0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Article |

Exposure to Prenatal and Childhood Infections and the Risk of Schizophrenia:  Suggestions From a Study of Sibship Characteristics and Influenza Prevalence FREE

Tine Westergaard, MD; Preben B. Mortensen, MD, PhD; Carsten B. Pedersen, MSc; Jan Wohlfahrt, MSc; Mads Melbye, MD, DMSc
[+] Author Affiliations

From the Department of Epidemiology Research, Danish Epidemiology Science Centre, Statens Serum Institut, Copenhagen, Denmark (Drs Westergaard and Melbye and Messrs Pedersen and Wohlfahrt); and the Department of Psychiatric Demography, Institute for Basic Psychiatric Research, Psychiatric Hospital, Aarhus, Denmark (Dr Mortensen).


Arch Gen Psychiatry. 1999;56(11):993-998. doi:10.1001/archpsyc.56.11.993.
Text Size: A A A
Published online

Background  It has been proposed that infections, perhaps prenatal exposure to the influenza virus, might increase the risk of schizophrenia. To address this hypothesis, we studied the possible influence on schizophrenia risk of sibship characteristics and ecological influenza prevalence data. Birth order and influenza prevalence were used as proxy measures for exposure to prenatal infection, and sibship size and interval to siblings were used as proxy measures for exposure to common childhood infections.

Methods  We established a population-based cohort of 1,746,366 persons whose mothers were Danish-born women born since 1935 by using data from the Civil Registration System. Schizophrenia in cohort members (n=2669) and their parents was identified by linkage with the Danish Psychiatric Case Register. Birth order, sibship size, and interval to siblings were calculated for each cohort member based on person-identifiable information on all siblings. The number of notifications of influenza per month in Denmark was obtained from the National Board of Health and Statens Serum Institut.

Results  There was no association between birth order and schizophrenia risk or between schizophrenia risk and influenza prevalence during any month of prenatal life. Coming from a large sibship was associated with an increased schizophrenia risk. The relative risks were 1.26 (95% confidence interval [CI], 1.11-1.44) and 1.46 (95% CI, 1.22-1.75) for sibships of 4 and 5 or more, respectively, vs a sibship of 2. Short interval (<2 years) to the nearest older sibling and nearest younger sibling was associated with a risk of 1.22 (95% CI, 1.05-1.38) and 1.15 (95% CI, 1.03-1.28), respectively, compared with longer intervals.

Conclusions  Our findings do not support the hypothesis that schizophrenia is associated with prenatal exposure to common infections or influenza. However, they are compatible with the hypothesis that environmental exposure, perhaps to common infections in childhood, may be a risk factor, although other explanations are also possible.

Figures in this Article

MANY HAVE hypothesized that prenatal exposure to infectious agents may increase the risk of schizophrenia. If such an association exists, the risk of schizophrenia might increase with the number of older siblings a child has (ie, birth order). This rationale is based on findings from several studies that the risk of a large variety of common infections is likely to increase with the number of children in the family.17 Thus, the more siblings a person has while in utero, the more likely that a sibling would introduce common infections into the family and thereby increase the risk of maternal infection. An association between birth order and the risk of schizophrenia was reported in a study by Sham et al,8 who in particular found that the risk was increased in subjects with siblings who were 3 to 4 years older. However, results from studies on family structure have been inconsistent,917 which may be explained in part by the methods used. Lack of appropriate reference groups has been a major concern in many of these studies, particularly in studies that lacked an actual control group but instead generated an internal comparison group based on the sibship constellations of cases only. Such a procedure may introduce serious bias because of changes in birth rate and family size over time.1821

The influenza virus is an infectious agent that has received much attention as a possible risk factor for schizophrenia. In particular, an association between in utero exposure to influenza during the second trimester and subsequent risk of schizophrenia has been suggested.22 However, although many studies have reported on this possible association, the methods used have varied considerably and the results have been inconsistent. Thus, while several ecological studies have reported an association between influenza epidemics in the population during fetal life and the risk of schizophrenia,2230 others, including 2 studies that obtained individual information on maternal influenza infection during fetal life,31,32 found no support for such an association.3338

While most attention has focused on prenatal exposure to infection as a risk factor for schizophrenia, some authors have also suggested that infection in childhood may be important.39,40 Coming from a large sibship17 and having a short interval to siblings7 is likely to increase the risk of common infections in childhood and could potentially be associated with an increased schizophrenia risk. Because birth order, sibship size, and age interval between siblings are highly correlated, we studied these factors together to estimate their possible independent effects and to attempt to distinguish between the hypotheses of a possible influence of prenatal and childhood exposure on schizophrenia risk.

In the present study, we used a large, population-based cohort design to address these hypotheses. Specifically, we studied the possible influence on schizophrenia risk of birth order, sibship size, interval between siblings, and influenza prevalence in the population during fetal life.

