Mortality in anorexia nervosa in Denmark during the period

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1 ACTA PSYCHINRICA SCANDINAVICA ISSN YOX Mortality in anorexia nervosa in Denmark during the period Moiler-Madsen S, Nystrup J, Nielsen S. Mortality in anorexia nervosa in Denmark during the period Acta Psychiatr Scand 1996: 94: Munksgaard In this nation-wide register linkage study of the mortality among psychiatric in-patients with anorexia nervosa who were admitted between 1970 and 1986 (n=853), SO deaths were recorded during a mean follow-up period of 7.8 years (6680 person-years of observation). Among male subjects, five of 63 probands died, and the mean age at death was 24.5 years (range years). Among female subjects, 45 of 790 probands died, and the mean age at death was 36 years (range years). The standardized mortality ratio (SMR) was 9.1 in both sexes. A significantly increased SMR was demonstrated in males up to S years after index admission, and for females up to 15 years. There was no mortality among childhood-onset female subjects, but among males one death was recorded in this age group. In male subjects the highest SMR was found among those with index admission in the second decade of life, and in females among those with index admission in the third decade of life. The SMR was maximal during the first year after index admission. Suicide was the dominant cause of death among subjects 1 who died from unnatural causes (18 of 22 cases). Among those who died from natural causes (24 subjects), 13 individuals died from anorexia nervosa I and 11 individuals died from other illnesses. S. Msller-Mad~err',~, J. Nystr~p'.~. S. Niel~ed,~ 'Department of Psychiatry, Roskilde County Psychiatric Hospital, Roskilde, 'Psychosomatic Unit, University Clinic of Child and Adolescent Psychiatry, Bispebjerg Hospital, Copenhagen and 3Department of Psychiatric Demography, Psychiatric Hospital in Aarhus, Risskov. Denmark Key words: anorexia nervosa, mortality; causes of death: register study Susanne Maller-Madsen, Odensevej 48, DK-4000 Roskilde. Denmark Accepted for publication May 12, 1996 Introduction Mortality in anorexia nervosa has been studied by a number of authors, the majority of whom have reported only crude mortality rates (1). These crude rates range from 0% to 20%, and have been shown to increase with time (1). Only a few studies (2-6) have used a more sophisticated design, and to the best of our knowledge only four studies (3-6) have calculated the standardized mortality ratio (SMR). None of the published studies have stated the 95% confidence intervals (95% CI) of the reported SMR data, but in some instances it is possible to perform the necessary calculations using the information provided in the papers. The most thorough of these studies was conducted by Patton (3) who, for the whole group of eating disorders studied (n=460), reported an SMR of 6.17 after a mean follow-up period of 7.6 years. Crisp et al. (4) reported an SMR of 1.36 (non-significant) for the St George's sample (n=105) and 4.71 for the Aberdeen sample (n=63) after a 22-year follow-up period. Norring and Sohlberg (5) found an SMR of 17.8 in their cohort (n=48) at the 6-year follow-up, and Deter and Herzog (6) reported an SMR of 14.4 (9.6 for subjects discharged after the initial admission) in a group of 84 anorexia nervosa patients with an average follow-up period of 11.8 years. These four papers yielded results from a total of five cohorts and 760 patients, and the limited evidence provided by these studies is not consistent. A major problem is lack of information (wide confidence intervals), as most study samples are small, with very few deaths. The objective of this study was to obtain data for the mortality of a large sample of psychiatric anorexia nervosa in-patients, the details of which have been reported previously (7-9). We have no information about anorexia nervosa out-patients or somatic in-patients. As this investigation is a register study, some caution is needed in interpretation of our findings, and this will be dealt with in the relevant sections of the paper. The null hypothesis is that having been admitted as a psychiatric inpatient with anorexia nervosa as the main or 454

