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Observations on congenital heart disease in a mortality study of children with cleft lip and palate
J Cbroa
Dls 1971, Vol. 24, pp. 39-43. Pergamon Press. Printed in Great Britain
OBSERVATIONS ON CONGENITAL HEART DISEASE IN A MORTALITY STUDY OF CHILDREN WITH CLEFT LIP AND PALATE MURIEL MACKEPRANG, M.A.
and SYLVIA HAY, B.A.
Congenital Anomalies Section, Epidemiology Branch, Dental Health Center, Division of Dental Health, Bureau of Health Professions, Education and Manpower Training, National Institutes of Health, Public Health Service, U.S. Department of Health, Education and Welfare, San Francisco, California, U.S.A. (Received
14 September
1970)
THE ASSOCIATIONof
congenital heart disease with cleft lip and palate is difficult to ascertain at birth, when the heart disease is often not yet evident. A mortality study provides a unique opportunity to obtain a conservative measure of this association. MATERIALS
AND
METHODS
In order to explore the relationships of clefts and congenital heart disease, birth and death certificates collected by the Dental Health Center, through its National Cleft Lip and Palate Intelligence Service, were utilized. A total of 12,572 birth certificates registered in 28 states and 2 cities from 1956 through 1965 reported the presence of a cleft lip or palate. The registers at each area of birth were searched through 1966 for deaths occurring to these children; 1840 death certificates were identified from the search, and these certificates were copied for our use. The numbers of births and deaths in this study are shown by type of cleft in Table 1. TABLE
1.
BIRTHS AND DEATHS BY REPORTEDATBIRTH
Type of cleft Isolated cleft Cleft lip and Isolated cleft Pierre Robin Bifid uvula Total
lip palate palate syndrome
TYPE
OF
CLEFT
No.
No.
of births
of deaths
3378 5328 3646 201 19
239 800 740 59 2
12,572
1840
The certificates were classified according to diagnosis at birth. In addition to the cases reported as Pierre Robin syndrome, a number of cleft palate cases with micrognathia and glossoptosis as associated malformations were reclassified as“PierreRobin syndrome” and were removed from the isolated cleft palate category. 39
MURIEL MACKEPRANGand SYLVIA HAY
40
RESULTS
Cause of death was coded according to the Seventh Revision of the International Classification of Diseases. Table 2 shows the distribution of deaths by cause of death. TABLE 2.
NUMBER OF DECEASED CHILDREN BORN WITH CLEFTS BY CAUSE OF DEATH
ICD No. (Seventh revision)
No.
Cause of death
750 751 752 753 754 755 756 757 758 759 760-773 774-776 490-493 alo-
All other
53 44 71
Monstrosity Spina bifida Congenital hydrocephalus Other congenital malformations of nervous system Congenital heart disease Cleft palate and harelip Congenital malformations of digestive system Congenital malformations of genito-urinary system Congenital malformations of bone and joint Other and unspecified congenital malformations Certain diseases of early infancy Immaturity Pneumonia Accidents All other
a4
347 129 45 22 22 325 329 114 73 27 155 1840
Total
There were 347 deaths, or 19 per cent of the total, attributed to congenital heart disease. Autopsy confirmed the diagnosis in 68 per cent of these cases. Reliance upon the stated underlying cause of death gives only part of the relationship between congenital heart disease and clefts of the lip and palate. Such causes of death as “cleft palate and harelip”, “unspecified congenital malformations”, or “immaturity” are examples of potential hiding places for defective hearts. To compensate in part for this problem, all references to heart malformations on the birth and death certificates were inspected. Both specified and unspecified types were included, but heart murmurs were not counted. In Table 3 it can be seen that heart malformaTABLE 3.
NUMBER OF HEART MALFORMATIONS REPORTED AMONG CHILDREN WITH CLEFTS BY SOURCE OF REPORT
DECEASED
Certificate reporting heart malformations
Type of cleft
Total
Death certificate only
Both death and birth certificate
Birth certificate only
Cleft lip ClefL lip and palate Cleft palate Pierre Robin syndrome Bifid uvula
66 205 209 10 2
46 136 131 9 1
13 49 55 1
7 20 23 1 -
Total deaths with congenital heart disease
492
323 ___ 441
118
51 ___ 169
Observationson CongenitalHeart Disease
41
tions were mentioned on the birth certificates of 169 of the 1840 infants who died, with 51 of the reports appearing only on birth certificates and not on death certificates. In addition to the 118 children whose heart defects were noted on both documents, death certificates disclosed 323 congenitally malformed hearts that were not reported on birth certificates. Using information on both birth and death certificates, it was found that 492, or 27 per cent of all the decedents born with a cleft, had associated congenital heart disease. Table 4 shows, according to type of cleft reported at birth, the rates for all deaths TABLE
4.
