Long-term Survival of Patients With Anorexia Nervosa: A Population-Based Study in Rochester, Minn

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Original Article

Long-term Survival of Patients With Anorexia Nervosa: A Population-Based Study in Rochester, Minn SERGIO R. KORNDÖRFER, MD; ALEXANDER R. LUCAS, MD; VERA J. SUMAN, PHD; CYNTHIA S. CROWSON, BS; LOIS E. KRAHN, MD; AND L. JOSEPH MELTON III, MD

• Objective: To estimate long-term survival of unselected patients with anorexia nervosa from Rochester, Minn. • Patients and Methods: In this population-based retrospective cohort study, all 208 Rochester residents who presented with anorexia nervosa (193 women and 15 men) for the first time from 1935 through 1989 were monitored for up to 63 years. Subsequent survival was compared with that expected for Minnesota white residents of similar age and sex, and standardized mortality ratios were determined on the basis of age- and sex-specific death rates for the US population in 1987. • Results: Survival was not worse than expected in this cohort (P=.16). The estimated survival 30 years after the initial diagnosis of anorexia nervosa was 93% (95% confidence interval, 88%-97%) compared with an expected 94%. During 5646 person-years of follow-up (median, 22 years per patient), 17 deaths occurred (14 women and 3

men) compared with an expected 23.7 deaths (standardized mortality ratio, 0.71; 95% confidence interval, 0.421.09). One woman died of complications of anorexia nervosa, 2 women committed suicide, and 6 patients (5 women and 1 man) died of complications of alcoholism. Other causes of death were not increased. • Conclusions: Long-term survival of Rochester patients with anorexia nervosa did not differ from that expected. This finding suggests that overall mortality was not increased among the spectrum of cases representative of the community. Mayo Clin Proc. 2003;78:278-284 CI = confidence interval; DSM-III-R = Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition; ICD-9CM = International Classification of Diseases, Ninth Revision, Clinical Modification; SMR = standardized mortality ratio

O

pected for similar individuals without the disease. These problems are overcome by estimating standardized mortality ratios (SMRs), which indicate that death rates among patients with anorexia nervosa are 1.4 to 17 times higher than expected.9-20 Although these figures suggest that anorexia nervosa has a substantial negative effect on survival, most of the studies were performed at referral centers, which tend to treat severely affected patients who have had multiple treatments and relapses.

utcomes among patients with anorexia nervosa are extremely variable. Many patients recover fully, others have recurrent episodes or have chronic disease, and some die of complications of their disease.1(pp186-208),2 A general belief is that the overall risk of death is increased among these patients, but investigations that have addressed this issue have varied in study population, diagnostic criteria, extent of follow-up, and period analyzed.3 Most of the early investigations reported crude mortality (the proportion of patients who died during follow-up) ranging from 0% to 22%.4,5 One review indicated that the crude mortality appeared to have declined over time, from about 10% in the 1950s to about 4% in the 1980s,6 with recent rates of 2% to 6%.7-9 However, these calculations do not account for variability in the duration of follow-up, and they do not compare survival to that which would be ex-

For editorial comment, see page 273. In contrast to the high mortality rates reported in clinical studies, an average of 145 deaths annually (from more than 10 million deaths registered with the National Center for Health Statistics for 1986-1990) were attributed to anorexia nervosa.21 Although undoubtedly an underestimate because anorexia nervosa may not be noted as the immediate or underlying cause of death, this suggests that the death rate might be much lower than generally surmised from clinical studies. To obtain a more representative picture, we examined the survival of a population-based cohort of residents of Rochester, Minn, who met diagnostic criteria for anorexia nervosa during the 55-year period 1935 through 1989 and who were subsequently monitored for up to 63 years.

From the Department of Psychiatry and Psychology (S.R.K., A.R.L., L.E.K.) and Department of Health Sciences Research (V.J.S., C.S.C., L.J.M.), Mayo Clinic, Rochester, Minn. Dr Korndörfer is now with Children’s Hospital, Harvard Medical School, Boston, Mass. This study was supported in part by research grant AR30582 from the National Institutes of Health, US Public Health Service. Address reprint requests and correspondence to L. Joseph Melton III, MD, Department of Health Sciences Research, Mayo Clinic, 200 First St SW, Rochester, MN 55905. Mayo Clin Proc. 2003;78:278-284