2 Mortality in anorexia nervosa secondary diagnosis does not affect mortality as estimated by the standardized mortality ratio (SMR). Some of our approaches will be of a descriptive and exploratory nature, which we consider justified in view of the present epistemiological status of this field of research. Material and methods The null hypothesis will be tested for subgroups of patients if possible, i.e. with regard to sex, age at admission, length of follow-up, and time period. We shall report the estimated SMR values with their corresponding 95 % confidence intervals (95% CI). Subject selection All patients whose data appeared in the Danish Central Register on Psychiatric Admission (10) in the period between 1 January 1970 and 31 December 1986 with ICD-8 (11) anorexia nervosa diagnosis as the main or secondary diagnosis were eligible for inclusion in the present study. Mortality and causes of death were ascertained by linking information from the above-mentioned register (10) to the Danish Central Persons Registry (CPR registry) by the unique person identifier (CPR number) and the Register on Causes of Death at the Danish National Health Board. In compliance with Danish legislation on pooling information from different public registers, and after obtaining permission from the relevant committees on ethics of scientific research, the record linkage was undertaken in a manner that ensured the anonymity of the probands. In addition, we asked the Register on Causes of Death at the Danish National Health Board for a list of individuals who had ICD-8 ED diagnoses on their death certificate and had never been psychiatric in-patients. The purpose of this was to obtain an estimate of the bias involved in using the psychiatric register as the sole source of information. Data handling A disc file containing the following variables was prepared by the Institute of Psychiatric Demography (10): month and year of birth; sex; ICD-8 ED diagnosis; time and age at admission (i.e. first anorexia nervosa admission); time and age at time of leaving the study; reason for leaving the study (death or censoring); number of former non-ed psychiatric admissions. Two types of censoring can occur. The patient may have been alive at the time when his or her vital status was ascertained (i.e. endpoint of study), or he or she may have emigrated on a certain day and been lost to follow-up from that time onward. The data-file was delivered by the end of 1994, and some discrepancies with the original file (7) were noted, the reasons for these differences being late reporting to the register and correction of data in the register. All dates and time periods were calculated by the decimal-years method (12), and most calculations were performed on a personal computer. For cross-tabulations and grouping of data the GLIM (13) and STATISTIX (14) software packages were used. Paired t-tests were performed in STATISTIX (14), and confidence intervals were calculated using the methods of Gardner and Altman (15) and the Confidence Interval Analysis (CIA) software package (16). Mortality Vital status was ascertained on 15 November SMR values for the relevant subgroups were calculated by the Danish Institute for Clinical Epidemiology as the observed number of deaths divided by the expected number of deaths for each group, taking into account sex, age group and time period. The expected mortality for a group is the sum of the expected mortalities for each individual in that group. The significance of the estimated SMR values was calculated following the recommendations of Breslow & Day (17); we used Equation (2.10) (a Chi-square test with continuity correction) in most cases and, in the case of fewer than five expected deaths in a group, a standard normal deviate method, Equation (2.11). The data for male subjects were only analysed in detail if significant mortality was found in the initial analysis. The separate analysis by sex is justified because of the well-known sex differences in the incidence and prevalence of these disorders. Results The study sample consisted of 853 probands, of whom 50 subjects were known to have died by the time of ascertainment of vital status. The total observation period encompassed 6680 personyears. The ascertainment rate for vital status was 853/853= 1.00, and the ascertainment rate for cause of death was 47/50=0.94. Causes of death Of the 50 fatal cases, cause of death could not be ascertained for three cases, due to late reporting to the register (10). In one case, cause of death remained unknown after ascertainment. Of the

