sources of individual exposure considered were: active and passive cigarette smoking, alcohol consumption, socioeconomic status (SES), occupational and environmental exposures related to air pollutants from vehicular traffic only. The obtained results were assessed according to the evaluation criteria on the epidemiological evidence related to the association between the outcome and exposures predefined and published by the SENTIERI working group (WG). For the evidence assessment, the SENTIERI WG criteria favoured firstly primary sources and quantitative metanalyses, secondly, consistency among sources. The evaluation of the epidemiological evidence for the association between outcome and the exposure has been classified into three categories: sufficient (S), limited (L), inadequate (I). RESULTS Industries: during the period under review, six single studies evaluating the association between industrial sites exposure and the risk of CAs were found. The epidemiological evidence of association between outcome and exposure has been considered limited. Mines: from the bibliographic research, three single studies investigating possible cause-effect relationship between maternal residential proximity to mines and the risk of CAs have been collected providing inadequate epidemiological evidence. Landfills: during the period under review, one systematic review and one literature review evaluating the causal associations between maternal residential proximity to landfills and CAs were identified. The epidemiological evidence is limited and concerns almost exclusively sites containing industrial or hazardous waste. Incinerators: a systematic review has been selected; it concludes that the evidence for the association between maternal residential proximity to incinerators and CAs are inadequate. Cigarette smoking: the literature search identified eight systematic reviews with metanalysis, five multicentre studies, and ten single studies assessing the causal association between maternal and/or paternal exposure to smoking and the risk of CAs in the offspring providing sufficient evidence for a causal association between maternal exposure to cigarette smoke and the risk of congenital heart defects, oro-facial clefts, neural tube defects, and gastrointestinal malformations. Alcohol: three systematic reviews with metanalysis, two metanalyses, one multicentre study, and four single studies were collected for the period under review. The acquired literature has provided limited epidemiological evidence for associations between alcohol consumption and CAs in the nervous system, particularly for anencephaly and spina bifida. Socioeconomic status: the evidence of an association with socioeconomic factors was inadequate due to an insufficient number of studies selected during the period under consideration. Occupational exposure: the literature search collected one metanalysis, eight multicentre studies, and five single studies. The epidemiological evidence for associations between paternal occupational exposure to solvents and neural tube defects and between maternal pesticide exposure and gold-facial clefts were judged limited. Air pollution: two systematic reviews with metanalyses, two multicentre studies, and nine single studies were selected by literature search; the epidemiological evidence for a causal association between air pollutants exposure and the risk of CAs is still to be considered limited. CONCLUSIONS For future epidemiological studies, a better exposure assessment, using in particular more accurate spatial measurements or models, a standardized case definition, a larger sample and more accurate control of the recognized or presumed confounding variables are needed.
INTRODUZIONE Le anomalie congenite (AC) sono considerate tra le principali cause di mortalità neonatale e infantile, nonché tra le principali fonti di disabilità a lungo periodo. Le AC sono da lungo tempo oggetto di attività sistematica di registrazione in molte aree geografiche, in Europa e a livello internazionale. Queste patologie, oltre a essere associate molto spesso a disabilità di varia natura e gravità, sono responsabili di una quota considerevole di mortalità infantile anche nei Paesi sviluppati. Secondo l'organizzazione mondiale della sanità (OMS), le AC colpiscono nel mondo circa 3,2 milioni di nati per anno e circa 300.000 neonati affetti da AC muoiono ogni anno entro i primi 28 giorni di vita. In Europa, le AC rappresentano la principale causa di morte perinatale: il network europeo di sorveglianza delle anomalie congenite "European Surveillance of Congenital Anomalies" (EUROCAT) ha registrato una mortalità perinatale del 9,2 per 10.000 nati nel periodo 2008-2012. Il Ministero della salute stima che, in Italia, su 500.000 nati mediamente ogni anno, circa 25.000 presentino almeno un'AC. Sempre in Italia, circa il 25% della mortalità infantile è dovuta ad AC e circa il 50% a stati morbosi perinatali, quasi sempre di origine prenatale. Per quanto riguarda la sopravvivenza a lungo termine, un recente studio di popolazione condotto nel Regno Unito ha stimato una sopravvivenza a 20 anni dell'85,5% per i bambini nati con almeno una AC tra il 1985 e il 2003. Secondo il Centre for Disease Control and Prevention, approssimativamente il 3,3% dei nati vivi negli Stati Uniti ha un grave difetto congenito. Il costo sociale ed economico delle AC è, dunque, elevato e la loro prevenzione primaria rappresenta una priorità di sanità pubblica. Riguardo all'eziologia, si ipotizza che le AC possano essere originate durante il primo trimestre di gravidanza come risultato di difetti poligenici ereditari o di un'interazione gene-ambiente, ma in molti casi la causa è ancora sconosciuta. L'eziologia è prevalentemente multifattoriale, determinata da complesse interazioni tra geni e ambiente che alterano il corretto sviluppo embrio-fetale, soprattutto nella fase di organogenesi. In particolare, i fattori ambientali (sostanze chimiche, agenti infettivi, malattie della madre e altri fattori esogeni) possono avere azione mutagena preconcezionale, azione teratogena postconcezionale, azione d'interferenza endocrina e azione epigenetica. Per le cause genetiche, si tratta di aberrazioni genico-cromosomiche o di disgenesie. I fattori socioeconomici agiscono, invece, differenziando l'esposizione ai fattori di rischio e l'accesso alle misure di prevenzione. Negli ultimi anni e stata messa in evidenza l'importanza dell'ambiente come uno dei maggiori fattori di rischio riproduttivo. L'individuo può essere esposto a inquinanti presenti sul luogo di lavoro, ma la stessa popolazione locale può essere esposta a molteplici fonti di contaminazione attraverso le matrici ambientali acqua, suolo e aria. La donna in gravidanza e il feto in via di sviluppo sono particolarmente vulnerabili agli effetti delle aggressioni ambientali. OBIETTIVO Lo scopo principale di questo lavoro è di produrre una revisione aggiornata delle evidenze epidemiologiche sul rischio di AC associato alle esposizioni ambientali e ai fattori di rischio socioeconomici e individuali, quali il fumo di sigaretta e il consumo di alcol, in linea con il metodo utilizzato da Pirastu et al. 2010 nell'ambito del Progetto SENTIERI. DISEGNO E METODO La ricerca bibliografica è stata eseguita su PubMed selezionando gli articoli in inglese e in italiano di studi condotti sull'uomo e pubblicati nel periodo 2011-1016. Per la rassegna, sono stati selezionati sia gli articoli originali di studi descrittivi e analitici epidemiologici (di coorte, caso-controllo, trasversali ed ecologici) sia le revisioni sistematiche e le metanalisi che presentavano stime di associazione tra l'esito (AC) e almeno uno dei fattori di rischio considerati. Come in Pirastu et al., le fonti di esposizione ambientale sono state classificate in quattro macrocategorie: industrie, miniere, discariche e inceneritori. Le fonti di esposizione individuale considerate sono state: il fumo di sigaretta attivo e passivo, il consumo di alcol, lo stato socioeconomico (SES), le esposizioni occupazionali e ambientali riferite ai soli inquinanti atmosferici da traffico veicolare. I risultati ottenuti sono stati valutati secondo i criteri di valutazione sull'evidenza epidemiologica relativa all'associazione tra l'esito e le esposizioni stabiliti e pubblicati dal gruppo di lavoro SENTIERI. I criteri messi a punto dal gruppo di lavoro SENTIERI per la valutazione dell'evidenza epidemiologica privilegiano le fonti primarie e la metanalisi quantitativa e, in seconda istanza, la coerenza tra le fonti. L'evidenza epidemiologica relativa all'associazione tra esito ed esposizione è stata classificata in tre categorie: sufficiente (S), limitata (L) e inadeguata (I). RISULTATI Industrie: nel periodo in esame sono stati raccolti sei studi singoli che esaminano l'associazione tra esposizione a siti industriali e rischio di AC. L'evidenza epidemiologica relativa all'associazione tra esito ed esposizione è da considerarsi limitata. Miniere: dalla ricerca bibliografica sono stati raccolti tre studi singoli che valutano la possibile relazione causa-effetto tra la prossimità residenziale materna a miniere e l'insorgenza di AC, fornendo evidenze epidemiologiche inadeguate. Discariche: nel periodo in esame sono state individuate una revisione sistematica e una rassegna relative a studi che valutano le associazioni causali tra la prossimità residenziale materna a discariche e le AC. Le evidenze epidemiologiche risultano limitate e riguardano quasi esclusivamente siti contenenti rifiuti industriali o pericolosi. Inceneritori: è stata individuata una revisione sistematica che conclude che le evidenze relative all'associazione tra la prossimità residenziale materna a inceneritori e l'insorgenza di AC risultano inadeguate. Fumo: la ricerca bibliografica ha individuato otto revisioni sistematiche con metanalisi, cinque studi multicentrici e dieci studi singoli che hanno esaminato l'associazione causale tra l'esposizione materna e/o paterna al fumo e il rischio di AC nella prole fornendo evidenze sufficienti sulla presenza di un'associazione causale tra l'esposizione materna al fumo di sigaretta e il rischio di cardiopatie congenite, schisi oro-facciali, difetti del tubo neurale e malformazioni gastrointestinali. Alcol: nel periodo in esame sono state raccolte 3 revisioni sistematiche con metanalisi, due metanalisi, uno studio multicentrico e tre studi singoli. La letteratura esaminata fornisce evidenze epidemiologiche limitate di associazione tra il consumo di alcol e le AC del sistema nervoso, in particolare l'anencefalia e la spina bifida. Livello socioeconomico: le evidenze di associazione con i fattori socioeconomici risultano inadeguate a causa di un numero insufficiente di studi individuati nel periodo in esame. Esposizione occupazionale: la ricerca bibliografica ha selezionato una metanalisi, otto studi multicentrici e cinque studi singoli. Emergono evidenze epidemiologiche limitate di associazione tra l'esposizione occupazionale paterna a solventi e i difetti del tubo neurale e tra l'esposizione materna pesticidi e le schisi oro-facciali. Inquinamento atmosferico: in letteratura sono state selezionate due revisioni sistematiche con metanalisi, due studi multicentrici e nove studi singoli. Le evidenze epidemiologiche relative all'associazione tra l'esposizione a inquinanti atmosferici e il rischio di AC sono da considerarsi ancora limitate. CONCLUSIONI Per i futuri studi epidemiologici sono auspicabili migliori metodi di valutazione dell'esposizione, in particolare misure o modelli spaziali più accurati, una definizione standardizzata dei casi, un campione più ampio e un controllo più accurato dei fattori confondenti principali o presunti.
Environmental and individual exposure and the risk of congenital anomalies: a review of recent epidemiological evidence
GORINI, FRANCESCA;PIERINI, ANNA;BALDACCI, SILVIA;MINICHILLI, FABRIZIO;SANTORO, MICHELE;BIANCHI, FABRIZIO
2018
Abstract
INTRODUCTION Congenital anomalies (CAs) represent one of the main cause of foetal death, infant mortality and morbidity, and long-term disability. CAs have been object of systematic registration activity for a long-time in many geographical areas in Europe and worldwide. CAs are often associated with disabilities of different types and severity, including the developed Countries worldwide. According to the World Health Organization (WHO), each year approximately 3,2 million of children worldwide are born with a CA and approximately 300,000 newborns with a diagnosis of birth defect die within the first 28 days of life. In Europe, CAs are the leading cause of perinatal mortality: the European Surveillance of Congenital Anomalies (EUROCAT) network estimated a perinatal mortality associated with CAs of 9.2 per 10,000 births in 2008-2012. In Italy, the Ministry of Health estimates that, on the average of 500,000 births each year, about 25,000 present at least one CA. Moreover, approximately 25% of infant mortality is due to CAs and about 50% of infant mortality is attributable to perinatal morbidity, almost always of prenatal origin. Regarding long-term survival, a recent population study conducted between 1985 and 2003 in the UK estimated a 20.5-year survival of 85.5% of children born with at least one CA. According to the Centre for Disease Control and Prevention, approximately 3.3% of live births in the United States have a severe birth defect. Since CAs represent a significant public health issue, an effective primary prevention strategy should be a priority for public policies and healthcare system. Regarding aetiology, although in many cases the cause is still unknown, it has been hypothesized that CAs may be developed during the first trimester of pregnancy as a result of hereditary polygenic defects or of a gene-environment interaction. The aetiology is predominantly multifactorial, caused by complex interactions between genes and environment, which modify the normal embryo-foetal development, especially during the organogenesis phase. In particular, environmental factors (e.g., chemical toxicants, infection agents, maternal disease, and exogenous factors) can have preconceptional mutagenic action, postconceptional teratogenic effects, periconceptional endocrine disruption or epigenetic action. Regarding genetic causes, there are geneticchromosomal aberrations or dysgeneses. Furthermore, socioeconomic factors affect reproductive health by differentiating the exposure to the other risk factors as well as the access to prevention measures. In recent years, the importance of the environment as a major factor of reproductive risk has been highlighted. An individual may be exposed to pollutants present in the workplace and the population may be exposed to multiple sources of environmental contamination of water, soil, and air matrices. Pregnant women and the developing foetus are particularly sensitive to the effects of environmental exposure. OBJECTIVE The aim of the present working paper is to produce an updated review of the epidemiological evidence on the risk of CAs associated with environmental exposures, socioeconomic, and main individual risk factors, such as cigarette smoking and alcohol consumption, according to the approach proposed by Pirastu et al. 2010 in the framework of the SENTIERI Project (the Italian Epidemiological Study of Residents in National Priority Contaminated Sites). DESIGN AND METHODS Literature search was carried out in PubMed, following the SENTIERI project criteria to evaluate evidence, by selecting articles in English or Italian language published from 2011 to 2016 regarding human studies. For this review, descriptive and analytical epidemiological studies (cohort, case-control, cross-sectional, and ecological), systematic reviews, and metanalyses reporting association estimates between the outcome and at least one of the risk factors were selected. As in Pirastu et al., the sources of environmental exposure have been classified into four macrocategories: industries, mines, landfills, and incinerators. The sources of individual exposure considered were: active and passive cigarette smoking, alcohol consumption, socioeconomic status (SES), occupational and environmental exposures related to air pollutants from vehicular traffic only. The obtained results were assessed according to the evaluation criteria on the epidemiological evidence related to the association between the outcome and exposures predefined and published by the SENTIERI working group (WG). For the evidence assessment, the SENTIERI WG criteria favoured firstly primary sources and quantitative metanalyses, secondly, consistency among sources. The evaluation of the epidemiological evidence for the association between outcome and the exposure has been classified into three categories: sufficient (S), limited (L), inadequate (I). RESULTS Industries: during the period under review, six single studies evaluating the association between industrial sites exposure and the risk of CAs were found. The epidemiological evidence of association between outcome and exposure has been considered limited. Mines: from the bibliographic research, three single studies investigating possible cause-effect relationship between maternal residential proximity to mines and the risk of CAs have been collected providing inadequate epidemiological evidence. Landfills: during the period under review, one systematic review and one literature review evaluating the causal associations between maternal residential proximity to landfills and CAs were identified. The epidemiological evidence is limited and concerns almost exclusively sites containing industrial or hazardous waste. Incinerators: a systematic review has been selected; it concludes that the evidence for the association between maternal residential proximity to incinerators and CAs are inadequate. Cigarette smoking: the literature search identified eight systematic reviews with metanalysis, five multicentre studies, and ten single studies assessing the causal association between maternal and/or paternal exposure to smoking and the risk of CAs in the offspring providing sufficient evidence for a causal association between maternal exposure to cigarette smoke and the risk of congenital heart defects, oro-facial clefts, neural tube defects, and gastrointestinal malformations. Alcohol: three systematic reviews with metanalysis, two metanalyses, one multicentre study, and four single studies were collected for the period under review. The acquired literature has provided limited epidemiological evidence for associations between alcohol consumption and CAs in the nervous system, particularly for anencephaly and spina bifida. Socioeconomic status: the evidence of an association with socioeconomic factors was inadequate due to an insufficient number of studies selected during the period under consideration. Occupational exposure: the literature search collected one metanalysis, eight multicentre studies, and five single studies. The epidemiological evidence for associations between paternal occupational exposure to solvents and neural tube defects and between maternal pesticide exposure and gold-facial clefts were judged limited. Air pollution: two systematic reviews with metanalyses, two multicentre studies, and nine single studies were selected by literature search; the epidemiological evidence for a causal association between air pollutants exposure and the risk of CAs is still to be considered limited. CONCLUSIONS For future epidemiological studies, a better exposure assessment, using in particular more accurate spatial measurements or models, a standardized case definition, a larger sample and more accurate control of the recognized or presumed confounding variables are needed.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
