Acta Odontologica Scandinavica

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/iode20

Molar-incisor hypomineralization: an umbrella

review

Luísa Bandeira Lopes, Vanessa Machado, João Botelho & Dorte Haubek

To cite this article: Luísa Bandeira Lopes, Vanessa Machado, João Botelho & Dorte Haubek
(2021): Molar-incisor hypomineralization: an umbrella review, Acta Odontologica Scandinavica,
DOI: 10.1080/00016357.2020.1863461

To link to this article: https://doi.org/10.1080/00016357.2020.1863461

© 2021 The Author(s). Published by Informa

UK Limited, trading as Taylor & Francis
Group on behalf of Acta Odontologica
Scandinavica Society.

Published online: 01 Feb 2021.

Submit your article to this journal

Article views: 875

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

https://www.tandfonline.com/action/journalInformation?journalCode=iode20
ACTA ODONTOLOGICA SCANDINAVICA
https://doi.org/10.1080/00016357.2020.1863461

REVIEW ARTICLE

Molar-incisor hypomineralization: an umbrella review

Lu
ısa Bandeira Lopesa,b , Vanessa Machadob , Jo~ao Botelhob and Dorte Haubekc
a
Dental Pediatrics Department, Clinical Research Unit (CRU), Centro de Investigaç~ao Interdisciplinar Egas Moniz (CiiEM), Egas Moniz -
Cooperativa de Ensino Superior, CRL, Almada, Portugal; bEvidence-Based Hub, CRU, CiiEM, Egas Moniz - Cooperativa de Ensino Superior,
CRL, Almada, Portugal; cDepartment of Dentistry and Oral Health, Aarhus University, Aarhus, Denmark

ABSTRACT ARTICLE HISTORY

Objective: In recent years, Molar Incisor Hypomineralization (MIH) has become a subject that concerns Received 11 September 2020
the Paediatric Dentistry Community. The aim of the present umbrella review was to analyse previously Revised 3 December 2020
published systematic reviews (SRs) on MIH in children and adolescents. Accepted 8 December 2020
Methods: Electronic database search was conducted (including PubMed, Embase, Scopus, Cochrane,
KEYWORDS
Web of Science, and LILACS) until July 2020. Studies were included, if they were SR on MIH in children Molar-incisor hypominerali-
and adolescents. The methodological quality of SRs was judged by use of the MeaSurement Tool to zation; developmental
Assess systematic Reviews 2. The primary outcomes included prevalence, aetiology, and clinical man- dental defects; enamel
agement of MIH. Data extraction and methodological quality assessment were performed. defect; oral health;
Results: Eighteen systematic reviews were included for data extraction. Among these, two were focus- paediatric dentistry
sing on prevalence, five addressed aetiology, one highlighted the mechanical and chemical character-
istics of enamel in MIH, one underlined the association between MIH and dental caries, six addressed
the treatment, and one focussed on hypomineralization of primary teeth as a predictor of MIH. The
results showed a high worldwide prevalence of MIH and an unknown aetiology of MIH, but reporting
that the aetiology is most likely multifactorial. Different treatment approaches used were desensitizing
and remineralizing products, resin infiltration, fissure sealant, atraumatic restorative treatment, resin
composite restoration, and stainless steel crown (SSC), but also extraction associated with orthodontic
treatment of the permanent first molars (PFMs) was reported on. The AMSTAR criteria 2 was applied,
where six studies were assessed as having critically low quality, two studies as having low quality, and
nine studies as having moderate quality.
Conclusions: MIH is highly prevalent worldwide and has most likely a multifactorial aetiology.
Different treatment approaches according to the degree of severity of lesion(s) are reported on. The
quality of evidence produced by the available SRs was not favourable. More well-designed clinical tri-
als and high standard systematic reviews are necessary to elucidate better MIH characteristics and
treatment outcomes.

Introduction elasticity when compared to sound enamel [5,8,11,13,16].

