Aetiology of molar-incisor hypomineralisation: a systematic review.
Amelogenesis has been divided into three major stages of the ameloblast life cycle, namely secretory, transition, and maturation.
Stage 1. At the secretory stage, ameloblasts secrete large amounts of enamel matrix proteins within which long thin ribbons of enamel mineral, mainly hydroxyapatite, are formed almost immediately as the enamel matrix is laid down. The formation of enamel starts at the cusp tips and extends in a cervical direction (Fig. 1a, b). Throughout the secretory stage enamel crystals grow primarily in length and enamel layer thickness. The mineral phase of secretory enamel is approximately 10-20% by volume, with the remaining portion occupied by matrix protein and water.
Stage 2. Once the full thickness of enamel has been deposited, the secretory ameloblasts transform through a short transitional phase into maturation stage ameloblasts responsible for enamel matrix degradation accompanied by massive mineralisation of the enamel (Fig. 1c).
Stage 3. The mature ameloblasts regulate the final mineralisation of enamel. The enamel layer hardens as the crystallites grow in width and thickness resulting in a mineralised tissue that contains more than 95% mineral by weight.
Tooth development is strictly genetically controlled but sensitive to environmental disturbances. Once teeth have been formed, they do not undergo remodeling. Therefore, the effects of any insult to the ameloblasts are detectable as defects in the mature enamel. In general, systemic factors that disturb the ameloblasts during the secretory stage cause restriction of crystal elongation and result in pathologically thin, or hypoplastic enamel. Disturbances during the transitional and maturation stage of amelogenesis result in pathologically soft (hypomaturated, hypomineralised) enamel of normal thickness. At the early stage of the maturation, ameloblasts are highly sensitive to environmental disturbances [Suga, 1989].
The first permanent molars (FPM) start to develop during the fourth month of gestation. Documents on the mineralisation of FPM rely on histological and radiographic studies and they show that the first signs of mineralisation are seen in the cusp tips around or soon after birth (Fig. 1A) [Hess et al., 1932; Logan et al., 1933]. Around the age of six months the four cusps become united (Fig. 1B) [Logan et al., 1933]. In the end of the first year deposition of the enamel matrix is completed in the occlusal half of the crown and maturation is ongoing (early maturation phase, Fig. 1C). Enamel formation as a whole takes approximately one thousand days [Reid and Dean, 2006] and two thirds of this time is devoted to the maturation stage of amelogenesis.
Enamel hypomineralisation of systemic origin of 1-4 FPMs and frequently also of incisors is known as Molar-Incisor Hypomineralisation (MIH), [Weerheijm et al., 2001]. While the enamel is affected to an extent ranging from mild to severe, changes in dentine seem to be mild. In a study by Heijs et al. , no morphological changes in the dentine were found by polarized light microscopy except for the presence of interglobular dentine under the affected enamel. Also an overall reduction of about 5% was measured in the mineral concentrations of both the apparently normal enamel and dentine within the MIH teeth compared with those of control teeth studied by an x-ray microtomography [Fearne et al., 2004].
It has been suggested that the most critical period for enamel defects of FPM and incisors is the first year of life coinciding with early maturation. However, as enamel maturation in the FPM takes several years (later maturation stage), hypomineralisations may develop later.
The aim of the present paper was to assess the literature on potential systemic factors of MIH. Because in humans only clinical observations can be made, controlled animal experiments are included in this review on possible aetiological factors that have been suggested on the basis of clinical studies. However, applicability of animal experiments to humans has to be assessed critically.
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A systematic search on Medline[R] online database was performed using the words molar incisor hypomineralisation and aetiology. The titles were first assessed and then abstracts appropriate titles were studied and finally the full articles were evaluated for their strength of evidence. Case reports, studies on inherited conditions, trauma, rare medical conditions, syndromes and studies exclusively concerning fluorosis, hypoplasia, discolouration, prevalence, or primary teeth were excluded.
A total of 1,142 articles were identified among which there was one critical review [Crombie et al., 2009]. For a detailed evaluation the 28 articles were selected according to the criteria above. Most of the studies were retrospective, cohort or case-control studies. A wide variety of factors were analysed. The articles were grouped by age periods (prenatal, perinatal or postnatal) and by the putative factors likely to be present during those periods.
