PUBLIC HEALTH BRIEFS
to be infected with HBV in a county jail had markers for HDV, two with antigen and two with antibody.4 In the current study all participants were healthy at the time of screening, and the anti-delta positive results presumably represent past infection. Although one of the five cases of HBV in the outbreak that precipitated the screening/ vaccination program contained IgM anti-delta, specimens from persons in this program were not evaluated for the presence of HDV antigen or IgM anti-delta. Thus some acute HDV infections could have been missed. The proportion of specimens containing anti-delta (14/173, 8 percent) from inmates in this study, however, approximates the proportion of HDV antibody noted in inmates by the study by Jacobson, et al.4 As with HBV, IVDU was strongly associated with the presence of anti-delta; of the 14 inmates with markers for HDV, 12 (86 percent) gave a history of IVDU. Ponzetto, et al, previously reported that 10 percent of drug addicts participating in a Veterans Administration (VA) cooperative study had evidence of infection with HDV.13 Measures that protect against HBV infection, such as use of hepatitis B vaccine, are also effective in preventing HDV infection. Implementation of HBV preventive guidelines in corrections facilities should reduce the risk of HDV. ACKNOWLEDGMENTS We would like to thank Richard Hovestadt for technical assistance in processing and testing the specimens.
REFERENCES 1. Rizzetto M: The delta agent. Hepatology 1983; 3:729-737. 2. Caredda F, Rossi E, Monforte A, Zampini L, Re T, Meroni B, Moroni M: Hepatitis B virus-associated coinfection and superinfection with delta agent: Indistinguishable disease with different outcome. J Infect Dis 1985; 151:925-928. 3. Centers for Disease Control: Hepatitis Surveillance. Atlanta: CDC, 1985; 7-8. 4. Jacobson IM, Dienstag JL, Werner BG, Brettler DB, Levine PH, Mushahwar IK: Epidemiology and clinical impact of hepatitis D virus (delta) infection. Hepatology 1985; 5:188-191. 5. Decker MD, Vaughn WK, Brodie JS, Hutcheson RH, Schaffner W: Seroepidemiology of hepatitis B in Tennessee prisoners. J Infect Dis 1984; 150:450-459. 6. Koplan JP, Walker JA, Bryan JA: Prevalence of hepatitis B surface antigen and antibody at a state prison in Kansas. J Infect Dis 1978; 137:505-506. 7. Chiaramonte M, Trivello R, Renzulli G, Zampieri L, Fanecco A, Floreani A, Naccarato R: Hepatitis B virus infection in prisons: A seroepidemiological survey in prisoners and attending staff. J Hyg Camb 1982; 89:53-58. 8. Hull HF, Lyons LH, Mann JM, Hadler SC, Steece R, Skeels MR: Incidence of hepatitis B in the penitentiary of New Mexico. Am J Public Health 1985; 75:1213-1214. 9. Kaufman ML, Faiver KL, Harness JK: Hepatitis B markers among Michigan prisoners (letter). Ann Intern Med 1983; 98:558. 10. Anda RF, Perlman SB, D'Alessio DJ, Davis JP, Dodson VN: Hepatitis B in Wisconsin male prisoners: Considerations for serologic screening and vaccination. Am J Public Health 1985; 75:1182-1185. 11. Miettinen OS: Estimability and estimation in case-referent studies. Am J Epidemiol 1976; 103:226-235. 12. Gart J: The comparison of proportions: A review of signification. Rev Int Stat Instit 1971; 39:148-169. 13. Ponzetto A, Seeff LB, Buskell-Bales Z, Ishak KG, Hoofnagle JH, Zimmerman HJ, Purcell RH, Gerin JL, Veterans Administration Hepatitis Cooperative Study Group: Hepatitis B markers in United States drug addicts with special emphasis on the delta hepatitis virus. Hepatology 1984; 4:1111-1115.
Influenza Epidemics and Anencephaly LAURI SAXEN, MD, PHD, PETER C. HOLMBERG, MD, PHD, KARI KURPPA, MD, PHD, EEVA KUOSMA, MSC, AND REUO PYHALA, PHD Abstract: To explore the postulated association between maternal influenza and congenital defects of the central nervous system, 14 virologically verified epidemics in Finland, 1969-82, were studied. Mothers of 248 anencephalic children were grouped into those whose first trimester had occurred during an epidemic period and those whose pregnancy had commenced during a non-epidemic period. No significant differences in prevalence of anencephaly were noted in these groups. (Am J Public Health 1990; 80:473-475.)
