Molar-Incisor-Hypomineralisation (MIH).
A retrospective clinical study in Greek children.
II. Possible medical aetiological factors
N. A. Lygidakis, G. Dimou, D. Marinou.
Dept. of Paediatric Dentistry, Community Dental Center for Children, Athens, Greece.
Abstract
Aim: This was to examine the potential medical aetiologi-
cal factors involved in the development of MIH. Methods:
During the years 2003-2005, all MIH cases diagnosed ac-
cording to set criteria were selected from the new patients
clinic of a Community Dental Centre for Children (Athens).
The age, gender and teeth involved were recorded. A control
group of socio-demographically matched controls was also
identified. The potential aetiological factors were retrieved
through personal interview with the parents and from each
child and mother’s medical book. Only verified aetiological
factors were recorded. Evaluation of the correlation of af-
fected teeth and the timing of the insult was performed in a
separate group of 225 affected children aged 8-12 with their
entire 12 ‘index’ teeth erupted. Results: From the 3,518, 5.5
to 12 years old children examined, 360 (10.2%) had MIH.
Aetiology of MIH: 44 children (12.2%), presented without any
relevant medical history, the remaining 316 (87.8%) recorded
various medical problems associated with MIH, compared
with 18.9% for controls. Perinatal (163, 33.6%) and postnatal
(162, 33.9%) problems were the most frequently found and
prenatal the least (33, 8.6%). For 42 children (11.7%) prob-
lems occurred in more than one chronological period, mainly
during both the perinatal and postnatal period (11.1%). The
most common prenatal problem was repeated episodes of
high fever (12/33), in the perinatal period birth by Caesar-
ean section (92/163) and other birth complications (34/163).
Various respiratory conditions (88/162), repeated episodes
of high fever (31/162) and neonatal illness (28/162) were the
commonly reported problems in the postnatal period. Many
MIH cases presented with more than one medical problem
during the peri-and postnatal period. Statistical analysis:
Children with MIH recorded 68.9% more frequent medical
problems than controls (p<0.0001). A positive correlation
(p<0.001) between the total number and type of affected
teeth with the timing of the insult was observed in the 225
MIH children with all their ‘index’ teeth erupted. Conclusion:
Children with MIH present with more medical problems than
controls during their prenatal, perinatal and postnatal period.
The majority of these illnesses may produce hypocalcaemia,
hypoxia and pyrexia to the child or the mother. The number
of affected teeth was associated with the timing of the pos-
sible insult; children with prenatal, perinatal and postnatal
problems present more affected teeth in increasing order.
Key words: molar-incisor-hypomineralisation, clinical study, aetiology
Postal address: Dr Nick A. Lygidakis, 2 Papadiamantopoulou St., Athens 11528, Greece.
Email: lygidakis@ath.forthnet.gr
Introduction
Molar-incisor-hypomineralisation (MIH) is defined as the de-
velopmentally derived dental defect that involves hypom-
ineralisation of 1 to 4 permanent first molars (FPM) that is
frequently associated with similarly affected permanent inci-
sors. The defect is clinically presented as demarcated enamel
opacities of different colour in the affected teeth, occasion-
ally undergoing post-eruptive breakdown due to soft and
porous enamel. This may result in atypical cavities or even
complete coronal distortion, requiring extensive restorative
treatment [Lygidakis et al., 2003; Mathu-Muju and Wright,
2006]. Due to profound sensitivity of affected teeth, children
are reluctant to carry out effective oral hygiene (OH) and to
accept dental treatment, being at risk of developing dental
phobias and presenting behaviour management problems
[Javelik and Klingberg, 2002]. Histologically the defective
enamel is partly hypomineralised, with well-defined borders
between the defective and normal enamel [Javelik and No-
ren, 2000].
Prevalence. Following the establishment of the presently
used diagnostic criteria [Weerheijm et al., 2003], very few
well-documented studies have been undertaken concerning
the prevalence of MIH [Jasulaityte et al., 2007; Lygidakis et
al., 2008]. Previous studies using a variety of criteria have
shown that the prevalence of the defect is between 3.6 and
25% in Europe, while there is a relative lack of data concern-
ing the Americas and elsewhere [William et al., 2006; Jasu-
laityte et al., 2007].
Aetiology. A variety of systematically acting medical factors
have been proposed as contributing to or causing MIH, in-
cluding prenatal, perinatal and postnatal illnesses, low birth
weight, antibiotic consumption and toxins from breast-feed-
ing [William et al., 2006]. Children with poor health during
the first years of life, the critical period for crown formation
of the FPM and incisors, are more likely to be at increased
risk for MIH [Jalevik and Noren, 2000]. It also has been pro-
posed that there could be an underlying genetic predisposi-
tion that contributes to the risk of developing MIH in at least
some cases [Brook and Smith, 1998]. The varying degree
of enamel defects in FPM and incisors, that develop at the
same time, suggest that not all teeth are equally susceptible
to enamel defects and developmental disturbances. Either
genetic or spatial differences could play a part in the devel-
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European Archives of Paediatric Dentistry // 9 (4). 2008
Lygidakis et al.
opment and variability observed clinically in MIH. Collective-
ly, the majority of previous studies imply that the aetiology of
MIH is complex with undetermined systematic and genetic
factors disrupting normal amelogenesis in the affected teeth
[Mathu-Muju and Wright, 2006].