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PATIENTS AND METHODS Population-based epidemiological research can be conducted in Rochester because local residents receive their medical care through a limited number of institutions, and the resultant medical records are available from almost all providers.22 Mayo Clinic provides primary and specialized care for the local population and has maintained a common medical record with its 2 affiliated hospitals (Saint Marys and Rochester Methodist) for more than 90 years. This dossier-type record contains both inpatient and outpatient data, and the diagnoses and surgical procedures recorded in these records are entered into a computerized index.23 Diagnostic information from the other providers who serve the Rochester population, most notably the Olmsted Medical Group and its affiliated Olmsted Community Hospital (Olmsted Medical Center), is indexed into the same system (the Rochester Epidemiology Project) and is also available for study.22 After approval from the Mayo Foundation Institutional Review Board, we used this unique database to identify all 208 Rochester residents who had lived in the community for at least 1 year when they presented with anorexia nervosa for the first time in 1935 through 1989. As detailed previously,24 the diagnostic indices were accessed to obtain a listing of individuals with any one of the following conditions: anorexia nervosa, eating disorder, bulimia, compulsive eating, anorexia, appetite loss, rumination, amenorrhea, oligomenorrhea, menstrual irregularity, abnormal menses, menstrual dysfunction, delayed menses, anovulation, nutritional disturbance, inadequate diet, malnutrition, starvation, weight loss, and being underweight. The complete (inpatient and outpatient) medical records were then screened to identify patients who met criteria from the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R)25 and Pathology of Eating Group26 for definite, probable, or possible anorexia nervosa as follows: (1) self-imposed weight loss of at least 15% from prior weight or weight 15% less than that projected for those still growing; (2) amenorrhea in female patients (premenarcheal or absence of periods for at least 2 consecutive menstrual cycles) and suggestive evidence of endocrine dysfunction in male patients (decreased testosterone and libido); (3) psychological disorder manifested by fear of fatness or loss of control of eating, expressed or implied; and (4) no physical illness to account for weight loss. Based on the completeness of information in each patient’s medical record, definite cases met all 4 criteria. Probable cases met 3 criteria including criteria 1 and 4 (either 2 or 3 was unknown or absent), whereas possible cases fulfilled criteria 1 and 4 (both 2 and 3 were unknown or absent). Of note, one of us (A.R.L.) carefully reviewed the patient records and applied his best clinical judgment to

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ensure that all patients were indeed significantly underweight rather than having simply lost 15% or more from an above-average weight. Review of these medical records for research was authorized in accordance with Minnesota state law.27 After additional approval by the institutional review boards of the Mayo Foundation and the Olmsted Medical Center, these patients were then followed up through their linked medical records in the community (retrospective cohort study) until death or the most recent clinical contact. Vital status was further updated through commercial sources and patient contact letters. The termination date for contact was June 30, 2000. Among decedents, the underlying cause of death was assigned from death certificate data by a trained nosologist, and all deaths were coded to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM).28 The distribution of survival times was estimated by using the Kaplan-Meier method.29 The expected survival was determined for an age- and sex-matched cohort from the Minnesota white population by first obtaining the expected cumulative hazard of death for each individual in the reference cohort from life tables and then weighting these individual cumulative hazards to construct the expected survival curve for the matched cohort.30,31 A 1-sample Gehan generalized Wilcoxon test was performed to compare the survival of the patients with anorexia nervosa to that of the age- and sex-matched cohort.32 A log-rank test was used to compare survival among the patients with definite, probable, and possible anorexia nervosa. All reported P values are 2tailed, and P<.05 is considered statistically significant. Overall and cause-specific SMRs were determined for the entire period of observation to evaluate deaths due to specific causes. For each specific cause of death, the expected number of deaths was based on a person-years analysis.33 Because Minnesota data were not available, ageand sex-specific death rates for the US population in 1987 were used to calculate the expected numbers.34 We included all major diagnostic groupings whether or not any deaths due to these causes were observed. Confidence interval (CI) calculations were based on Taylor-series expansion and normality assumptions.35 RESULTS Altogether, 208 Rochester residents (193 women and 15 men) first met the criteria for anorexia nervosa in the 55year period 1935 through 1989. The patients ranged in age from 10 to 57 years, with a median age at diagnosis of 19 years (mean, 21.5 years), which was similar in women and men. All the patients were white, reflecting the racial composition of the community (99% white in 1970). Eightytwo patients (39%) had definite anorexia nervosa, 92

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100

Observed

Survival (%)

80

Expected

60 40 20 0 0

10

20

30

40

50

60

Years after diagnosis

Figure 1. Observed and expected survival among Rochester, Minn, residents first diagnosed with anorexia nervosa from 1935 through 1989.