Introduction
There is ample evidence that certain virus infections can be transmitted to the embryo during pregnancy and cause impaired fetal development expressed as congenital defects. ' Among these potential teratogens, influenza virus has been frequently mentioned, but evidence for or against such harmful effects has remained inconclusive.2,3 We have conducted a population study based on recorded influenza Address reprint requests to Lauri Saxen, MD, PhD, Professor of Experimental Pathology, Department of Pathology, University of Helsinki, Haartmaninkatu 3, SF-00290 Helsinki, Finland. Drs. Holmberg and Kurppa and Ms. Kuosma are with the Institute of Occupational Health, Helsinki; Dr. Pyhala is with the National Institute of Health, Helsinki. This paper, submitted to the Journal April 18, 1989, was revised and accepted for publication August 28, 1989. © 1990 American Journal of Public Health 0090-0036/90$1.50
AJPH April 1990, Vol. 80, No. 4
epidemics and one particular marker defect, anencephaly. This defect has several advantages for investigative purposes: its detection rate is high in stillbirths and in newborn infants, the diagnostic means have not changed during our 15-year-study period, notification rate of this severe defect is high, and finally, as it is a lethal condition, the reports to the Register of Congenital Malformations can be confirmed and completed from the compulsory death certificates. Moreover, defects of the central nervous system (CNS) have often been mentioned in the context of maternal influenza.2-6 Methods The material was collected from the files of the Finnish Register of Congenital Malformations operating since 19637,8 and completed with data from the death certificates obtained from the Central Statistical Bureau. These sources cover the entire population of 4.9 million; the present analysis includes all mothers whose last menstruation occurred between October 1, 1968 and March 31, 1982, comprising 858,917 deliveries. Altogether 248 cases of anencephaly were recorded in children weighing 600 g or over at birth. Of these, 201 cases were single defects and, in 47, additional malformations were reported. Influenza activity in the Finnish population has been monitored by the Central Public Health Laboratory since 1969 with virus isolation and serodiagnostics of acute respiratory infections. Our study covered 14 epidemic periods during which influenza etiology was confirmed. Excluding sporadic cases and small local outbreaks, the epidemic time A73
PUBLIC HEALTH BRIEFS TABLE 1-Occurrence of Influenza epidemics in Finland and serological infection percentages in samples of serum pairs from pregnant women.
Influenza A Number of serum pairs
Epidemic periods January 69-February 69 December 69-February 70 April 71-May 71 November 71-December 71 January 73-February 73 January 74-Apnl 74 January 75-March 75 January 76-March 76 March 77-April 77 January 78-March 78 January 79-April 79 January 80-February 80 January 81-March 81 February 82-June 82
(a)
137 91 106 144 397 636 651 549 576 674 291
H1Nl (%)
H3N2 (%)
-
(b)
1
(b)
3 -
10 1
Influenza B
27 20 23 17 15 14 8 3 25 2 1
(b) -
18 -
7 -
2 -
4 1
quencies among pregnant women in Finland.9 Serum pairs of pre-epidemic and post-epidemic specimens from a total of 4,252 women were studied for haemagglutination-inhibiting antibodies to influenza A and B viruses including the epidemic variant, and, for detection of anamnestic antibody response, the serotypes of the near past (Table 1). A fourfold or higher rise in antibody titers was considered indicative of serological influenza infection.9 For the occurrence of anencephaly in infants, mothers whose first trimester (14 weeks from the start of the mother's previous menstruation) had coincided wholly or in part with a virologically verified influenza epidemic (407,200 mothers) and mothers whose first trimester had occurred completely during a non-epidemic period (314,841 mothers) were compared after exclusion of the borderline months. Power calculations were performed according to Schlesselman.'0 The heterogeneity test was performed and confidence limits for rate ratio estimates were calculated as suggested by Miettinen.1" Trend analysis for the proportion of rates of anencephaly was performed according to Armitage.12
(a) The pairs consisted of pre-epidemic and postepidemic specimens (b) Epidemic activity recorded, but infection frequency among pregnant women not studied
Results was 37 months of the total 162 months monitored during the study period. To create a "non-epidemic" control material, the month preceding and following each epidemic was excluded because of timing uncertainties. Altogether, 26 such borderline months with 46 anencephalic children were thus excluded. Since the end of 1971, the influenza surveillance program has included annual monitoring of serological infection fre-
Epidemics caused by influenza A and B viruses, and serological infection frequencies in the follow-up samples of pregnant women are listed in Table 1. Figure 1 shows the rates of anencephaly when the first trimester had occurred during the influenza epidemics or during the non-epidemic periods. In the epidemic group, 117 anencephalics were reported and in the non-epidemic group, 85; prevalence 0.29 per mil and 0.27 per mil, respectively.