The aim of the present study was to assess the potential
medical aetiological factors in a group of MIH children diag-
nosed according to the recently set criteria. A control group
was used in order to evaluate whether any findings were dif-
ferent from the ‘normal’ population. Finally, various correla-
tions in the MIH group were examined for possible interrela-
tions between the number and type of teeth involved and the
timing of the insult onset.
Material and Methods
Population. During the years 2003-2005, all MIH cases were
selected from the new patients clinic of the Community Dental
Center for Children in Athens, which accepts for dental treat-
ment children up to the age of 12 years. A pilot study under-
taken in 2002 set the clinical procedure for the fulfilment of the
present study [Lygidakis et al., 2004]. The criteria used for the
diagnosis of MIH were those described in a European meeting
held in Athens in 2003 [Weerheijm et al 2003]. All children with
MIH had at least one FPM erupted, at least partly, during the
time of examination as has been suggested as a diagnostic
requirement [Jalevik and Noren, 2000].
Recording of defects. The age, gender, teeth involved and
the severity of the defect were recorded. In order to evaluate
more precisely the potential interrelation between the timing
of the medical insult and the total number and type of teeth
affected, a separate sub-group of MIH children with their en-
tire 12 ‘index’ teeth erupted (4 FPM and 8 incisors) was iden-
tified. There were 7 children that had 1-3 canines affected in
addition to FMPs and incisors and these were regarded as
having only incisors and molars affected in order to conform
to the MIH criteria.
Following a professional cleaning of the teeth, clinical ex-
amination of the cases was performed in a dental chair us-
ing mirror, probe and dental light, by either one of the first
two authors or by both of them, who were previously cali-
brated for the diagnosis of MIH in the pilot study [Lygidakis
et al., 2004]. Inter-examiner reproducibility was calculated
and was found to be high in all parameters examined (kap-
pa=0.92-0.95).
Aetiology. Possible medical aetiological factors were record-
ed by a) a detailed personal interview with the parents where
all childhood and pregnancy medical history was asked,
b) from the child’s official State medical book and c) their
mother’s medical history during pregnancy and delivery as
recorded in their medical insurance book. All patients and
families were insured with the same ‘Social Security Insur-
ance’, covering all privately employed Greeks. All Greek
children have an additional medical book in which all their
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European Archives of Paediatric Dentistry // 9 (4). 2008
illnesses and treatments provided are recorded, usually up
to the age of 6 years. The parents completed a consent form
in order to have the medical history retrieved from the medi-
cal book.
Aetiological factors were divided into prenatal, perinatal and
postnatal according to the timing of the insult. Postnatal
problems were defined as those appearing up to the age of
1 year, thus including the neonatal (up to1st month) and in-
fancy period. Low birth weight and twinning were classified
in the perinatal problems, as delivery problems were also im-
plicated. Only verified aetiological factors, as written in the
medical records, were recorded.
Control population. A separate group of children was selected
from the same child population, examined in the new patients
clinic during 2003-2005, as a control group. Accordingly, 360
children examined exclusively for orthodontic problems were
included in the control group. In order to form a random and
representative control group, children were matched for age,
gender, ethnicity and socio-economic family status. In a con-
sistent way every 3rd ‘normal’ child that was fulfilling the pre-
viously mentioned criteria was included in the ‘control’ group.
Medical information of the child and the mother was retrieved
the same way as for the MIH children.
Statistical analysis. This was performed using a SPSS pro-
gram for Windows. Parametric and non-parametric statistical
test were used and the significance level was set at p<0.05.
Results
Population. During the three year period, 6,983 children aged
1-12 years, were examined for a first time, from these 3,518
were 5.5 to 12 years old, the remaining being of preschool
age. By the end of the third year of the study 360 children
with MIH had been identified, the overall prevalence in the
study population being 10.2%. The age span of the affected
children at the time of examination was 5.5-12 years (mean
age 8.17±1.38). Further demographic details of the patients
have been presented in the Part I of the present clinical trial
together with number, type and severity of affected teeth
[Lygidakis et al, 2008]. All cases except for 24 belonged to
different families, with no relationship between them. The 24
cases consisted of 2 brothers of a diabetic mother, 12 twins
(six sets) and 5 sets of first cousins.
Distribution of potential aetiological factors in the MIH chil-
dren. As shown in Table 1, 44 children (12.2%), presented
without any type of medical history. The remaining 316
(87.8%) revealed various medical problems that have been
associated with MIH. Regarding the time of the insult, peri-
natal (33.6%) and postnatal (33.9%) problems were the most
frequently found, while prenatal were the least (8.6%). Prob-
lems in more than one chronological period occurred in 42
affected children (11.7%). The major occurrence in this cat-
egory was the combination of perinatal and postnatal medi-
cal conditions (11.1%).

Table 1. Distribution of the timing of the possible aetiological factors in 360 MIH children, 225 MIH children with all their 12 ‘index’
teeth erupted and 360 controls in a Greek population.
Aetiological factor MIH cases with all their ‘index’
Total MIH cases (360)
timing
Number % Number
Unknown 44 12.2
Prenatal 31 8.6
Perinatal 121 33.6
Postnatal 122 33.9
Perinatal+postnatal 40 11.1
Prenatal+perinatal 2 0.6
Concerning the actual type of the medical condition re-
corded, in the prenatal group cases of repeated episodes of
high fever were more frequent (12/33), in the perinatal group
Caesarean section (92/163) and in the postnatal group vari-
ous upper and lower respiratory medical problems (88/162).