TOTALDEATHSAND
DEATHSWTHMENTI~NOFC~NG~~N~TALHEARTDISEASE OFCLEFTREPORTED ATBIRTH
BYSEX AND rym
-
Total deaths
Deaths with congenital heart disease
Type of cleft
No. of births
No.
Rate*
No.
Rate*
Total Isolated cleft lip Cleft lip and palate Isolated cleft palate
3378 5328 3646
239 800 740
70.8 150.1 203.0
66 205 209
19.5 38.5 57.3
201 19
59 2
293.5 ---t
10 2
49.7 --‘i
2073 3509 1761 95 11
128 473 372 30 1
61.7 134.8 211.2 315.8 --t
36 114 91 5
17.4 32.5 51.7 52.6
1305 1819 1885 106 8
111 323 366 29 1
85.1 177.6 194.2 273.6 --t
30 91 117 5 1
Pierre Robin syndrome Bifid uvula Male Isolated cleft Cleft lip and Isolated cleft Pierre Robin Bifid uvula
lip palate palate syndrome
Female Isolated cleft Cleft lip and Isolated cleft Pierre Robin Bifid uvula
lip palate palate syndrome
1
--t 23.0 50.0 62.1 47.2 --t
*Rate per 1000 births. tRates not calculated for small numbers.
those with associated heart disease. Children born with isolated cleft palate or Pierre Robin syndrome had higher death rates than children born with isolated cleft lip or combined cleft lip and palate. The lowest death rate, 70.8, is evident for children born with isolated cleft lip. The deceased children born with isolated cleft palate or Pierre Robin syndrome were more likely to have heart malformations than were children born with isolated cleft lip or combined cleft lip and palate. Because of their small number, the 19 children who were reported to have bifid uvula at birth are shown without rate calculations. This condition is subject to gross underreporting. Meskin, Gorlin, and Isaacson [l] reported a prevalence of ab out one in 70 individuals. If, as they suggest, a cleft uvula is a minor manifestation of cleft palate, it is interesting that the two deaths of infants born with bifid uvula were both due to congenital heart disease. A number of investigators have observed that more severe manifestations of clefts are found in females than in males [2-51. It might be expected, then, that a higher rate and for
42
MURIEL MACKEPRANCIand SYLVIA HAY
of deaths in females than in males would be observed in this study and probably a higher association with heart disease in females as well. Table 4 shows that total death rates were higher for females than for males when cleft lip, with or without cleft palate, was present, whereas Pierre Robin syndrome and isolated cleft palate presented total death rates that were slightly higher for males. Females who died showed higher rates for associated heart malformations than males in all categories except Pierre Robin syndrome. Observations for Pierre Robin syndrome, however, are limited by small numbers. Incomplete and inaccurate reporting could be significant factors when attempting to assess the effect of race in this type of study. Only 992 infants, 8 per cent of all births reported to have facial clefts, were born to non-white parents. Among the 1840 deaths were 196 decedents classified as non-white. The death rate for non-whites far exceeds the rate for all babies under study. However, the 41 deaths reported to have had heart defects among non-whites represents a rate only slightly higher than that for the total study population. The small numbers that would result from additional breakdown preclude investigating this variable further. Table 5 shows age at death for these deaths in which heart malformations were TABLE
5.