(44%) had probable anorexia, and 34 (16%) had possible anorexia. Of the female incidence cases, 80 (41%) were definite cases of anorexia nervosa, 84 (44%) were probable cases, and 29 (15%) were possible cases. Among the male incidence cases, 2 (13%) were definite cases, 8 (53%) were probable cases, and 5 (33%) were possible cases. After anorexia nervosa was initially recognized, the study cohort was followed up for a total of 5646 personyears. This represents 92% of the total duration of followup that would have been possible if all surviving patients had been observed until the termination of update activities (6106 person-years). The mean duration of follow-up was 27.1 years (median, 22 years; range, 1 day to 63 years), and 96% of patients were followed up for at least 10 years. At last contact, 17 patients (14 women and 3 men) had died. The expected number of deaths in the age- and sexmatched reference cohort of Minnesota white people was 23.7 (19.3 for women and 4.4 for men) for an overall SMR of 0.71 (95% CI, 0.42-1.09). Thus, overall survival among the patients with anorexia nervosa was not worse than that expected (P=.16) (Figure 1) and did not differ between the patients diagnosed in the first 30 years of the study and those diagnosed in the last 25 years (P=.15). By 30 years after the initial diagnosis, an estimated 93% (95% CI, 88%97%) of the patients were still alive compared to an expected 94%. The SMR for this more restricted period of observation was 1.30 (95% CI, 0.62-2.38). Six of the deaths occurred among the 82 patients (7%) with definite anorexia nervosa, 8 among the 92 patients (9%) with probable anorexia nervosa, and 3 among the 34 patients (9%) with possible anorexia nervosa. Survival did not differ among these groups (P=.88), and the SMRs were 0.92 (95% CI, 0.30-2.14), 0.87 (95% CI, 0.40-1.65), and 0.38 (95% CI, 0.08-1.10), respectively.

The causes of death are shown in Table 1. Of note, one woman died of cardiac arrest at age 41 years (13 years after her initial diagnosis), and anorexia nervosa was listed on the death certificate as the underlying cause. This patient had never sought treatment. When she was brought to the emergency department, she was moribund and in a state of severe inanition. She had a cardiac arrest and died shortly after being admitted to the hospital. Anorexia nervosa was not listed on the death certificates for the other patients. However, 2 women committed suicide (carbon monoxide poisoning in each instance) at ages 33 and 47 years; this was 14 and 17 years, respectively, after the initial diagnosis of anorexia nervosa. Five women (ages 27, 33, 37, 70, and 71 years) and 1 man (age 48 years) died of complications of alcoholism 15, 14, 2, 51, 13, and 22 years, respectively, after diagnosis. Other than for mental disorders, the distribution of underlying causes of death did not differ significantly from that expected (Table 2). DISCUSSION In this first population-based study of unselected cases of anorexia nervosa from Rochester, we found no reduction in long-term survival compared with that expected for Minnesota white women and men of comparable age. Only 1 patient died of complications directly related to anorexia nervosa. This relatively benign prognosis compared to previous reports is probably primarily due to the mild clinical spectrum represented by unselected patients from the general population. Indeed, most of the Rochester patients had never seen a psychiatrist for anorexia nervosa, and few had been hospitalized for the condition.24 However, all the patients were identified on the basis of signs, symptoms, or diagnoses consistent with anorexia nervosa, and care was taken to use the standard DSM-III-R criteria25 extant at the time of the study as well as the Pathology of Eating Group criteria.26 The resulting incidence rates for anorexia nervosa,24,36 which have been widely accepted as the standard in the field, are in close agreement with the best studies in other countries.1(pp59-76),37,38 This suggests that the diagnostic criteria used herein were not excessively broad and that they resulted in a number of community cases similar to those reported by others. However, there were 2 suicides and 6 deaths related to alcoholism; thus, all the underlying psychiatric problems may not have been resolved.2 An association of anorexia nervosa with depression has long been recognized,39-41 and an increase in deaths due to suicide has been reported previously.17,19,42,43 In contrast, data from the National Center for Health Statistics suggest that suicide rates are not increased among women when anorexia nervosa is listed on the death certificate as an underlying cause or accompanying cause of death.44 Although clinical studies are

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Table 1. Deaths Among Rochester, Minn, Residents First Diagnosed With Anorexia Nervosa, 1935-1989* Year of Dx

Age at Dx (y)

Weight recovered

Clinical condition

Age at death (y)

1950

35

Yes

Probable

Alcoholism

37

2

Hepatic failure

1960

27

No

Definite

Inanition

41

13

Cardiac arrest

1973

57

No

Probable

Alcoholism

71

13

Pneumonia

1977

18

No

Probable

33

14

Suicide

1980

12

Yes

Probable

27

15

1962

20

Yes

Definite

36

16

Acute alcohol toxicity Astrocytoma

1942

30

Yes

Possible

Alcoholism, depression Alcoholism, depression Diabetes mellitus Depression

47

17

Suicide

1936

34

No

Probable

Pulmonary tuberculosis

59

25

1939

12

Yes

Definite

Malignancy

41

29

1944

48

Yes

Possible

84

36

1941

20

Yes

Definite

Cardiac disease Malignancy

60

39

1938

19

No

Probable

Alcoholism

70

51

Generalized convulsive disorder Pulmonary metastatic malignancy Coronary insufficiency Adenocarcinoma of pancreas Hepatic failure

1936

22

Yes

Probable

Depression

75

53

1937

35

Yes

Definite

Cardiac disease

94

58

Diagnostic certainty

Years after Dx

Immediate cause of death

Underlying cause of death (ICD-9-CM)

Other important underlying condition

Women

Alzheimer disease Congestive heart failure

Alcoholic cirrhosis (571.2) Anorexia nervosa (307.1) COPD (496.0) Carbon monoxide poisoning (986) Alcohol poisoning (980.9) Astrocytoma (191.9) Carbon monoxide poisoning (986) Seizure disorder NOS (780.3)

None None Atherosclerotic vascular disease Acute alcohol intoxication Alcoholism Seizure disorder None Generalized arteriosclerosis

Malignant neoplasm of cervix (180.9)

None

Coronary atherosclerosis (414.0) Adenocarcinoma of pancreas (157.9) Chronic liver disease (572.8) Alzheimer disease (290.1) Heart failure (428.0)

Old myocardial infarction None Malnutrition None Hypertension, COPD

Men 1936

25

Yes

Probable

Alcoholism

48

22

1962

49

Yes

Possible

85

35

1935

12

Yes

Probable

Cardiac disease Depression

75

62

Lobar pneumonia Sudden cardiac death Pneumonia

Lobar pneumonia (486) Heart disease NOS (429.9) Pneumonia unspecified (486)

None Aspiration pneumonia Alzheimer dementia, anoxic encephalopathy

*COPD = chronic obstructive pulmonary disease; Dx = diagnosis; ICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical Modification; NOS = not otherwise specified.

skewed in the direction of greater pathology, death certificates likely underestimate the frequency of anorexia nervosa as a cause of death and as a contributing cause of suicide. Indeed, anorexia nervosa was not mentioned on the death certificate of 16 of our 17 patients who died. Deaths due to alcoholism appear to be common among patients with eating disorders19,45 but have received little detailed attention46-48 despite the fact that alcohol dependence is overrepresented among patients with anorexia nervosa.49 Conversely, Peveler and Fairburn50 reported that

19% of women attending an alcohol treatment program had a history of anorexia nervosa. Also, first-degree relatives of patients with anorexia nervosa have significantly more alcoholism than do relatives of controls, suggesting that there may be a similar predisposition to the 2 disorders.51 The association of alcoholism with bulimia nervosa is particularly strong.48 Patients with bulimia nervosa, compared with those with anorexia nervosa, are prone to impulsive behaviors, including experimentation with alcohol, and it is well known that a significant proportion of patients with

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Table 2. Number of Deaths Observed and Expected and Standardized Mortality Ratio by Underlying Cause Among Rochester, Minn, Residents First Diagnosed With Anorexia Nervosa, 1935-1989* No. of deaths Underlying cause (ICD-9-CM)

Observed

Expected

SMR

95% CI

Infectious and parasitic diseases (001-139) Neoplasms (140-239) Endocrine and metabolic diseases (240-279) Diseases of the blood (280-289) Mental disorders (290-319) Diseases of the nervous system (320-389) Diseases of the circulatory system (390-459) Diseases of the respiratory system (460-519) Diseases of the digestive system (520-579) Diseases of the genitourinary system (580-629) Complications of pregnancy (630-676) Diseases of the skin (680-709) Diseases of the musculoskeletal system (710-739) Congenital and perinatal conditions (740-779) Ill-defined conditions (780-799) Injury and poisoning (800-999)

0 3 0 0 2 0 3 3 2 0 0 0 0 0 1 3

0.45 7.75 0.70 0.10 0.22 0.47 10.40 1.87 1.03 0.39 0.00 0.04 0.12 0.07 0.32 2.21

0.00 0.39 0.00 0.00 9.14 0.00 0.29 1.60 1.95 0.00 … 0.00 0.00 0.00 3.08 1.36

0.00-8.20 0.08-1.13 0.00-5.26 0.00-37.0 1.11-32.9† 0.00-7.87 0.06-0.84 0.33-4.67 0.24-7.02 0.00-9.36 … 0.00-103 0.00-31.7 0.00-50.1 0.08-17.1 0.28-3.96