4-
Lo
m 0 0 0 a)
ILL w
z z w
EPIDEMICS VIRUS
A A 1969 -70
A A B A A,B A A,B A A,B A A,B A,B -71 -72 -73 -74 -75 -76 -77 -78 -79 -80 -81 -82 YEAR
FIGURE 1-Prevalence of Anencephaly in Children Whose first 12 Weeks of Development Coincided either with an Influenza Epidemic or with the Non-Epidemic Periods
474
AJPH April 1990, Vol. 80, No. 4
PUBLIC HEALTH BRIEFS
When the rates of anencephaly were examined in relation to the serologically verified influenza epidemics, the April-May 1971 B-influenza epidemic showed an apparently high rate in comparison with other periods (Figure 1). However, the heterogeneity test indicated that within the study period of 1969-82, none of the observed rates showed statistically significant elevation (p = 0.75). It was evident that influenza epidemics in general were not associated with the occurring of anencephaly. The rate ratio point estimate for anencephaly was 1.0 (95% confidence limits 0.8, 1.3), when the infants of mothers whose first trimester had coincided with an influenza epidemic were compared with the infants whose sensitive period of development had occurred during a non-epidemic period. Trend analysis showed no change in the rate of anencephaly for the period of 1969-82 (regression slope -0.0000028, SE 0.0000026).
Discussion Two previous studies in the same population suggest, as we do here, that an influenza virus infection of the mother might not be a major cause of neural tube defects: serological screening of mothers to defective children showed no elevated titers against influenza virus antibodies as compared with matched-pair controls,'3 and CNS defects showed no seasonal variations in 1965-73 despite the definite winter excess of influenza.'4 The latter finding confirms similar observations in other populations.'5 An exception to the negative findings listed above seems to be provided by the Asian influenza pandemic in 1957 caused by a new subtype (H2N2) of the influenza A virus. Several independent studies reported an association of this epidemic and an increased risk of defects of the CNS, anencephaly included. 1416-20 Caused by a new subtype of the virus, the epidemic attacked a highly susceptible population, which might explain the association. In the present material, a similar effect could not be found for the 1968/69 pandemic in which the new subtype H3N2 was involved. The present analysis did not reveal any association between an increased risk of anencephaly and maternal influenza infection. The power of the study was about 80 percent to detect a rate ratio
AJPH April 1990, Vol. 80, No. 4
of 1.4 for all epidemics combined and almost 100 percent to detect rate ratios of 1.7 or greater (at = 0.05, one-sided). REFERENCES
1. Kurent JE, Sever JL: Infectious diseases. In: Wilson JG, Fraser FC (eds): Handbook of Teratology, Vol. 1. New York and London: Plenum Press, 1977; 225-259. 2. MacKenzie JS, Houghton M: Influenza infections during pregnancy. Association with congenital malformations and subsequent neoplasms in children and potential hazards of live virus vaccination. Bacteriol Rev 1974; 38:356-370. 3. Larsen JW Jr: Influenza epidemic and congenital defects. Clin Obstet Gynecol 1982; 25:599-603. 4. Hakosalo J, Saxen L: Influenza epidemic and congenital defects. Lancet 1971; 2:1346-1347. 5. Sever LE- Influenza and congenital malformations of the central nervous system. Lancet 1972; 1:910-911. 