There were also repeated episodes of high fever due to com-
mon cold/coryza (31/162) and neonatal problems during the
first month of life (28/162) (Table 2). An important finding was
the frequent recording of more than one medical problem
during the perinatal and postnatal period. There were 163
children with MIH who reported 185 medical problems in
the perinatal period, whilst 162 children with MIH were as-
sociated with 203 medical problems in the postnatal period.
An example of multiple problems was the association of 45
from the 92 born by Caesarean sections with problems in the
perinatal (complicated delivery/ preterm birth) and postnatal
(frequent respiratory illnesses) (Table 2).
Distribution of medical problems in the ‘control’ group. As
can be seen in Table 1, in 68 children (18.9%) of the 360
control subjects medical problems of the same type as those
recorded in the MIH group were noted. There were no cases
of prenatal medical conditions, while more postnatal (45,
12.5%) than perinatal (23, 6.3%) problems were found. Peri-
natally the more frequent problem was prolonged/difficult
delivery (10/23), followed by Caesarean section (8/23) and
premature birth (5/23); postnatally respiratory problems, eg.
otitis, bronchitis, asthma (25/45). There were also repeated
episodes of high fever due to common cold/coryza (13/45)
and other less frequently found conditions, such as neonatal
illnesses, seizures, encephalitis and urinary infection (8/45).
In contrast to the MIH cases, in the control group children
there were no cases of multiple illnesses in the same or in
more than one chronological period.
Comparison between MIH cases and controls. There was a
statistically significant difference between affected and con-
trol group, in the number of children recording medical prob-
lems with 87.7% of MIH cases being associated with a med-
ical complication as compared with only 18.9% in the control
MIH Aetiology
Controls
teeth erupted (225) (360)
% Number %
28 12.4 -
20 8.9 0 0
79 35.1 23 6.4
72 32.0 45 12.5
25 11.1 0 0
1 0.4 0 0
group (Table 1) (McNemar test, p<0.0001). That means that
MIH children presented 68.9% (95%CI=[60%-77.8%]) more
frequent medical conditions than controls. Similar significant
differences were found for separate comparisons in the cas-
es of perinatal (p<0.001) and postnatal medical history alone
(p<0.001). In the case of perinatal aetiology, MIH children
presented 38.9% (95%CI=[31.8%-46.0%]) more frequently
with medical conditions than controls, while in the postnatal
group, 33.1% (95%CI=[25.8%-40.5%]). There were no cas-
es of prenatal problems in the control group as compared
with the MIH cases.
Correlations between number of affected teeth in MIH cases
with their entire ‘index’ teeth erupted (age 8-12) and the tim-
ing of possible aetiological factor. In order to evaluate these
possible correlations, a separate group was formed of af-
fected children aged 8-12 years with their entire 12 ‘index’
teeth erupted. The distribution of aetiological factors in this
sub-group of 225 children is also shown in Table 1. As is
apparent, when they are compared with the results from the
‘total’ MIH cases, both groups reveal similar percentages, in-
dicating the persistence and value of the results. In Figure 1
the distribution of the number of teeth affected in correlation
with the timing of each aetiological factor is shown. Exclud-
ing cases of unknown aetiology (n=28), children recording
medical problems during the combined perinatal/postnatal
periods had significantly more affected teeth than those ex-
posed to complications in the postnatal and perinatal period
alone; children with problems in the prenatal period pre-
sented with significantly less affected teeth (Kruskal Wallis
test=23,65, p< 0.001). It is worth mentioning that all 7 chil-
dren with canines affected in addition to FPM and incisors,
although not assessed as noted in Materials and Methods,
belonged to the combined perinatal/postnatal group.
As it can be seen in Figure 1, correlations were also evaluated
regarding the total separate number of incisors and FPM af-
fected. Statistically significant differences were found in both
cases (for FMP Kruskal Wallis test=25,83, p=0.001, for inci-
sors Kruskal Wallis test=12,79, p=0.005), the number of af-
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European Archives of Paediatric Dentistry // 9 (4). 2008
Lygidakis et al.
Fig 1. Distribution of MIH affected teeth (total number, molars, incisors) in comparison with the timing of the known potential
aetiological factor, in the sub-group of 225 Greek children with all their ‘index’ teeth erupted. Combined prenatal/perinatal prob-
lems were excluded, due to small numbers.
Mean (±SD) number of affected teeth
fected teeth being as noted previously, greater in cases of
combined perinatal/postnatal aetiology followed by those in
postnatal, perinatal and prenatal period in descending order.
Correlations between the type and location of affected teeth
in MIH cases with their entire ‘index’ teeth erupted (age 8-12)
and the timing of possible aetiological factor. Table 3 sum-
marises the relationship between the type and location of af-
fected teeth with the timing of the medical problem. Overall,
maxillary teeth in total were more frequently affected than
mandibular, irrespective of the insult period (p=0.000-0.005).
For posterior teeth, both affected mandibular FPM were sta-
tistical significantly less frequently found in cases of prenatal
aetiology and more in the cases of combined perinatal/post-
natal aetiology (p<0.001), while both maxillary molars were
very frequently found (85-96%) in all different cases of aeti-
ology. However, their distribution within the aetiology groups
was statistically non-significant (p>0.005) (Table 3). Overall,
maxillary and mandibular affected molars were equally found
in all MIH children, regardless of aetiology, with the excep-
tion of prenatal aetiology, where maxillary molars were more
frequently found than mandibular (p=0.013) (Table 3).