3 Meller-Madsen et al. cases for whom cause of death was known, 24 subjects had died from natural causes and, of these, 13 subjects died as a direct consequence of anorexia nervosa. In two cases only anorexia nervosa appeared on the death certificate, but in the remaining 11 cases the following additional diagnoses were found: stroke (seven cases; one male and six female), pulmonary oedema (one case), pneumonia (one case), thrombophlebitis (one case) and fatty embolism (one case). Eleven patients died from other illnesses - four from cancer (one male case), three from hepatic cirrhosis, one from pneumonia, one from myocardial infarction, one from stroke and one from a collagenosis. Among the 22 cases of unnatural cause of death, suicide was the dominant mode of death (18 of 22 cases). The suicides were of a violent nature in 10 of the 18 cases. There were five cases of hanging (four females and one 14-year-old male), three female cases of drowning, one female case of jumping from a height and one 21-year-old male case of throat cutting. The remaining eight suicides (all female) involved drug overdose. Of the two cases who died as a result of accidents, one died from a fracture of the base of the skull and the other from a combination of thorax lesions and alcohol intoxication. In two cases the cause of death could not be established with sufficient certainty, despite a full post-mortem examination. Intoxication by alcohol and drugs was established as the immediate cause of death, but it was unclear whether death was due to suicide or accident. Thus anorexia nervosa and suicide together accounted for about 60% of the entire mortality in former psychiatric anorexia nervosa patients. Mortality rates The overall mortality rates according to sex are shown in Table 1. It can be seen that SMR was significantly increased in both sexes. There was no significant difference in SMR between male and female subjects. The ratio of the two standardized ratios was 1.12, with 95% CI of (16). With regard to mortality by length of follow-up, the initial analysis was performed separately for each sex. Male patients seem to die early in the course of their disease; the SMR is 20 in the first 5-year period after the psychiatric index admission. In males the difference in mean age at index admission between main and secondary diagnoses was not statistically significant (two-sample t-test with unequal variances: t=1.19, df=5.4, P=0.28) (14). The findings for female patients are summarized in Table 2. We found a significant difference in age Table 1 Mortality according to sex for anorexia nervosa patients Observed Expected Sex n mortality mortality SMR 95% CI Male " Female " Total a " * P<OOOl Table 2 Mortality according to length of follow-up for female anorexia nervosa patients (n=7901 Length of follow-up Observed Expected (years) rf mortality mortality SMR 95% CI <l o " " " " "" o Total " a Number of cases at the beginning of each observation period * P<O.OOl, ** P>0.1 (non-significant) at first psychiatric admission between females with anorexia nervosa as main diagnosis and those with anorexia nervosa as secondary diagnosis (main diagnosis, mean age 21.3 years, n=663, SD=7.5 years; secondary diagnosis, mean age 27.4 years, n=127, SD=12.1 years). The results of the twosample t-test with unequal variances were as follows: t=5.53, df=144.9, P<O.OOl (14). We did not find any significant difference in SMR values between the two diagnostic subgroups (the ratio of the two standardized ratios was 1.72, with 95% CI of ) (16). This overall finding was supplemented by a detailed analysis by length of follow-up, and in no case was a significant ratio of the two standardized ratios (SMR values) obtained. Thus we consider the analysis of female anorexia nervosa patients with main and secondary anorexia nervosa diagnosis together to be justified. SMR is significantly increased for female anorexia nervosa patients up to 14 years after the first psychiatric admission. There is a 13-fold increase in SMR in the first 5-year period, and an almost sixfold increase in the next two 5-year periods. The influence of age at first psychiatric admission for female anorexia nervosa patients is summarized in Table 3. We did not observe any mortality for female patients whose first psychiatric admission occurred before 15 years of age. SMR is maximally increased for patients whose first psychiatric admission took 456

