Long term follow up study of survival associated with cleft lip and palate at birth
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《英国医生杂志》
1 Center for the Prevention of Congenital Malformations, Institute of Public Health, University of Southern Denmark, DK-5000 Odense, Denmark, 2 National Institute of Public Health, DK-2100 Copenhagen, Denmark, 3 Odense University Hospital, Department of Pediatrics, DK-5000 Odense, Denmark, 4 University of Iowa, Department of Pediatrics, Iowa City, IA 52242, USA
Correspondence to: K Christensen kchristensen@health.sdu.dk
Abstract
We followed 5331 people with cleft lip and palate for a total of 170 421 person years. The expected number of deaths was 259, but 402 occurred: standardised mortality ratio 1.4 (95% confidence interval 1.3 to 1.6) for males and 1.8 (1.5 to 2.1) for females. The increased risk was almost constant for the three intervals of follow up: first year of life, 1-17 years, and 18-55 years (table 1).
Table 1 Overall mortality from 1943 to 1998 for 5331 Danish people born with cleft lip and palate between 1943 and 1987
Deaths from cancer (36 v 28 expected) and cardiovascular events (15 v 13 expected) were only marginally increased in people with cleft lip and palate. The risk of suicide, however, was significantly increased and of similar magnitude in both sexes (standardised mortality ratio 1.6). We found no increased risk for deaths due to accidents, which sometimes comprises "masked" suicides (table 2). Around half of overall deaths were attributed to "other causes." This category comprised mostly "cleft lip and palate" as the cause of death and mainly deaths within the first year of life. As cleft lip and palate is not lethal in itself, we traced 79 of the death certificates for information on the immediate cause of death. In 39% of cases it was prematurity, whereas pneumonia and bronchopneumonia accounted for 28% of deaths and postoperative complications for 10%. The remaining cases included asphyxia, aspiration, sepsis, and unknown cause. Other causes of death were mainly attributed to respiratory diseases, infectious diseases, and diseases of the central nervous system. All but diseases of the central nervous system showed moderately increased, but non-significant, standardised mortality ratios (range 1.2-1.6). Mortality due to diseases of the central nervous system, however, showed a significant increased risk for females (9 observed v 2.6 expected). Of the nine cases, six were due to epilepsy (1.2 expected, standardised mortality ratio 8.3, 1.7 to 14.2).
Table 2 Mortality from 1943 to 1998 for 5331 people born with cleft lip and palate between 1943 and 1987
We stratified the analysis for type of anomaly (cleft lip only, cleft lip and palate, cleft palate only). The cleft lip only group had only a slight and non-significant increased risk of mortality, whereas it was significant for the cleft lip and palate and cleft palate only groups (table 3).
Table 3 Overall mortality from 1943 to 1998 for 5331 people with cleft lip and palate born between 1943 and 1987 stratified for type of cleft lip and palate
Discussion
Children born with cleft lip and palate and no other known malformations seem to have an increased risk of mortality not only in the first year of life but throughout childhood and adulthood. One explanation could be that we included people with discrete malformations associated with cleft lip and palate. This is unlikely since more than 80% of our cases were described by a surgeon, who was a leading expert throughout the period of ascertainment.13 14
Adults with cleft lip and palate have an increased incidence of structural brain anomalies, including major differences in the sizes of the cerebrum and cerebellum associated with mild cognitive impairments.16 Such malformations, likely to be missed in routine examination, may predispose to seizures, which were observed as an increased cause of death in this study. These anomalies of the midline are more commonly associated with cleft palate than with cleft lip, and this observation is consistent with the higher risk of early mortality in patients with cleft palate than cleft lip only, as seen in this study. We also observed an increased risk of suicide in both sexes. The cause of suicide is complex, but recognition of potential risk factors affords opportunities for treatment and prevention in people born with birth defects.
The increased risk associated with all major causes of death suggests that the cause of excess mortality is complex and multi-factorial. We did not have information on birth weight and gestational age, and it is possible that such factors could have attenuated the excess mortality for people with cleft lip and palate.
We hypothesised an increased mortality due to cancer on the basis of reports of an increased occurrence of cleft lip and palate in children with leukaemia and an increased risk of cancer in parents of children with cleft lip and palate.8 17 We found only a marginally increased mortality due to cancer among people with cleft lip and palate compared with the general population. Thus our data do not support these previous observations.
Considerable attention is paid to the health of children born with congenital malformations or other disabilities, but this is concentrated on the first years of life. As more infants are surviving serious birth defects into adult life it will be increasingly important to understand the clinical course of these disorders to provide optimal preventive health care and to anticipate treatable causes of morbidity and mortality.
What is already known on this topic
Infants with cleft lip and palate have an increased risk of mortality in the first years of life
Cleft lip and palate may be associated with an increased risk of cancer
What this study adds
Cleft lip and palate is associated with an increased risk of mortality in infancy and up to age 55
The risk of mortality due to cancer is not substantially increased
The increased risk of mortality in people with cleft lip and palate was attributable to all major causes of death
Contributors: KC was responsible for the content, conception, and design of the study, data collection and interpretation, drafting of the manuscript, obtaining funding, administrative support, and supervision. He will act as guarantor for the paper. AMH was responsible for part of the content, for conception and design, interpretation of data, critical revision of the manuscript, and technical support. KJ was responsible for part of the content, analysis and interpretation of the data, critical revision of the manuscript, and statistical expertise. JCM was responsible for the clinical perspective of the content, for analysis and interpretation of the data, critical revision of the manuscript, and supervision.
Funding: The Center for the Prevention of Congenital Malformations is supported by a grant from the Egmont Foundation. The Danish Cleft Lip and Palate Database has received support from the National Institute of Dental and Craniofacial Research (grant No R01 DE 11948) and the Egmont Foundation.
Competing interests: None declared.
Ethical approval: The Danish Scientific-Ethical Committee (project Nos 90/251 and 95/32).
References
Stringer MD, Oldham KT, Mouriquand PDE, Howard ER. Pediatric surgery and urology: long term outcomes. London: WB Saunders, 1998.
Mackeprang M, Hay S. Cleft lip and palate mortality study. Cleft Palate J 1972;9: 51-63.
Hujoel PP, Bollen AM, Mueller BA. First-year mortality among infants with facial clefts. Cleft Palate Craniofac J 1992;29: 451-5.
Hunt GM, Oakeshott P. Outcome in people with open spina bifida at age 35: prospective community based cohort study. BMJ 2003;326: 1365-6.
Windham GC, Bjerkedal T, Langmark F. A population-based study of cancer incidence in twins and in children with congenital malformations or low birth weight, Norway, 1967-1980. Am J Epidemiol 1985;121: 49-56.
Mili F, Khoury MJ, Flanders WD, Greenberg RS. Risk of childhood cancer for infants with birth defects. I. A record-linkage study, Atlanta, Georgia, 1968-1988. Am J Epidemiol 1993;137: 629-38.
Mili F, Lynch CF, Khoury MJ, Flanders WD, Edmonds LD. Risk of childhood cancer for infants with birth defects. II. A record-linkage study, Iowa, 1983-1989. Am J Epidemiol 1993;137: 639-44.
Zhu JL, Basso O, Hasle H, Winther JF, Olsen JH, Olsen J. Do parents of children with congenital malformations have a higher cancer risk? A nationwide study in Denmark. Br J Cancer 2002;87: 524-8.
Ramstad T, Ottem E, Shaw WC. Psychosocial adjustment in Norwegian adults who had undergone standardised treatment of complete cleft lip and palate. II. Self-reported problems and concerns with appearance. Scand J Plast Reconstr Surg Hand Surg 1995;29: 329-36.
Christensen K, Mortensen PB. Facial clefting and psychiatric diseases: a follow-up of the Danish 1936-1987 facial cleft cohort. Cleft Palate Craniofac J 2002;39: 392-6.
Christensen K, Schmidt MM, Vaeth M, Olsen J. Absence of an environmental effect on the recurrence of facial-cleft defects. N Engl J Med 1995;333: 161-4.
Christensen K. The 20th century Danish facial cleft population—epidemiological and genetic-epidemiological studies. Cleft Palate Craniofac J 1999;36: 96-104.
Christensen K, Fogh-Andersen P. Etiologic subgroups in non-syndromic isolated cleft-palate—a genetic-epidemiologic study of 52 Danish birth cohorts. Clin Genetics 1994;46: 329-35.
Fogh-Andersen P. Inheritance of harelip and cleft palate. Copenhagen: Arnold Busck, 1942.
Juel K, Helweg-Larsen K. The Danish registers of causes of death. Dan Med Bull 1999;46: 354-7.