Pre--Peri--and Post-natal periods
Prenatal period. There was some evidence that medical problems during pregnancy were associated with MIH. In one study a specific illness, urinary infection, during the last trimester was associated with MIH-like lesions [Freden et al., 1980]. In two other studies specific diseases were not associated with MIH but the authors reported that medical problems were more common in mothers of MIH children than in those mothers whose children did not have MIH [Whatling and Fearne, 2008; Lygidakis et al., 2008].
Perinatal period. In the perinatal period different medical conditions alone or in combination may affect the welfare of a child. In a Greek study, where the most common perinatal problems/conditions were Caesarian section, prolonged delivery, premature birth and twining, MIH was more frequently seen in the study than in the control group children [Lygidakis et al., 2008]. On the other hand, in an English study [Whatling and Fearne, 2008] or in a German study [Diedrich et al., 2003] perinatal problems could not be linked with MIH.
Hypoxia. This can be associated with medical problems related to birth, such as prematurity, respiratory stress and excessively prolonged duration of birth. It has been suggested that the causative factor of MIH or opacities in molars and incisors, could have been oxygen lack in active ameloblasts [van Amerongen and Kreulen, 1995; Seow, 1996; Aine et al., 2000; Lygidakis et al., 2008]. In the Australian study [Seow, 1996], prematurely born children whose birth weight was very low (< 1,500 g) had more opacities, but had not more hypoplastic FPM than control children.
In an experimental study, hypoxia in rats was induced by maintaining the animals in a hypobaric chamber at 0.5 atm for 24 hrs [Baumgardner et al., 1996]. Oxygen tension markers showed little variation in mature ameloblasts of the test rat incisors compared with those of the control animals while hypoxic disturbances were observed in the cells of the pulp and surrounding periodontium. This study suggested that short periods of hypoxia does not cause enamel defects. However, another study with a long period of oxygen shortage showed that hypoxia (respiratory acidosis) induced by 10% CO2 for 42 days caused enamel hypomineralisation in rat incisors [Whitford et al., 1995].
Hypocalcaemia. This may occur in the perinatal period but also in prenatal and postnatal periods. The finding that calcium, but not so clearly phosphate levels, was very low in MIH lesions suggests that they were caused by impaired calcium metabolism of the ameloblasts [Jalevik et al., 2001b]. Hypocalcaemia can be associated with several conditions such as maternal diabetes, vitamin D deficiency during the prenatal and/or perinatal period and prematurity. In a prospective study it was found that MIH-like lesions and enamel hypoplasia were significantly more common in premature infants than in controls [Aine et al., 2000]. Calcium and phosphate supplementation until infant reached the body weight of 2,000g did not have an effect on the incidence of MIH-like lesions. In children with nutritional rickets associated with hypocalcaemia, enamel hypoplasia has been a finding rather than hypomineralisation [Grahnen and Selander, 1954].
Results of experimental studies on the effects of hypocalcaemia on developing dental hard tissues seem to be related to the duration of hypocalcaemia. In a Japanese study a reduction in dentine thickness became prominent within several weeks after initiation of the diet, while enamel was normal in rats on a Ca-deficient diet [Namiki et al., 1990]. When the Ca-deficiency was prolonged over 10 weeks, hypoplastic responses were finally induced in the secretory enamel. Also, in some other studies, a period extending less than 3 weeks did not induce morphological alterations [Ranggard and Noren, 1994; Yamaguti et al., 2005]. In a long-term study diet-induced hypocalcaemia caused aberrations in maturing incisor enamel with both cellular and extracellular events [Nanci et al., 2000]. Furthermore, enamel of rat pups nursed by dams on a low calcium diet and weaned with the calcium-deficient diet developed hypomineralized incisor enamel [Bonucci et al., 1994].
Postnatal period. Several reports suggest that postnatal medical problems are associated with MIH. In a Swedish cohort study a correlation between diseases at 0-1 year of age and MIH was only found in boys [Jalevik et al., 2001]. A Dutch case control study children with MIH had had illnesses during the first 4 years of life than children without [Beentjes et al., 2002]. However, a Spanish study found that frequent paediatric care in each of the first 4 years showed a strong correlation with dental enamel defects in the FPMs [Tapias-Ledesma et al., 2003].