4 ~ Mortality in anorexia nervosa place while they were in their twenties. There was a significant increase in SMR, even in female patients whose first psychiatric admission took place when they were above 3.5 years of age. The few male deaths show a somewhat different pattern. One case with first psychiatric admission at the age of 14 years also died at 14 years of age. Three cases with first psychiatric admission at the ages of 18 and 19 years died between the ages of 18 and 21 years. The last mortality occurred in a male patient with first psychiatric admission at the age of 48 years, who also died at the same age. Among male patients, the SMR is maximal in those with first psychiatric admission for anorexia nervosa when 1.5 to 19 years of age. Table 3. Mortality according to age at first psychiatric admission for female anorexia nervosa patients (n=790) Age at first psychiatric admission Observed Expected (years) n mortality mortality SMR 95%CI t ~ " " " "" a " Total " * PiOOOl. ** P<0005 Period effects To assess any possible change in SMR over time, we conducted a separate analysis of SMR in female patients, covering three 5-year periods, namely , and To reduce bias caused by the length of the follow-up (the SMR is highest in the first few years of follow-up), we omitted the cases who were first admitted during the years 1985 and The findings from this analysis are summarized in Table 4. In all periods the SMR was significantly increased (P<O.OOl), and in all pairwise analyses the 95% C1 around the ratio of the two standardized ratios (the SMR values) contained 'one' and thus we could not demonstrate a statistically significant period effect on SMR of the the first 5 years after index admission ( vs , ratio of the two SMR values=0.969, 9.5% CI= ; vs , ratio of the two SMR values=1.71, 9.5% CI=O ; vs , ratio of the two SMR values= 1.66, 95% CI=O ). Discussion Compared with previous publications in this field, this study is the largest record linkage register study of psychiatrically admitted anorexia nervosa patients drawn from an entire population over an extended time period. The present study thus has the following advantages. (i) The size of the study population is more than twice the size of the largest study sample reported to date (3). (ii) The duration of the follow-up period was up to 17 years, with a mean value of almost 8 years. (iii) Mortality rates were standardized against age, sex and period in the population from which the patients were drawn. (iv) High ascertainment rates were achieved for vital status and cause of death. (v) All deaths are recorded if a person lives in the area where the Table 4 Mortality according to period of first psychiatric admissioii for female anorexia nervosa patients (n=658) (follow-up period limited to the first 5 years) Observed Expected Period n mortality mortality SMR 95% CI " " " " * P<O001 CPR registry is enforced (i.e. the whole of Denmark except for the Faroe Islands). There are, of course, some limitations inherent in a register study. We have no clinical data and thus no way of ascertaining the validity of the clinical diagnoses or controlling for generally accepted important predictor variables. The catchment area study by Jorgensen (18) suggests that about one-third of the eating disorder patients who appear on the psychiatric register (10) do not fulfil the DSM-I11 criteria for eating disorders. On the other hand, only about 60% of the eating disorder patients were hospitalized, and thus the true number of eating disorder patients existing in the community seems to be fairly well reflected by the number of eating disorder cases appearing in the register (10). Hoek (19) made a similar observation in The Netherlands, where only 63% of the incident cases of anorexia nervosa were referred to health care services. The corresponding figure for bulimia nervosa was 58%. How do our findings compare with previous reports of the SMR in eating disorders'? The study by Patton (3) had a similar average length of follow-up to ours, and he also found a decrease in SMR with increasing duration of follow-up. As our sample is larger, we could demonstrate a significant 457

5 Msller-Madsen et al. increase in the SMR for a longer period than in his study. The analysis of SMR by age at presentation yielded different results. Patton found the highest SMR in those with presentation before the age of 20 years (3), whereas we found the highest SMR in female patients with first psychiatric admission in their twenties. In males, the highest SMR was found among subjects with first psychiatric admission at the age of years. Our findings do not support Patton s hypothesis that early-onset anorexia nervosa is a more malignant disorder, at least not in the case of female patients. In male subjects the situation might very well be different. Crisp et al. (4) reported so few deaths that a more detailed analysis is not possible. The non-significant increase in the St George s sample and the significant increase in SMR in the Aberdeen sample are interpreted as a treatment effect. Selection bias could be an alternative explanation. The