COHORT

Data from the Civil Registration System were used to generate a complete sibship database for persons born to Danish-born women. All liveborn children and new residents of Denmark are recorded in the Civil Registration System and assigned a unique personal identification number.41 Individual information is kept under this identification number in all national registers, enabling secure linkage of information between registers. The registration system also includes person-identifiable information on parents and offspring of individuals as well as information on date of birth, sex, place of birth, and continuously updated information on vital status. We established a population-based sibship database by extracting data on all woman born in Denmark on April 1, 1935, or later and all their offspring who were alive on April 1, 1968, or born between that date and December 31, 1988. The offspring constituted the study cohort, which was similar to that of a previous study.42

IDENTIFICATION OF CASES AND PARENTS WITH SCHIZOPHRENIA

Members of the study cohort and their parents were linked with the Danish Psychiatric Case Register. The Danish Psychiatric Case Register is a national register that has been computerized since April 1, 1969. It contains data on all admissions to Danish psychiatric inpatient facilities.43 No private facilities exist, and there is no fee for psychiatric inpatient treatment in Denmark. The diagnostic system used during the study period was the International Classification of Diseases, Eighth Revision; persons with schizophrenia were identified under International Classification of Diseases, Eighth Revision, code 295.

SIBSHIP CHARACTERISTICS

Using the complete person-identifiable information on all cohort members, we calculated their birth order, sibship size, and interval to nearest older and younger siblings. Birth order was calculated as 1 plus the number of children born to the same mother who were alive at the child's birth. Sibship size was defined as birth order plus the number of liveborn children who had been born to the mother after the child's birth and was calculated as a time-dependent variable.

INFLUENZA REGISTRATIONS

Monthly registrations of the number of mandatorily reported cases of influenza in Denmark were obtained from the National Board of Health for the period from 1950 through 1979 and from Statens Serum Institut from 1980 through 1988. The size of the Danish population per year was obtained from Statistics Denmark, Copenhagen.

DATA ANALYSIS

Overall, the study cohort consisted of 1,746,366 persons who were followed up for a diagnosis of schizophrenia from their fifth birthday or April 1, 1970, whichever came last, until the first day of the first admission for which the discharge diagnosis was schizophrenia (the onset date), the date of death, the date of emigration, or December 31, 1993, whichever came first. Poisson regression models were used to estimate the possible effect on schizophrenia risk of birth order, sibship size, interval to the nearest older and younger siblings, and influenza prevalence during fetal life.44 The analyses were performed using the SAS GENMOD procedure.45 Ratios of incidence rates were used as a measure of the relative risk (RR). The P values were based on 2-tailed likelihood ratio tests, and 95% confidence intervals (CIs) were calculated using the Wald test.

All RRs were adjusted for age and the interaction with sex, calendar period, month of birth, degree of urbanization of place of birth, maternal and paternal age at birth of the child, and schizophrenia in the mother and/or father. Selection of these adjustments was based on a previous study42 and was made to account for a possible confounding effect of these factors. Month of birth (seasonality) was described using a sine function that estimated both the amplitude and the time peak.42 Parents were registered as being affected with schizophrenia if they had ever been admitted with this diagnosis. For categorical variables, the category with the largest number of cases was chosen as the reference.

The possible association between schizophrenia and number of reported influenza cases per population during the month of birth and for each of the 9 months preceding the month of birth was investigated using 2 different models for the exposure. First, risk of exposure to influenza during a month was arbitrarily categorized as low, intermediate, or high, respectively, if the number of influenza notifications was less than 5, 5 to less than 10, or 10 or more per 1000 persons in the population. Second, the number of notifications of influenza per 100 population for a given month was treated as a continuous variable, using a log-linear association between the risk of schizophrenia and the prevalence of influenza. We focused on the prevalence of influenza 3 to 5 months prior to birth, since most studies reporting positive associations found associations between influenza exposure during these months and schizophrenia risk. For both models of exposure to influenza, all 9 months prior to birth and the month of birth were initially included in the model. We then tested whether months 0 through 2 and 6 through 9 prior to birth could be omitted from the model; they could be, leaving months 3, 4, and 5 prior to birth in the model. For each of these months, we then tested whether the 2 other months could be omitted from the model; they could be. Finally, we separately included each of the other 9 months prior to birth and the month of birth in the model.

Population-attributable risks were estimated as described by Bruzzi et al,46 based on adjusted RRs and the distribution of the exposure among cases.

Overall, 2669 cohort members (1857 males and 812 females) developed schizophrenia during the 24,933,115 person-years of follow-up. Thirty-five cases (1.3%) were aged 5 to 14 years at diagnosis, 635 (24%) were 15 to 19 years, 1152 (43%) were 20 to 24 years, 659 (25%) were 25 to 29 years, 170 (6%) were 30 to 34 years, and 18 (<1%) were 35 years or older. Overall, 27 cases (1%) were born from 1950 to 1954, 378 (14%) from 1955 to 1959, 938 (35%) from 1960 to 1964, 916 (34%) from 1965 to 1969, 379 (14%) from 1970 to 1974, and 31 (1%) from 1975 to 1984. Fifty-nine patients had at least 1 sibling with schizophrenia at the time of their diagnosis.

