Molar incisor hypomineralisation (MIH).

Amoxicillin May Cause Molar Incisor Hypomineralization

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.

The early use of amoxicillin is among the causative factors of molar incisor hypomineralization.

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⇓) (Jälevik et al., 2001; Beentjes et al., 2002; Whatling and Fearne, 2008) or with fluorosis-like lesions affecting teeth that mineralize during the first years of life (Hong et al., 2005). The β-lactam antibiotics prescribed for common childhood infections—for example, otitis media—have been considered of low risk for infants. However, the finding that amoxicillin, penicillin, and cephalosporin interfere with rat embryonic kidney development in a dose-dependent manner implies that these antibiotics may be toxic (Nathanson et al., 2000). Erythromycin therapy in mothers during early pregnancy has been found to increase the risk for cardiovascular malformations in their children, suggesting the teratogenicity of erythromycin (Källén et al., 2005). Our aim was to study whether the use of amoxicillin, penicillin V, the cephalosporins, the macrolides, and sulfonamide and trimethoprim was associated with MIH, and whether amoxicillin, the most common antibiotic used in childhood, disturbs mouse embryonic molar tooth development in culture.

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.