6. Granroth G: Defects of the central nervous system in Finland. III. Diseases and drugs in pregnancy. Early Human Dev 1978; 2:147-162. 7. Saxen L, Klemetti A, Haro AS: A matched-pair register for studies of selected congenital defects. Am J Epidemiol 1974; 100:297-306. 8. Saxen L: Twenty years of study of the etiology of congenital malformations in Finland. In: Kalter H (ed): Issues and Reviews in Teratology, Vol. 2. New York and London: Plenum Press, 1983; 73-110. 9. Pyhala R, Aho K: Serum HI antibody and protection against influenza: a follow-up survey at community level of three epidemics caused by different H3N2-variants. Int J Epidemiol 1975; 4:127-129. 10. Schlesselman II: Sample size requirements in cohort and case-control studies of disease. Am J Epidemiol 1974; 99:381-384. 11. Miettinen OS: Theoretical Epidemiology. New York: John Wiley and Sons, 1985. 12. Armitage P: Test for linear trends in proportions and frequencies. Biometrics 1955; 11:375-386. 13. Koskimies 0, Lapinleimu K, Saxen L: Infection and other maternal factors as risk indicators for congenital malformations: a case-control study with paired serum samples. Pediatrics 1978; 61:832-837. 14. Granroth G, Hakama M, Saxen L: Defects of the central nervous system in Finland. I. Variation in time and space, sex distribution and parental age. Br J Prev Soc Med 1977; 31:164-170. 15. Record RG: Anencephaly in Scotland. BrJ Prev Soc Med 1961; 15:93-105. 16. Coffey VP, Jessop WJE: Maternal influenza and congenital deformities, a prospective study. Lancet 1959; 2:935-938. 17. Coffey VP, Jessop WJE: Maternal influenza and congenital deformities, a follow-up study. Lancet 1963; 1:748-751. 18. Doll R, Hill AB, Sakula J: Asian influenza in pregnancy and congenital defects. Br J Prev Soc Med 1960; 14:167-172. 19. Saxen L, Hjelt L, Sjostedt JE, Hakosalo J, Hakosalo H: Asian influenza during pregnancy and congenital malformations. Acta Pathol Microbiol Scand A 1960; 49:114-126. 20. Wilson MG, Stein AM: Teratogenic effects of Asian influenza. An extended study. JAMA 1969; 210:336-337.
475
to be infected with HBV in a county jail had markers for HDV, two with antigen and two with antibody.4 In the current study all participants were healthy at the time of screening, and the anti-delta positive results presumably represent past infection. Although one of the five cases of HBV in the outbreak that precipitated the screening/ vaccination program contained IgM anti-delta, specimens from persons in this program were not evaluated for the presence of HDV antigen or IgM anti-delta. Thus some acute HDV infections could have been missed. The proportion of specimens containing anti-delta (14/173, 8 percent) from inmates in this study, however, approximates the proportion of HDV antibody noted in inmates by the study by Jacobson, et al.4 As with HBV, IVDU was strongly associated with the presence of anti-delta; of the 14 inmates with markers for HDV, 12 (86 percent) gave a history of IVDU. Ponzetto, et al, previously reported that 10 percent of drug addicts participating in a Veterans Administration (VA) cooperative study had evidence of infection with HDV.13 Measures that protect against HBV infection, such as use of hepatitis B vaccine, are also effective in preventing HDV infection. Implementation of HBV preventive guidelines in corrections facilities should reduce the risk of HDV. ACKNOWLEDGMENTS We would like to thank Richard Hovestadt for technical assistance in processing and testing the specimens.