SIBSHIP CHARACTERISTICS

There was no association between birth order and schizophrenia risk (Table 1), while there was a significant association between sibship size and schizophrenia risk (P<.001). Coming from a sibship size of 4 or 5 or more increased the risk compared with a sibship size of 2 (RR, 1.26 [95% CI, 1.11-1.44] and RR, 1.46 [95% CI, 1.22-1.75], respectively). The risk of schizophrenia for combinations of birth order and sibship size is illustrated in Table 2. The table shows that, for a given birth order, the risk of schizophrenia generally increased with increasing sibship size, while for a given sibship size the birth order estimates remained fairly stable. There was no interaction between birth order and sex or between sibship size and sex. Adjustment for schizophrenia in siblings or omission of adjustment for seasonality had negligible effects on the estimates in Table 1 and Table 2.

Table Graphic Jump LocationTable 1. Relative Risk (RR) of Developing Schizophrenia According to Sibship Characteristics in a Population-Based Cohort of 1.7 Million Persons Where 2669 Developed Schizophrenia*
Table Graphic Jump LocationTable 2. Relative Risk of Schizophrenia According to Combinations of Birth Order and Sibship Size*

A short interval to the nearest older sibling and a short interval to the nearest younger sibling were also associated with an increased risk of schizophrenia after adjustment for birth order and sibship size (Table 1). The RRs for schizophrenia were 1.22 (95% CI, 1.07-1.38) for an interval of less than 2 years vs 2 years or more to the nearest older sibling and 1.15 (95% CI, 1.03-1.28) for an interval of less than 2 years vs 2 years or more to the nearest younger sibling. Adjustment for interval to nearest older sibling and/or nearest younger sibling had only a minor effect on the risk estimates associated with birth order and sibship size for persons with siblings.

The impact of large sibship size and short intervals between siblings on the population level was evaluated by population-attributable risks. It was estimated that the fraction of persons with schizophrenia in the population would be reduced by 5.8% if the risk for persons with large sibship size (3, 4, or 5+) could be reduced to the risk of persons with a sibship size of 2. The population-attributable risks for short intervals (<2 years) to the nearest older and younger siblings were 2.8% and 2.3%, respectively. Overall, these sibship characteristics accounted for 10.3% of the cases of schizophrenia in the population.

INFLUENZA

The monthly prevalence of influenza in the population from 1950 to 1988 is shown in Figure 1. There was no association between schizophrenia risk and the prevalence of influenza 3, 4, or 5 months prior to the month of birth; during any other month prior to birth; or during the month of birth. The results for influenza exposure 3, 4, and 5 months prior to birth analyzed as a categorical variable are shown in Table 3. The results when analyzed as a continuous variable were as follows: the relative increases in schizophrenia risk per percentage of the population notified with influenza 3, 4, and 5 months prior to the month of birth were 0.96 (95% CI, 0.88-1.04), 1.00 (95% CI, 0.92-1.09), and 1.01 (95% CI, 0.93-1.10), respectively. Including all 3 months in the model at the same time instead of each month separately had a negligible effect on the results.

Place holder to copy figure label and caption

The monthly influenza prevalence in Denmark from 1950 to 1988.

Graphic Jump Location
Table Graphic Jump LocationTable 3. Relative Risk (RR) of Schizophrenia According to the Prevalence of Influenza 3, 4, and 5 Months Prior to the Month of Birth*

There was no interaction between sex and influenza exposure or between birth order and influenza exposure in either model. Adjustment for seasonality of birth in 12 categories instead of by a sine function or omission of adjustment for seasonality did not affect the result. Adjusting for sibship size or omission of adjustment for degree of urbanization of the place of birth also had no effect on the risk estimates.

To our knowledge, the present study is the first to use a population-based cohort design to address the possible association between birth order, interval to siblings, sibship size, and the risk of schizophrenia. This design clearly reduces the risk of selection bias and avoids problems with inappropriate reference groups, which have been of concern in previous studies on family structure. Furthermore, we were able to adjust the analyses for schizophrenia in parents and siblings and other potential confounders, such as maternal age, degree of urbanization, and seasonality of birth.

Overall, we found no association between birth order and risk of schizophrenia or between influenza prevalence during fetal life and schizophrenia risk. Thus, our study does not support the hypothesis that in utero exposure to influenza or other common infections may increase the risk of developing schizophrenia. Separate analyses were performed that particularly addressed the suggestion made by Sham et al8 of increased risk associated with having siblings 3 to 4 years older. These analyses did not support such an association.