distribution across causes of death is similar to our findings: about 50% die from anorexia nervosa and 50% from suicide. The small number of dead probands does not ensure stable figures. One difference from our findings is the relatively large number of late deaths reported by Crisp et al. (4). We observed the highest number of deaths in the first 5 years, and especially in the first year after the initial psychiatric admission for anorexia nervosa. The findings of Crisp et al. (4) are thus more similar to those of Theander (20) than to our own findings. Norring & Sohlberg (5) based their calculations of SMR on only three deaths (one case of anorexia nervosa and two cases of bulimia nervosa). Their finding of a higher SMR in bulimia than in anorexia nervosa is similar to the results reported by Patton (3). The estimated SMR values are necessarily rather inaccurate compared to our values. We have a larger number of dead probands than their entire sample of probands. Deter & Herzog (6) calculated an SMR of 14.4 for their 84 patients, and the SMR was 9.6 for patients only admitted once. They only report two suicides among the nine patients who died; the other deaths were due to sequelae of anorexia nervosa. Of special interest is their finding of a fourfold increase in somatic morbidity at follow-up (32% of anorexia nervosa cases vs. 8% in the background population). What is the magnitude and direction of bias introduced by using the psychiatric register (10) instead of a more comprehensive, but also more expensive, approach? The Danish National Health Board found that 42 subjects who had never had a psychiatric ED admission died from eating disorders. In total, 34 subjects had died from natural causes, three as a result of accidents, one from suicide, and in four cases the cause of death was unknown. The mean age at death was higher (50.5 years) than in the former psychiatric patients. From the additional diagnoses on the death certificates it emerged that many of these patients were elderly people in a cachectic stage at the time of death, and thus not typical anorexia nervosa cases. It appears that 17 cases with a mean age of 30.8 years at the time of death were probably genuine cases of anorexia nervosa; one of them died when 13 years old. Thus a rather conservative estimate is that the mortality from anorexia nervosa during the period of interest is increased by one-third by the adoption of a more comprehensive approach. The use of a time window for entry to the study tends to reduce the SMR, as some probands will have been ill for some time before the opening of the time window, that is, the resulting period at risk during which they might contribute to the denominator (expected mortality) cannot be seen. We have no way of estimating the bias stemming from this in the present study, but information from other studies of our sample (21) indicate that the effect of this does not alter the main conclusions. In no case could this bias change a significant finding to a non-significant one. How do our findings compare with those from studies of mortality in other groups of psychiatric inpatients? Mortensen & Juel (22), in a study of mortality and causes of death in first-admission schizophrenic patients, found similar suicide rates to those reported in the present study. An increased SMR during the first year after contact is similar to our own findings. The SMR for anorexic males is twice as high as the corresponding value for schizophrenic males, and for females the SMR is almost four times higher for anorexics than for schizophrenics. Licht et al. (23) studied mortality in Danish psychiatric long-stay patients (with more than 1 year of continuous hospitalization as an inpatient). After the necessary corrections of the anorexia nervosa data, the overall SMR was fourfold higher for female anorexic patients than for female long-stay patients. These comparisons might not be entirely appropriate without a detailed knowledge of the age structure in the long-stay patients (17, 24). In a long-term catchment area study from Bavaria, Fichter et al. (25) found a limited effect on mortality of mental illness alone (OR= 1.22), whereas comorbidity with certain somatic disorders had a significant effect (OR=2.12). Patients with no mental illness but with somatic illness had an OR of 2.0. Mortality was influenced by the severity of mental illness. In conclusion, psychiatric anorexia nervosa is a severe disorder with an SMR well above that for most other severe mental disorders, and a suicide rate identical to that observed for schizophrenia.