REFERENCES 1. Rizzetto M: The delta agent. Hepatology 1983; 3:729-737. 2. Caredda F, Rossi E, Monforte A, Zampini L, Re T, Meroni B, Moroni M: Hepatitis B virus-associated coinfection and superinfection with delta agent: Indistinguishable disease with different outcome. J Infect Dis 1985; 151:925-928. 3. Centers for Disease Control: Hepatitis Surveillance. Atlanta: CDC, 1985; 7-8. 4. Jacobson IM, Dienstag JL, Werner BG, Brettler DB, Levine PH, Mushahwar IK: Epidemiology and clinical impact of hepatitis D virus (delta) infection. Hepatology 1985; 5:188-191. 5. Decker MD, Vaughn WK, Brodie JS, Hutcheson RH, Schaffner W: Seroepidemiology of hepatitis B in Tennessee prisoners. J Infect Dis 1984; 150:450-459. 6. Koplan JP, Walker JA, Bryan JA: Prevalence of hepatitis B surface antigen and antibody at a state prison in Kansas. J Infect Dis 1978; 137:505-506. 7. Chiaramonte M, Trivello R, Renzulli G, Zampieri L, Fanecco A, Floreani A, Naccarato R: Hepatitis B virus infection in prisons: A seroepidemiological survey in prisoners and attending staff. J Hyg Camb 1982; 89:53-58. 8. Hull HF, Lyons LH, Mann JM, Hadler SC, Steece R, Skeels MR: Incidence of hepatitis B in the penitentiary of New Mexico. Am J Public Health 1985; 75:1213-1214. 9. Kaufman ML, Faiver KL, Harness JK: Hepatitis B markers among Michigan prisoners (letter). Ann Intern Med 1983; 98:558. 10. Anda RF, Perlman SB, D'Alessio DJ, Davis JP, Dodson VN: Hepatitis B in Wisconsin male prisoners: Considerations for serologic screening and vaccination. Am J Public Health 1985; 75:1182-1185. 11. Miettinen OS: Estimability and estimation in case-referent studies. Am J Epidemiol 1976; 103:226-235. 12. Gart J: The comparison of proportions: A review of signification. Rev Int Stat Instit 1971; 39:148-169. 13. Ponzetto A, Seeff LB, Buskell-Bales Z, Ishak KG, Hoofnagle JH, Zimmerman HJ, Purcell RH, Gerin JL, Veterans Administration Hepatitis Cooperative Study Group: Hepatitis B markers in United States drug addicts with special emphasis on the delta hepatitis virus. Hepatology 1984; 4:1111-1115.
Influenza Epidemics and Anencephaly LAURI SAXEN, MD, PHD, PETER C. HOLMBERG, MD, PHD, KARI KURPPA, MD, PHD, EEVA KUOSMA, MSC, AND REUO PYHALA, PHD Abstract: To explore the postulated association between maternal influenza and congenital defects of the central nervous system, 14 virologically verified epidemics in Finland, 1969-82, were studied. Mothers of 248 anencephalic children were grouped into those whose first trimester had occurred during an epidemic period and those whose pregnancy had commenced during a non-epidemic period. No significant differences in prevalence of anencephaly were noted in these groups. (Am J Public Health 1990; 80:473-475.)
Introduction
There is ample evidence that certain virus infections can be transmitted to the embryo during pregnancy and cause impaired fetal development expressed as congenital defects. ' Among these potential teratogens, influenza virus has been frequently mentioned, but evidence for or against such harmful effects has remained inconclusive.2,3 We have conducted a population study based on recorded influenza Address reprint requests to Lauri Saxen, MD, PhD, Professor of Experimental Pathology, Department of Pathology, University of Helsinki, Haartmaninkatu 3, SF-00290 Helsinki, Finland. Drs. Holmberg and Kurppa and Ms. Kuosma are with the Institute of Occupational Health, Helsinki; Dr. Pyhala is with the National Institute of Health, Helsinki. This paper, submitted to the Journal April 18, 1989, was revised and accepted for publication August 28, 1989. © 1990 American Journal of Public Health 0090-0036/90$1.50
AJPH April 1990, Vol. 80, No. 4
epidemics and one particular marker defect, anencephaly. This defect has several advantages for investigative purposes: its detection rate is high in stillbirths and in newborn infants, the diagnostic means have not changed during our 15-year-study period, notification rate of this severe defect is high, and finally, as it is a lethal condition, the reports to the Register of Congenital Malformations can be confirmed and completed from the compulsory death certificates. Moreover, defects of the central nervous system (CNS) have often been mentioned in the context of maternal influenza.2-6 Methods The material was collected from the files of the Finnish Register of Congenital Malformations operating since 19637,8 and completed with data from the death certificates obtained from the Central Statistical Bureau. These sources cover the entire population of 4.9 million; the present analysis includes all mothers whose last menstruation occurred between October 1, 1968 and March 31, 1982, comprising 858,917 deliveries. Altogether 248 cases of anencephaly were recorded in children weighing 600 g or over at birth. Of these, 201 cases were single defects and, in 47, additional malformations were reported. Influenza activity in the Finnish population has been monitored by the Central Public Health Laboratory since 1969 with virus isolation and serodiagnostics of acute respiratory infections. Our study covered 14 epidemic periods during which influenza etiology was confirmed. Excluding sporadic cases and small local outbreaks, the epidemic time A73
PUBLIC HEALTH BRIEFS TABLE 1-Occurrence of Influenza epidemics in Finland and serological infection percentages in samples of serum pairs from pregnant women.