When anterior teeth were considered non-significant asso-
ciations (p>0.005) were found in cases of mandibular lateral
incisors when correlated with the period of insult, both of
them being much less frequently found than the rest of the
affected teeth in all cases of aetiology (0-16%) (Table 3). Ad-
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European Archives of Paediatric Dentistry // 9 (4). 2008
ditionally, both mandibular central incisors were statistical
significantly less frequently affected in cases of prenatal aeti-
ology (5%) and more with postnatal aetiology (35.4/36.7%)
(p=0.023-0.34) (Table 3). Furthermore, both maxillary central
incisors were statistical significantly more frequently affected
in cases of combined perinatal/natal aetiology (84/88%) and
less in cases of prenatal aetiology (50/55%) (p<0.001). Re-
gardless of aetiology, maxillary incisors were always more
frequently affected than mandibular (p<0.005) (Table 3).
Discussion
MIH is an interesting disorder, although the so called ‘exten-
sive disruption of molar enamel’ was evident centuries ago,
as has been proven recently in sub-adults retrieved from the
post-medieval Broadgate cemetery in London [Ogden et al.,
2007]. Only in the last decade has the condition attracted the
interest of the dental profession. The decline of dental caries
in the ‘Western’ world has allowed researchers to concen-
trate on problems that were attracting less interest in the past.
Concerning aetiology, as early as 1981, Nikiforuk and Fraser,
made an attempt to explain the aetiology of what was called
at that time ‘hypoplasia’ of non-genetic or local aetiology. In
their pioneer work it was concluded that ‘hypocalcaemia dur-
ing amelogenesis is a crucial factor that can lead to ‘enamel
hypoplasia’ of environmental aetiology’. They studied cases
of rickets and hypoparathyroidism and found that enamel hy-
poplasia was evident only in those cases with hypocalcaemia
 MIH Aetiology

Table 2. Distribution of the possible aetiological factors in a group of Greek children affected by MIH according to the onset
chronological period.

Prenatal aetiology Perinatal aetiology Postnatal aetiology

Possible aetiological factor
(33 cases) (163 cases) (162 cases)
% in the total % in the total % in the total
N (%) N (%) N (%)
MIH group MIH group MIH group
Multiple episodes of maternal high
12 (36.3) 3.3%
fever/viral infection during last month
Prolonged medication (myometrium
6 (18.2) 1.6%
spasmolytics) during last month
Maternal diabetes 5 (15.1) 1.38%
Prolonged vomiting up to last month 5 (15.1) 1.38%
Malnutrition 2 (6) 0.5%
Chicken pox last month of pregnancy 1 (0.3) 0.27%
Renal deficiency 1 (0.3) 0.27%
Maternal hypertension 1 (0.3) 0.27%
Caesarean section 92 (50.5) 25.5%
Prolonged/complicated delivery 34 (18.3) 9.4%
Twins 29 (15.6) 8%
Premature birth-low birth weight 29 (15.6) 8%
Hemorrhage + detachment during
1 (0.5) 0.27%
delivery
Repeated (>5) episodes of high fever
31 (15.2) 8.6%
due to common cold/coryza
Otitis 34 (6.7) 9.4%
Bronchitis 21 (10.3) 5.8%
Asthma 15 (7.3) 4.1%
Bronchiolitis 7 (3.4) 1.9%
Laryngitis 6 (2.9) 1.6%
Tonsillitis 5 (2.4) 1.38%
Neonatal (first month of infancy) (respira-
tory problems, incubator, exanthematous 28 (13.7) 7.7%
disease, high fever, seizures)
Prolonged use of medication other than
16 (7.8) 4.4%
antipyretics
Seizures afebrile/febrile 12 (5.9) 3.3%
Urinary infection 9 (4.4) 2.5%
Encephalitis 4 (1.9) 1.1%
Gastroenteritis 4 (1.9) 1.1%
Exanthematous disease 2 (0.9) 0.5%
Other (endocrine disturbance, anaemia,
9 (4.4) 2.5%
operations, cleft palate, salmonellas)
T0TAL ILLNESSES 33 185 203

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Lygidakis et al.

(vitamin dependent rickets and hypoparathyroidism) and not
evident in cases of hypophosphataemia (X-linked rickets), re-
vealing normal calcium levels in the blood.
In an attempt to explain the possible aetiological factors in
the MIH cases it is important to remember that between 28th
week in utero and the first 10 days of life ameloblasts initiate
amelogenesis in the first permanent teeth to be formed, the
FPM, followed by other teeth later in time [Welbury, 1997].
This time schedule has been recorded in previous studies
providing the dental development charts, although there
are chronology diversions not easily detected as a result of
methodology difficulties in neonates and infants [Moorrees
et al., 1963]. It has been clearly shown that ameloblasts be-
long to the most sensitive cells of the human body. If their
function is interrupted, temporarily or permanently, then de-
pending upon the time of insult, enamel hypoplasia or hy-
pomineralisation is produced [Simmer, 2001; Fearne et al.,
2004]. Experiments have shown that conditions affecting
the enamel matrix pH, i.e. respiratory acidosis and abnor-
mal oxygen levels resulting from hypoventilation in various
respiratory diseases, inhibit the action of the proteolytic en-
zymes and the development of the crystal hydroxyapatite re-
sulting to enamel hypomineralisation [Whitford and Angmar-
Mansson, 1995; Sui et al., 2003]. Ameloblastic function itself
might be additionally affected by low oxygen levels found
during the birth of preterm children [Johnsen et al., 1984;
Aine et al., 2000]. It has been also suggested that the lack
of calcium phosphate in the area of the crystallites might re-
sult in reduced calcium deposits and lower ratio of calcium/
phosphorous leading again to enamel hypomineralisation
[Van Amerongen and Kreulen, 1995; Jalevik et al., 2001a].