Molecularly, MIH-affected enamel presents a high amount of
Hypomineralization of tooth enamel was firstly reported on
proteins, like serum albumin, type I collagen among others,
in the late 1970s, where several researchers described fre-
and it is suggested that the presence of these proteins inhib-
quent congenital hypomineralization of the permanent first its the growth of hydroxyapatite crystals and enzymatic
molars (PFMs) and incisors of the permanent dentition [1–3]. activity during enamel maturation, which results in a reduc-
Later in 2000 at the European Academy of Paediatric tion of the mineral content of enamel in MIH cases [8,17]. As
Dentistry (EAPD) Congress in Bergen, this condition was a consequence, hypomineralized enamel leads to post-erup-
named as Molar-Incisor Hypomineralization (MIH) [4]. tive breakdown and hypersensitivity, and it is prone to devel-
MIH is defined as a qualitative developmental defect of opment of carious lesions and pain [5,7,9,13]. However, the
enamel in children and adolescents, affecting at least one full understanding of the aetiology of MIH is still not
PFM with or without involvement of the incisors [3,5–14]. obtained [9,10,12–14].
MIH is clinically characterized by more or less well-defined From an epidemiologic standpoint, MIH is the most fre-
opacities that vary in size and can be discoloured from white quent enamel defect. However, the prevalence varies signifi-
to yellow-brownish [5,10,11,15]. cantly in studies available in the literature. A study based on
The hypomineralized enamel is friable and has inferior Danish children showed that the prevalence of demarcated
mechanical properties as well as reduced modulus of opacities, eventually complicated by loss of tooth substance

CONTACT Lu
ısa Lopes luisabpmlopes@gmail.com Dental Pediatrics Department, Egas Moniz Dental Clinic, Clinical Research Unit (CRU), Egas Moniz
Interdisciplinary Research Center (EMIRC), Egas Moniz University, Campus Universit
ario, Quinta da Granja, Monte de Caparica, Caparica, Almada, 2829 - 511, Portugal
ß 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of Acta Odontologica Scandinavica Society.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in
any way.
2 L. BANDEIRA LOPES ET AL.

in any PFM was 37.3% (95% confidence interval (95% CI) Online), EMBASE (The Excerpta Medica Database), LILACS
33.6 ± 41.0%) and 6.3% (95% CI 4.7 ± 8.5%), respectively [18]. (Latin-American scientific literature in health sciences), and
On the other hand, a study on Brazilian children displayed a TRIP (Turning Research Into Practise). We merged keywords
prevalence of 40.2%, where the number of affected incisors and subject headings in accordance with the thesaurus of
increased with increasing number of affected molars [19]. each database and applied exploded subject headings, so
Latest studies presented a prevalence of 3 to 22% in Europe the final search was Molar-Incisor Hypomineralization,
[8,18], and 2 to 40% worldwide [9,13,19]. Developmental Dental Defects and Enamel Defect. The
Due to pain, fragile enamel and increased treatment need search was based on the reference of the systematic reviews
at an early point of time in life, MIH represents a clinical and meta-analyses [20,21], and since the criterion for the
challenge. Due to a demand for more information and diagnosis of MIH was not published before 2003, the search
understanding of the condition, a large number of systematic covered the period from September 2003 to August 2020.
reviews have been published concerning MIH in the last dec-
ade, and therefore an umbrella review encompassing all
available information at present time would be of Study selection
great interest.
Two researchers (LL and JB) independently screened titles and
This umbrella review aimed to summarize the existing sys-
abstracts. The agreement between the reviewers was assessed
tematic reviews on MIH in children and adolescents, with a
by Kappa statistics. Any paper classified as potentially eligible
particular focus on diagnosis, prevention, clinical manage-
ment and quality of evidence. by either reviewer was ordered as a full text and independ-
ently screened by the reviewers. All disagreements were
resolved through discussion with a third reviewer.
Methods
The present systematic review was performed following the Data extraction process and data items
Preferred Reporting Items for Systematic Reviews and Meta-
Analyses (PRISMA) guidelines [20], expanded with the guide Two researchers (LL and JB) extracted independently the fol-
on systematic reviews of systematic reviews [21]. The review lowing data from the SRs: Authors, objective/focussed ques-
protocol was approved a priori by all authors. tion, databases searched, number of studies included, type
of studies included, main results and main conclusions. All
disagreements were resolved through discussion with a third
Eligibility criteria reviewer (VM).
The inclusion criteria were as follows: A paper (1) defined as
a systematic review or a meta-analysis; (2) retrieving data Risk of bias assessment
from human studies; (3) investigating clinical characteristics
of MIH in children and adolescents, in either dentition and/ Two researchers employed the MeaSurement Tool to Assess
or in relation to the use of clinical procedures. No restrictions Systematic Reviews (AMSTAR 2) to determine the methodo-
to publication year or language were applied. Grey literature logical quality of the included reviews [22]. The agreement
was searched through appropriate databases and registers between the reviewers was assessed by Kappa statistics.
(opensigle.inist.fr, https://www.ntis.gov/, https://www.apa.org/ AMSTAR 2 is a comprehensive 16-item tool that rates the
pubs/databases/psycextra). overall confidence of the results of the review. According to
PECO the AMSTAR guidelines, the quality of the systematic reviews
was considered as follows: High means ‘Zero or one non-crit-