Influenza A Number of serum pairs
Epidemic periods January 69-February 69 December 69-February 70 April 71-May 71 November 71-December 71 January 73-February 73 January 74-Apnl 74 January 75-March 75 January 76-March 76 March 77-April 77 January 78-March 78 January 79-April 79 January 80-February 80 January 81-March 81 February 82-June 82
(a)
137 91 106 144 397 636 651 549 576 674 291
H1Nl (%)
H3N2 (%)
-
(b)
1
(b)
3 -
10 1
Influenza B
27 20 23 17 15 14 8 3 25 2 1
(b) -
18 -
7 -
2 -
4 1
quencies among pregnant women in Finland.9 Serum pairs of pre-epidemic and post-epidemic specimens from a total of 4,252 women were studied for haemagglutination-inhibiting antibodies to influenza A and B viruses including the epidemic variant, and, for detection of anamnestic antibody response, the serotypes of the near past (Table 1). A fourfold or higher rise in antibody titers was considered indicative of serological influenza infection.9 For the occurrence of anencephaly in infants, mothers whose first trimester (14 weeks from the start of the mother's previous menstruation) had coincided wholly or in part with a virologically verified influenza epidemic (407,200 mothers) and mothers whose first trimester had occurred completely during a non-epidemic period (314,841 mothers) were compared after exclusion of the borderline months. Power calculations were performed according to Schlesselman.'0 The heterogeneity test was performed and confidence limits for rate ratio estimates were calculated as suggested by Miettinen.1" Trend analysis for the proportion of rates of anencephaly was performed according to Armitage.12
(a) The pairs consisted of pre-epidemic and postepidemic specimens (b) Epidemic activity recorded, but infection frequency among pregnant women not studied
Results was 37 months of the total 162 months monitored during the study period. To create a "non-epidemic" control material, the month preceding and following each epidemic was excluded because of timing uncertainties. Altogether, 26 such borderline months with 46 anencephalic children were thus excluded. Since the end of 1971, the influenza surveillance program has included annual monitoring of serological infection fre-
Epidemics caused by influenza A and B viruses, and serological infection frequencies in the follow-up samples of pregnant women are listed in Table 1. Figure 1 shows the rates of anencephaly when the first trimester had occurred during the influenza epidemics or during the non-epidemic periods. In the epidemic group, 117 anencephalics were reported and in the non-epidemic group, 85; prevalence 0.29 per mil and 0.27 per mil, respectively.
4-
Lo
m 0 0 0 a)
ILL w
z z w
EPIDEMICS VIRUS
A A 1969 -70
A A B A A,B A A,B A A,B A A,B A,B -71 -72 -73 -74 -75 -76 -77 -78 -79 -80 -81 -82 YEAR
FIGURE 1-Prevalence of Anencephaly in Children Whose first 12 Weeks of Development Coincided either with an Influenza Epidemic or with the Non-Epidemic Periods
474
AJPH April 1990, Vol. 80, No. 4
PUBLIC HEALTH BRIEFS
When the rates of anencephaly were examined in relation to the serologically verified influenza epidemics, the April-May 1971 B-influenza epidemic showed an apparently high rate in comparison with other periods (Figure 1). However, the heterogeneity test indicated that within the study period of 1969-82, none of the observed rates showed statistically significant elevation (p = 0.75). It was evident that influenza epidemics in general were not associated with the occurring of anencephaly. The rate ratio point estimate for anencephaly was 1.0 (95% confidence limits 0.8, 1.3), when the infants of mothers whose first trimester had coincided with an influenza epidemic were compared with the infants whose sensitive period of development had occurred during a non-epidemic period. Trend analysis showed no change in the rate of anencephaly for the period of 1969-82 (regression slope -0.0000028, SE 0.0000026).