Our finding of an increased risk of schizophrenia associated with having many siblings, independent of birth order and short interval to the nearest older or younger sibling, is suggestive of environmental factors being involved in the etiology.47,48 The association between sibship size and schizophrenia risk could be indicative of a possible association between schizophrenia and exposure to infections in childhood.39,40 In addition, the increased risk of schizophrenia associated with short intervals to the nearest older and younger siblings supports this hypothesis, assuming that the risk of transmission of common infections between children is likely to increase the closer they are in age.

However, although childhood infection may explain our findings, sibship characteristics are only proxy measures for exposure to infections. Other physical factors or particular psychological or psychosocial factors that may be associated with such sibship constellations could also in theory explain our findings. Large sibship sizes have in some cultures been associated with low socioeconomic status.49 However, a large population-based study from Denmark found that what seemed to be an association between low socioeconomic status and large sibships in large part could be explained by the degree of urbanization,50 a factor that we were able to adjust for in our analyses. Religious beliefs and ethnicity are other factors that have been associated with sibship size.49 However, all cohort members had mothers born in Denmark, a country composed mainly of Protestants or nonreligious residents and with relatively few immigrants.

The finding of an increased risk of schizophrenia associated with a short interval (<2 years) to the nearest older sibling could also suggest that nutritional deficiency during fetal brain development is involved in the etiology of schizophrenia in some cases. Folate deficiency has been associated with neural tube defects51; furthermore, this neurodevelopmental disorder has been associated with short interval to the previous pregnancy.52 In addition, prenatal famine has been associated with both neural tube defects and schizophrenia.53 If a link between short pregnancy interval, nutritional deficiency, and schizophrenia exists, the association would most likely be strongest for very short intervals. However, the RRs of schizophrenia for persons with an interval of less than 1 year to their nearest older sibling (RR, 0.87 [95% CI, 0.58-1.30]) did not differ significantly from the RR associated with an interval of 1 to less than 2 years (reference group), but the estimate was only based on 25 cases.

As opposed to other ecological studies on influenza prevalence in the population during fetal life and the possible association with schizophrenia risk, we were able to take into account the actual person-years at risk in the population developing schizophrenia and to adjust for several potential confounders, and we are confident that we included only incident cases of schizophrenia in the study. There have been 3 previous ecological studies from Denmark on the same topic.24,26,30 Barr et al24 studied births from 1911 through 1950 in Denmark and reported an association between schizophrenia risk and relatively high levels of influenza exposure for the season during the sixth month of gestation. However, a larger study by Adams et al26 that included the birth cohorts studied by Barr et al24 (birth cohorts 1911-1965) and used more suitable models found no consistent association between fetal exposure to influenza and schizophrenia risk.

Takei et al30 studied births in Denmark from 1915 to 1970, but in contrast to Barr et al24 and Adams et al,26 they entered the influenza notifications during a month as a continuous variable into their model. They found that the risk of schizophrenia increased, with an RR of 1.10 (95% CI, 1.00-1.21) per 100,000 notifications of influenza 4 months prior of birth. We performed an additional analysis in which we analyzed our data in exactly the same way as Takei et al had done (data not shown), but we again found no association (RR, 1.00). Theoretically, the differences between our findings could be caused by an effect of fetal exposure to influenza in the older birth cohorts that is not present in more recent times, or the association may be restricted to those in whom schizophrenia develops at an older age, since our study only included young adults. Alternatively, the association found by Takei et al could be the result of multiple testing or the presence of outliers in the older data. A model in which the exposure is entered as a continuous variable is particularly vulnerable to outliers. However, irrespective of which of the above explanations accounts for the differing findings, our data do not support a general effect of influenza prevalence during fetal life on schizophrenia risk.

We found no association between birth order or influenza prevalence during fetal life and the risk of schizophrenia. Thus, our study does not support an association between schizophrenia risk and prenatal exposure to the influenza virus or other common infections. The finding of an association between schizophrenia risk, large sibship size, and short interval to the nearest older sibling as well as the nearest younger sibling is compatible with the hypothesis that environmental exposure, perhaps to common infections in childhood, may be a risk factor for schizophrenia, although other explanations may also be possible.

Accepted for publication July 28, 1999.

This study was supported by the Danish National Research Foundation, Hellerup, Denmark (Dr Melbye); the Danish Medical Research Council, Copenhagen, Denmark (Dr Melbye); and the Theodore and Vada Stanley Foundation, Washington, DC (Dr Mortensen).

Reprints: Tine Westergaard, MD, Department of Epidemiology Research, Danish Epidemiology Science Centre, Statens Serum Institut, 5 Artillerivej, DK-2300 Copenhagen S, Denmark (e-mail: twe@ssi.dk).