To support this theory, recent experiments in animals using
immunocytochemical analysis have shown that hypocalcae-
mia affects enamel during the late secretory and early matu-
ration stages, interfering with both cellular and extracellular
elements resulting in hypomineralisation [Nanci et al., 2000;
Yamaguti et al., 2005].

Table 3. Correlations between type of teeth affected with MIH and the chronology of possible aetiological factor, in the sub-group
of 225 children with all their ‘index’ teeth erupted.

Perinatal+postnatal Statis-
Tooth Prenatal (20 cases) Perinatal (72 cases) Postnatal (79 cases)
(25 cases) tics**
% % % %
FDI Present Absent Present Absent Present Absent Present Absent p
presence presence presence presence
T11 10 10 50 48 24 66.7 51 28 64.6 22 3 88 0.050*
T12 2 18 10 8 64 11.1 13 66 16.5 9 16 36 0.028*
T21 11 9 55 45 27 62.5 43 36 54.4 21 4 84 0.061*
T22 2 18 10 9 63 12.5 13 66 16.5 8 17 32 0.119
T31 1 19 5 17 55 23.6 29 50 36.7 9 16 36 0.023*
T32 0 20 0 7 65 9.7 9 70 11.4 4 21 16 0.344
T41 1 19 5 16 56 22.2 28 51 35.4 7 18 28 0.034*
T42 1 19 5 8 64 11.1 7 72 8.9 3 22 12 0.830
T16 19 1 95 68 4 94.4 73 6 92.4 24 1 96 0.901
T26 17 3 85 64 8 88.9 72 7 91.1 24 1 96 0.616
T36 10 10 50 63 9 87.5 72 7 91.1 24 1 96 0.000*
T46 10 10 50 63 9 87.5 72 7 91.1 24 1 96 0.000*
Maxillary vs.
mandibular teeth Z=-3.066,p=0.002* Z=-4.650, p=0.000* Z=-2.811, p=0.005* Z=-3.115, p=0.002*
(total)
Maxillary vs man-
Z=-2.495,p=0.013* Z=-1.035, p=0.301 Z=-.354, p=0.723 Z=.000, p=1.000
dibular molars
Maxillary vs man-
Z=-2.810,p=0.005* Z=-4.604, p=0.000* Z=-2.877, p=0.004* Z=-3.203, p=0.001*
dibular incisors
(*Statistically significant,**Pearson chi-square, z=Wilcoxon signed Ranks test)

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European Archives of Paediatric Dentistry // 9 (4). 2008

In the present retrospective clinical study a wide spectrum
of medical conditions of the mother and the child appear to
be associated with MIH. It is known that retrospective stud-
ies of this kind reveal problems that may reduce their value,
including the lack of definite diagnostic criteria in the past,
the use of parents as the only source of medical information
during their child’s first year of life, the frequent coexistence
of more than one medical problem of the subjects, the wide
time spectrum of enamel formation of the affected teeth, etc.
Taking these factors into account and until the completion
of well-organised prospective studies, the present research
made an effort to minimise these drawbacks in order to at-
tain valuable results. In the present study, apart from the
parents’ interview, medical information was retrieved from
each child’s medical book and mother’s illnesses during
pregnancy was verified from their insurance medical record.
The retrieval of this information from these records means
that illnesses were recorded only when a doctor had exam-
ined a child, thus excluding various everyday illnesses that
do not require medical attention. This might underestimate
some medical problems, but it is an accurate method to re-
trieve medical history. Also in the MIH group only children
that fulfilled the clinical criteria set recently were included
while questionable subjects were excluded. Finally an effort
was made that the ‘control’ group used for comparison was
as representative as possible taking into account, apart from
age and gender, the socioeconomic status and the ethnic
origin of the children.
Prenatal medical conditions. In the present study 33/360 of
the MIH children (8.6%) revealed maternal prenatal prob-
lems, compared with none of the control group. Aetiologi-
cal factors acting during this period produce fewer cases
of MIH compared with all other periods, indicating that chil-
dren are probably protected in utero. During the last gesta-
tional months, multiple maternal episodes of high fever, due
to common cold or infections, were frequently found to be
associated with MIH. This finding of maternal pyrexia has
been shown experimentally to have a detremental influence
on amelogenesis, ranging from ameloblastic dysfunction
to complete cellular degeneration [Kreshover and Clough,
1953]. Similar to our results were those reported in a study of
33 children with MIH [Jälevik and Noren, 2000], where 15%
of them recorded maternal chronic diseases during pregnan-
cy, eg. syphilis, hypertension, elevated blood glucose, and
prolonged use of drugs. However, in a later study the same
group could not find any association of these conditions with
MIH [Jalevik et al., 2001a].
Other prenatal medical problems evident in the present study
included maternal diabetes, prolonged vomiting and use of
spasmolytic medication in the late gestational weeks. Al-
though these conditions have not been reported before, it is
known that maternal diabetes produces hypocalcaemia in the
mother and oxygen shortage problems to the infant that may
result, as it was discussed before, in enamel hypomineralisa-
MIH Aetiology
tion. A recent study has shown that 15% of infants of diabetic
mothers suffer from hypocalcaemia and another 15% from
oxygen shortage [Alam et al., 2006]. In addition, in cases of
prolonged maternal nausea and vomiting, fluids and electro-
lytes, as well as nutritional status, are jeopardised leading oc-
casionally to foetal biochemical disturbance [Nelson-Piercy,
1998]. If prolonged vomiting is present during the last ges-
tational days neonatal hypoxia might be produced [Cyna et
al., 2006]. Finally, although the prolonged use of myometrium
spasmolytics has not been clearly implicated with enamel de-
fects in the past, there is evidence that repeated use of b-
Adrenergic antagonists during gestation, found in the present
study in 6/33 the cases with prenatal problems, might have,
among other side effects, maternal nausea and vomiting and
foetal hypocalcaemia [Norwitz et al., 1999]. These side-effects
might be a reason for MIH in these cases.
Some other prenatal problems were detected in the mother’s
medical book in the present study. These included malnutri-
tion, chicken pox, renal deficiency, hypertension, also asso-
ciated with hypocalcaemia, indicating again potential links
with MIH.
Perinatal medical conditions. In the present study 121/360 of
MIH children (33.6%) revealed perinatal problems, compared
with 6.3% of the controls. Caesarean section, prolonged de-
livery, premature birth and twining were the most frequently
found conditions. Previous studies have shown association
of perinatal problems and MIH. In a group of 21 children
with MIH, 48% of them recorded perinatal problems similar
to those found in this study, e.g. premature birth, prolonged
delivery, cyanosis, [Van Amerongen and Kreulen, 1995]. In
another group of 40 premature children with low birth weight
(<1500 gr), 43% of them were found to have a higher pro-
portion of enamel hypomineralisation, when compared with
‘control’ children born at due time having ‘normal’ weight
[Seow, 1996]. Additionally, in a group of 32 children with
enamel anomalies, 83% were born prematurely and it was
concluded that ameloblast function might be affected by low
oxygen levels present during birth [Aine et al., 2000], an ex-
planation that has been given before for enamel ‘hypoplasia
[Johnsen et al., 1984]. In contrast with the previous reports,
two more clinical studies found no correlation between re-
ported perinatal problems and presence of MIH [Beentjes et
al., 2002; Jalevik et al., 2001b].
Many of the perinatal problems identified in the present
study and in previous studies, appear to be associated with
hypocalcaemia and hypoxia. In the present study, of those
children with MIH and perinatal medical history, 15.6% were
born prematurely with low birth weight and 18.3% were the
outcome of difficult and prolonged delivery. It is well docu-
mented that early neonatal hypocalcaemia is present in ap-
proximately 30-75% of cases of preterm low birth neonates,
particularly in those with respiratory distress and birth as-
phyxia due to complicated, prolonged or difficult, delivery
[Rosli and Fanconi, 1973; Behrman and Vaughan, 1987].
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European Archives of Paediatric Dentistry // 9 (4). 2008
Lygidakis et al.
The reason is that two-thirds of an individual’s stores of cal-
cium and phosphorus accumulate during the last trimester
of pregnancy and preterm infants miss much of this mineral
accretion [Tsang et al., 1976]. Additionally to hypocalcaemia,
prolonged and difficult delivery has also been clearly associ-
ated with hypoxia of the newborn. In a study of 2,371 births,
multivariate analysis showed that prolonged second stage
labour was significantly associated with newborn hypoxia
[Chandra et al., 1997], suggesting a potential association
with MIH with this perinatal condition.
An interesting finding of the present study was the high pro-
portion of children born by Caesarean section; 49.7% of
those with perinatal medical history and 25.5% of the to-
tal MIH group, percentages significantly higher than in the
‘control’ group. All children of the present study were born
during 1990-2000, when the proportion of Caesarean sec-
tions in the population was much less than 20% compared
with more than 30% during more recent years [Roussos et
al., 2003]. Although in some European countries, including
Greece, this type of delivery is nowadays considered as ‘nor-
mal’, it is still an operation with various implications for the
mother and the neonate. For example a recent study report-
ed in the obstetric literature has shown that neonatal hypoxia
was more frequent in infants following second-stage Cesar-
ean section [Cebekulu and Buchmann, 2006]. Furthermore,
in a large Danish study during 2007 it was clearly shown
that, compared with newborns delivered vaginally, those
delivered by elective Caesarean section, at around full-term
had an increased risk of overall and serious respiratory ill-
nesses, conditions often associated with hypoxia [Hansen et
al., 2007]. Finally, the commonly used spinal anaesthesia for
Caesarean section has a frequent complication of maternal
hypotension that can be associated with severe nausea or
vomiting which occasionally produces infant hypoxia [Cyna
et al., 2006]. Therefore is seems that Caesarean section is
associated with oxygen storage problems in the newborn
and this way potentially linked with MIH in these children.