PERCENTAGE
hlALFORMATIONS WITH
CLEFTS
Age at death All ages Under 1 day l-6 days 7-28 days l-l 1 months 1 yr or more
AND
OF
DEATHS
WXH
OTHER
DEATHS
IN
ACCORDING
HEART
CHILDREN
TO AGE AT DEATH
Per cent with heart malformations
‘$9 3
Per cent of all other deaths 100 39 24) 73 10 21 6
present and for all other deaths. Although a greater percentage of children who did not have heart malformations died immediately after birth, the subsequent pattern of age at death indicates that there is little difference in the proportions of infants with clefts who died, with or without heart involvement, during the first year of life, or even within the first 28 days. COMMENT
At least a dozen well-known syndromes of malformations include clefts of the lip and palate and cardiac defects. The frequent association of heart disease with clefts may have etiological significance that a study of birth and death certificates cannot explore. Examination of clinical records may lead to more revealing associations between clefts and specific types of heart defects. Comparable studies of the association between congenital heart lesions and other malformations will be necessary to assess the uniqueness and significance of the associations observed with clefts. In a recent article Shah, Pruzansky, and Harris [6] also reported a high association between clefts and congenital heart disease. However, their study sample was small and consisted of autopsy and other records of deceased children with clefts and a
Observations
on Congenital Heart Disease
43
group of cleft lip and palate clinic patients, some of whom were already known to have congenital heart disease. An assessment of the actual concurrent incidence of clefts and heart defects could not be made from that sample. Neither could an accurate assessment be made in the present study which was limited to birth and death certificates. Research is needed in which a large well-defined population of births with clefts is carefully followed for a number of years to establish the actual incidence of various heart malformations in that population. SUMMARY
An analysis of data based upon 1840 deaths of children born with facial clefts showed a strong association of congenital heart disease with cleft lip and cleft palate. Nineteen per cent of all deaths in children born with facial clefts were due to congenital heart disease. A more illuminating association of heart disease and clefts was discovered by including all heart defects mentioned on birth and death certificates of infants born with cleft lip or palate no matter what the underlying cause of death. From this analysis it was found that heart malformations had been recorded on birth or death certificates of 27 per cent of the deceased children. Total death rates for children born with facial clefts ascended progressively from isolated cleft lip through combined cleft lip and palate, to isolated cleft palate and Pierre Robin syndrome. The association of heart defects followed the same general pattern. There was a higher total death rate for females than males for clefts involving the lip, and higher rates for males with isolated cleft palate and Pierre Robin syndrome. Females with all types of clefts except Pierre Robin syndrome had higher rates of deaths with associated congenital heart disease than males. REFERENCES I.
2. 3. 4. 5. 6.
Meskin LH, Gorlin RJ and Isaacson RJ: Abnormal morphology of the soft palate-I. The prevalence of cleft uvula. Cleft Palate J 1: 342, 1964 Fogh-Andersen P: Inheritance of harelip and cleft palate. Copenhagen: Nyt nordisk forlag, A. Busch, 1942 Rank BK and Thomson JA : Cleft lip and palate in Tasmania. Med J Aust 47 : 681,196O Knox G and Braithwaite F: Cleft lips and palates in Northumberland and Durham. Arch Dis Child 38: 66. 1963 Meskin LH, Pruzansky S and Gullen WH: An epidemiologic investigation of factors related to the extent of facial clefts--I. Sex of patient. Cleft Palate J 5: 23, 1968 Shah CV, Pruxansky S and Harris WS: Cardiac malformations with facial clefts. Amer J Dis Child 119: 238, 1970
Dls 1971, Vol. 24, pp. 39-43. Pergamon Press. Printed in Great Britain
OBSERVATIONS ON CONGENITAL HEART DISEASE IN A MORTALITY STUDY OF CHILDREN WITH CLEFT LIP AND PALATE MURIEL MACKEPRANG, M.A.
and SYLVIA HAY, B.A.
Congenital Anomalies Section, Epidemiology Branch, Dental Health Center, Division of Dental Health, Bureau of Health Professions, Education and Manpower Training, National Institutes of Health, Public Health Service, U.S. Department of Health, Education and Welfare, San Francisco, California, U.S.A. (Received
14 September
1970)
THE ASSOCIATIONof
congenital heart disease with cleft lip and palate is difficult to ascertain at birth, when the heart disease is often not yet evident. A mortality study provides a unique opportunity to obtain a conservative measure of this association. MATERIALS
AND
METHODS
In order to explore the relationships of clefts and congenital heart disease, birth and death certificates collected by the Dental Health Center, through its National Cleft Lip and Palate Intelligence Service, were utilized. A total of 12,572 birth certificates registered in 28 states and 2 cities from 1956 through 1965 reported the presence of a cleft lip or palate. The registers at each area of birth were searched through 1966 for deaths occurring to these children; 1840 death certificates were identified from the search, and these certificates were copied for our use. The numbers of births and deaths in this study are shown by type of cleft in Table 1. TABLE
1.
BIRTHS AND DEATHS BY REPORTEDATBIRTH
Type of cleft Isolated cleft Cleft lip and Isolated cleft Pierre Robin Bifid uvula Total
lip palate palate syndrome
TYPE
OF
CLEFT
No.
No.
of births
of deaths
3378 5328 3646 201 19
239 800 740 59 2
12,572
1840
The certificates were classified according to diagnosis at birth. In addition to the cases reported as Pierre Robin syndrome, a number of cleft palate cases with micrognathia and glossoptosis as associated malformations were reclassified as“PierreRobin syndrome” and were removed from the isolated cleft palate category. 39
MURIEL MACKEPRANGand SYLVIA HAY
40
RESULTS
Cause of death was coded according to the Seventh Revision of the International Classification of Diseases. Table 2 shows the distribution of deaths by cause of death. TABLE 2.
NUMBER OF DECEASED CHILDREN BORN WITH CLEFTS BY CAUSE OF DEATH
ICD No. (Seventh revision)
No.
Cause of death
750 751 752 753 754 755 756 757 758 759 760-773 774-776 490-493 alo-
All other
53 44 71
Monstrosity Spina bifida Congenital hydrocephalus Other congenital malformations of nervous system Congenital heart disease Cleft palate and harelip Congenital malformations of digestive system Congenital malformations of genito-urinary system Congenital malformations of bone and joint Other and unspecified congenital malformations Certain diseases of early infancy Immaturity Pneumonia Accidents All other
a4
347 129 45 22 22 325 329 114 73 27 155 1840
Total
There were 347 deaths, or 19 per cent of the total, attributed to congenital heart disease. Autopsy confirmed the diagnosis in 68 per cent of these cases. Reliance upon the stated underlying cause of death gives only part of the relationship between congenital heart disease and clefts of the lip and palate. Such causes of death as “cleft palate and harelip”, “unspecified congenital malformations”, or “immaturity” are examples of potential hiding places for defective hearts. To compensate in part for this problem, all references to heart malformations on the birth and death certificates were inspected. Both specified and unspecified types were included, but heart murmurs were not counted. In Table 3 it can be seen that heart malformaTABLE 3.
NUMBER OF HEART MALFORMATIONS REPORTED AMONG CHILDREN WITH CLEFTS BY SOURCE OF REPORT
DECEASED
Certificate reporting heart malformations
Type of cleft
Total
Death certificate only
Both death and birth certificate
Birth certificate only
Cleft lip ClefL lip and palate Cleft palate Pierre Robin syndrome Bifid uvula
66 205 209 10 2
46 136 131 9 1
13 49 55 1
7 20 23 1 -
Total deaths with congenital heart disease
492
323 ___ 441
118
51 ___ 169
Observationson CongenitalHeart Disease
41
tions were mentioned on the birth certificates of 169 of the 1840 infants who died, with 51 of the reports appearing only on birth certificates and not on death certificates. In addition to the 118 children whose heart defects were noted on both documents, death certificates disclosed 323 congenitally malformed hearts that were not reported on birth certificates. Using information on both birth and death certificates, it was found that 492, or 27 per cent of all the decedents born with a cleft, had associated congenital heart disease. Table 4 shows, according to type of cleft reported at birth, the rates for all deaths TABLE
4.
TOTALDEATHSAND
DEATHSWTHMENTI~NOFC~NG~~N~TALHEARTDISEASE OFCLEFTREPORTED ATBIRTH
BYSEX AND rym
-
Total deaths
Deaths with congenital heart disease
Type of cleft
No. of births
No.
Rate*
No.
Rate*
Total Isolated cleft lip Cleft lip and palate Isolated cleft palate
3378 5328 3646
239 800 740
70.8 150.1 203.0
66 205 209
19.5 38.5 57.3
201 19
59 2
293.5 ---t
10 2
49.7 --‘i
2073 3509 1761 95 11
128 473 372 30 1
61.7 134.8 211.2 315.8 --t
36 114 91 5
17.4 32.5 51.7 52.6
1305 1819 1885 106 8
111 323 366 29 1
85.1 177.6 194.2 273.6 --t
30 91 117 5 1
Pierre Robin syndrome Bifid uvula Male Isolated cleft Cleft lip and Isolated cleft Pierre Robin Bifid uvula
lip palate palate syndrome
Female Isolated cleft Cleft lip and Isolated cleft Pierre Robin Bifid uvula
lip palate palate syndrome
1
--t 23.0 50.0 62.1 47.2 --t
*Rate per 1000 births. tRates not calculated for small numbers.
those with associated heart disease. Children born with isolated cleft palate or Pierre Robin syndrome had higher death rates than children born with isolated cleft lip or combined cleft lip and palate. The lowest death rate, 70.8, is evident for children born with isolated cleft lip. The deceased children born with isolated cleft palate or Pierre Robin syndrome were more likely to have heart malformations than were children born with isolated cleft lip or combined cleft lip and palate. Because of their small number, the 19 children who were reported to have bifid uvula at birth are shown without rate calculations. This condition is subject to gross underreporting. Meskin, Gorlin, and Isaacson [l] reported a prevalence of ab out one in 70 individuals. If, as they suggest, a cleft uvula is a minor manifestation of cleft palate, it is interesting that the two deaths of infants born with bifid uvula were both due to congenital heart disease. A number of investigators have observed that more severe manifestations of clefts are found in females than in males [2-51. It might be expected, then, that a higher rate and for
42
MURIEL MACKEPRANCIand SYLVIA HAY
of deaths in females than in males would be observed in this study and probably a higher association with heart disease in females as well. Table 4 shows that total death rates were higher for females than for males when cleft lip, with or without cleft palate, was present, whereas Pierre Robin syndrome and isolated cleft palate presented total death rates that were slightly higher for males. Females who died showed higher rates for associated heart malformations than males in all categories except Pierre Robin syndrome. Observations for Pierre Robin syndrome, however, are limited by small numbers. Incomplete and inaccurate reporting could be significant factors when attempting to assess the effect of race in this type of study. Only 992 infants, 8 per cent of all births reported to have facial clefts, were born to non-white parents. Among the 1840 deaths were 196 decedents classified as non-white. The death rate for non-whites far exceeds the rate for all babies under study. However, the 41 deaths reported to have had heart defects among non-whites represents a rate only slightly higher than that for the total study population. The small numbers that would result from additional breakdown preclude investigating this variable further. Table 5 shows age at death for these deaths in which heart malformations were TABLE
5.
PERCENTAGE
hlALFORMATIONS WITH
CLEFTS
Age at death All ages Under 1 day l-6 days 7-28 days l-l 1 months 1 yr or more
AND
OF
DEATHS
WXH
OTHER
DEATHS
IN
ACCORDING
HEART
CHILDREN
TO AGE AT DEATH
Per cent with heart malformations
‘$9 3
Per cent of all other deaths 100 39 24) 73 10 21 6
present and for all other deaths. Although a greater percentage of children who did not have heart malformations died immediately after birth, the subsequent pattern of age at death indicates that there is little difference in the proportions of infants with clefts who died, with or without heart involvement, during the first year of life, or even within the first 28 days. COMMENT
At least a dozen well-known syndromes of malformations include clefts of the lip and palate and cardiac defects. The frequent association of heart disease with clefts may have etiological significance that a study of birth and death certificates cannot explore. Examination of clinical records may lead to more revealing associations between clefts and specific types of heart defects. Comparable studies of the association between congenital heart lesions and other malformations will be necessary to assess the uniqueness and significance of the associations observed with clefts. In a recent article Shah, Pruzansky, and Harris [6] also reported a high association between clefts and congenital heart disease. However, their study sample was small and consisted of autopsy and other records of deceased children with clefts and a
Observations
on Congenital Heart Disease
43
group of cleft lip and palate clinic patients, some of whom were already known to have congenital heart disease. An assessment of the actual concurrent incidence of clefts and heart defects could not be made from that sample. Neither could an accurate assessment be made in the present study which was limited to birth and death certificates. Research is needed in which a large well-defined population of births with clefts is carefully followed for a number of years to establish the actual incidence of various heart malformations in that population. SUMMARY
An analysis of data based upon 1840 deaths of children born with facial clefts showed a strong association of congenital heart disease with cleft lip and cleft palate. Nineteen per cent of all deaths in children born with facial clefts were due to congenital heart disease. A more illuminating association of heart disease and clefts was discovered by including all heart defects mentioned on birth and death certificates of infants born with cleft lip or palate no matter what the underlying cause of death. From this analysis it was found that heart malformations had been recorded on birth or death certificates of 27 per cent of the deceased children. Total death rates for children born with facial clefts ascended progressively from isolated cleft lip through combined cleft lip and palate, to isolated cleft palate and Pierre Robin syndrome. The association of heart defects followed the same general pattern. There was a higher total death rate for females than males for clefts involving the lip, and higher rates for males with isolated cleft palate and Pierre Robin syndrome. Females with all types of clefts except Pierre Robin syndrome had higher rates of deaths with associated congenital heart disease than males. REFERENCES I.
2. 3. 4. 5. 6.
Meskin LH, Gorlin RJ and Isaacson RJ: Abnormal morphology of the soft palate-I. The prevalence of cleft uvula. Cleft Palate J 1: 342, 1964 Fogh-Andersen P: Inheritance of harelip and cleft palate. Copenhagen: Nyt nordisk forlag, A. Busch, 1942 Rank BK and Thomson JA : Cleft lip and palate in Tasmania. Med J Aust 47 : 681,196O Knox G and Braithwaite F: Cleft lips and palates in Northumberland and Durham. Arch Dis Child 38: 66. 1963 Meskin LH, Pruzansky S and Gullen WH: An epidemiologic investigation of factors related to the extent of facial clefts--I. Sex of patient. Cleft Palate J 5: 23, 1968 Shah CV, Pruxansky S and Harris WS: Cardiac malformations with facial clefts. Amer J Dis Child 119: 238, 1970