Dingle  JHBadger  GFJordan  WSJ Illness in the Home: A Study of 25,000 Illnesses in a Group of Cleveland Families.  Cleveland, Ohio The Press at Western Reserve University1964;
Leeder  SRCorkhill  RIrwig  LMHolland  WW Influence of family factors on the incidence of lower respiratory illness during the first year of life. Br J Prev Soc Med. 1976;30203- 212
Golding  J Bronchitis and pneumonia. Butler  NRGolding  Jeds.From Birth to Five: A Study of the Health and Behaviour of Britain's 5-Year olds. Oxford, England Pergamon Press1986;201- 214
Black  FL Measles antibodies in the population of New Haven, Connecticut. J Immunol. 1959;8374- 82
Hammon  WSather  GEHollinger  N Preliminary report of epidemiological studies on poliomyelitis and streptococcal infections. Am J Public Health. 1950;40293- 306
Fox  JPCooney  MKHall  CE The Seattle virus watch, V: epidemiologic observations of rhinovirus infections, 1965-1969, in families with young children. Am J Epidemiol. 1975;101122- 143
Valeur-Jensen  AKPedersen  CBWestergaard  TJensen  IPLebech  MAndersen  PKAaby  PPedersen  BNMelbye  M Risk factors for parvovirus B19 infection in pregnancy. JAMA. 1999;2811099- 1105
Sham  PCMacLean  CJKendler  KS Risk of schizophrenia and age difference with older siblings: evidence for a maternal viral infection hypothesis? Br J Psychiatry. 1993;163627- 633
Malama  IMPapaioannou  DJKaklamani  EPKatsouyanni  KMKoumantaki  IGTrichopoulos  DV Birth order sibship size and socio-economic factors in risk of schizophrenia in Greece. Br J Psychiatry. 1988;152482- 486
Hare  EHPrice  JS Birth rank in schizophrenia: with a consideration of the bias due to changes in birth-rate. Br J Psychiatry. 1970;116409- 420
Schooler  C Birth order and hospitalization for schizophrenia. J Abnorm Soc Psychol. 1964;69574- 579
Hinshelwood  RD The evidence for a birth order factor in schizophrenia. Br J Psychiatry. 1970;117293- 301
Erlenmeyer-Kimling  L The problem of birth order and schizophrenia: a negative conclusion. Br J Psychiatry. 1969;115659- 678
Sundararaj  NSridhara  BSRao  R Order of birth and schizophrenia. Br J Psychiatry. 1966;1121127- 1129
Barry  H  IIIBarry  H  Jr Birth order, family size, and schizophrenia. Arch Gen Psychiatry. 1967;17435- 440
Granville-Grossman  KL Birth order and schizophrenia. Br J Psychiatry. 1966;1121119- 1126
Burton  ABird  JW Family constellation and schizophrenia. J Psychol. 1963;55329- 336
Birtchnell  J Birth rank and mental illness. Nature. 1971;234485- 487
Hare  EHPrice  JS Birth order and family size: bias caused by changes in birth rate. Br J Psychiatry. 1969;115647- 657
Price  JSHare  EH Birth order studies: some sources of bias. Br J Psychiatry. 1969;115633- 646
Berglin  CG Birth order as a quantitative expression of date of birth. J Epidemiol Community Health. 1982;36298- 302
Mednick  SAMachon  RAHuttunen  MOBonett  D Adult schizophrenia following prenatal exposure to an influenza epidemic. Arch Gen Psychiatry. 1988;45189- 1921
O'Callaghan  ESham  PTakei  NGlover  GMurray  RM Schizophrenia after prenatal exposure to 1957 A2 influenza epidemic. Lancet. 1991;3371248- 1250
Barr  CEMednick  SAMunk-Jorgensen  P Exposure to influenza epidemics during gestation and adult schizophrenia: a 40-year study. Arch Gen Psychiatry. 1990;47869- 874
Sham  PCO'Callaghan  ETakei  NMurray  GKHare  EHMurray  RM Schizophrenia following pre-natal exposure to influenza epidemics between 1939 and 1960. Br J Psychiatry. 1992;160461- 466
Adams  WKendell  REHare  EHMunk-Jorgensen  P Epidemiological evidence that maternal influenza contributes to the aetiology of schizophrenia: an analyses of Scottish, English, and Danish data. Br J Psychiatry. 1993;163522- 534
Takei  NSham  PO'Callaghan  EMurray  GKGlover  GMurray  RM Prenatal exposure to influenza and the development of schizophrenia: is the effect confined to females? Am J Psychiatry. 1994;151117- 119
Takei  NOs  JVMurray  RM Maternal exposure to influenza and risk of schizophrenia: a 22 year study from the Netherlands. J Psychiatr Res. 1995;29435- 445