Twins comprised 15.6% of those children recorded with
perinatal medical history in the present study, the majority
of them (22/29) being the result of in vitro fertilisation (IVF),
while 8/29 of them were delivered by Caesarian section. Pre-
vious studies have shown that the postnatal health of twins,
particularly those born after IVF, was worse as a result of
frequent problems in the neonatal period [Koivurova et al.,
2003] and the increased incidence of low birth weight and
prematurity [Ludwig et al., 2006]. These problems might be
a potential aetiological factor for MIH in these children, to-
gether with complicated deliveries and Caesarean section.
Postnatal medical conditions. In the present study, 33.9%
of MIH children recorded postnatal problems, as compared
with 12.5% of the control group. Respiratory illnesses, re-
peated episodes of high fever, various neonatal period prob-
lems and afebrile/febrile seizures were found more frequent-
ly compared with controls. The majority of these medical
214
European Archives of Paediatric Dentistry // 9 (4). 2008
conditions have been reported before in studies on smaller
samples of MIH children. In a group of 21 children with MIH,
67% of them revealed various respiratory illnesses such as
bronchitis, asthma, pneumonia and upper respiratory track
infections [Van Amerongen and Kreulen, 1995]. In a Swed-
ish study that also used a ‘control’ group, 77 children with
MIH presented with more medical problems during their first
year of life, most frequently asthma, pneumonia, otitis media
and upper respiratory tract infections [Jalevik et al., 2001b].
In a Dutch study 24 children with MIH were compared with
21 controls, revealing statistically different presence of oti-
tis media, pneumonia, infections and high fever, during their
first 4 years of life [Beentjes et al., 2002].
The present and the previous studies have shown potential
association of various illnesses during the first year of life with
MIH, such as various upper and lower respiratory illnesses of
viral/bacterial origin and asthma. Hypoxic episodes, a com-
mon characteristic in some of the lower respiratory tract ill-
nesses, can be linked as previously discussed with enamel
hypomineralisation. Hypoxia is amongst the other symptoms
found in many respiratory tract infections caused by certain
viruses, such as RSV [McBride, 1999]. In addition to hypox-
ia, upper respiratory infections caused by certain bacteria,
such as meningococcus, may also produce hypocalcaemia,
as has been reported in a recent Cohort study where 70%
of children admitted to hospital with such an infection, re-
vealed low total and ionised calcium concentrations in the
blood [Banes et al., 2000]. Hypocalcaemia is also a frequent
finding in other illnesses during infancy. Viral gastroenteritis,
found in the present study and usually caused by Rotavirus,
is closely linked with hypocalcaemia in infants [Foldenauer et
al., 1998]. It is also known that even healthy full-term babies
undergo a physiological nadir in serum calcium levels by 24-
48 hours of age, related to the delayed response of parathy-
roid and calcitonin hormones in a newborn. This nadir may
drop to hypocalcaemic levels in high-risk neonates including
infants of diabetic mothers, preterm infants and infants with
perinatal asphyxia due to complicated delivery [Aggarwal
et al., 2001], correlating the various neonatal problems with
MIH. In the present study, neonatal problems accounted for a
high percentage of infants with MIH (13.7% in the MIH group
compared with 1.3% in controls). The majority of them were
neonates requiring hospitalisation and time in an incubator
due to respiratory and other illnesses related with delivery
problems and preterm birth.
In addition to previous problems, any infection, particu-
larly these of the respiratory tract, during the neonatal and
postnatal period may produce prolonged episodes of high
fever. In the present study 31/162 children with postnatal
problems recorded repeated episodes of high fever, usually
due to common cold/coryza. Only children with more than 5
episodes during their first year of life were recorded, as less
than those are ‘normally’ found in infants up to the 1st year
of life [Behrman and Vaughan, 1987]. The rest of respiratory

illnesses found in the present study (otitis media, bronchitis,
bronchiolitis, laryngitis, tonsillitis) may also present with high
fever, as the great majority of them are complications of up-
per respiratory infections that have high fever as one of their
clinical symptoms [Behrman and Vaughan, 1987].
This association of high fever during infancy with enamel hy-
pomineralsation has recently been proven, as experimental
studies showed that a pattern of persistent high fever influ-
enced the process of enamel formation, producing disori-
entation of enamel prism and crystal-free area [Tung et al.,
2006]. Repeated episodes of high fever can also be one of
the main clinical symptoms of urinary tract bacterial infection
in infants [Behrman and Vaughan, 1987], found in affected
cases of the present study and this way explaining their as-
sociation with MIH.
Seizures were also more frequently reported in the MIH group
when compared with controls. Febrile seizures are the result
of high fever and in this way apparently linked to MIH, and
shown before whilst a febrile condition might be frequently
associated with infant hypocalcaemia [Scarfone et al., 2000],
explaining why an association with enamel hypomineralisa-
tion might occur.
Lastly, more children with MIH recorded prolonged use of
medications other than antipyretics when compared with
controls, indicating the inferior infant health in some of the
affected children. All children with prolonged use of medica-
tion presented in the present study with respiratory or urinary
tract problems requiring repeated use of corticosteroids and
antibiotics. Although a recent study associated the use of
amoxicillin with MIH [Ess et al., 2008], there is little litera-
ture to support the link between prolonged infant medication
and MIH [Mathu-Muju and Wright, 2006]. More research is
needed on this subject and for the present it appears that
the defect is probably linked with the illnesses themselves
[Jalevik et al., 2001a].
Combinations of medical conditions. In our study, 44 cases
(11.7%) of MIH affected children revealed medical prob-
lems in more that one chronological period, the majority of
them (40 cases) being during the peri- and postnatal period.
