Research

JAMA Otolaryngology–Head & Neck Surgery | Original Investigation

Association of Long-term Risk of Respiratory, Allergic,
and Infectious Diseases With Removal of Adenoids
and Tonsils in Childhood
Sean G. Byars, PhD; Stephen C. Stearns, PhD; Jacobus J. Boomsma, PhD

IMPORTANCE Surgical removal of adenoids and tonsils to treat obstructed breathing or

recurrent middle-ear infections remain common pediatric procedures; however, little is
known about their long-term health consequences despite the fact that these lymphaticorgans play important roles in the development and function of the immune system.

Invited Commentary
page 603
Supplemental content

OBJECTIVE To estimate long-term disease risks associated with adenoidectomy,
tonsillectomy, and adenotonsillectomy in childhood.
DESIGN, SETTING, AND PARTICIPANTS A population-based cohort study of up to 1 189 061
children born in Denmark between 1979 and 1999 and evaluated in linked national registers
up to 2009, covering at least the first 10 and up to 30 years of their life, was carried out.
Participants in the case and control groups were selected such that their health did not differ
significantly prior to surgery.
EXPOSURES Participants were classified as exposed if adenoids or tonsils were removed
within the first 9 years of life.
MAIN OUTCOMES AND MEASURES The incidence of disease (defined by International
Classification of Diseases, Eighth Revision [ICD-8] and Tenth Revision [ICD-10] diagnoses) up
to age 30 years was examined using stratified Cox proportional hazard regressions that
adjusted for 18 covariates, including parental disease history, pregnancy complications, birthweight, Apgar score, sex, socioeconomic markers, and region of Denmark born.
RESULTS A total of up to 1 189 061 children were included in this study (48% female); 17 460
underwent adenoidectomy, 11 830 tonsillectomy, and 31 377 adenotonsillectomy; 1 157 684
were in the control group. Adenoidectomy and tonsillectomy were associated with a 2- to
3-fold increase in diseases of the upper respiratory tract (relative risk [RR], 1.99; 95% CI,
1.51-2.63 and RR, 2.72; 95% CI, 1.54-4.80; respectively). Smaller increases in risks for
infectious and allergic diseases were also found: adenotonsillectomy was associated with a
17% increased risk of infectious diseases (RR, 1.17; 95% CI, 1.10-1.25) corresponding to an
absolute risk increase of 2.14% because these diseases are relatively common (12%) in the
population. In contrast, the long-term risks for conditions that these surgeries aim to treat
often did not differ significantly and were sometimes lower or higher.
CONCLUSIONS AND RELEVANCE In this study of almost 1.2 million children, of whom 17 460

had adenoidectomy, 11 830 tonsillectomy, and 31 377 adenotonsillectomy, surgeries wereassociated with increased long-term risks of respiratory, infectious, and allergic diseases.
Although rigorous controls for confounding were used where such data were available, it ispossible these effects could not be fully accounted for. Our results suggest it is important toconsider long-term risks when making decisions to perform tonsillectomy or adenoidectomy.

JAMA Otolaryngol Head Neck Surg. 2018;144(7):594-603. doi:10.1001/jamaoto.2018.0614
Published online June 7, 2018.
594

Author Affiliations: Melbourne
Integrative Genomics, University of
Melbourne, Parkville, Victoria,
Australia (Byars); Centre for Social
Evolution, Department of Biology,
University of Copenhagen,Copenhagen, Denmark (Byars,
Boomsma); Department of Ecology
and Evolutionary Biology, Yale
University, New Haven, Connecticut(Stearns).
Corresponding Authors: Sean G.
Byars, PhD, Melbourne Integrative
Genomics, School of BioSciences,
Building 184, The University of
Melbourne, Victoria 3010, Australia(sean.byars@unimelb.edu.au).
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Association of Respiratory, Allergic, and Infectious Diseases With Removal of Adenoids and TonsilsA

denoids and tonsils are commonly removed inchildhood.1-4 Conventional wisdom suggests their absence has negligible long-term costs,3 but little support for this claim is available beyond estimates of short-termrisks. Understanding the longer-term impact of these surgeries is critical because the adenoids and tonsils are parts of theimmune system,3,5 have known roles in pathogen detection
and defense,3,5 and are usually removed at ages when thedevelopment of the immune system is sensitive.6-10 Some
single-disease studies have shown subtle short-term changes
in risk after surgery,11-14 but no estimates of longer-term risk
for a broad range of diseases are available. Here we analyze
the long-term risks after surgery for 28 diseases in approximately 1.2 million individuals who were followed from birth
up to age 30 years, depending on whether adenoidectomy,
tonsillectomy, or adenotonsillectomy occurred during thefirst 9 years of life.
Current research suggests that tonsils and adenoids playspecialized roles in immune system development andfunction. 15 The tonsils protect against pathogens both
directly 3,5 and indirectly by stimulating other immune
responses.3,5,16 The pharyngeal, palatine, and lingual tonsils
form Waldeyer’s ring around the apex of the respiratory anddigestive tract, providing early warnings for inhaled or ingested pathogens.3,5,16 Evidence now suggests that altering
early life immune pathways (including dysbiosis)17 can havelasting effects on adult health, warranting concern that thelong-term impact of removing adenoids and tonsils in childhood may not yet be fully appreciated.
Physicians often remove adenoids and tonsils to treat
recurrent tonsillitis or middle ear infections. Research on
consequences mostly relates to perioperative risks3,18 andshort-term changes in the symptoms treated. That tonsils(particularly the adenoids) shrink with age, being largest inchildren and absent in adults,1 suggests that their absence
might not affect adult health.3 However, their activity inearly-life could still be critical for normal immune systemdevelopment,3,5 especially given results on how perturbations to early growth and development alter risk of many
adult diseases.19,20
Except for rhinosinusitis, ear and throat infections,21,22 andsleep apnea,23 there has been little work on consequences ofremoving the adenoids or tonsils in childhood. Evidence thatadenoidectomy affects the risk of asthma is mixed.14 Tonsillectomy did not reduce the risk of respiratory diseases in adults,
but it may increase inflammatory bowel disease risk,13 and improvements in sleep apnea of children may be less than hopedfor.23 Surgery may change the risk of nonrespiratory diseases: tonsillectomy is associated with increased risks for certain cancer types11,24,25 and premature acute myocardial
infarctions,12 although mechanistic explanations for these associations remain elusive. Reduction of mucosa-associatedpathogens with tonsillectomy has been used to treat kidneydisease26,27 although beneficial effects are not consistent.28
These single-disease studies make clear that a comprehensive assessment of long-term health risks is needed.
In this study, we estimated disease risk depending onwhether adenoids, tonsils, or both were removed in the firstjamaotolaryngology.com

Original Investigation Research

Key Points
Questions Are there long-term health risks after having adenoids
or tonsils removed in childhood?
Findings In this population-based cohort study of almost 1.2
million children, removal of adenoids or tonsils in childhood was
associated with significantly increased relative risk of later
respiratory, allergic, and infectious diseases. Increases in long-term
absolute disease risks were considerably larger than changes inrisk for the disorders these surgeries aim to treat.
Meaning The long-term risks of these surgeries deserve carefulconsideration.

9 years of life. In contrast to previous single-disease, singlesurgery studies of short-term risks, we:
1. examined effects of all 3 surgeries at ages these are mostcommonly performed (both generally1,29 and in Denmark)(Figure 1) and most sensitive for immune development;
2. calculated long-term risks up to age 30 years for 28 diseases in 14 groups;
3. estimated relative and absolute risks and number ofpatients needed to treat (NNT) to obtain a first case of harm,
to adjust for background rates of disease, and produce clinically applicable numbers;
4. compared long-term postsurgical absolute risks and benefits for diseases and conditions that these surgeries aim totreat; and5. tested for general health differences between those in thecase group and those in the control group within the first 9
years of life to establish that individuals who had surgery
were not sicklier on average than the controls presurgery.

Methods
Study Sample Obtained From the Danish Health Registries
We used data from the Danish Birth Registry of approximately 1.2 million individuals born as singletons between 1979
and 1999 whose health was evaluated up to 2009. To match
initial health of cases and controls, we only included those notdiagnosed with the outcome diseases prior to surgery in thefirst 9 years of life (sample sizes presented in eTable 1 in the
Supplement). The Danish electronic medical records collected from birth to death reliably sample health sequelae.30,31
Individuals who had surgery after age 9 years were not included; most operations occurred before then (Figure 1). Large
sample sizes ensured high statistical power helping to avoid
type-2 errors (false-negative resuts). Having access to entire
medical histories from birth allowed us to match the health ofcases and controls prior to surgery within the first 9 years oflife. This reduced potential confounding from reverse causality so that Cox regression became the preferable approach visà-vis propensity analysis (eMethods in the Supplement). The
many covariates reduced the potential for confounding fromthose sources. We included individuals with 1 to 21 years of follow-up after age 9 years and those with nonoutlying values forbirth weights (1850-5400 g), gestation lengths (30-42 weeks),(Reprinted) JAMA Otolaryngology–Head & Neck Surgery July 2018 Volume 144, Number 7© 2018 American Medical Association. All rights reserved.

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Association of Respiratory, Allergic, and Infectious Diseases With Removal of Adenoids and Tonsils

paternal ages (15-60 years), and maternal ages (15-46 years) atbirth. We excluded individuals with missing covariate data andthose born before 1979 because their early-life health records
were incomplete (eMethods in the Supplement). The characteristics of the study population are shown in the Table.
Covariate data were obtained from the Danish Birth Registry and others: Danish Patient Registry with nationwide hospital admission and ICD-8 and ICD-10 diagnosis data; Danish
Psychiatric Registry with psychiatric diagnoses for inpatient admissions; and the Danish Civil Registration and Cause of Death
Registries with dates of death, migration, socioeconomic, andother information. We combined individual-level informationfrom different registries using unique deidentified personal identification numbers. Because data are collected for all Danish residents with a personal identification number assigned at birth(or on taking up residency), we are confident that we obtainedcomplete health and socioeconomic histories of the approximately 1.2 million individuals in the analyses.

Figure 1. Age at Adenoidectomy, Tosillectomy, and Adenotonsillectomy
for 1 753 100 Danes Born Between 1979 to 2009 and the Selected
Surgery Observation Window of 9 Years
A Adenoidectomy

5000

4000

Surgeries, No.

Research Original Investigation

3000

2000

1000

0
1

5

10

15

20

25

30

20

25

30

20

25

30

Age at Surgery
B

Tonsillectomy
3500

Defining Surgery Groups

3000
2500

Surgeries, No.

Of the 3 main types of tonsils—pharyngeal (the adenoids), palatine (the tonsils), and lingual—we focused on surgery removing the first 2 (adenoidectomy, tonsillectomy), because lingual
tonsils are not commonly removed, and on adenotonsillectomy,
where both are removed in the same surgery.
Surgery codes are based on ICD operation classification
codes from Statistics Denmark (up to 1996) and the Nordic
Medico-Statistical Committee (NOMESCO) Classification of Surgical Procedures (NCSP) from 1996 onwards including: adenoidectomy, 2618, EMB30; tonsillectomy, 2614, EMB10; adenotonsillectomy, EMB20. Prior to 1996, when there was nocode for adenotonsillectomy, we recorded this procedure whenboth codes (2618, 2614) had matching entry dates.

2000
1500
1000
500
0
1

5

10

15

Age at Surgery
C

Adenotonsillectomy
9000
8000

Selecting Disease Groups

Covariates
To account for possibly confounding effects on the prevalenceof outcome diseases, we included these covariates in Cox regressions: binary variables for maternal preexisting conditions (eTable 2 in the Supplement) including hypertension (primary or secondary hypertension, hypertensive heart, or renal
disease), diabetes (types 1 and 2, malnutrition-related, other or
596

Surgeries, No.

7000

We selected diseases thought to be affected by changes toimmunity (infections, allergies) and other disorders examined in studies of short-term health impacts of these procedures (respiratory infections). We also included broader disease groups (all circulatory, nervous system, endocrine, andautoimmune diseases) because immune dysfunction or dysbiosis could affect many processes (eTable 2 in the Supplement). In Denmark, ICD-8 and ICD-10 codes were used
before and after 1994, respectively. To reduce the likelihoodof false-negative results, we did analyses of statistical powerusing R statistical software (version 3.4.1, R Foundation);
this excluded some diseases with insufficient outcomes toadequately test the null hypothesis of no association
between surgery and incident disease (eMethods in the
Supplement).

6000
5000
4000
3000
2000
1000
0
1

5

10

This cut-off for inclusion as surgery cases (dark blue bars) was deemed optimal
because the first decade of life is critical for normal immune system development, it
represents most of the period in which these surgeries are usually performed, andmaximized the number of years available for disease follow-up after surgery. For
tonsillectomy this meant that we ignored a second peak at approximately 16 to 17
years because inclusion of these surgeries would have implied insufficient time forfollow-up (to 30 years). Our study thus explores the impact of the 3 types of surgery when performed during childhood rather than adolescence. Individuals withthese surgeries beyond the 9-year observation end point (dotted vertical line) were
not included as either cases or controls. Individuals were also excluded if they had
multiple surgeries at different ages, ie, some individuals underwent adenoidectomy followed by tonsillectomy years later or vice versa. Such cases were rare in
the sample (<0.2%).

unspecified), previous spontaneous or induced abortions; maternal pregnancy-related variables including gestation length

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15

Age at Surgery

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Association of Respiratory, Allergic, and Infectious Diseases With Removal of Adenoids and Tonsils

Original Investigation Research

Table. Characteristics of the Initial Study Sample (N = 1 753 100) for Surgery and Control Groupsa
No. (SD)
Characteristic

Adenoidectomy

Tonsillectomy

Adenotonsillectomy

Control

Total

Sample size, No. (%)

22 637 (1.3)

39 685 (2.3)

42 384 (2.4)

1 648 394 (94.0)

1 753 100

Paternal age mean (SD), y

30.1 (5.8)

29.7 (5.6)

30.1 (5.7)

31.3 (5.7)

Maternal age mean (SD), y

27.0 (4.9)

26.8 (4.7)

27.2 (4.8)

28.5 (4.8)

31.2 (5.7)
28.4 (4.9)

Gestation length, mean (SD),weeks

39.4 (1.9)

39.7 (1.6)

39.6 (1.7)

39.7 (1.6)

40.0 (1.6)

Maternal bleeding, % (SD)

9.6 (0.3)

8.1 (0.2)

9.0 (0.2)

7.3 (0.2)

7.4 (0.2)

Fetal oxygen deprivation, % (SD)0.13 (0.04)

0.13 (0.04)

0.09 (0.03)

0.09 (0.03)

0.09 (0.03)

Pregnancy edema, % (SD)1.44 (0.12)

1.42 (0.12)

1.08 (0.10)

0.79 (0.09)

0.82 (0.09)

Apgar score 1-10, mean (SD)

9.8 (0.7)

9.8 (0.5)

9.8 (0.6)

9.8 (0.6)

9.8 (0.6)3377 (597)3443 (537)3448 (574)3499 (541)3495 (543)Birth weight, mean (SD), grams
Preexisting hypertension (%)

0.26 (0.05)

0.15 (0.04)

0.27 (0.05)

0.33 (0.06)

Preexisting diabetes, % (SD)0.40 (0.06)

0.35 (0.06)

0.50 (0.07)

0.39 (0.06)

0.39 (0.06)

Previous induced abortion (%)

20.2 (0.4)

19.5 (0.4)

19.6 (0.4)

18.2 (0.3)

18.3 (0.3)

Previous spontaneous abortion,% (SD)

16.3 (0.3)

15.5 (0.3)

15.6 (0.3)

14.2 (0.3)

14.3 (0.3)

Education, combined total years,
mean (SD)24.4 (4.9)

24.5 (4.6)

24.4 (4.6)

25.6 (4.7)

25.5 (4.8)

381 030 (188 098)

394 585 (163 759)

361 933 (145 965)

362 241 (172 797)

363 188 (172 296)

7.69 (0.27)

6.89 (0.25)

6.83 (0.25)

Income, combined average,
mean (SD), DKK
Nationality (other than Danish)% (SD)

5.58 (0.23)

4.33 (0.2)

0.32 (0.06)

Region in Denmark most lived in,% (SD)
Hovedstaden

29.1 (0.4)

27.4 (0.4)

23.6 (0.4)

28.7 (0.4)

28.5 (0.4)

Sjælland21.8 (0.4)

18.6 (0.3)

16.2 (0.3)

14.5 (0.3)

14.7 (0.3)

Syddanmark23.1 (0.4)

19.7 (0.4)

22.1 (0.4)

22.4 (0.4)

22.3 (0.4)

Midtjylland

15.0 (0.3)

23.3 (0.4)

24.9 (0.4)

23.7 (0.4)

23.6 (0.4)

Nordjylland

10.8 (0.3)

10.7 (0.3)

13.0 (0.3)

10.5 (0.3)

Birth year, mean (SD)1988 (8)1987 (6)1991 (7)1994 (8)10.6 (0.3)
1993 (8)Birth season, month 1-12, mean(SD)

6.4 (3.3)

6.3 (3.3)

6.4 (3.3)

6.4 (3.3)

6.4 (3.3)

Female sex, % (SD)40.7 (0.4)

58.9 (0.4)

44.5 (0.5)

48.6 (0.5)

48.7 (0.5)

First born

46.2 (0.5)

45.5 (0.5)

47.9 (0.5)

44.1 (0.5)

44.3 (0.5)

Second born

37.2 (0.4)

38.2 (0.4)

35.1 (0.4)

37.3 (0.4)

37.3 (0.4)

Third born

12.0 (0.3)

12.3 (0.3)

12.6 (0.3)

13.8 (0.3)

13.7 (0.3)

Fourth (or higher born)

4.33 (0.20)

3.84 (0.19)

4.33 (0.20)

4.7 (0.21)

4.67 (0.21)

Demographic parity, % (SD)a

Numbers, means, percentages, and SDs are provided. This is the study sample
before outlying values and exclusions were applied; for exact sample sizes

used in Cox regression analyses for each disease group, see eTable 1 in the
Supplement.

(in weeks) and variables indicating maternal bleeding (hemorrhage, placenta praevia), fetal oxygen deprivation (hypoxia, asphyxia), and pregnancy edema. Parental variables included abinary code for whether either parent had ever been diagnosed within the same disease group as their child (accounting for familial transmission), education (total years summed
for both parents), and average income (summed 1979-2009
across both parents). Birth-related variables included birthweight (in grams), season (calendar month, 1-12) and cohort (3yearly between 1979-1999 accounting for putative changes indiagnostic criteria over time), and Apgar score of 1 to 10 (maximally 2 points for each category) given to newborns at 5 minutes of life ranging from poor to excellent health. Other childrelated variables included sex (male, female), nationality (Danish
national, immigrant), parity (first, second, third, fourth or higherborn), and the region in Denmark (Hovedstaden/Copenhagen,Sjælland, Syddanmark, Midtjylland, or Nordjylland) that individuals had resided in most, accounting for possible regional differences in diagnoses. Accurate data on parental and/or patient smoking status (a potentially important confounder) were
not available (ie, only available from 1993 onwards and assessed in a small percentage of parents).

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Statistical Design and Analysis
We used Cox regressions to estimate relative risk for the 28 diseases up to age 30 (with age as timescale), depending onwhether surgery occurred within the first 9 years of life. Cox
regression model assumptions were confirmed and proportional hazards ensured by stratifying for sex, birth cohort, birth
season and demographic parity while also accounting for 18
further covariates. To reduce chances of type-1 errors, Cox
regression P values were Bonferroni corrected for the 78 analy-(Reprinted) JAMA Otolaryngology–Head & Neck Surgery July 2018 Volume 144, Number 7© 2018 American Medical Association. All rights reserved.

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Research Original Investigation

Association of Respiratory, Allergic, and Infectious Diseases With Removal of Adenoids and Tonsils

ses performed (Bonferroni-corrected α P value <.05/
78 = 0.000641). To provide clinically useful results, absoluterisks and number of patients needed to treat (NNT) before causing benefit or harm to one of them were calculated from relative risks and disease prevalence within the first 30 years oflife (eMethods in the Supplement).
Each of the 3 surgeries was compared with controls (no surgeries during the study period) after ensuring they were otherwise of comparable health (see Testing for Biases in General Health Before Surgery section). Fewer than 0.2% of
individuals in the original sample underwent more than 1 surgery at different times, indicating no need to test for interaction effects between surgeries and later disease risks.

Estimating Risks for Nonimmune Diseases
and Conditions That Surgeries Aim to Treat
To weigh potential disease risks against benefits of surgery, we
calculated relative risks, absolute risks, and NNTs for the conditions that these surgeries treat using the same samples andstatistical setup described herein. Conditions included obstructive sleep apnea, sleep disorders, abnormal breathing,(chronic) sinusitis, otitis media, and (chronic) tonsillitis (eTable
2 in the Supplement). As a control, we tested whether surgeries were associated with diseases unrelated to the immune system, estimating risk for osteoarthritis, cardiac arrhythmias, heart
failure, acid-peptic disease and alcoholic hepatitis (eTable 2 in
the Supplement) using the same sample and statistical setup described herein. Results (eTable 3 in the Supplement) showed thatsurgery was not associated with these nonimmune diseases up
to age 30 years.

Testing for Biases in General Health Before Surgery
With complete medical records from birth, we tested whether
general health of cases and controls was different presurgery.
The null hypotheses tested were that there was no differencein general health between cases and controls for: (1) age at any
disease diagnosis, or (2) age at first diagnosis for diseases recorded before surgery. Neither null hypothesis was rejected, suggesting that cases were no less healthy than controls presurgery in the first 9 years of life. Power analyses confirmed
sufficient sample sizes and power to compare general health of
those in the case with those in the control groups (eMethods in
the Supplement).

Results
Association of Surgery With Risk of Respiratory Disease
Up to 1 189 061 children were analyzed in this study (48% female); 17 460 underwent adenoidectomy, 11 830 tonsillectomy, and 31 377 adenotonsillectomy; 1 157 684 were in the control group (eTable 1 in the Supplement). Tonsillectomy was
associated with nearly tripled relative risk of diseases of theupper respiratory tract (RR = 2.72; 95% CI, 1.54-4.80) (Figure 2)(eTables 4 and 5 in the Supplement) with a substantial increase in absolute risk (absolute risk difference [ARD], 18.61%)(eTable 4 in the Supplement) and a small number needed totreat (NNT-harm, 5) (eTable 4 in the Supplement), suggesting
598

that only about 5 tonsillectomies would need to be performed for an additional upper respiratory tract disease to be
associated with one of those patients. The degree to which tonsillectomy is associated with this disease in the overall population later in life may therefore be considerable.
Adenoidectomy was associated with more than doubled
relative risk of chronic obstructive pulmonary disorder([COPD]; RR = 2.11; 95% CI, 1.53-2.92) (Figure 2) (eTables 4 and6 in the Supplement) and nearly doubled relative risk of upper respiratory tract diseases (RR = 1.99; 95% CI, 1.51-2.63) andconjunctivitis (RR = 1.75; 95% CI, 1.35-2.26). This corresponds to a substantial increase in absolute risk for upper respiratory tract diseases (ARD = 10.7%; 95% CI, 5.49-17.56)(eTable 4 in the Supplement), but small increases for COPD
(ARD = 0.29%; 95% CI, 0.13-0.48) and conjunctivitis(ARD = 0.16%; 95% CI, 0.07-0.26), consistent with the NNT values (NNT-harm: diseases of upper respiratory tract = 9;
COPD = 349; conjunctivitis = 624) (eTable 4 in the Supplement). Although relative risk increases were similar for these
diseases, the large differences in absolute risk reflect the prevalence of these disorders in the population. Diseases of the upper respiratory tract occur 40 to 50 times more frequently (in10.7% of those in the control group aged ≤30 years) than do
COPD (0.25%) and conjunctivitis (0.21%).

Other Significant Effects on Long-term Disease Risks
For some diseases, even modest increases in relative risk (RR,
1.17-1.65) resulted in relatively large increases in absolute risk
(2%-9%) and low NNTs (NNT-harm <50) because of the highprevalence of these diseases in the population (control risk, 5%20%) (eTable 4 in the Supplement). These were mainly respiratory diseases (groups: all, lower, lower-chronic, asthma,pneumonia), infectious/parasitic diseases (all), skin diseases(all), musculoskeletal (all), and eye/adnexa (all). For example, adenotonsillectomy was significantly associated with
17% increased relative risk of infectious diseases (RR = 1.17; 95%
CI, 1.10-1.25) (eTables 4 and 7 in the Supplement). However,
because infectious diseases are relatively common (12%)(eTable 4 in the Supplement), the absolute risk increase of
2.14% was lower, but still suggested approximately 47 adenotonsillectomies would need to be performed for an extra
infectious disease to be associated with one of those patients(eTable 4 in the Supplement).
When all 28 disease groups were considered, there were
small but significant increases in relative risk for 78% of themafter Bonferroni correction. The negative health consequences of these surgeries within the first 30 years of life thus
appear to be consistent, affecting a range of tissues and organsystems. This highlights the importance of adenoids and tonsils for normal immune system development and suggests that
their early-life removal may slightly but significantly perturb
many processes important for later-life health.

Later-Life Risk of Conditions That Surgeries
Directly Aimed to Treat Were Mixed
Risks for conditions that surgeries aimed to treat were mixed(eTable 8 in the Supplement). Surgery was associated with significantly reduced long-term relative risk for 7 of 21 conditions

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Association of Respiratory, Allergic, and Infectious Diseases With Removal of Adenoids and Tonsils

Original Investigation Research

Figure 2. Risk of Disease Up to Age 30 Years After Removal of Tonsils and Adenoids in the First 9 Years of Life

DiseaseSurgery type
Adenoidectomy

Tonsillectomy

520

Adenotonsillectomy

Infectious/parasitic
AllergicAll
Rhinitis
Conjunctivitis
Eczema/dermatitis
Urticaria/angioedema
Skin
Autoimmune
Respiratory
All
Upper
Lower
Lower-chronic
AsthmaInfluenza
Pneumonia
COPD
Digestive
EndocrineAll
Obesity
GenitourinaryAll
Kidney infection
Musculoskeletal
Neoplasms
All
BenignCirculatory
NervousEye/adnexa
Mental
0.5

1.0

1.5

2.0

2.5

3.0

Relative Risk (RR)

0

10

15

Absolute Risk Difference

2 5

20

100

500

5000

Number Needed to Treat

Abbreviation: COPD, chronic obstructive pulmonary disorder. Relative risks (RR)
and 95% CIs are the exponents from Cox regressions that capture risk of eachdisease up to age 30 years depending on whether surgery was performed. The
RR P values significant after Bonferroni corrections for 78 tests are shown by ablue point above the upper confidence interval for each disease. The RR values
are presented only for analyses with sufficient power for hypothesis testing (seemethods). Absolute risk differences (ARD) and 95% CIs were estimated as
ARD = 100 × CR × (1-RR), where CR (control risk) is the risk of the disease in thecontrol sample and RR is the relative risk of disease in individuals post-surgery
relative to the disease risk in the control sample that did not undergo surgery.
Numbers needed to treat (NNT) and 95% CIs were estimated as
NNT = 100/ARD. The NNT values above or below zero indicate harm or benefit

associated with surgery, respectively, with values closer to 0 indicating harm
occurring more often to patients. For example, for risk of asthma after
adenoidectomy (ie, RR = 1.45; 95% CI, 1.33-1.57), the event rate in the control
group (or control risk, CR) for asthma up to age 30 years in our dataset was
5.8%, ARD = |100 × 0.058 x (1−1.45)| = 2.6 and NNT = 100/2.6 = 38. Relativerisk of asthma was 1.45 and thus 45% higher after adenoidectomy comparedwith controls (no surgery), which translates to an absolute risk difference of
2.6% or 2.6 more cases of asthma per 100 treated patients. In other words,
approximately 38 adenoidectomies would need to be performed for an
additional asthma diagnosis to be associated with one of those patients in thefirst 30 years of life. Note: urinary tract infections were not included in thekidney infection group.

(33% of our disease-specific analyses), with no changes for 9(43%) other conditions and significant increases for 5 (24%).
For example, adenoidectomy was associated withsignificantly reduced relative risk for sleep disorders(RR = 0.30; 95% CI, 0.15-0.60; ARD = −0.083%; 95% CI,−0.10 to −0.05), and all surgeries were associated with significantly reduced risk for tonsillitis and chronic tonsillitis(ie, RR = 0.09-0.54; ARD, −0.29% to −2.10%). For abnormal
breathing, there was no significant change in relative risk up
to 30 years of age after any surgery and no change in relativerisk for sinusitis after adenoidectomy or tonsillectomy. Con-

ditions where relative risk significantly increased included
otitis media, which showed a 2- to 5-fold increase postsurgery (RR, 2.06-4.84; ARD, 5.3%-19.4%), and sinusitis, which
increased significantly after adenotonsillectomy (RR = 1.68;
95% CI, 1.32-2.14; ARD = 0.11%; 95% CI, 0.05-0.19) (eDiscussion in the Supplement).
Thus, short-term health benefits of these surgeries forsome conditions may not continue up to age 30 years.
Indeed, apart from the consistently reduced risk for tonsillitis(after any surgeries) and sleep disorders (after adenoidectomy), longer-term risks for abnormal breathing, sinusitis,

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Research Original Investigation

Association of Respiratory, Allergic, and Infectious Diseases With Removal of Adenoids and Tonsils

Figure 3. Disease Risk Patterns for Covariates
Relative Risk
1.90+
1.70-1.90
1.50-1.70
1.30-1.50
1.10-1.30
1.01-1.10

Surgery type1.00
0.90-0.99
0.70-0.90
0.50-0.70
0.30-0.50
0-0.30Tonsillectomy

Adenoidectomy
Adenotonsillectomy

All

Infectious/parasitic

All
Rhinitis
Allergic

Conjunctivitis
Eczema/dermatitis
Urticaria/angioedema
All
All

Skin
Autoimmune

All
Upper
Lower
Respiratory

Lower-chronic
AsthmaInfluenza
Pneumonia
COPD
All

Digestive

All

Endocrine

Obesity
GenitourinaryAll
Kidney infection

Musculoskeletal
Neoplasms

All
All
BenignAll

NervousAll

Eye/adnexa

All

Mental

All

Pa
te
r
Ge Mat nal
Fe M st ern Ag
ta a ati a el O te on l A
xy rn Le ge
ge al ng
Pr n D Blee th
eg ep dina riv ng
nc at
Pr
ee
Ap y Ed ion
xi
st B gar emai
Pr Pre Pr ng irth Sco
ev v ee Hy W reio iou xi pe ei
us s st rt gh
Sp Ind ing en t
on uc D sio
ta ed iab n
ne A eto b e
Ed us A orti s
uc bo on
Pa at rtre io iont n L n
al ev
In el
c
Re
Re g Co om
gi ion un e
on S tRe Sy jœ ry
g d l
R io da lan
M egi n M nm dot on id aht rFa er Nor ylla k
th Wi dj nd
er th yl
W Di lanith so d
Di rdeso rrder

Circulatory

chronic sinusitis, and otitis media were either significantly
higher after surgery or not significantly different.

Risk Patterns for Covariates
The many associations between disease risk and covariateshighlight the complexity of the factors affecting diseases(Figure 3) (eTables 5-7 in the Supplement). Consider thosesignificantly associated with upper respiratory tract diseases (Figure 3) and their largest increases in relative (RR,
1.99-2.72) and absolute risks (ARD, 10.77%-18.61%) after
adenoidectomy and tonsillectomy (Figure 2). Risks for these
diseases slightly but significantly decreased for offspringborn to older mothers (RR = 0.96; 95% CI, 0.95-0.98; bothsurgeries), slightly increased (tonsillectomies) when maternal bleeding occurred during pregnancy (RR = 1.07; 95% CI,
1.03-1.12), increased (both analyses) with Apgar score(RR = 1.09; 95% CI, 1.04-1.13, both surgeries), increased600(both analyses) when mothers had a previous induced abortion (RR = 1.09; 95% CI, 1.06-1.12; both surgeries), increased
in immigrants relative to Danish nationals (RR = 1.40; 95%
CI, 1.33-1.47; both surgeries), decreased in those living anywhere in Denmark other than Copenhagen (RR, 0.69-0.93),
and increased when fathers or mothers had a history of thesame disease (RR, 1.29-1.38). Parental history of disease wassignificantly associated with prevalence in children foralmost all diseases (RR, 1.10-3.71).
Parental education, income, and country of origin had
many significant effects, but risk direction varied depending on the disease considered and were generally modest,
consistent with free health care for all residents in Denmark. For example, mental disorders were less frequent
in Danish nationals than immigrants (RR, 0.48-0.49),
but influenza risk was higher in Danes (RR, 1.89-2.06).
Endocrine and mental diseases were associated with

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Relative risk magnitude and direction
correspond to red (increased relativerisk) and purple (decreased relativerisk) colors derived from Cox
regressions capturing the risk of
diseases (vertical axis) within the first
30 years of life depending on 21
covariates (horizontal axis). Withineach circle there are 3 divisions
corresponding to surgery type.
A black border indicates whether risk
for that particular disease-covariate
combination was significant after
Bonferroni correction for 78 tests; acomplete black border surrounding acircle indicates that risks weresignificant for all 3 surgeries. Diseaserisks for the covariate region most
lived in Denmark are relative to
Hovedstaden (Copenhagen region).
Note: Urinary tract infections were
not included in the kidney infectiongroup.

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Association of Respiratory, Allergic, and Infectious Diseases With Removal of Adenoids and Tonsils

many covariates suggesting complex causation. We discuss
other associations with covariates in the eResults in the
Supplement.

Discussion
We estimated relative risks, absolute risks, and number
needed to treat to gain a balanced view of how adenoidectomy and tonsillectomy performed between birth and 9
years were associated with disease up to age 30 years inDenmark. Disease risks typically increased after surgery andfor some disorders relative risks translated into substantialchanges in absolute risk; for these, low NNT values suggested that only a few surgeries would need to be performed for an extra case of disease to be associated with oneof those patients.
Although otorhinolaryngologists are sensitive to shortterm consequences of procedures for the symptoms thatthey treat,18,32-34 they have had no evidence to evaluate thefull range of long-term risks. Using the Danish public healthdata allowed us to control for many medical, socioeconomic, and statistical confounders so that credible estimates of long-term risks of surgery could be made. We
found that tonsillectomy was associated with a nearly
tripled risk of upper respiratory tract diseases, and thatadenoidectomy was associated with doubled risk of COPD
and upper respiratory tract diseases and nearly doubled riskof conjunctivitis. Large increases in absolute risk for upper
respiratory tract diseases also occurred. Smaller elevatedrisks for a broad range of other diseases translated into
detectable increases in absolute disease risks with highprevalence in the population (infectious/parasitic, skin,musculoskeletal, and eye/adnexa diseases). These findings
add to previous research on single diseases that showed
increased risks of breast cancer11 and premature acute myocardial infarctions12 associated with these surgeries. In contrast, the long-term benefits of surgery were generally
minor and provided a neutral spectrum of sometimes
decreasing and sometimes increasing risk for the conditions
they aimed to treat.
Our results raise the important issue of when the benefits of operating outweigh overall short- and long-term
morbidity risks. For much of the past century these operations were common, but they have declined recently35,36
with the emergence of alternative treatments for infections
in ear, oral, and nasal cavities, coinciding with heightened
appreciation of the short-term risks of surgery.37 The longterm risk associations presented herein add a new perspective to these considerations. They suggest that revived discussion may be timely, because these surgical procedures
remain among the most common medical interventions inchildhood. 3,4 It is important to note that the cumulative
long-term impact of surgery depends on the prevalence ofspecific conditions in the population because these trends
are not straightforward to extrapolate from relative risks.
Thus, the potential impacts of tonsillectomy and adenoidectomy on the absolute risk of upper respiratory tract diseases
jamaotolaryngology.com

Original Investigation Researchwere substantial because these conditions were prevalent,
whereas those of adenoidectomy on the absolute risks of
COPD and conjunctivitis were small because those diseases
have low prevalence.
Apart from the specific cases above, our results suggest amore general association between removal of immune organs in the upper respiratory tract during childhood and increased risk of infectious/parasitic diseases later in life. Given
that tonsils and adenoids are part of the lymphatic system andplay a key role both in the normal development of the immune system and in pathogen screening during childhood andearly-life,3 it is not surprising that their removal may impair
pathogen detection and increase risk of later respiratory andinfectious diseases. However, the associations between thesesurgeries and diseases of the skin, eyes, and musculoskeletal
system are not likely to be directly linked to removal of the tonsils or adenoids and need further investigation. The growing
body of research on developmental origins of disease19,38 hasconvincingly demonstrated that even small perturbations tofetal and childhood growth and development can havelifelong consequences for general health.

Limitations
Our study did not address risks of diseases in those older than
30 years, the limit of our sample, and even though records ofthe entire population of Denmark were available, we did nothave large enough samples for rarer diseases to obtain reliable risk estimates. A strength of our study is its large coverage of a relatively homogeneous population with equal access to health care irrespective of socioeconomic status, but
this may mean that some results will not generalize to otherpopulations. Although many controls were employed to minimize confounding and reverse causation between surgery anddisease risk, it is possible that we could not completely remove these effects. Because this study is the first to assess longterm risks associated with these surgeries, we could not compare our results with other studies. We therefore recommend
additional studies to validate our findings. We could not include parental smoking data in our analyses as a potential confounding effect, which is a limitation for assessing offspring
respiratory disease risk.39 However, we note that our parental education covariate is correlated with smoking, and should
thus have partially covered risks of exposure to parental smoking during childhood.40,41 The socioeconomic variables that
we were able to include were also quantitative and available
without missing values, whereas smoking scores are often selfreported and of more dubious quality.42

Conclusions
To our knowledge, this is the first study to estimate longterm disease associations with early-life tonsillectomies andadenoidectomies for a broad range of diseases. Risks were significant for many diseases and large for some. We showed thatabsolute risks and the number of patients needed to treat
before enhanced health risks later in life become apparent
were more consistent and widespread than the immediate(Reprinted) JAMA Otolaryngology–Head & Neck Surgery July 2018 Volume 144, Number 7© 2018 American Medical Association. All rights reserved.

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Research Original Investigation

Association of Respiratory, Allergic, and Infectious Diseases With Removal of Adenoids and Tonsils

population-wide benefits of childhood surgery for subsequent health within the first 30 years of life. The associations

ARTICLE INFORMATIONREFERENCES

Accepted for Publication: March 19, 2018.

1. Casselbrant ML. What is wrong in chronic
adenoiditis/tonsillitis anatomical considerations. Int
J Pediatr Otorhinolaryngol. 1999;49(suppl 1):S133S135.

Published Online: June 7, 2018.
doi:10.1001/jamaoto.2018.0614
Author Contributions: Dr Byars had full access toall of the data in the study and takes responsibility
for the integrity of the data and the accuracy of thedata analysis.
Study concept and design: All authors.
Acquisition, analysis, or interpretation of data:
Byars, Boomsma.
Drafting of the manuscript: Byars, Boomsma.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Byars.
Obtained funding: Boomsma.
Administrative, technical, or material support:
Boomsma.
Study supervision: Stearns, Boomsma.
Conflict of Interest Disclosures: All authors havecompleted and submitted the ICMJE Form forDisclosure of Potential Conflicts of Interest andnone were reported.
Funding/Support: The Centre for Social Evolution
and its Evolutionary Medicine program were
funded by a grant from the Danish National
Research Foundation to J.J. Boomsma (grant
number DNRF57). S. G. Byars was also funded by aMarie Curie International Incoming Fellowship(grant number FP7-PEOPLE-2010-IIF-276565).
Role of the Funder/Sponsor: The Danish National
Research Foundation had no role in the design andconduct of the study; collection, management,
analysis, and interpretation of the data;preparation, review, or approval of the manuscript;
and decision to submit the manuscript for
publication.
Additional Information: Data were made available
by public authorities in accordance with The Danish
Act on Processing of Personal Data (Act No. 429 of
31 May 2000) and deposited under terms of acontract at Statistics Denmark (https://www.dst.dk). They cannot leave the servers at Statistics
Denmark. Access to the data used here can be
granted to other researchers through an affiliation
with the Centre for Social Evolution, University of
Copenhagen, if approved by Statistics Denmark.
For further information please contact Professor
Jacobus J Boomsma, Centre for Social Evolution(JJBoomsma@bio.ku.dk) and the Head of Division
for Research Services, Ivan Thaulow (ITH@DST.dk),
Statistics Denmark.
Additional Contributions: Statistics Denmark
provided access to all deidentified data hosted on asecure computer server. We thank Birgitte
Hollegaard, PhD, Copenhagen University, forassistance in gaining access to data; Charlotte
Nielsen, PhD, and Morten Lindboe at Statistics
Denmark for facilitating data access and technicalsupport. We thank Professor Ruslan Medzhitov,
PhD; Dr James Childs, ScD; both at Yale University;and Dr Jay F. Piccirillo, MD, Washington University;
Dr Louise Davies, MD, Dartmouth Institute; and 3
anonymous reviewers for comments on previous
versions of this study.

602

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17. Donaldson GP, Lee SM, Mazmanian SK. Gut
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18. Subramanyam R, Varughese A, Willging JP,
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Hjalgrim H, Melbye M. Tonsillitis, tonsillectomy and
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Invited Commentary

Old Barbers, Young Doctors, and Tonsillectomy
Richard M. Rosenfeld, MD, MPH

When tonsillectomy was a right of childhood passage, choosing an experienced surgeon may have been the best way to
avoid the uncommon, but occasionally fatal, hemorrhage associated with the procedure. Franklin’s old adage “beware of
the young doctor and the oldbarber” was sage advice for
Related article page 594
families seeking a surgeon,
and what better place to find one than the Tonsil Hospital in
New York city, where 50 experienced doctors operated on thousands of children annually for 3 decades.1 Yet even in this bygone era of surgical excess the hospital’s director, Robert
Fowler, wisely noted “…it is very likely that in the future [physicians] will be able to provide rational guides which will eventually be accepted by the public” (emphasis original).2
Perhaps now, when clinical practice guidelines and shareddecision-making are the standard of care,3 a younger surgeon
may be the best choice, because they are most likely to beversed in current best evidence. But before the article by Byars
and colleages4 in this issue, it was unlikely that their discussion with families would include cautions about a long-termrisk of respiratory, allergic, and infectious diseases after surgery. More likely, they would have emphasized gizmos, newtechnology, and partial techniques that allegedly make the operation safer and limit the short-term morbidity.

Unique and Provocative Research
The study by Byars and colleagues4 is unique in providing longterm risk estimates (up to 30 years), based on complete medical records from birth in national health registries, for over
60 000 Danish children who had tonsillectomy (11 830), adenoidectomy (17 460), or both (31 377) at 9 years or younger.
Comparisons were made with nonsurgical controls from a registry of up to 1.2 million singleton births between January 1979
and 2009. The authors hypothesized that surgery could increase subsequent risk for immune-related disorders (allergic,
jamaotolaryngology.com

infectious, circulatory, autoimmune, endocrine, and nervous
system), but not for disorders unrelated to immune function.
Adenoidectomy had a number needed to harm (NNH) of
38 for asthma, meaning that after 38 surgeries 1 additional patient would be diagnosed with asthma by age 30 years. Adenoidectomy had an NNH of 9 for upper respiratory infections, 349 for chronic obstructive pulmonary disease (COPD),
and 624 for conjunctivitis. For infectious disease, in general,
tonsillectomy and adenoidectomy had an NNH of 47, but
tonsillectomy alone had an NNH of 5 for diseases of the upper
respiratory tract. Significant associations were seen for 78%
of the 28 disease groups analyzed, with the most clinicallyimportant results for asthma, COPD, pneumonia, infectious
diseases, skin conditions, and upper and lower respiratory
disorders.
Analyses related to surgery showed mixed results regarding the number needed to treat (NNT) for benefit. A slightly
reduced incidence of chronic tonsillitis (NNT, 48) and tonsillitis (NNT, 345) was noted after surgery, and adenoidectomy
had a very small benefit for sleep disorders (NNT, 1205). Abnormal breathing did not change after any surgery, but otitis
media increased (NNH, 5 to 19), as did sinusitis after tonsillectomy and adenoidectomy (NNH, 909), but not after adenoidectomy or tonsillectomy alone. The authors concluded
that increases in long-term disease risks (eg, asthma, COPD)
were much larger than benefits observed.

Caveats and Risk of Bias
All research has limitations, such as confounding andreverse causation (mentioned briefly by the authors), whichalong with selection bias and measurement bias can form
the Achilles heel of observational research.5 For the present
study, each of these could have a considerable impact on
our confidence in results and their generalizability beyond
the study sample:(Reprinted) JAMA Otolaryngology–Head & Neck Surgery July 2018 Volume 144, Number 7© 2018 American Medical Association. All rights reserved.

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