Kunugi  HNanko  STakei  NSaito  KHayashi  NKazamatsuri  H Schizophrenia following in utero exposure to the 1957 influenza epidemics in Japan. Am J Psychiatry. 1995;152450- 452
Takei  NMortensen  PBKlæning  UMurray  RMSham  PCO'Callaghan  EMunk-Jorgensen  P Relationship between in utero exposure to influenza epidemics and risk of schizophrenia in Denmark. Biol Psychiatry. 1996;40817- 824
Crow  TJDone  DJJohnstone  EC Schizophrenia and influenza. Lancet. 1991;338116- 117
Cannon  MCotter  DCoffey  VPSham  PCTakei  NLarkin  CMurray  RMO'Callaghan  E Prenatal exposure to the 1957 influenza epidemic and adult schizophrenia: a follow-up study. Br J Psychiatry. 1996;6368- 371
Kendell  REKemp  IW Maternal influenza in the etiology of schizophrenia. Arch Gen Psychiatry. 1989;46878- 882
Torrey  EFBowler  AERawlings  R Schizophrenia and the 1957 influenza epidemic. Schizophr Res. 1992;6100
Susser  ELin  SPBrown  ASLumey  LHErlenmeyer-Kimling  L No relation between risk of schizophrenia and prenatal exposure to influenza in Holland. Am J Psychiatry. 1994;151922- 924
Erlenmeyer-Kimling  LFolnegovic  ZHrabak-Zerjavic  VBorcic  BFolnegovic-Smalc  VSusser  E Schizophrenia and prenatal exposure to the 1957 A2 influenza epidemic in Croatia. Am J Psychiatry. 1994;1511496- 1498
Selten  JPSlaets  JP Evidence against maternal influenza as a risk factor for schizophrenia. Br J Psychiatry. 1994;164674- 676
Morgan  VCastle  DPage  AMontgomery  PGurrin  LBurton  PFazio  SJablensky  A Influenza epidemics and the incidence of schizophrenia, affective disorders and mental retardation: further data from Western Australia [abstract]. Schizophr Res. 1998;2918
Rantakallio  PJones  PMoring  Jvon Wendt  L Association between central nervous system infections during childhood and adult onset schizophrenia and other psychoses: a 28-year follow-up. Int J Epidemiol. 1997;26837- 843
Torrey  EFYolken  RH Is household crowding a risk factor for schizophrenia? Schizophr Res. 1998;2912- 13
Malig  C The Civil Registration System in Denmark.  Bethesda, Md International Institute for Vital Registration and Statistics December1996;1- 9IIVRS Technical Papers, No. 66.
Mortensen  PBPedersen  CBWestergaard  TWohlfahrt  JEwald  HMors  OAndersen  PKMelbye  M Effects of family history and place and season of birth on the risk of schizophrenia. N Engl J Med. 1999;340603- 608
Munk-Jorgensen  PMortensen  PB The Danish Psychiatric Central Register. Dan Med Bull. 1997;4482- 84
Breslow  NEDay  NE Statistical Methods in Cancer Research: The Design and Analysis of Cohort Studies. Vol 2 Lyon, France International Agency for Research on Cancer1987;
SAS Institute, The GENMOD procedure. SAS/STAT Software: Changes and Enhancements for Release 6.12. Cary, NC SAS Institute1996;21- 42
Bruzzi  PGreen  SBByar  DPBrinton  LASchairer  C Estimating the population attributable risk for multiple risk factors using case-control data. Am J Epidemiol. 1985;122904- 914
Susser  MSusser  E Separating heredity and environment, I: genetic and environmental indicators. Susser  Med.Epidemiology, Health and Society: Selected Papers. New York, NY Oxford University Press1987;103- 114
Khoury  MJBeaty  THCohen  BH Fundamentals of Genetic Epidemiology.  New York, NY Oxford University Press1993;131
Ernst  CAngst  J Birth Order: Its Influence on Personality.  Berlin, Germany Springer-Verlag1983;
Hansen  EJ Who Breaks the Social Inheritance? The Final Report From the Longitudinal Survey of a Generation of Adolescents' Educational and Occupational Choice, Parts I and II [in Danish, with an English summary].  Prepared for The Danish National Institute of Social Research. Copenhagen, Denmark: Teknisk Forlag1982;Publication 112.
Brown  ASSusser  ESButler  PDAndrews  RRKaufmann  GAGorman  JM Neurobiological plausibility of prenatal nutritional deprivation as a risk factor for schizophrenia. J Nerv Ment Dis. 1996;18471- 85
Myrianthopoulos  NCMelnick  M Studies in neural tube defects, I: epidemiologic and etiologic aspects. Am J Med Genet. 1987;26783- 796
Susser  EHoek  HWBrown  A Neurodevelopmental disorders after prenatal famine: the story of the Dutch famine study. Am J Psychiatry. 1998;147213- 216

Figures

Place holder to copy figure label and caption

The monthly influenza prevalence in Denmark from 1950 to 1988.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Relative Risk (RR) of Developing Schizophrenia According to Sibship Characteristics in a Population-Based Cohort of 1.7 Million Persons Where 2669 Developed Schizophrenia*
Table Graphic Jump LocationTable 2. Relative Risk of Schizophrenia According to Combinations of Birth Order and Sibship Size*
Table Graphic Jump LocationTable 3. Relative Risk (RR) of Schizophrenia According to the Prevalence of Influenza 3, 4, and 5 Months Prior to the Month of Birth*

References

Dingle  JHBadger  GFJordan  WSJ Illness in the Home: A Study of 25,000 Illnesses in a Group of Cleveland Families.  Cleveland, Ohio The Press at Western Reserve University1964;
Leeder  SRCorkhill  RIrwig  LMHolland  WW Influence of family factors on the incidence of lower respiratory illness during the first year of life. Br J Prev Soc Med. 1976;30203- 212
Golding  J Bronchitis and pneumonia. Butler  NRGolding  Jeds.From Birth to Five: A Study of the Health and Behaviour of Britain's 5-Year olds. Oxford, England Pergamon Press1986;201- 214
Black  FL Measles antibodies in the population of New Haven, Connecticut. J Immunol. 1959;8374- 82
Hammon  WSather  GEHollinger  N Preliminary report of epidemiological studies on poliomyelitis and streptococcal infections. Am J Public Health. 1950;40293- 306
Fox  JPCooney  MKHall  CE The Seattle virus watch, V: epidemiologic observations of rhinovirus infections, 1965-1969, in families with young children. Am J Epidemiol. 1975;101122- 143
Valeur-Jensen  AKPedersen  CBWestergaard  TJensen  IPLebech  MAndersen  PKAaby  PPedersen  BNMelbye  M Risk factors for parvovirus B19 infection in pregnancy. JAMA. 1999;2811099- 1105
Sham  PCMacLean  CJKendler  KS Risk of schizophrenia and age difference with older siblings: evidence for a maternal viral infection hypothesis? Br J Psychiatry. 1993;163627- 633
Malama  IMPapaioannou  DJKaklamani  EPKatsouyanni  KMKoumantaki  IGTrichopoulos  DV Birth order sibship size and socio-economic factors in risk of schizophrenia in Greece. Br J Psychiatry. 1988;152482- 486
Hare  EHPrice  JS Birth rank in schizophrenia: with a consideration of the bias due to changes in birth-rate. Br J Psychiatry. 1970;116409- 420
Schooler  C Birth order and hospitalization for schizophrenia. J Abnorm Soc Psychol. 1964;69574- 579
Hinshelwood  RD The evidence for a birth order factor in schizophrenia. Br J Psychiatry. 1970;117293- 301
Erlenmeyer-Kimling  L The problem of birth order and schizophrenia: a negative conclusion. Br J Psychiatry. 1969;115659- 678
Sundararaj  NSridhara  BSRao  R Order of birth and schizophrenia. Br J Psychiatry. 1966;1121127- 1129
Barry  H  IIIBarry  H  Jr Birth order, family size, and schizophrenia. Arch Gen Psychiatry. 1967;17435- 440
Granville-Grossman  KL Birth order and schizophrenia. Br J Psychiatry. 1966;1121119- 1126
Burton  ABird  JW Family constellation and schizophrenia. J Psychol. 1963;55329- 336
Birtchnell  J Birth rank and mental illness. Nature. 1971;234485- 487
Hare  EHPrice  JS Birth order and family size: bias caused by changes in birth rate. Br J Psychiatry. 1969;115647- 657
Price  JSHare  EH Birth order studies: some sources of bias. Br J Psychiatry. 1969;115633- 646
Berglin  CG Birth order as a quantitative expression of date of birth. J Epidemiol Community Health. 1982;36298- 302
Mednick  SAMachon  RAHuttunen  MOBonett  D Adult schizophrenia following prenatal exposure to an influenza epidemic. Arch Gen Psychiatry. 1988;45189- 1921
O'Callaghan  ESham  PTakei  NGlover  GMurray  RM Schizophrenia after prenatal exposure to 1957 A2 influenza epidemic. Lancet. 1991;3371248- 1250
Barr  CEMednick  SAMunk-Jorgensen  P Exposure to influenza epidemics during gestation and adult schizophrenia: a 40-year study. Arch Gen Psychiatry. 1990;47869- 874
Sham  PCO'Callaghan  ETakei  NMurray  GKHare  EHMurray  RM Schizophrenia following pre-natal exposure to influenza epidemics between 1939 and 1960. Br J Psychiatry. 1992;160461- 466
Adams  WKendell  REHare  EHMunk-Jorgensen  P Epidemiological evidence that maternal influenza contributes to the aetiology of schizophrenia: an analyses of Scottish, English, and Danish data. Br J Psychiatry. 1993;163522- 534
Takei  NSham  PO'Callaghan  EMurray  GKGlover  GMurray  RM Prenatal exposure to influenza and the development of schizophrenia: is the effect confined to females? Am J Psychiatry. 1994;151117- 119