Nopoulos P. Structural brain anomalies in adult males with clefts of the lip and/or palate. Genet Med 2002;4: 1-9.
Zack M, Adami HO, Ericson A. Maternal and perinatal risk factors for childhood leukemia. Cancer Res 1991;51: 3696-701.(Kaare Christensen, profes)
Correspondence to: K Christensen kchristensen@health.sdu.dk
Abstract
We followed 5331 people with cleft lip and palate for a total of 170 421 person years. The expected number of deaths was 259, but 402 occurred: standardised mortality ratio 1.4 (95% confidence interval 1.3 to 1.6) for males and 1.8 (1.5 to 2.1) for females. The increased risk was almost constant for the three intervals of follow up: first year of life, 1-17 years, and 18-55 years (table 1).
Table 1 Overall mortality from 1943 to 1998 for 5331 Danish people born with cleft lip and palate between 1943 and 1987
Deaths from cancer (36 v 28 expected) and cardiovascular events (15 v 13 expected) were only marginally increased in people with cleft lip and palate. The risk of suicide, however, was significantly increased and of similar magnitude in both sexes (standardised mortality ratio 1.6). We found no increased risk for deaths due to accidents, which sometimes comprises "masked" suicides (table 2). Around half of overall deaths were attributed to "other causes." This category comprised mostly "cleft lip and palate" as the cause of death and mainly deaths within the first year of life. As cleft lip and palate is not lethal in itself, we traced 79 of the death certificates for information on the immediate cause of death. In 39% of cases it was prematurity, whereas pneumonia and bronchopneumonia accounted for 28% of deaths and postoperative complications for 10%. The remaining cases included asphyxia, aspiration, sepsis, and unknown cause. Other causes of death were mainly attributed to respiratory diseases, infectious diseases, and diseases of the central nervous system. All but diseases of the central nervous system showed moderately increased, but non-significant, standardised mortality ratios (range 1.2-1.6). Mortality due to diseases of the central nervous system, however, showed a significant increased risk for females (9 observed v 2.6 expected). Of the nine cases, six were due to epilepsy (1.2 expected, standardised mortality ratio 8.3, 1.7 to 14.2).
Table 2 Mortality from 1943 to 1998 for 5331 people born with cleft lip and palate between 1943 and 1987
We stratified the analysis for type of anomaly (cleft lip only, cleft lip and palate, cleft palate only). The cleft lip only group had only a slight and non-significant increased risk of mortality, whereas it was significant for the cleft lip and palate and cleft palate only groups (table 3).
Table 3 Overall mortality from 1943 to 1998 for 5331 people with cleft lip and palate born between 1943 and 1987 stratified for type of cleft lip and palate
Discussion
Children born with cleft lip and palate and no other known malformations seem to have an increased risk of mortality not only in the first year of life but throughout childhood and adulthood. One explanation could be that we included people with discrete malformations associated with cleft lip and palate. This is unlikely since more than 80% of our cases were described by a surgeon, who was a leading expert throughout the period of ascertainment.13 14
Adults with cleft lip and palate have an increased incidence of structural brain anomalies, including major differences in the sizes of the cerebrum and cerebellum associated with mild cognitive impairments.16 Such malformations, likely to be missed in routine examination, may predispose to seizures, which were observed as an increased cause of death in this study. These anomalies of the midline are more commonly associated with cleft palate than with cleft lip, and this observation is consistent with the higher risk of early mortality in patients with cleft palate than cleft lip only, as seen in this study. We also observed an increased risk of suicide in both sexes. The cause of suicide is complex, but recognition of potential risk factors affords opportunities for treatment and prevention in people born with birth defects.
The increased risk associated with all major causes of death suggests that the cause of excess mortality is complex and multi-factorial. We did not have information on birth weight and gestational age, and it is possible that such factors could have attenuated the excess mortality for people with cleft lip and palate.
We hypothesised an increased mortality due to cancer on the basis of reports of an increased occurrence of cleft lip and palate in children with leukaemia and an increased risk of cancer in parents of children with cleft lip and palate.8 17 We found only a marginally increased mortality due to cancer among people with cleft lip and palate compared with the general population. Thus our data do not support these previous observations.
Considerable attention is paid to the health of children born with congenital malformations or other disabilities, but this is concentrated on the first years of life. As more infants are surviving serious birth defects into adult life it will be increasingly important to understand the clinical course of these disorders to provide optimal preventive health care and to anticipate treatable causes of morbidity and mortality.
What is already known on this topic
Infants with cleft lip and palate have an increased risk of mortality in the first years of life
Cleft lip and palate may be associated with an increased risk of cancer
What this study adds
Cleft lip and palate is associated with an increased risk of mortality in infancy and up to age 55
The risk of mortality due to cancer is not substantially increased
The increased risk of mortality in people with cleft lip and palate was attributable to all major causes of death
Contributors: KC was responsible for the content, conception, and design of the study, data collection and interpretation, drafting of the manuscript, obtaining funding, administrative support, and supervision. He will act as guarantor for the paper. AMH was responsible for part of the content, for conception and design, interpretation of data, critical revision of the manuscript, and technical support. KJ was responsible for part of the content, analysis and interpretation of the data, critical revision of the manuscript, and statistical expertise. JCM was responsible for the clinical perspective of the content, for analysis and interpretation of the data, critical revision of the manuscript, and supervision.
Funding: The Center for the Prevention of Congenital Malformations is supported by a grant from the Egmont Foundation. The Danish Cleft Lip and Palate Database has received support from the National Institute of Dental and Craniofacial Research (grant No R01 DE 11948) and the Egmont Foundation.
Competing interests: None declared.
Ethical approval: The Danish Scientific-Ethical Committee (project Nos 90/251 and 95/32).
References
Stringer MD, Oldham KT, Mouriquand PDE, Howard ER. Pediatric surgery and urology: long term outcomes. London: WB Saunders, 1998.
Mackeprang M, Hay S. Cleft lip and palate mortality study. Cleft Palate J 1972;9: 51-63.
Hujoel PP, Bollen AM, Mueller BA. First-year mortality among infants with facial clefts. Cleft Palate Craniofac J 1992;29: 451-5.
Hunt GM, Oakeshott P. Outcome in people with open spina bifida at age 35: prospective community based cohort study. BMJ 2003;326: 1365-6.
Windham GC, Bjerkedal T, Langmark F. A population-based study of cancer incidence in twins and in children with congenital malformations or low birth weight, Norway, 1967-1980. Am J Epidemiol 1985;121: 49-56.
Mili F, Khoury MJ, Flanders WD, Greenberg RS. Risk of childhood cancer for infants with birth defects. I. A record-linkage study, Atlanta, Georgia, 1968-1988. Am J Epidemiol 1993;137: 629-38.
Mili F, Lynch CF, Khoury MJ, Flanders WD, Edmonds LD. Risk of childhood cancer for infants with birth defects. II. A record-linkage study, Iowa, 1983-1989. Am J Epidemiol 1993;137: 639-44.
Zhu JL, Basso O, Hasle H, Winther JF, Olsen JH, Olsen J. Do parents of children with congenital malformations have a higher cancer risk? A nationwide study in Denmark. Br J Cancer 2002;87: 524-8.
Ramstad T, Ottem E, Shaw WC. Psychosocial adjustment in Norwegian adults who had undergone standardised treatment of complete cleft lip and palate. II. Self-reported problems and concerns with appearance. Scand J Plast Reconstr Surg Hand Surg 1995;29: 329-36.
Christensen K, Mortensen PB. Facial clefting and psychiatric diseases: a follow-up of the Danish 1936-1987 facial cleft cohort. Cleft Palate Craniofac J 2002;39: 392-6.
Christensen K, Schmidt MM, Vaeth M, Olsen J. Absence of an environmental effect on the recurrence of facial-cleft defects. N Engl J Med 1995;333: 161-4.
Christensen K. The 20th century Danish facial cleft population—epidemiological and genetic-epidemiological studies. Cleft Palate Craniofac J 1999;36: 96-104.
Christensen K, Fogh-Andersen P. Etiologic subgroups in non-syndromic isolated cleft-palate—a genetic-epidemiologic study of 52 Danish birth cohorts. Clin Genetics 1994;46: 329-35.
Fogh-Andersen P. Inheritance of harelip and cleft palate. Copenhagen: Arnold Busck, 1942.
Juel K, Helweg-Larsen K. The Danish registers of causes of death. Dan Med Bull 1999;46: 354-7.
Nopoulos P. Structural brain anomalies in adult males with clefts of the lip and/or palate. Genet Med 2002;4: 1-9.
Zack M, Adami HO, Ericson A. Maternal and perinatal risk factors for childhood leukemia. Cancer Res 1991;51: 3696-701.(Kaare Christensen, profes)