Population (P) – Children and Adolescents with Molar- ical weakness’; Moderate means ‘More than one non-critical
Incisor Hypomineralization weakness’; Low means ‘One critical flaw with or without non-

Exposure (E) – Prevalence, prevention, clinical manage- critical weaknesses’; and Critically low means ‘More than one
ment and aesthetics critical flaw with or without non-critical weaknesses’. The

Comparison (C) – Prevention, treatment of hypersensitiv- estimation of the AMSTAR quality rate for each study was
ity and/or treatment of affected teeth (through restora- calculated through the AMSTAR 2 online tool (https://amstar.
tive, endodontic, prosthetic, surgical or ca/Amstar_Checklist.php).
orthodontic approaches)

Outcome (O) – Diagnosis and a variety of dental treat-
ment types Results
Study selection
Information sources search
Electronic searches retrieved a total of 48 titles through the
Electronic data search was performed in seven electronic database searching. After manual assessment of title/abstract
databases that cover life sciences, health sciences, and phys- and removal of duplicates, 23 potentially eligible full-texts
ical sciences: PubMed-Medline, Scopus, Cochrane Database were screened. Full-text screening excluded five studies with
of Systematic Reviews, Scielo (Scientific Electronic Library reasons (Figure 1), resulting in 18 systematic reviews that
 ACTA ODONTOLOGICA SCANDINAVICA 3

fulfilled the inclusion criteria. Inter-examiner reliability at the entirely the AMSTAR 2 Criteria (Table 2). Overall, nine pre-
full-text screening was recorded as high (kappa score ¼ 1.00). sented moderate quality [6–8,10,11,13–15,25] and seven were
assessed as having critically low quality [4,5,9,12,23,24,26].
Study characteristics
Synthesis of results
In total, 18 systematic reviews were included in the present
umbrella review (Table 1). Prevalence of MIH
Most systematic reviews covered a defined timeframe, Due to the fact that MIH was named at the EAPD meeting in
however, four did not mention such information [4,11,14,23]. 2003, multiple examination criteria were found among
Regarding language restriction, two systematics reviews papers reporting the prevalence of MIH [4]. Consequently,
studies applying the EAPD definition were found to report
higher prevalence of MIH (14.5%) than those using other
case definitions (10.2%) [13].
Overall, MIH is currently estimated to have a prevalence
of 14.2% [24] and to affect 17.5 million children and adoles-
cents worldwide (ranging from 15.8 to 19.4 million) [13], and
this prevalence does not differ between females and males
(OR: 0.92; 95% confidence interval: 0.81–1.04) [13]. In terms
of cases with need for care (i.e. with symptoms or post-erup-
tive breakdown), the prevalence was estimated to
27.4% [13].
In Europe, two nation-wide studies carried out in
Germany and Bulgaria [4] reported a prevalence close to
2.4%, while in the city of Leeds (in the United Kingdom) a
prevalence of 40% was reported [4]. In South America, a
study carried out in Rio de Janeiro, Brazil reported 40.2%
[19]. In Africa, a Kenyan study reported 13.7% of MIH cases,
while in Sydney, Australia the MIH prevalence was reported
to be 44% [4]. The prevalence of MIH was found to be ele-
vated in high-income countries from Southeast Asia, East
Asia, and Oceania. At country/geographic region level, India,
China and the United States had the highest prevalence
Figure 1. Diagram showing the exclusion and inclusion process of the litera- rates [13].
ture review.

