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INFLUENZA EPIDEMIC AND CONGENITAL DEFECTS
1346
INFLUENZA EPIDEMIC AND CONGENITAL DEFECTS
JUKKA HAKOSALO LAURI SAXÉN
Department of Pathology, University of Oulu, and Third Department of Pathology, University of Helsinki, Finland A clear positive correlation has been shown between the 1957 Asian influenza epidemic in Finland and the incidence of malformations of the central nervous system. There was no increase of other congenital defects. During the sales of were much epidemic, drugs increased, and thus the infection as such may not necessarily be the
Sum ary
teratogenic factor. Introduction
INFLUENZA virus is often regarded as potentially teratogenic to the human embryo. 1,2 Yet even a cursory study of the literature reveals inconsistent data and differences of opinion. Influenza epidemics, especially those of "Asian ’flu", have presented excellent opportunities for testing whether correlations exist between the disease and congenital malformations, and there have been many positive reports. 3-8 On
the other hand, several careful studies have failed to show such correlations,9-13 and, correspondingly, immunological investigations with paired serumsamples have not revealed elevated antibody titres against the virus in mothers of defective children. 14, 15 An analysis of the consequences of the Asian influenza epidemic in Helsinki in 1957 suggested an increased incidence of congenital malformations among children who were in their 3rd to 9th week of development during the epidemic.16 This study has now been extended by a follow-up examination of the series. The 1957
Epidemic in Finland The first elevated antibody titres against influenza A2 virus were detected in Finland at the end of August, 1957, and the virus was isolated four weeks later." The
among adults in the district of Helsinki was be 32%,1’ and the estimate for pregnant The actual dates of the epidemic women was z were based on sickness-absenteeism figures for several
morbidity estimated
to
groups of
employees in Helsinki 18 (fig. 1).
Material Approximately two-thirds of the mothers in the district of Helsinki deliver at the women’s clinic of the University Central Hospital. Consequently, all mothers delivered there between Jan. 15 and Oct. 31, 1958, were included in this study. All infants who weighed over 600 g. at birth were thoroughly examined by a paediatrician, and a necropsy was performed on all stillborn children and on those who died during the neonatal period (148). The series consisted of 6147 infants. A re-examination in 1969-70 was made possible by the centralised medical care available in Finland. Children born in the Helsinki district will be taken to one of a few medical centres, where they can easily be traced (two children’s hospitals in the city of Helsinki, two institutions for mentally retarded children, and the special wards and outpatient clinics of the University Central Hospital). All clinical and necropsy records of these institutions were carefully reviewed, and check-up studies based on the files of the child-welfare centres TABLE I-NUMBER OF CHILDREN AND INCIDENCE OF CONGENITAL DEFECTS IN THE STUDY GROUP AND THE TWO CONTROL
(II)
GROUPS
(I
AND
III)
suggested that less than 5% of all malformations were lost in this study.19 A total of 3255 children (52-9%) belonging to the original series were traced for re-examination. In these patients all congenital malformations in the widest sense were recorded, but these were subsequently divided into two categories: certain defects not necessarily reflecting maldevelopment during the organogenetic period were excluded from the group of " congenital malformations "
in the more restricted sense. The defects excluded were the abdominal hernias, pyloric stenosis, talipes, dislocation of the hip, hydrocele testis, and cryptorchism. The final group of malformations is roughly comparable to the classification used in our previous study of these children. 16
Results
Fig. 1-Influenza epidemic in Helsinki, 1957, sickness absenteeism."
as
indicated by
The subjects could be divided into three groups in relation to the influenza epidemic and the " sensitive period " of development: those children whose mothers were in the sensitive stage of pregnancy during the epidemic (5th to llth week of gestation), those who were beyond this stage in October-November, 1957, and finally those conceived after the short epidemic. The sensitive period used here is, of course, rather arbitrary, but experimental data, experience of rubella epidemics, and theoretical calculations led us to limit the period of probable damage to the 3rd to 9th weeks of intrauterine development.
1347 TABLE II-INCIDENCE OF MALFORMATIONS OF THE CENTRAL NERVOUS SYSTEM, THE CIRCULATORY SYSTEM, AND THE UROGENITAL SYSTEM IN THE STUDY GROUP GROUPS (I AND III)
(II)
AND IN THE TWO CONTROL
anencephalic children in the study group adds one more suggestive finding to those already reported .4, 10,13,16 However, the suggested seasonal variashould be taken into consideration. Data compiled in our register of congenital malformations do not show such seasonal variations in Finland (1964-66) 22; and if there is any indication of an annual peak, this seems to be in February-March,23 and so would fall into our control We therefore believe that the correlation group. between the epidemic and the increased incidence of C.N.s. defects is biologically meaningful and calls for a further analysis of other series. Whatever the causal mechanism underlying this correlation, the expressivity of the teratogen(s) is low. If the 8 extra defects of the C.N.S. in the study group are viewed in relation to the 1600 mothers with a
tion of the
The distribution of the children with malformations in these three groups and the original findings of 1957 are shown in table 1. The significant difference between the study and control groups detected at birth disappeared in the follow-up study, in which all malformations were included. The 200 "true" malformations (3-25%) detected in the extended study were subsequently divided into categories of different organ systems, following the International Classification of Diseases. Most of the resulting subgroups became too small for any meaningful comparisons, but suggestive differences were found in two groups, malformations of the central nervous system (C.N.S.) and of the circulatory system. The X2 test showed that the difference in the incidence of C.N.S. defects between the study and control groups was significant at the 1 % level, whereas the increase in the defects of the circulatory system remains only
C.N.S.
defects
20,21
morbidity of 30%,
a teratogenic effect of about 2% be estimated. This low expressivity would explain why the effect has usually been overlooked. Another, and perhaps more plausible, explanation is that the teratogen is not the virus itself, but some agent contingent on the disease it causes, such as intense medication ; this will vary both quantitatively and qualitatively in different study populations. To see whether the epidemic had led to increased drug consumption in Helsinki, we examined the sales figures of the two largest pharmacists in the city (fig. 2). These figures showed a clear and significant peak during the 1957 epidemic. We conclude that the teratogen(s) responsible for the excess of c.N.s. defects correlated with the influenza epidemic may well be one of these drugs, although its identification, with our present knowledge and methods, seems a distant
can
goal. Requests for reprints should be addressed to L. S., Third Department of Pathology, University of Helsinki, SF-00290 Helsinki 29, Finland.
suggestive (table 11). Discussion
The results suggesting an increased risk of C.N.S. defects after an influenza epidemic corroborate the findings of Coffey and Jessop,3,4and the clustering of
REFERENCES 1. Sever, J., White, L. R. A. Rev. Med. 1968, 19, 471. 2. Saxén, L., Rapola, J. Congenital Defects. New York, 1969. 3. Coffey, V. P., Jessop, W. J. E. Lancet, 1959, ii, 935. 4. Coffey, V. P., Jessop, W. J. E. ibid. 1963, i, 748. 5. Pleydell, M. J. Br. med. J. 1960, i, 309. 6. Hardy M. B., Azerowicz, E. N., Mannini, A., Medearis, D. N., Cooke, R. E. Am. J. publ. Hlth, 1961, 51, 1182. 7. Leck, I., Hay, S., Witte, J. J., Greene, J. C. Publ. Hlth Rep., Wash. 1969, 84, 971. 8. Meindert, D. D., deGroot, J. W. Ned. Tijdschr. Geneesk. 1967, 111, 861. 9. Walker, W. M., McKee, A. P. Obstet. Gynec. 1959, 13, 394. 10. Doll, R., Hill, A. B., Sakula, J. Br. J. prev. soc. Med. 1960, 14, 167. 11. Hewitt, D. Am. J. publ. Hlth, 1962, 52, 1676. 12. Widelock, D., Csizmas, L., Klein, S. Publ. Hlth Rep., Wash. 1963,
78, 1.
Fig. 2-Sales figures of December, 1956-59.
two
pharmacists in Helsinki in July
The units of sales
to
13. Wilson, M. G., Stein, A. M. J. Am. med. Ass. 1969, 13, 336. 14. Evans, T. N., Brown, G. C. Am. J. Obstet. Gynec. 1963, 87, 749. 15. Korones, S. B., Todaro, J., Roane, J. A., Sever, J. L. J. Pediat. 1970, 77, 245. 16. Saxén, L., Hjelt, L., Sjöstedt, J. E., Hakosalo, J., Hakosalo, N. Acta path. microbiol. scand. 1960, 49, 114. 17. Ohela, K., Kaipainen, W. J. Ann. Med. int. Fenn. 1959, 48, 111. 18. Penttinen, K. Medisiinari, 1958, 2, 1. 19. Hakosalo, J. Acta path. microbiol. scand. (in the press). 20. McKeown, T., Record, R. G. Lancet, 1951, i, 192. 21. Edwards, J. H. Ann. hum. Genet. 1961, 25, 89. 22. Lapinleimu, K., Koskimies, O., Cantell, K., Saxén, L. Teratology 23.
are
104 Finnmarks.
(in the press). Klemetti, A., Saxén, L. Hlth Serv. Res. natn. Bd Hlth, Finland, 1970, 9, 1.