Furthermore, in a Greek study postnatal problems during the first year were clearly more common in children with MIH than in those without [Lygidakis et al., 2008]. In a recent Turkish study, children with MIH had a disease history from the first 3 years of life more often than children without MIH [Kuscu et al., 2008].
Childhood illnesses/high fever
Special attention has been paid to infectious childhood illnesses, high fever, medication (antibiotics), environmental toxicants, breast-feeding and use of fluorides. Illnesses such as otitis media [Beentjes et al., 2002], pneumonia [Beentjes et al., 2002; Jalevik et al., 2001], asthma [Jalevik et al., 2001], urinary tract infections [Tapias-Ledesma et al., 2003] and chickenpox [Whatling and Fearne, 2008] have been positively associated with MIH, although controversial results exist concerning some specific illnesses [Jalevik et al., 2001; Whatling and Fearne, 2008].
A common symptom of infectious childhood illnesses is fever and therefore its role is difficult to distinguish from that of the disease itself. However, in an experimental study it was possible to show that an exogenous pyrogen, turpentine, induced enamel hypomineralisation in rat incisors [Tung et al., 2006]. In this study the febrile state lasted for 57 hrs and the average temperature of the test rats rose 1.5[degrees]C higher than that of the controls. After 5 days a radiolucent line along with the incremental line was seen in microradiographs indicating enamel formation was influenced by high fever.
Some studies link antibiotic use with MIH [Jalevik et al., 2001; Beentjes et al., 2002; Whatling and Fearne, 2008; Laisi et al., 2009]. However, again it is not possible to be sure if childhood illness/fever or the treatment with an antibiotic is the causative factor or if both are involved.
The use of amoxicillin during the first year of life has been found to increase the risk of MIH [Laisi et al., 2009] and fluoride-like defects in the permanent incisors and FPMs [Hong et al., 2005]. Also, in an English study, MIH was more common among children for whom amoxicillin was the only antibiotic they had received during the first 4 years, but not in children with mixed antibiotic use including amoxicillin [Whatling and Fearne, 2008)]. In a Spanish study, MIH prevalence did not differ between children who had received amoxicillin during their first, second or third years and those who had not. 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]. If the use of antibiotics was involved, it could not be amoxicillin, as amoxicillin was not available on the market in Sweden before 1975.
The effects of amoxicillin on tooth development were studied in tooth culture in mice [Laisi et al., 2009]. Tooth explants were dissected on embryonic day 18 when the enamel matrix secretion was about to start. Teeth were cultured for 10 days with/without amoxicillin at concentrations of 100 microg/ mL-4 mg/mL. While ameloblasts of the control molars and those with low exposure to amoxicillin were transformed to the maturation stage, the ameloblasts of molars exposed to 4 mg/mL remained elongated after 10 days culture: altered patterns of amelogenesis may interfere with mineralisation.
Erythromycin use during the first year of life was found to be more common in children with MIH than in those without MIH [Laisi et al., 2009]. A significantly higher risk for enamel defects was also noted in FPM for children with higher intake of macrolides over the first 3 years of life [Tapias-Ledesma et al., 2003]. Whatling and Fearne  also included the use of erythromycin in their medical interview of mothers, but the number of reported subjects with early use of erythromycin was too low for further conclusions.
An experimental study suggested that a macrolide caused enamel defects in rats [Abe et al., 2003]. In that study a macrolide administered orally at a dose of 5,000 mg/kg/day for 5 weeks represented a high and long-lasting exposure. Pathological changes in the ameloblasts were observed at the transitional and maturation stages by histological methods. A hypomineralisation zone in incisors was seen after 4 weeks indicating developmental toxicity of the macrolide.
