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Amoxicillin May Cause Molar Incisor Hypomineralization
1 Health Center, Ylämaa, Finland; Correspondence: satu.alaluusua{at}helsinki.fi
The etiology of molar incisor hypomineralization (MIH) is unclear. Our hypothesis was that certain antibiotics cause MIH. We examined 141 schoolchildren for MIH and, from their medical files, recorded the use of antibiotics under the age of 4 yrs. MIH was found in 16.3% of children. MIH was more common among those children who had taken, during the first year of life, amoxicillin (OR = 2.06; 95% CI, 1.01–4.17) or the rarely prescribed erythromycin (OR = 4.14; 95% CI, 1.05–16.4), compared with children who had not received treatment. Mouse E18 teeth were cultured for 10 days with/without amoxicillin at concentrations of 100 µg/mL–4 mg/mL. Amoxicillin increased enamel but not dentin thickness. An altered pattern of amelogenesis may have interfered with mineralization. We conclude that the early use of amoxicillin is among the causative factors of MIH.
Key Words: amoxicillin • penicillin V • macrolide • erythromycin • enamel defects • MIH
The developing tooth is susceptible to detrimental influences of both genetic and environmental factors. Many disturbances of growth and development may ameliorate in time, but since dental hard tissues are not renewed, these faults remain. Disturbances in tooth development can affect not only the number of teeth, but also the formation and quality of dentin and enamel.
There are only a few drugs recognized to disturb dental hard tissue formation. Among them are anticancer drugs, such as cyclophosphamide, and the tetracyclines, which cause discoloration of developing teeth (Satoh et al., 2001). It has also been suggested that the use of antibiotics is associated with so-called ‘molar incisor hypomineralization’ (MIH; Fig. 1
Clinical Study Two hundred and seventeen pupils attending the second to fifth years of comprehensive schools were invited to join the study. They were all born and living in Lammi, a town in Southern Finland. Of those invited, 147 children were included, with informed parental consent. The parents completed a health-related questionnaire relative to their child’s early years. The Ethics Committee at South Karelia Hospital District, Lappeenranta, Finland, approved the study. With permission from the Ethics Committee, information on the use of antibiotics was obtained from medical records of the health center. Information on amoxicillin, penicillin V, cephalosporin, macrolide, and sulfonamide and trimethoprim therapies was gathered for the first, second, third, and fourth years. Six children were further excluded. Of the six, three had incomplete medical records, one had low birthweight (< 2000 g), and two had not used health center services. Customarily, children receive pediatric health care in the health center, with only a few exceptions. Thus, finally, 141 children (65 girls and 76 boys) were included in the study. Their mean age was 10.7 yrs (SD 1.3), with a range of 7.8–12.7 yrs. The fluoride content of drinking water in the Lammi region in communal pipe water is < 0.1 mg/L, and in wells in the sparsely populated areas, it is mostly < 0.2 mg/L. Therefore, it was recommended that the children take additional fluoride as tablets: 0.25 mg/day from age 6 mos to 2 yrs, 0.5 mg/day from 2 to 6 yrs, and 1 mg/day after 6 yrs. The children were examined in the dental clinic for the presence and severity of MIH (Alaluusua et al., 1996). Briefly, each permanent first molar was screened for demarcated opacity (mild defect) or broken- down hypomineralized enamel/atypical restorations replacing affected enamel (severe defect). Lesions smaller than 2 mm in diameter were not included. Children with lesions in more than one molar or with severe lesion(s) were categorized as severely affected. Dental examinations were carried out by one dentist (SL). The intra-examiner kappa coefficient for teeth with developmental defects of enamel was 0.91, and that for classified defects (diffuse opacity, demarcated opacity, and hypoplasia) was 0.90. Corresponding interexaminer kappa coefficients were 0.96 and 0.81.
Statistical Analysis
Experimental Study
Exposure of Tooth Explants to Amoxicillin
Histological Examination
Statistical Analysis
Clinical Study In total, 529 antibiotic courses were prescribed to the 141 children during the 4 yrs, the range being from 0 to 19 per child. Only 15% of the children had taken no antibiotics, and 43% had received two or more different antibiotics. Penicillin V and amoxicillin were the most commonly used antibiotics (Table  ). During the first year of life, 34.8% of the children had taken either penicillin or amoxicillin or both. MIH was found in 23 children (16.3%). The number of courses given to the child during the first 4 yrs correlated with MIH (P < 0.03) and the severity of MIH (P < 0.006), but the number of different antibiotics was not associated with MIH.
Of the 23 children with MIH, 12 (52.2%) had taken antibiotics during the first year, compared with 40 of the 118 children (33.9%) without MIH (P > 0.05). The number of amoxicillin courses was significantly associated with MIH (P < 0.04) and the severity of MIH (P < 0.002). Significant correlations were also found for penicillin V and the severity of MIH (P < 0.05), and for erythromycin, the only macrolide used during the first year, and MIH (P < 0.02) or the severity of MIH (P < 0.003). Cephalosporin or sulfonamide and trimethoprim use was not associated with MIH (P < 0.05). MIH was more common among those children who had taken amoxicillin (OR = 2.06; 95% CI, 1.01–4.17) or erythromycin (4.14; 95% CI, 1.05–16.4) than in those who had not taken these antibiotics during the first year of life. The odds ratio for having MIH after exposure to penicillin V was 1.71 (95% CI, 0.89–3.27). When those children who had taken amoxicillin during the first year were excluded from the data matrix, a significantly increased risk was not found for any of the antibiotics for the second year. Analysis with mutually exclusive single-antibiotic-use groups was not possible because of the low number of non-users and the users of a single antibiotic.