*CI = confidence interval; ICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical Modification; SMR = standardized mortality ratio. †Statistically significant increase, P<.05.

anorexia nervosa develop bulimia nervosa as their illness progresses.52 Therefore, it is likely that some of our patients became bulimic and began abusing alcohol. However, we do not have sufficient clinical information to confirm this supposition because many of the patients were not seen in treatment. Most patients with anorexia nervosa do not use alcohol. However, some young women may secretly begin abusing alcohol, become malnourished, and present with weight loss that is diagnosed as anorexia nervosa. In at least one of our patients, alcohol abuse occurred before she fulfilled the diagnostic criteria for anorexia nervosa, but the alcohol abuse was not known until years later. In addition, some deaths due to pneumonia are attributable to alcoholism among patients with psychiatric problems.53 Of importance, the 6 deaths due to alcoholism and/or pneumonia, which might directly or indirectly relate to anorexia nervosa, occurred a median of 13.5 years after the initial diagnosis of anorexia nervosa. This suggests that a thorough elicitation of history is necessary in patients with anorexia nervosa to identify alcohol abuse. Additionally, clinicians should monitor drinking behavior in such patients and provide close follow-up to ensure that this type of behavior is identified and treated. In a similar vein, we previously documented an increase in the risk of osteoporotic fractures among these patients, but the problem did not become evident for decades after the diagnosis of anorexia nervosa had first been made.54 Several previous reports have also compared observed with expected survival, but the results show considerable

variation that is attributable to selection of the study population. To our knowledge, no previous study has been strictly population based. Perhaps closest to this ideal was a study of patients with anorexia nervosa enumerated on the Aberdeen case register.11 The SMR for that group was 4.7, which was marginally significant given the 8 deaths observed; however, more than half of the patients had required hospitalization, and 20% had undergone electroconvulsive therapy. Consequently, these patients seem to have a more serious spectrum of disease compared with our community patients. Two studies of patients in specialized clinics reported an SMR of 14,12,13 whereas SMRs for patients requiring hospitalization have varied from 1.4 to 17.9-11,14-16,18-20 These findings indicate that no one “best” estimate of excess mortality exists and that prognosis relates to the clinical spectrum of disease in the patients being studied. The major strengths of our study are the inclusion of a representative sample of patients with anorexia nervosa from the general population and the long-term follow-up that is possible because of the unique medical records system in Rochester. Corresponding limitations relate to the relatively small number of patients diagnosed earlier in the study period and the restriction of the study to white patients due to the demographic composition of the community. However, the socioeconomic characteristics of the local population resemble those of the US white population in general.22 Moreover, the incidence of anorexia nervosa in our population36 is comparable to that in other recent population-based studies.55,56 Follow-up was relatively complete in our cohort (96% of subjects were followed up

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Mayo Clin Proc, March 2003, Vol 78

for at least 10 years), but the number of deaths was low. The limited numbers precluded a definitive exploration of the distribution of causes of death, particularly in the men. In addition, our data were insufficient to define precisely the subgroups of patients who might have had an increased risk of death. Specifically, we saw no difference in survival by diagnostic certainty (definite, probable, or possible anorexia nervosa), but diagnostic certainty is not synonymous with disease severity, although the two tend to be correlated in practice. Anorexia nervosa is a serious, often recurrent, and potentially fatal illness that has been increasing in frequency among young females.36 Although previous studies suggest that a diagnosis of anorexia nervosa implies a severe negative effect on survival, we found that survival in our population-based cohort of patients did not differ from that expected. This probably relates to the relatively mild disease expressed by these unselected community patients, few of whom were hospitalized or treated in a specialized outpatient center and most of whom eventually recovered.24 Prognosis is clearly worse among patients referred to tertiary centers for treatment of anorexia nervosa. Although our data suggest that overall mortality is not increased among community patients with anorexia nervosa in general, these findings should not lead to complacency in clinical practice because deaths do occur. In addition, more research is needed to define the association of suicide and alcoholism in patients with anorexia nervosa. Early recognition of anorexia nervosa and its appropriate treatment are warranted. This requires a sensitive balance between empathic support and the expectation of restoring normal eating patterns and weight. Efforts to enforce weight gain that are too aggressive can reinforce patient resistance and lead to chronicity. Associated psychological issues also need to be addressed. We acknowledge the participation of Mark I. Holub, MD, Margaret M. Saracino, MD, and Kenneth P. Offord, MS, in the review of patient records and the follow-up protocol. We thank Sara J. Achenbach, MS, for assistance with data analysis and Mary G. Roberts for help in preparing the submitted manuscript.

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