Accidental exposure to high levels of dioxins or polychlorinated biphenyls (PCBs) in early childhood has been found to be associated with demarcated opacity and/or hypoplasia [Alaluusua et al., 2004; Jan et al., 2007]. Those studies showed a dose-response relationship between the pollutant exposure (serum concentration) and developmental enamel defects in permanent teeth. The prevalence of developmental enamel defects was also higher in children living in a PCB contaminated area than in a control area in Slovenia [Jan and Vrbic, 2000]. In a Finnish study, a significant correlation between MIH and the exposure of the children to dioxins via mother's milk was found [Alaluusua et al., 1996b]. However, in a more recent study of children born 10 years later exposed to lower levels of dioxins, no correlation was found [Laisi et al., 2008]. A Turkish study showed a similar prevalence of MIH in children living in an urban area polluted by dioxins and in those living in an area with low pollution [Kuscu et al., 2009].
Several animal experiments have shown that teeth are among the most sensitive organs to the effects of dioxins [Alaluusua and Lukinmaa, 2006]. The most toxic dioxin congener, 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD) arrests degradation and/or removal of enamel matrix proteins in developing molars of rat pups exposed via their dams' milk. As a prerequisite for the completion of enamel mineralisation is the removal of enamel matrix, this apparently leads to disturbances in mineralisation [Gao et al., 2004].
A long duration of breastfeeding has been associated with MIH in a Finnish study [Alaluusua et al., 1996a]. Those authors suggested that pollutants in human milk may have been involved but as the levels of pollutants, such as dioxins, in milk were not measured, the role of pollutants remained speculative. Results from other Finnish or European studies have not suggested that duration of breast-feeding was associated with MIH [Jalevik et al., 2001; Whatling and Fearne, 2008].
Fluoride is thought to affect enamel crystal formation mainly during the maturation stage inducing defects described as diffuse opacities. The FDI index [FDI, 1992] is most often used in screening and differentiation of demarcated opacities and diffuse opacities. A very substantial majority of these studies have reported a strong association between the diffuse defects and the level of fluoride in drinking water or fluoride supplementation. No association between the prevalence of demarcated opacities and fluoride exposure has been found [Rugg-Gunn et al., 1997; Hiller et al., 1998; Ekanayake and van der Hoek, 2003; Mackay and Thomson, 2005] except in one study [Angelillo et al., 1990]. In that study the prevalence of diffuse opacities, but also demarcated opacities, was increased in respect to water fluoridation level. In three studies the association between fluoride supplementation and MIH was studied [Koch et al., 1987; Alaluusua et al., 1996b; Whatling and Fearne, 2008]. No significant association was found.
Although a number of putative factors have been investigated, aetiology of MIH remains unclear. It is likely that MIH is not caused by one specific factor but many different factors. Several harmful agents/conditions may act together and increase the risk of MIH additively or even synergistically. Harmful health conditions or agents can affect during prenatal, perinatal or postnatal period.
The problem of most clinical studies relating MIH or MIH-like lesions with medical conditions/problems, so far, is that they are retrospective. The information has been obtained by questionnaires or an interview, which rely on individual memory and can lead to inaccuracies. Reliability is increased if the information of the putative factor during early childhood has been obtained from medical records or medical notebooks. Approximately half of the clinical studies in this review totally or partly relied on such information and they dealt with prenatal [Freden, et al., 1980], perinatal [van Amerongen and Kreulen, 1995; Seow, 1996; Aine et al., 2000] and postnatal medical problems [Tapias-Ledesma et al., 2003; Kuscu et al., 2008; Laisi et al., 2009]. The study of Lygidakis et al.  covered all the natal periods.
Only two studies relying on medical records are available on the use of antibiotics and MIH [Tapias-Ledesma et al., 2003; Laisi et al., 2009]. However, in one further study on fluoride-like lesions in FPMs and incisors information on the use of antibiotics was obtained by a questionnaire every 3 months, which is likely to be a period short enough for the mother to remember the illnesses or their treatment [Hong et al., 2005].
In the two studies on environmental toxicant relating MIH and dioxin exposure of the child, the concentration of dioxins in mother's milk or in placenta was measured but the duration of breast-feeding was obtained by a questionnaire when the child was 6-8 years old [Alaluusua et al., 1996b; Laisi et al., 2008]. In a study on accidental exposure of children to dioxins [Alaluusua et al., 2004] and in another to PCBs [Jan et al., 2007]), the concentration of the toxicant was measured in serum fat and it was related to developmental enamel defects. In both studies a positive correlation was found. However, these studies reported on the demarcated opacities and/or hypoplasia in all permanent teeth but not specifically MIH.