6 Mortality in anorexia nervosa In female subjects, the highest SMR is found among individuals in their twenties at first psychiatric admission. In males, the SMR is highest for subjects aged years at first psychiatric admission. The SMR is particularly high in the first year after initial admission. This calls for vigorous treatment efforts, especially in the first year after presentation, and for controlled treatment studies. One-third of the entire anorexia nervosa-related mortality could not be found by means of the psychiatric admission register. Studies on mortality in the eating disorders using the Standardized Rate Ratio (SRR) (17, 24) are warranted, as they will facilitate comparisons between studies. Acknowledgements This study was generously supported by Fru C. Hermansens Mindelegat, Snedkermester J. Wichmann og fru Else Wichmann s fond, Dansk Psykiatrisk Forskningsfond af 1967 and the Foundation for Research into Mental Disorders (grant no. 75). Methodological and statistical advice was provided by the Consultant Service (Jm and Jar )) of the Danish Medical Research Council. References 1. S~JLLIVAN PF. Mortality in anorexia nervosa. Am J Psychiatry 1995: 152: ISAGtK T, BRINCH M, KREINER S, TOISTRUP K. Death and relapse in anorexia nervosa: survival analysis in IS1 cases. J Psychiatr Res 1985: PAT-roru GC. Mortality in eating disorders. Psychol Med 1988: 1X: CRISP AH, CALLENDAR JS, HALEK C, Hsii LKG. Long-term mortality in anorexia nervosa. Br J Psychiatry 1992: 161: NORRING CEA, SOHLBERG SS. Outcome, recovery, relapse and mortality across six years in patients with clinical eating disorders. Acta Psychiatr Scand 1993: 87: DETER H-C, HERZOG W. Anorexia nervosa in a long-term perspective: results of the Heidelberg-Mannheim study. Psychosom Med 1994: 56: M~LLER-MADSEN S. NYSTRCJP J. Incidence of anorexia nervosa in Denmark. Acta Psychiatr Scand 1992: 86: M~LLER-MAUSEN SM, NYSTRUP J. Increased incidence of anorexia nervosa in Denmark (in Danish). Ugeskr Lzeger 1994: 156: M~LLEK-MADSEN SM, NYSTRUP J. Anorexia nervosa in Denmark - changes in diagnosis (in Danish). Ugeskr Lzeger 1994: 1.56: DUPONT A. A national psychiatric case register as a tool for mental health planning, research and administration. The Danish Model. In: LASKA EM et al., ed. Information support to mental health programs. New York: Human Sciences Press, 1983: World Health Organization. lnternational classification of diseases, 8th edn. Geneva: World Health Organization, 1965 (Danish version: Klassifikation af sygdomme. Copenhagen: Sundhedsstyrelsen, ). 12 TANNER JM. Foetus into man. Cambridge, MA: Harvard University Press, PAYNE CD (ed.). The GLIM system, release Oxford: Numerical Algorithms Group, Analytical Software. STATISTIX, Version 4.1. User s manual. Tallahassee, FL: Analytical Software, GAKDNER MJ, ALTMAN DG. Statistics with confidence. London: Br Med J, GARDNER MJ. GARDNER SB, WINTEK PD. Confidence interval analysis (CIA). London: Br Med J, BKESLOW NE, DAY NE. Statistical methods in cancer research. Vol. 11. The design and analysis of cohort studies. Lyon: International Agency for Research on Cancer J0RCiENSEN J. The epidemiology of eating disorders in Fyn County, Denmark, Acta Psychiatr Scand 1992: 85: HOEK HW. Review of the epidemiological studies of eating disorders. Int Rev Psychiatry 1993: 5: THEANDER S. Anorexia nervosa with an early onset: sclection, gender, outcome and results of a longterm follow-up study. J Youth Adolesc 1996: 25: NIELSEN S, MOLLER-MADSEN S. [SAGER T. J~RGENSEN J. PAGSBEKG, THEANDER S. Standardized mortality in eating disorders - a collaborative study. Paper presented at the Seventh New York International Conference on Eating Disorders, April, MOK-IENSEN PB, JLIEL K. Mortality and cause of death in first admitted schizophrenic paticnts. Br J Psychiatry 1993: 163: LICHT RW, MORTENSEN PB, GOULIAEV G, LOND J. Mortality in Danish psychiatric long-stay patients Acta Psychiatr Scand 1993: 87: RO.I.HMAN KJ. Modern epidemiology. Boston: Little, Brown and Company FICHTER MM, REHM J, ELTON M, DILLIN(; H, ACHATZ F. Mortality risk and mental disorders: longitudinal results from the Upper Bavarian Study. Psychol Med 1995: 25: