DOI: 10.1111/j.1365-263X.2011.01199.x

molars in childhood cancer sur

Microdontia and hypodontia of premolars and permanent

vivors after chemotherapy

LISBETH BØNLØKKE PEDERSEN1, NIELS CLAUSEN2, HENRIK SCHRØDER2, MALENE SCHMIDT1

& SVEN POULSEN1

1Department of Pediatric Dentistry, School of Dentistry, Faculty of Health Sciences, Aarhus University, and 2Department of

Pediatrics, Aarhus University Hospital, Aarhus C, Denmark

International Journal of Paediatric Dentistry 2012; 22:

239–243

Background. Adverse long-term general and dental

health effects of cancer and cancer therapy during

childhood have been reported.

Aim. To examine the association between chemo-

therapy before the age of 8 years and (1): micro-

dontia; (2): hypodontia of premolars and

permanent molars.

Material and methods. In The Danish Registry of

Childhood Cancer (DBCR), we identified 203 chil-

dren who met the following inclusion criteria: (1)

age below 8 years at the start of treatment; (2)

age between 12 to 18 years upon dental examina-

tion; (3) had received chemotherapy The exclu-

sion criterion was radiotherapy to the head and

neck. A total of 150 children fulfilled the inclusion

Correspondence to:

S. Poulsen, Faculty of Health Sciences, Department of

Pediatric Dentistry, School of Dentistry, Aarhus University,

Vennelyst Boulevard 9, DK-8000 Aarhus C, Denmark.

E-mail: sven.poulsen@odontologi.au.dk

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International Journal of Paediatric Dentistry � 2011 BSPD, IAPD and Bla

criteria. As controls, a random sample of 193 age-

matched unexposed children was included.

Results. Microdontia was found in a total of 88

teeth in 29 (19.3%) of the 150 children who had

been exposed to chemotherapy, while none of the

controls had microdontia of premolars or perma-

nent molars (difference: 19.3%; 95% CL: 13.5%;

26.4%). The earlier the exposure, the more fre-

quent was microdontia. We found a total of 27

missing premolars and permanent molars in 14

(9.3%) of the exposed children and a total of 18

missing premolars and permanent molars in 8

(4.1%) of the controls (difference: 5.2%; 95% CL:

)0.1%; 11.3%).

Conclusion. The present study confirms findings

from previous studies that chemotherapy, especially

in very young children, causes microdontia and

hypodontia of premolars and permanent molars.

Introduction

The annual incidence of childhood cancer in

0- to 15-year-old Danish children is approxi-

mately 15 per 100,000 children. The past

25 years have brought improved survival

with 5-year survival rates reaching 50–95%.

The most common cancer types are leukae-

mias, lymphomas, central nervous system

tumours, sarcomas of bone and soft tissues,

and renal and sympathetic nervous system

tumours. The high survival rates have raised

concern about the long-term adverse health

effects within several areas like learning,

motor functions, growth, fertility, cardiac and

renal function, vision, hearing, and a risk of

second cancers. The adverse late effects may

be caused by surgery, irradiation, chemother-

apy, or combinations of these modalities1,2.

Adverse effects of cancer and cancer ther-

apy during childhood on dental health have

also been reported in terms of mineralisation

disturbances3–8, dental caries3,5,6,8–10, micro-

dontia3,8,11–16, hypodontia3–5,7,9,12,14,15,17,

root stunting3,6,12,14,15,17, and taurodon-

tism9,11,12,18.

Only few previous studies have analysed the

association of these dental anomalies with

specific types of cancer treatment (i.e.,

chemotherapy, irradiation, surgery, etc.), and

the number of exposed children has been rather

low (£50 children) in some of the exposure

groups4,15,16. Furthermore, these studies have

been based on children of highly variable age

and only few studies have compared their find-

ings in exposed children to findings in control

groups4,16, siblings11,14, or with survey data6.

The purpose of this study was to examine

the association between exposure to chemo-

ckwell Publishing Ltd 239

240 L. B. Pedersen et al.

therapy for childhood cancer before the age

of 8 years and (i) microdontia; (ii) hypodontia

of premolars and permanent molars.

Material and methods

This study is based on data drawn from The

Danish Registry of Childhood Cancer (DBCR)19,

which is hosted at the Department of Pedi-

atrics, Aarhus University Hospital, Aarhus,

Denmark. The Registry was established in 2003

by merging information on childhood cancer

held in different local databases. Key variables

include: civil registration number, age, gender,

age at diagnosis, diagnosis, and treatment.

Using the child’s civil registration number

which is a unique 10-digit number identifying

all Danish citizens, we identified the munici-

pality in which the child was a resident and

contacted the municipal dental clinic the

child was attending to obtain clinical records

and radiographs. Presence of microdontia and

missing teeth was recorded by two of the

authors (LBP and MS): microdontia was

recorded when the tooth visually was <50%

of its expected size; hypodontia was recorded

when no tooth or tooth germ was present in

the relevant tooth space, and there was no

history of extraction.

Data from the DBCR and the dental data were

merged using the civil registration number.

Inclusion criteria were: (i) age <8 years at the

start of treatment; (ii) age between 12 and

18 years at dental examination; (iii) had

received chemotherapy. The exclusion criterion

was radiotherapy to the head and neck area.

A random sample of 193 12- to 18-year-old

children drawn among children attending a

large municipal dental service (Herning

municipality) served as controls. Power calcu-

lations based on an expected number of

exposed children of 240 showed that 190

controls would be sufficient to detect a dou-

bling in the prevalence rate of hypodontia of

Table 1. Distribution of 150 childhood cancer survivors exposed

Age

<1 year 1 year 2 years 3 years 4 year

27 (18.0%) 21 (14.0%) 28 (18.7%) 24 (16.0%) 16 (10

International Journal of Pa

one or more premolars or permanent molars

(a = 0.05; b = 0.80).

Statistical analyses were performed using

SPSS 13.0 for Windows (SPSS Inc., Chicago,

IL, USA). Differences in proportions with

their 95% confidence limits (CL) were calcu-

lated for comparisons between exposed chil-

dren and controls. Odds ratios (OR) with

their 95% confidence limits (CL) were calcu-

lated to assess associations.

The study was approved by The Danish

National Board of Health (record #7-604-04-

2 ⁄136) and The Central Denmark Region

Committees on Biomedical Research Ethics

(record # M-20090091) and registered at The

Danish Data Protection Agency (record #;

2009-41-3865).

Results

The DBCR contained data on 203 children

who fulfilled the inclusion criteria. Further

record review showed that 25 children had

received radiotherapy and two children had

Down syndrome. All 27 were excluded. For

26 children, material from the municipal den-

tal clinics could not be retrieved. Thus, 150

children were available for analysis.

The age at the time of diagnosis varied from

below 1–7 years, with 66.7% being 3 years or

less (Table 1). The distribution of the patients

according to diagnosis and chemotherapeutic

regime is described in Table 2. The most fre-

quent diagnosis was leukaemia (46.0%). All

150 patients but three had received at least five

different agents. This comprised vincristine

and at least one alkylating agent plus a combi-

nation of etoposide and a platinol and ⁄or an

antibiotic derivative such as an antracyclin.

The leukaemia and lymphoma regimens

included methotrexate and asparaginase.

Microdontia of premolars or permanent

molars was found in a total of 88 teeth in 29

(19.3%) of the 150 children who had been

to chemotherapy according to age at diagnosis.

Totals 5 years 6 years 7 years

.7%) 13 (8.7%) 9 (6.0%) 12 (8.0%) 150 (100.0%)

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ediatric Dentistry � 2011 BSPD, IAPD and Blackwell Publishing Ltd

Table 2. Distribution of 150 childhood cancer survivors exposed to chemotherapy according to diagnosis andchemotherapeutic agent.

Diagnosis Number (%) Chemotherapeutic agents*

Leukaemia 69 (46.0%) V; Cyt: D; Asp; MLymphomas and other reticuloendothelial neoplasms 15 (10.0%) V; Cyt: D; Asp; MCNS and intracranial and intraspinal neoplasms 3 (2.0%) V; Cyc: J; E; MSympathetic nervous system tumours and retinoblastoma 25 (16.7%) V; Cyc: J+Cis; ERenal and hepatic neoplasms 19 (12.7%) V; Cyc: E; D+ActBone and soft tissues sarcoma 8 (5.3%) V; I: J; E; D+ActGonadal neoplasms 11 (7.3%) J; E: BTotal 150 (100.0%)

*V, vincristine; Cyt, cytarabine; Cyc, cyclophosphamide; I, ifosfamide; J, carboplatin; Cis, cisplatin; E, etoposide; D, doxorubicin; Act,dactinomycin; B, bleomycin; M, methotrexate; Asp, asparaginase.

Table 3. Distribution of 150 childhood cancer survivors exposed to chemotherapy according to number of premolars andpermanent molars with microdontia or hypodontia.

Number of teeth

Total0 1 2 3 4 5 6 7 8

Microdontia 121 (80.7%) 7 (4.7%) 9 (6.0%) 3 (2.0%) 4 (2.7%) 2 (1.3%) 1 (0.7%) 2 (1.3%) 1 (0.7%) 150 (100.0%)Hypodontia 137 (91.3%) 7 (4.7%) 4 (2.7%) 0 (0.0%) 1 (0.7%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (0.7%) 150 (100.0%)

Table 4. Distribution of affected teeth (microdontia andhypodontia) in 150 childhood cancer survivors exposed tochemotherapy according to type of tooth.

Microdontia Hypodontia

Chemotherapy Controls Chemotherapy Controls

1stpremolars

27 0 2 0

2ndpremolars

32 0 22 16

1stpermanentmolars

0 0 0 0

2ndpermanentmolars

29 0 3 2

Total 88 0 27 18

Table 5. Distribution of 150 childhood cancer survivorsexposed to chemotherapy according to time of exposure,and microdontia and hypodontia.

Time of exposure

£3 years >3 years

Microdontia Yes 24 (31.6%) 5 (6.8%)No 52 (68.4%) 69 (93.2%)

Hypodontia Yes 8 (10.5%) 5 (6.8%)No 68 (89.5%) 69 (93.3%)

Microdontia and hypodontia of premolars 241

exposed to chemotherapy (Table 3), whereas

none of the controls had microdontia of pre-

molars or permanent molars (difference:

19.3%; 95% CL: 13.5%; 26.4%). Both 1st and

2nd premolars and 2nd permanent molars

were affected, whereas no 1st permanent

molars were affected (Table 4). A causal rela-

tionship between exposure to chemotherapy

and microdontia was further supported by the

fact that we found an association between

presence of microdontia and exposure before

3 years of age (OR: 6.369; 95% CL: 2.277;

17.815) (Table 5). Only five of the children

diagnosed at 3 years of age or later had micr-

odontia of premolars and permanent molars.

We found a total of 27 missing premolars

and permanent molars in 14 (9.3%) of the

exposed children (Table 3) and a total of 18

missing premolars and permanent molars in 8

(4.1%) of the controls (difference: 5.2%; 95%

CL: )0.1%; 11.3%). The most frequently

affected teeth were 2nd premolars (82.1% and

88.9% of the affected teeth for childhood can-

cer survivors and controls, respectively)

(Table 4). We found an association between

early exposure to chemotherapy and hypodon-

tia (OR: 1.624; 95% CL: 0.506; 5.213), which

did not reach statistical significance (Table 5).

� 2011 The Authors

International Journal of Paediatric Dentistry � 2011 BSPD, IAPD and Blackwell Publishing Ltd

Table 6. Distribution of 150 childhood cancer survivorsexposed to chemotherapy according to presence ofmicrodontia and hypodontia.

Hypodontia

Yes No

Microdontia Yes 7 (24.1%) 22 (75.9%)No 6 (5.0%) 115 (95.0%)

242 L. B. Pedersen et al.

Finally, we found a strong correlation

between the presence of microdontia and

hypodontia in the same child (Table 6) (OR:

6.098; 95% CL: 1.870; 19.886).

Discussion

This study supports the observation of a high

occurrence of microdontia in childhood

cancer survivors exposed to chemotherapy. It

also confirms the hypothesis of an increased

risk of hypodontia, even if the association

between hypodontia and exposure to chemo-

therapy during childhood is slightly weaker

than that between exposure to chemotherapy

and microdontia. Occurrence of microdontia

and hypodontia was, however, strongly corre-

lated.

Outcome data for this study consisted of rou-

tine diagnostic material collected from the

municipal dental clinics where the children

were treated. If the diagnostic material was ini-

tially deemed insufficient for the purpose of

the study, we contacted the clinics and the

treating dentist to obtain supplementary mate-

rial. It should be noted that the Danish Muni-

cipal Dental Service for Children and

Adolescents has an almost 100% attendance

rate Statistics Denmark CD, 2011 Personal

Communication. We used the same diagnostic

criteria for microdontia as were used in a pre-

vious study8, in which these criteria were con-

sidered robust. The criterion for hypodontia

was also simple and must be considered robust.

To further increase the quality of our data, all

recordings were made by two independent

examiners who subsequently compared their

recordings and, in case of disagreement, dis-

cussed them until agreement was reached.

The association of microdontia with chemo-

therapy is well established3,8,11–16 and is also

International Journal of Pa

supported by the findings in present study. It

is interesting to note that microdontia of pre-

molars and permanent molars occurred most

frequently in children exposed before the age

of 3 years. According to Massler et al.20, for-

mation of the tip of the crown of premolars

and permanent molars is initiated at the age

of 3 years, whereas the crown of the 1st per-

manent molar is almost completely formed at

this age. Exposure during early odontogenesis

thus seems to cause microdontia, whereas

later exposure seems to result in less damage

to the tooth germ.

The finding of a higher frequency of hypo-

dontia in children exposed to chemotherapy

in our study supports findings from several

previous studies3–5,7,9,12,14,15,17, but was statis-

tically less convincing, probably owing to the

limited sample size of our study. The number

of exposed children in the database was fixed,

and if we had known beforehand that fewer

children than expected fulfilled the inclusion

criteria, we could have included a larger con-

trol group to increase the power of the study.

However, as we had access to data from a

recently conducted large study of Danish

school children21 we were able to recalculate

the proportion of children with hypodontia of

premolars or permanent molars in the back-

ground population of Danish school children

to be 5.3% (95% CL: 4.8%; 5.8%), which is

almost only half the size of the estimate

obtained in this study for childhood cancer

survivors who had received chemotherapy

(9.3%). Furthermore, the estimate in our

study is not embraced by the 95% CL of the

estimate for the background population,

which indicates that an association exists.

The complex composition of the chemo-

therapy makes an analysis of the single

agents’ influence on the dental development

impossible.

Finally, the association between the pres-

ence of microdontia and hypodontia attests to

the hypothesis that also hypodontia is caused

by chemotherapy.

Conclusion

This study confirms the findings from previous

studies that chemotherapy, especially in very

� 2011 The Authors

ediatric Dentistry � 2011 BSPD, IAPD and Blackwell Publishing Ltd

Microdontia and hypodontia of premolars 243

young children, causes microdontia and hyp-

odontia of premolars and permanent molars.

What this paper adds

� 2

Int

d Further evidence on microdontia and hypodontia after

chemotherapy for childhood cancer.d The effect is more prominent, the younger the child at

the time of treatment.

Why this paper is important to paediatric dentistsd With improved survival rates after childhood cancer,

more parents need counselling on long-term health

effects of childhood cancer and cancer treatment.d Knowledge about dental developmental disturbances is

important for long-term dental treatment planning.

Acknowledgements

The study was funded by The Danish Cancer

Society, Boernecancerfonden, ‘Dagmar

Marshalls Fond’, ‘Aase og Ejnar Danielsens

Fond’, ‘Apotekerfonden’, and The Danish

Dental Association.

Conflicts of interest

The authors report no conflicts of interest.

References

1 Haddy RI, Haddy TB. Lifetime follow-up care after

childhood cancer. J Am Board Fam Med 2010; 23:

647–654.

2 Landier W, Wallace WH, Hudson MM. Long-term

follow-up of pediatric cancer survivors: education,

surveillance, and screening. Pediatr Blood Cancer

2006; 46: 149–158.

3 Kaste SC, Hopkins KP, Bowman LC et al. Dental

abnormalities in children treated for neuroblastoma.

Med Pediatr Oncol 1998; 30: 22–27.

4 Alpaslan G, Alpaslan C, Gogen H et al. Disturbances

in oral and dental structures in patients with

pediatric lymphoma after chemotherapy: a

preliminary report. Oral Surg Oral Med Oral Pathol

Oral Radiol Endod 1999; 87: 317–321.

5 Minicucci EM, Lopes LF, Crocci AJ. Dental

abnormalities in children after chemotherapy

treatment for acute lymphoid leukemia. Leuk Res

2003; 27: 45–50.

6 Purdell-Lewis DJ, Stalman MS, Leeuw JA et al. Long

term results of chemotherapy on the developing

dentition: caries risk and developmental aspects.

Community Dent Oral Epidemiol 1988; 16: 68–71.

7 Maguire A, Murray JJ, Craft AW et al. Radiological

features of the long-term effects from treatment of

011 The Authors

ernational Journal of Paediatric Dentistry � 2011 BSPD, IAPD and Bla

malignant disease in childhood. Br Dent J 1987; 162:

99–102.

8 Hutton A, Bradwell M, English M et al. The oral

health needs of children after treatment for a solid

tumour or lymphoma. Int J Paediatr Dent 2010; 20:

15–23.

9 Vaughan MD, Rowland CC, Tong X et al. Dental

abnormalities in children preparing for pediatric

bone marrow transplantation. Bone Marrow

Transplant 2005; 36: 863–866.

10 Wogelius P, Dahllof G, Gorst-Rasmussen A et al. A

population-based observational study of dental

caries among survivors of childhood cancer. Pediatr

Blood Cancer 2008; 50: 1221–1226.

11 Nunn JH, Welbury RR, Gordon PH et al. Dental

caries and dental anomalies in children treated by

chemotherapy for malignant disease: a study in the

north of England. Int J Paediatr Dent 1991; 1: 131–

135.

12 Kaste SC, Hopkins KP, Jones D et al. Dental

abnormalities in children treated for acute

lymphoblastic leukemia. Leukemia 1997; 11: 792–796.

13 Holtta P, Alaluusua S, Saarinen-Pihkala UM et al.

Agenesis and microdontia of permanent teeth as late

adverse effects after stem cell transplantation in

young children. Cancer 2005; 103: 181–190.

14 Maguire A, Craft AW, Evans RG et al. The long-term

effects of treatment on the dental condition of

children surviving malignant disease. Cancer 1987;

60: 2570–2575.

15 Holtta P, Alaluusua S, Saarinen-Pihkala UM et al.

Long-term adverse effects on dentition in children

with poor-risk neuroblastoma treated with high-

dose chemotherapy and autologous stem cell

transplantation with or without total body

irradiation. Bone Marrow Transplant 2002; 29: 121–

127.

16 Nasman M, Forsberg CM, Dahllof G. Long-term

dental development in children after treatment for

malignant disease. Eur J Orthod 1997; 19: 151–159.

17 Sonis AL, Waber DP, Sallan S et al. The oral health

of long-term survivors of acute lymphoblastic

leukaemia: a comparison of three treatment

modalities. Eur J Cancer B Oral Oncol 1995; 31B:

250–252.

18 Lopes NN, Petrilli AS, Caran EM et al. Dental

abnormalities in children submitted to

antineoplastic therapy. J Dent Child (Chic) 2006; 73:

140–145.

19 Sørensen HT, Christensen T, Schlosser HK, Pedersen

L. (eds). Use of Medical Databases in Clinical

Epidemiology. Aarhun, Denmark: Department of

Clinical Epidemiology, 2009.

20 Massler M, Schour I, Poncher HG. Developmental

pattern of the child as reflected in the calcification

of the teeth. Am J Dis Child 1941; 62: 33–67.

21 Rølling S, Poulsen S. Agenesis of permanent teeth in

8138 Danish schoolchildren: prevalence and intra-

oral distribution according to gender. Int J Paediatr

Dent 2009; 19: 172–175.

ckwell Publishing Ltd