INFLUENZA EPIDEMIC AND CONGENITAL DEFECTS
JUKKA HAKOSALO LAURI SAXÉN
Department of Pathology, University of Oulu, and Third Department of Pathology, University of Helsinki, Finland A clear positive correlation has been shown between the 1957 Asian influenza epidemic in Finland and the incidence of malformations of the central nervous system. There was no increase of other congenital defects. During the sales of were much epidemic, drugs increased, and thus the infection as such may not necessarily be the
Sum ary
teratogenic factor. Introduction
INFLUENZA virus is often regarded as potentially teratogenic to the human embryo. 1,2 Yet even a cursory study of the literature reveals inconsistent data and differences of opinion. Influenza epidemics, especially those of "Asian ’flu", have presented excellent opportunities for testing whether correlations exist between the disease and congenital malformations, and there have been many positive reports. 3-8 On
the other hand, several careful studies have failed to show such correlations,9-13 and, correspondingly, immunological investigations with paired serumsamples have not revealed elevated antibody titres against the virus in mothers of defective children. 14, 15 An analysis of the consequences of the Asian influenza epidemic in Helsinki in 1957 suggested an increased incidence of congenital malformations among children who were in their 3rd to 9th week of development during the epidemic.16 This study has now been extended by a follow-up examination of the series. The 1957
Epidemic in Finland The first elevated antibody titres against influenza A2 virus were detected in Finland at the end of August, 1957, and the virus was isolated four weeks later." The
among adults in the district of Helsinki was be 32%,1’ and the estimate for pregnant The actual dates of the epidemic women was z were based on sickness-absenteeism figures for several
morbidity estimated
to
groups of
employees in Helsinki 18 (fig. 1).
Material Approximately two-thirds of the mothers in the district of Helsinki deliver at the women’s clinic of the University Central Hospital. Consequently, all mothers delivered there between Jan. 15 and Oct. 31, 1958, were included in this study. All infants who weighed over 600 g. at birth were thoroughly examined by a paediatrician, and a necropsy was performed on all stillborn children and on those who died during the neonatal period (148). The series consisted of 6147 infants. A re-examination in 1969-70 was made possible by the centralised medical care available in Finland. Children born in the Helsinki district will be taken to one of a few medical centres, where they can easily be traced (two children’s hospitals in the city of Helsinki, two institutions for mentally retarded children, and the special wards and outpatient clinics of the University Central Hospital). All clinical and necropsy records of these institutions were carefully reviewed, and check-up studies based on the files of the child-welfare centres TABLE I-NUMBER OF CHILDREN AND INCIDENCE OF CONGENITAL DEFECTS IN THE STUDY GROUP AND THE TWO CONTROL
(II)
GROUPS
(I
AND
III)
suggested that less than 5% of all malformations were lost in this study.19 A total of 3255 children (52-9%) belonging to the original series were traced for re-examination. In these patients all congenital malformations in the widest sense were recorded, but these were subsequently divided into two categories: certain defects not necessarily reflecting maldevelopment during the organogenetic period were excluded from the group of " congenital malformations "
in the more restricted sense. The defects excluded were the abdominal hernias, pyloric stenosis, talipes, dislocation of the hip, hydrocele testis, and cryptorchism. The final group of malformations is roughly comparable to the classification used in our previous study of these children. 16
Results
Fig. 1-Influenza epidemic in Helsinki, 1957, sickness absenteeism."
as
indicated by
The subjects could be divided into three groups in relation to the influenza epidemic and the " sensitive period " of development: those children whose mothers were in the sensitive stage of pregnancy during the epidemic (5th to llth week of gestation), those who were beyond this stage in October-November, 1957, and finally those conceived after the short epidemic. The sensitive period used here is, of course, rather arbitrary, but experimental data, experience of rubella epidemics, and theoretical calculations led us to limit the period of probable damage to the 3rd to 9th weeks of intrauterine development.
1347 TABLE II-INCIDENCE OF MALFORMATIONS OF THE CENTRAL NERVOUS SYSTEM, THE CIRCULATORY SYSTEM, AND THE UROGENITAL SYSTEM IN THE STUDY GROUP GROUPS (I AND III)
(II)
AND IN THE TWO CONTROL
anencephalic children in the study group adds one more suggestive finding to those already reported .4, 10,13,16 However, the suggested seasonal variashould be taken into consideration. Data compiled in our register of congenital malformations do not show such seasonal variations in Finland (1964-66) 22; and if there is any indication of an annual peak, this seems to be in February-March,23 and so would fall into our control We therefore believe that the correlation group. between the epidemic and the increased incidence of C.N.s. defects is biologically meaningful and calls for a further analysis of other series. Whatever the causal mechanism underlying this correlation, the expressivity of the teratogen(s) is low. If the 8 extra defects of the C.N.S. in the study group are viewed in relation to the 1600 mothers with a
tion of the
The distribution of the children with malformations in these three groups and the original findings of 1957 are shown in table 1. The significant difference between the study and control groups detected at birth disappeared in the follow-up study, in which all malformations were included. The 200 "true" malformations (3-25%) detected in the extended study were subsequently divided into categories of different organ systems, following the International Classification of Diseases. Most of the resulting subgroups became too small for any meaningful comparisons, but suggestive differences were found in two groups, malformations of the central nervous system (C.N.S.) and of the circulatory system. The X2 test showed that the difference in the incidence of C.N.S. defects between the study and control groups was significant at the 1 % level, whereas the increase in the defects of the circulatory system remains only
C.N.S.
defects
20,21
morbidity of 30%,
a teratogenic effect of about 2% be estimated. This low expressivity would explain why the effect has usually been overlooked. Another, and perhaps more plausible, explanation is that the teratogen is not the virus itself, but some agent contingent on the disease it causes, such as intense medication ; this will vary both quantitatively and qualitatively in different study populations. To see whether the epidemic had led to increased drug consumption in Helsinki, we examined the sales figures of the two largest pharmacists in the city (fig. 2). These figures showed a clear and significant peak during the 1957 epidemic. We conclude that the teratogen(s) responsible for the excess of c.N.s. defects correlated with the influenza epidemic may well be one of these drugs, although its identification, with our present knowledge and methods, seems a distant
can
goal. Requests for reprints should be addressed to L. S., Third Department of Pathology, University of Helsinki, SF-00290 Helsinki 29, Finland.
suggestive (table 11). Discussion
The results suggesting an increased risk of C.N.S. defects after an influenza epidemic corroborate the findings of Coffey and Jessop,3,4and the clustering of
REFERENCES 1. Sever, J., White, L. R. A. Rev. Med. 1968, 19, 471. 2. Saxén, L., Rapola, J. Congenital Defects. New York, 1969. 3. Coffey, V. P., Jessop, W. J. E. Lancet, 1959, ii, 935. 4. Coffey, V. P., Jessop, W. J. E. ibid. 1963, i, 748. 5. Pleydell, M. J. Br. med. J. 1960, i, 309. 6. Hardy M. B., Azerowicz, E. N., Mannini, A., Medearis, D. N., Cooke, R. E. Am. J. publ. Hlth, 1961, 51, 1182. 7. Leck, I., Hay, S., Witte, J. J., Greene, J. C. Publ. Hlth Rep., Wash. 1969, 84, 971. 8. Meindert, D. D., deGroot, J. W. Ned. Tijdschr. Geneesk. 1967, 111, 861. 9. Walker, W. M., McKee, A. P. Obstet. Gynec. 1959, 13, 394. 10. Doll, R., Hill, A. B., Sakula, J. Br. J. prev. soc. Med. 1960, 14, 167. 11. Hewitt, D. Am. J. publ. Hlth, 1962, 52, 1676. 12. Widelock, D., Csizmas, L., Klein, S. Publ. Hlth Rep., Wash. 1963,
78, 1.
Fig. 2-Sales figures of December, 1956-59.
two
pharmacists in Helsinki in July
The units of sales
to
13. Wilson, M. G., Stein, A. M. J. Am. med. Ass. 1969, 13, 336. 14. Evans, T. N., Brown, G. C. Am. J. Obstet. Gynec. 1963, 87, 749. 15. Korones, S. B., Todaro, J., Roane, J. A., Sever, J. L. J. Pediat. 1970, 77, 245. 16. Saxén, L., Hjelt, L., Sjöstedt, J. E., Hakosalo, J., Hakosalo, N. Acta path. microbiol. scand. 1960, 49, 114. 17. Ohela, K., Kaipainen, W. J. Ann. Med. int. Fenn. 1959, 48, 111. 18. Penttinen, K. Medisiinari, 1958, 2, 1. 19. Hakosalo, J. Acta path. microbiol. scand. (in the press). 20. McKeown, T., Record, R. G. Lancet, 1951, i, 192. 21. Edwards, J. H. Ann. hum. Genet. 1961, 25, 89. 22. Lapinleimu, K., Koskimies, O., Cantell, K., Saxén, L. Teratology 23.
are
104 Finnmarks.
(in the press). Klemetti, A., Saxén, L. Hlth Serv. Res. natn. Bd Hlth, Finland, 1970, 9, 1.