Experimental Study
After 10 days of culture, the presence of enamel was associated with amoxicillin concentration (P < 0.001). While enamel was present in only 8 of 22 control molars after 10 days of culture, all 9 molars exposed to 4 mg/mL amoxicillin had enamel (Fig. 2
It has been suggested that early childhood illnesses such as upper respiratory tract diseases or their treatment with antibiotics is associated with MIH (Jälevik et al., 2001; Beentjes et al., 2002). This raises the question whether the causative factor is the illness itself or the drugs used to treat it. We found that exposure of cultured mouse embryonic tooth explants to amoxicillin enhanced enamel formation, but had no effect on dentin formation. After 10 days in culture, enamel was present on all molars exposed to amoxicillin at a high concentration (4 mg/mL), but was present in only just over one-third of the controls. In addition, where enamel was present in either controls or in molars exposed to just 100 µg/mL amoxicillin, it was thinner than enamel present on molars treated with concentrations of amoxicillin  1 mg/mL. A possible explanation for these observations could be that amoxicillin induces earlier enamel formation and/or accelerates the accretion rate of the established enamel. The possibility still remains that amoxicillin had acted as a substitute for penicillin-streptomycin in the exposed but not control explants, the growth of which could have been retarded by infectious agents in the absence of an antibiotic. Although speculative, it is possible that amoxicillin interferes with ameloblast function and either advances the initiation of amelogenesis and/or accelerates the enamel accretion rate. If one assumes that this model reflects the situation in humans, disturbing the temporal sequence of events associated with amelogenesis (i.e., the correct temporal relationship between proteolytic degradation of the enamel matrix and the period of secondary crystal growth that leads to the production of fully mineralized enamel) could explain the production of hypomineralized enamel in MIH cases. Further in vitro culture studies examining the temporal expression of the enamel matrix proteins (e.g., amelogenin, enamelin, and ameloblastin) and the enamel proteinases responsible for their processing and ultimate degradation would help confirm this hypothesis. Our experimental results are thus in accord with previous findings that the structural tooth defect in MIH is confined to the enamel, as observed histologically (Jälevik and Norén, 2000). However, species differences in handling of the drugs and thresholds of adverse effects make the applicability of organ culture studies to humans uncertain. In the present study, the lowest amoxicillin concentration used, 100 µg/mL, was of the same order as in serum after therapeutic concentrations in humans, while the higher concentrations exceeded them (Dajani et al., 1994; Nathanson et al., 2000). An early study has suggested that the first year of life is the most critical period relative to the development of enamel defects (Schour and Massler, 1941). Therefore, if antibiotics are involved, it is important to analyze which particular antibiotics were prescribed during the first year. Every fifth child in our study had taken either penicillin V or amoxicillin, and every third had taken either penicillin V, amoxicillin, or both. Every sixth child had taken cephalosporins. Macrolides (erythromycin) and sulfonamide and trimethoprim were so rarely prescribed during the first year that their impact is difficult to assess. In a recent article, it was suggested that the early use of amoxicillin is associated with developmental enamel defects (Hong et al., 2005), but controversial results also exist (Tapias-Ledesma et al., 2003). We found that the putative antibiotics were amoxicillin and erythromycin. Since erythromycin was given only to seven children during the first year, the results concerning this antibiotic must be interpreted with caution. Hong and co-workers (2005) studied defects resembling fluorosis in incisors and permanent first molars. Because of a larger study population and more frequent use of amoxicillin than in the present study, they could analyze mutually exclusive amoxicillin-user groups. They concluded that fluorosis-like defects were common in children with early use of amoxicillin, especially during the first 6 mos. Although fluorosis is often described as diffuse opacity and MIH as demarcated opacity, it is not always possible to distinguish between these two conditions. Based on the clinical description given in the article by Hong and co-workers (2005), we expect the same phenomenon to be in question in the fluorosis study and in our study and that, hence, the results are in agreement. A classic Swedish study on MIH showed that children born in 1970 had more MIH (15.4%) than children born in 1966, 1969, 1971, 1972, or 1974 (range, 4.4%–7.3%) (Koch et al., 1987). The authors suggested that some environmental factor created the peak in 1970, but the etiological factor was not found. If the use of antibiotics was involved, it could not be amoxicillin, since amoxicillin was not on the market in Sweden before 1975. MIH causes many problems for the child. The teeth are very sensitive and often require extensive treatment. Furthermore, when incisors are affected, the esthetic problem may be considerable. Our present results suggest that the early use of amoxicillin is among the causative factors of MIH. Another putative antibiotic is erythromycin. However, its role needs to be studied further. Taken together, the benefits and drawbacks of amoxicillin use in early childhood should be carefully weighed for each child.
The study was supported by the Academy of Finland (Contract 130443) and by a grant from the Finnish Dental Society Apollonia to Anneli Ess. The statistical support of Jorma Torppa MSc, secretarial help of Ms. Anneli Sinkkonen and Ms. Raila Jalomeri, and the expert technical assistance of Ms. Marjatta Kivekäs and Ms. Pirjo Jutila are gratefully acknowledged. Received for publication November 1, 2007. Revision received September 30, 2008. Accepted for publication October 15, 2008.
Journal of Dental Research, Vol. 88, No. 2,
132-136 (2009) This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
2 test. Variables with P < 0.10 were further tested. Epidemiological association between MIH and the use of each antibiotic (yes/no) was determined by ORs and their 95% confidence intervals (Cl). To study the impact of amoxicillin on the development of MIH during the second year of life, we excluded children having received amoxicillin during the first year of life. 