Takei  NOs  JVMurray  RM Maternal exposure to influenza and risk of schizophrenia: a 22 year study from the Netherlands. J Psychiatr Res. 1995;29435- 445
Kunugi  HNanko  STakei  NSaito  KHayashi  NKazamatsuri  H Schizophrenia following in utero exposure to the 1957 influenza epidemics in Japan. Am J Psychiatry. 1995;152450- 452
Takei  NMortensen  PBKlæning  UMurray  RMSham  PCO'Callaghan  EMunk-Jorgensen  P Relationship between in utero exposure to influenza epidemics and risk of schizophrenia in Denmark. Biol Psychiatry. 1996;40817- 824
Crow  TJDone  DJJohnstone  EC Schizophrenia and influenza. Lancet. 1991;338116- 117
Cannon  MCotter  DCoffey  VPSham  PCTakei  NLarkin  CMurray  RMO'Callaghan  E Prenatal exposure to the 1957 influenza epidemic and adult schizophrenia: a follow-up study. Br J Psychiatry. 1996;6368- 371
Kendell  REKemp  IW Maternal influenza in the etiology of schizophrenia. Arch Gen Psychiatry. 1989;46878- 882
Torrey  EFBowler  AERawlings  R Schizophrenia and the 1957 influenza epidemic. Schizophr Res. 1992;6100
Susser  ELin  SPBrown  ASLumey  LHErlenmeyer-Kimling  L No relation between risk of schizophrenia and prenatal exposure to influenza in Holland. Am J Psychiatry. 1994;151922- 924
Erlenmeyer-Kimling  LFolnegovic  ZHrabak-Zerjavic  VBorcic  BFolnegovic-Smalc  VSusser  E Schizophrenia and prenatal exposure to the 1957 A2 influenza epidemic in Croatia. Am J Psychiatry. 1994;1511496- 1498
Selten  JPSlaets  JP Evidence against maternal influenza as a risk factor for schizophrenia. Br J Psychiatry. 1994;164674- 676
Morgan  VCastle  DPage  AMontgomery  PGurrin  LBurton  PFazio  SJablensky  A Influenza epidemics and the incidence of schizophrenia, affective disorders and mental retardation: further data from Western Australia [abstract]. Schizophr Res. 1998;2918
Rantakallio  PJones  PMoring  Jvon Wendt  L Association between central nervous system infections during childhood and adult onset schizophrenia and other psychoses: a 28-year follow-up. Int J Epidemiol. 1997;26837- 843
Torrey  EFYolken  RH Is household crowding a risk factor for schizophrenia? Schizophr Res. 1998;2912- 13
Malig  C The Civil Registration System in Denmark.  Bethesda, Md International Institute for Vital Registration and Statistics December1996;1- 9IIVRS Technical Papers, No. 66.
Mortensen  PBPedersen  CBWestergaard  TWohlfahrt  JEwald  HMors  OAndersen  PKMelbye  M Effects of family history and place and season of birth on the risk of schizophrenia. N Engl J Med. 1999;340603- 608
Munk-Jorgensen  PMortensen  PB The Danish Psychiatric Central Register. Dan Med Bull. 1997;4482- 84
Breslow  NEDay  NE Statistical Methods in Cancer Research: The Design and Analysis of Cohort Studies. Vol 2 Lyon, France International Agency for Research on Cancer1987;
SAS Institute, The GENMOD procedure. SAS/STAT Software: Changes and Enhancements for Release 6.12. Cary, NC SAS Institute1996;21- 42
Bruzzi  PGreen  SBByar  DPBrinton  LASchairer  C Estimating the population attributable risk for multiple risk factors using case-control data. Am J Epidemiol. 1985;122904- 914
Susser  MSusser  E Separating heredity and environment, I: genetic and environmental indicators. Susser  Med.Epidemiology, Health and Society: Selected Papers. New York, NY Oxford University Press1987;103- 114
Khoury  MJBeaty  THCohen  BH Fundamentals of Genetic Epidemiology.  New York, NY Oxford University Press1993;131
Ernst  CAngst  J Birth Order: Its Influence on Personality.  Berlin, Germany Springer-Verlag1983;
Hansen  EJ Who Breaks the Social Inheritance? The Final Report From the Longitudinal Survey of a Generation of Adolescents' Educational and Occupational Choice, Parts I and II [in Danish, with an English summary].  Prepared for The Danish National Institute of Social Research. Copenhagen, Denmark: Teknisk Forlag1982;Publication 112.
Brown  ASSusser  ESButler  PDAndrews  RRKaufmann  GAGorman  JM Neurobiological plausibility of prenatal nutritional deprivation as a risk factor for schizophrenia. J Nerv Ment Dis. 1996;18471- 85
Myrianthopoulos  NCMelnick  M Studies in neural tube defects, I: epidemiologic and etiologic aspects. Am J Med Genet. 1987;26783- 796
Susser  EHoek  HWBrown  A Neurodevelopmental disorders after prenatal famine: the story of the Dutch famine study. Am J Psychiatry. 1998;147213- 216

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 69

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Topics
JAMAevidence.com

Users' Guides to the Medical Literature
Influenza

The Rational Clinical Examination
Make the Diagnosis: Influenza