Another problem of the clinical studies on the aetiology of MIH is the small number of participants. Excluding the fluoride studies, in only 6 cohort studies did the number of participants exceed 100 [Alaluusua et al., 1996b; Jalevik, 2001; Kuscu et al., 2008, Laisi et al., 2008, Laisi et al., 2009; Hong et al., 2005] and in case control studies, the number of 50 subjects was exceeded only in 3 studies [Leppaniemi et al., 2001; Whatling and Fearne, 2008; Lygidakis et al., 2008]. For example, in Tapias-Ledesma et al.  tested 42 children divided into those children who had had certain antibiotics during their first, second and third years. As the authors did not give information about the number of children who used those antibiotics yearly, it is difficult to know if the negative result of certain antibiotics in MIH was due to a small size sample or not.
Experimental studies in rodents show that many systemic factors can disturb enamel development of the continuously erupting incisors. The effects of some factors, such as elevation of temperature, seem to be detectable within a couple of days while others, such as lack of calcium, need a long time period to occur. Medical conditions/factors, treatment of the diseases and exposure to environmental toxicants assessed in the present review, also lasted for a shorter or longer period of time.
Common childhood illnesses such as ear infections with or without fever and with or without antibiotic treatment is present for a short time while an exposure to an environmental toxicant may last for years because of a very long half-life . The minimum time period effective enough to cause abnormal ameloblast function is likely to depend on the sensitivity of the ameloblasts to the harmful factor and the power/concentration of this factor. So far the minimum time period in MIH-type lesions is difficult to define. An example with an animal model by Suga , who examined microradiograms taken from tooth germs of monkeys. Hypomineralisation and hypoplasia of the tooth germs, which were at the late secretory and/or the early maturation stage, were found 2 weeks after the monkeys had a sudden unknown systemic disorder.
As mentioned before it is likely that many factors act simultaneously. In humans it is difficult to study the effects of several different factors. However, experimentally this is possible and the first example was recently presented [Salmela et al., 2009]. It is known that both TCDD and sodium fluoride (NaF) impair enamel formation depending on the concentrations present. The aim of Salmela and co-workers was to investigate if simultaneous exposure to TCDD and NaF can have synergistic effects in vitro in cultured mouse teeth. A novel finding was that the combined effect of the two agents at concentrations, which alone caused no or barely detectable effects, was clear.
The aetiology of MIH is still unclear. An increasing number of studies have been published during recent years and several prospective studies are ongoing to clarify the aetiology. In the critical review by Crombie et al. , the conclusion was that there is currently insufficient evidence in the literature to establish aetiological factor/s relevant for MIH. There was moderate evidence that dioxin and PCB exposure was involved. After publication of that review, a new paper questioned the role of dioxins in MIH because the levels of dioxins have remarkably decreased during the last 20 years [Laisi et al., 2008]. The review of Crombie et al.  further concluded that the role of nutrition, birth and neonatal factors and acute or chronic childhood illness/treatment was weak.
New studies have shed more light on the role of medical problems during the prenatal, neonatal and postnatal period and increased their impact in MIH [Lygidakis et al., 2008]. The association between the use of amoxicillin in the early childhood and MIH has also been studied as well as the effect of amoxicillin in mouse tooth culture [Laisi et al., 2009] and these studies suggest the role of amoxicillin in MIH. However, further studies, especially prospective studies are needed to improve the level and strength of evidence of the role of the present putative factors and to reveal new factors that may be involved. Combined effect of several factors should also be taken into account. Experimental in vivo and in vitro studies are needed to evaluate dose/response and to find the molecular mechanisms behind the abnormal function of the ameloblasts.
This invited paper was presented at the 6th Interim Seminar and Workshop of the European Academy of Paediatric Dentistry in Helsinki, Finland, 2009
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Dept. Pediatric and Preventive Dentistry, Institute of Dentistry, University of Helsinki, Finland.
Postal address: Prof. S. Alaluusua. P.O.Box 41, Fl-00014 University of Helsinki, Helsinki, Finland
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|Publication:||European Archives of Paediatric Dentistry|
|Date:||Jun 1, 2010|
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