Discussion Two previous studies in the same population suggest, as we do here, that an influenza virus infection of the mother might not be a major cause of neural tube defects: serological screening of mothers to defective children showed no elevated titers against influenza virus antibodies as compared with matched-pair controls,'3 and CNS defects showed no seasonal variations in 1965-73 despite the definite winter excess of influenza.'4 The latter finding confirms similar observations in other populations.'5 An exception to the negative findings listed above seems to be provided by the Asian influenza pandemic in 1957 caused by a new subtype (H2N2) of the influenza A virus. Several independent studies reported an association of this epidemic and an increased risk of defects of the CNS, anencephaly included. 1416-20 Caused by a new subtype of the virus, the epidemic attacked a highly susceptible population, which might explain the association. In the present material, a similar effect could not be found for the 1968/69 pandemic in which the new subtype H3N2 was involved. The present analysis did not reveal any association between an increased risk of anencephaly and maternal influenza infection. The power of the study was about 80 percent to detect a rate ratio
AJPH April 1990, Vol. 80, No. 4
of 1.4 for all epidemics combined and almost 100 percent to detect rate ratios of 1.7 or greater (at = 0.05, one-sided). REFERENCES
1. Kurent JE, Sever JL: Infectious diseases. In: Wilson JG, Fraser FC (eds): Handbook of Teratology, Vol. 1. New York and London: Plenum Press, 1977; 225-259. 2. MacKenzie JS, Houghton M: Influenza infections during pregnancy. Association with congenital malformations and subsequent neoplasms in children and potential hazards of live virus vaccination. Bacteriol Rev 1974; 38:356-370. 3. Larsen JW Jr: Influenza epidemic and congenital defects. Clin Obstet Gynecol 1982; 25:599-603. 4. Hakosalo J, Saxen L: Influenza epidemic and congenital defects. Lancet 1971; 2:1346-1347. 5. Sever LE- Influenza and congenital malformations of the central nervous system. Lancet 1972; 1:910-911. 6. Granroth G: Defects of the central nervous system in Finland. III. Diseases and drugs in pregnancy. Early Human Dev 1978; 2:147-162. 7. Saxen L, Klemetti A, Haro AS: A matched-pair register for studies of selected congenital defects. Am J Epidemiol 1974; 100:297-306. 8. Saxen L: Twenty years of study of the etiology of congenital malformations in Finland. In: Kalter H (ed): Issues and Reviews in Teratology, Vol. 2. New York and London: Plenum Press, 1983; 73-110. 9. Pyhala R, Aho K: Serum HI antibody and protection against influenza: a follow-up survey at community level of three epidemics caused by different H3N2-variants. Int J Epidemiol 1975; 4:127-129. 10. Schlesselman II: Sample size requirements in cohort and case-control studies of disease. Am J Epidemiol 1974; 99:381-384. 11. Miettinen OS: Theoretical Epidemiology. New York: John Wiley and Sons, 1985. 12. Armitage P: Test for linear trends in proportions and frequencies. Biometrics 1955; 11:375-386. 13. Koskimies 0, Lapinleimu K, Saxen L: Infection and other maternal factors as risk indicators for congenital malformations: a case-control study with paired serum samples. Pediatrics 1978; 61:832-837. 14. Granroth G, Hakama M, Saxen L: Defects of the central nervous system in Finland. I. Variation in time and space, sex distribution and parental age. Br J Prev Soc Med 1977; 31:164-170. 15. Record RG: Anencephaly in Scotland. BrJ Prev Soc Med 1961; 15:93-105. 16. Coffey VP, Jessop WJE: Maternal influenza and congenital deformities, a prospective study. Lancet 1959; 2:935-938. 17. Coffey VP, Jessop WJE: Maternal influenza and congenital deformities, a follow-up study. Lancet 1963; 1:748-751. 18. Doll R, Hill AB, Sakula J: Asian influenza in pregnancy and congenital defects. Br J Prev Soc Med 1960; 14:167-172. 19. Saxen L, Hjelt L, Sjostedt JE, Hakosalo J, Hakosalo H: Asian influenza during pregnancy and congenital malformations. Acta Pathol Microbiol Scand A 1960; 49:114-126. 20. Wilson MG, Stein AM: Teratogenic effects of Asian influenza. An extended study. JAMA 1969; 210:336-337.
475