This was an interesting finding indicating the difficulties of
specifying precisely the aetiological factors involved in the
development of MIH. In the majority of these cases (28/40)
[Table 1, 2], Caesarean section was combined with neonatal
problems of the newborn, as it has been discussed before
[Hansen et al., 2007]. Additionally as it is clearly shown in
Table 2, in the same chronological period of particularly peri-
and postnatal, there was more than one medical problem
associated with MIH, as noted by others [Jalevik and Noren,
2000]. Of 163 cases of perinatal aetiology there were 186
medical problems whilst the greatest overlap was during the
postnatal period where 162 cases in that period recorded
237 medical problems, indicating these were children with
poor health. This finding highlights yet again the difficulty of
MIH Aetiology
specific links between certain medical conditions and MIH,
but clearly helps any future research to focus more on the
patho-physiology of these particular conditions rather than
the conditions themselves.
No obvious aetiology. Finally the present study found that
12.2% of the children with MIH were not associated with
any medical history. Previous studies on much smaller sam-
ples of children have found respective percentages of 9.5%
[VanAmerogen and Kreulen, 1995] and 24.2% [Jalevik and
Noren, 2000]. Limitations in retrospective studies concern-
ing the possible under-estimation of self-reported data, may
indeed lead to questionable results. However, considering
the detailed investigation into the medical history in the
methodology of the present study, and the large sample of
children evaluated, it seems reasonable to conclude that this
percentage might be a ‘true’ figure meaning that 1 out of 10
children MIH might have an aetiology, aside from the medical
problems studied herein. For example, environmental pollut-
ants, such as dioxins have been implicated in the past with
MIH [Alaluusua et al., 1996], although a more recent study
has not found this [Laisi et al., 2008].
The presence of an underlying genetic predisposition that
contributes to the risk of developing MIH in some cases
should not be under-estimated [Brook and Smith, 1998]. In
the present study there were 10 cases of children with MIH
(3.3%) that belonged to 5 families. The affected children in
each family were first cousins and 2 sets of them (4 chil-
dren) did not reveal any medical history. Additionally from
the 29 twins affected with MIH, 12 were the outcome of 6
gestations, all of them being homozygous. This group had
3 sets with no other aetiological factor apart from twinning,
2 sets delivered by Caesarean section and no other medical
history, and 1 set delivered varginally but with neonatal and
postnatal problems. The remaining 17 individuals had twin
offspring not affected by MIH, 5 being homozygotes and 12
heterozygotes, 4/17 delivered by Caesarean section, the re-
maining 13 with no obvious medical history. Although the
sample of twins is small and complex for statistical analysis,
it seems that there might be genetic factors implicated.
Correlation of the number and type of the affected teeth with
the insult period. The results of the present study (Figure 1)
revealed that in increasing order children with medical prob-
lems in pre-, peri- and postnatal periods present with more
MIH affected teeth, whilst the greatest number of affected
teeth was found in cases with combined peri-/postnatal
problems. Additionally the number of affected incisors in-
creased in the same order, more intensely than that of FPM.
This distribution of teeth affected by MIH appears to corre-
late well with the timing of the insult.
Previous studies on dental development chronology [Wel-
bury, 1997] have shown that only molars may have started
calcification prenatally; therefore medical factors acting dur-
ing this period are expected to mainly produce mainly af-
215
European Archives of Paediatric Dentistry // 9 (4). 2008
Lygidakis et al.
fected FPM and the least total number of affected teeth. Ac-
cordingly, during the perinatal period aetiological factors still
produce a restricted total number of affected teeth, although
more than those in the prenatal period as more FPM and few
incisors may have initiated calcification. During the postnatal
period, apart from molars, both central and lateral incisors
are well into the same process; therefore factors acting dur-
ing this period produce greater numbers of affected teeth.
Finally, in cases of combined perinatal/postnatal problems,
all teeth implicated in MIH have initiated calcification produc-
ing the greatest number of affected teeth of all types. It was
interesting to find that 7 cases that were presented with 1-3
canines affected together with the ‘typical’ MIH teeth, re-
vealed combined perinatal/postnatal problems indicating the
severity of the defect if medical conditions are found during
these periods.
Conclusion
Considering the limitations of the study design it was found
that:
1. 87.8% of the children with MIH presented with potential
medical aetiological factors acting during their prenatal,
perinatal or postnatal period. Children with MIH reveal
68.9% more frequently medical problems than controls.
2. Postnatal conditions (33.9%) followed by perinatal
(33.6%) were the most frequently found. 11.7% of the
affected children revealed combined perinatal/postnatal
problems. These children presented with the greatest
number of affected teeth.
3. The majority of medical conditions involved may produce
hypocalcaemia and hypoxia to the child or the mother.
Maternal and postnatal conditions associated with pro-
longed pyrexia might also be implicated.
4. The number of affected teeth was associated with the
timing of the possible insult; children with prenatal, peri-
natal and postnatal problems present more affected teeth
in increasing order.
5. In 12.2% of the cases there was no reported medical his-
tory, indicating the potential implication of other system-
atic or genetic aetiological factors.
Acknowledgements
The authors wish to thank Dr Polizois Velentzas, Paediatrician MD, Health
Center of Markopoulo, for his valuable assistance and Miss Eumorphia M
Delicha, BSc, MSc, Biostatistics Consultant for the statistical analysis of the
results.
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