failed to report this characteristic [6,23], seven had language Aetiology of MIH
restrictions [4,5,7,12,14,15,24], and the remaining had no lan- Six systematic reviews addressed the aetiology of MIH
guage restrictions [3,10,11,13,17,25,26]. [3,6,10,14,17,23], among which three computed meta-analy-
There were even two systematic reviews that mentioned ses where several parameters were evaluated. Overall, mul-
no language restriction were set, and studies in other lan- tiple aetiological factors associated with MIH were reported
guages than English or German were translated by native on and can be divided according to pre-, peri- and postna-
speakers [8,9]. tal periods.
Because MIH is a qualitative developmental defect of Regarding the prenatal period, the most striking factor
enamel, multiple sub-topics in the systematic reviews were was the existence of systemic conditions. For example, med-
addressed. For example, the included systematic reviews ical problems were more prevalent in mothers of children
addressed: aetiology [3,6,10,14,17,23], prevalence [4,13,24], with MIH in comparison to those mothers whose children
diagnosis [4], mechanical and chemical characteristic of did not have MIH [23]. Urinary infection during the last tri-
enamel in MIH [9], the association between MIH and dental mester of pregnancy was associated with higher risk of MIH
caries [5], and treatment [7,8,12,25,26]. A particular study in one study [23], however, in two other studies no associ-
aimed to review, if hypomineralization was a predictor of ation was found in relation to specific diseases [10,23].
MIH [15]. Furthermore, the role of maternal systemic conditions during
pregnancy is inconclusive, as a review reported no associ-
ation [14], and in another paper maternal illness was associ-
Risk of bias
ated with 40% higher odds of having MIH [10]. Furthermore,
Good inter-examiner reliability at the risk of bias screening maternal smoking and alcohol intake during pregnancy had
was recorded (kappa score ¼ 0.91; 95% confidence interval: no significant association with MIH, but maternal stress was
0.89–0.92). None of the included systematic reviews satisfied positively associated with MIH [10,14].
Table 1. Characteristics of the included systematic reviews.
Types/No. of Tool used for Method of
Author (Year) Search period studies included N Exposures quality assessment analysis Outcomes Findings
Bensi et al. (2020) Up to 12 January 2019 10 Cohort studies 13109 participants Relationship between NOS SR & MA Three times increased risk Strong association between
6 case control studies preterm birth and of developing DDE and preterm birth
4 Cross- developmental defects development defects in
sectional studies of enamel preterm children.
Lagarde et al. (2020) NA 6 laboratory studies NA Strategies to optimize Cochrane Risk Bias Tool SR Bond strength of Currently, there is very
4 clinical studies bonding of adhesive composite was not limited evidence of what can
materials to molar- incisor significantly different solve the issue of adhesion to
hypomineralization when using self-etch this tissue.
compared with etch-and-
rinse adhesives.
Deproteinization after
etching for etch-and-rinse
adhesives enhance
bond strength.
Fatturi et al. (2019) August 2017 to 15 Cross-sectional studies 24939 participants Systemic exposures NOS SR & MA Review, maternal illness, Interpreted with caution,
March 2018 5 Cohort studies associated with molar psychological stress, once the primary studies
9 case control studies incisor hypomineralization caesarean delivery, were observational, with
delivery complications, serious limitations according
respiratory diseases, fever to the risk of bias,
and childhood illnesses imprecision, and
were significantly inconsistency.
associated with MIH.
Elhennawy et al. (2019) Since 2001 17 randomized controlled 2124 participants Outcome and comparator SR & MA Outcomes reported in The high number of
trials choice treatments in MIH interventional trials for compared interventions
14 prospective the management and tested in only a few studies.
4 retrospective Cohort prevention of MIH
focused on the
performance of restorative
materials or and the
management of pain and
hypersensitivity associated
with MIH-affected teeth.
Da Cunha Coelho Until 30 May 2018 33 Teeth – 626 Prevention, treatment of Cochrane Handbook for SR Successful prevention (no Comparison of the reported
et al (2018) participants – 1212 hypersensitivity and/or Systematic Reviews need for further results provided by the
rehabilitation of affected interventions), improved different studies was difficult
teeth (through restorative, esthetics and/or given the variability of the
endodontic, prosthetic, successful rehabilitation methodology.
surgical or of affected teeth.
orthodontic methods)
Zhao 2018 Until April 2017 70 89520 participants Prevalence NA SR MIH has a high incidence It is imperative to develop
epidemiological studies globally, especially among more appropriate dental
children <10 years old. healthcare strategies to care
for these children and to
identify the etiology of MIH
to prevent it occurring.
Garot et al. (2018) 2001 to August 2017 3 - Cross-sectional studies 4662 participants Relationship between NOS SR & MA HSPM is predictive for Early detection and
2 - Cohort studies HSPM and MIH MIH, with greater MIH preventive intervention could
prevalence in the reduce MIH complications.
presence of mild HSPM.
Schwendicke et al. (2018) 2000 until 2017 99 observational studies 144 participants Prevalence NOS SR MIH is highly prevalent The consistently high
across the globe. prevalence and the large
proportion of cases in need
of care should be considered
(continued)
Table 1. Continued.
Types/No. of Tool used for Method of
Author (Year) Search period studies included N Exposures quality assessment analysis Outcomes Findings
by both clinicians in their
daily practice and healthcare
planners and policy makers.
Wu et al. (2018) From 2001 to May 2018 12 Cross-sectional studies 16414 participants Association of MIH with Agency for Health Care SR & MA Premature birth promoted Premature birth and low birth
4 Case-control studies birth or low birth weight Research the prevalence of MIH weight increase the
1 Cohort studies and Quality (AHRQ) (OR1/41.57, 95%CI: prevalence of MIH.
Method List 1.07–2.31). Low- birth-
weight neonates were
approximately three
times likely to suffer
from MIH (OR1/43.25,
95%CI: 2.28–4.62).
Elhennawy et al. (2017) 28 February 2017 to 1 23 201 teeth Have knowledge of the NA SR There is an understanding MIH-affected enamel is
January 2020 alterations of MIH- of the changes related to greatly different from
affected compared with MIH-affected enamel. unaffected enamel.
unaffected enamel This has implications for
is needed management strategies.
Americano et al. (2016) January 2003 to 15 Cross-sectional studies 14064 Association between MIH NOS SR Positive association Interpreter cautiously due to
November 2015 2 Cohort studies and caries between MIH and caries the lack of high-
was found. quality studies
Borges et al. (2016) 1990–2015 4 Non-randomized trials 676 Teeth Resin infiltration MINORS criteria for non- SR Resin infiltration No strong evidence
7 Randomized trials technique treatment. randomized (NRS) technique seems to be a supporting the clinical
comparative studies and feasible option for color recommendation
Cochrane Collaboration for masking of enamel
randomized clinical whitish discolorations.
trials (RCT)
Elhennawy et al. (2016) January 1, 1980, to May 14 139 participants Treatment management NOS SR Remineralization or No recommendations can be
1, 2016. sealants seem suitable given for MIH-incisors.
for MIH-molars with
limited severity and/or
hypersensitivity. For
severe cases, restorations
with composites or
indirect restorations or
preformed metal crowns
seem suitable. Prior to
tooth extraction as last
resort factors like the
presence of a general
malocclusion, patients’
age and the status of
neighboring teeth should
be considered.
Serna et al. (2016) January 1, 1965, to 10 case control studies 2692 participants Drugs related to NOS SR & MA Available evidence More well-designed,
September 29, 2014 6 Cross-sectional the etiology suggests that no drug prospective studies whose
studies can be said unequivocally investigators describe the
4 Cohort studies to produce MIH. time or age of drug exposure
and the kind of enamel
defect produced are needed.
(continued)
Table 1. Continued.
Types/No. of Tool used for Method of
Author (Year) Search period studies included N Exposures quality assessment analysis Outcomes Findings
Silva et al. (2016) NA 16 – Cohort studies 25415 participants Etiology NOS SR Prenatal and perinatal Further prospective studies
9 – case factors are infrequently that adjust for con- founding
control studies associated with MIH. based on biological
However, despite a lack principles, as well as genetic
of prospective studies, and epigenetic studies, are
early childhood illness needed because the etiology
(in particular fever) is likely to be multifactorial.
appears to be associated
with MIH.
Alaluusua 2010 NA 28 NA Etiology NA SR The etiology of MIH is There is currently insufficient
Retrospective, Cohort suntil unclear. evidence in literature to
or case-control studies establish etiological factor/s
relevant for MIH.
Jalevik 2010 NA 23 Cross-sectional, NA Prevalence and diagnosis NA SR Methodology differs Study design and methods
observational studies markedly from study to need to be standard for
1 retrospective study study making comparable results.
of records comparison difficult.
Lydidakis 2010 Since 2000 8 Prospective studies NA Treatment modalities in NA SR The information provided Long term clinical trials
2 Retrospective studies children with on treatment of MIH in supported by laboratory
1 Experimental with teeth affected by MIH the inter- national studies are needed to provide
control studies literature is limited and ‘guidelines’ for treating MIH.
empirical, relying mainly
on case reports and few
clinical studies. However,
advances in dental
materials have provided
clinical solutions in cases
that were regarded as
unrestorable in the past.
NA: Not available; SR: Systematic Review; MA: Meta-analysis; MIH: Molar-Incisor Hypomineralization; NOS: Newcastle-Ottawa Quality Assessment Scale.
 ACTA ODONTOLOGICA SCANDINAVICA 7

Table 2. Risk of bias of systematic reviews (AMSTAR 2 tool).

First author 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Review quality
Bensi et al. (2020) Y Y Y Y Y Y Y Y PY N Y Y Y Y Y Y Moderate
Lagarde et al. (2020) N N Y PY Y Y N Y Y N 0 0 Y Y 0 Y Moderate
Fatturi et al. (2019) Y Y Y PY N Y Y PY PY N Y Y Y Y Y N Moderate
Elhennawy et al. (2019) N Y N PY N Y N Y Y N 0 0 N N 0 N Critically Low
Da Cunha Coelho et al (2018) Y PY Y Y N Y Y Y PY N 0 0 Y Y 0 N Moderate
Zhao et al. (2018) N N Y PY N Y N Y N N Y N N N Y N Critically Low
Garot et al. (2018) Y Y Y PY Y Y Y PY PY N Y Y Y Y Y N Moderate
Schwendicke et al. (2018) N Y Y Y Y Y N Y Y Y 0 0 Y Y 0 Y Moderate
Wu et al. (2018) N Y Y Y Y Y N Y Y N Y Y N Y 0 Y Low
Elhennawy et al. (2017) Y PY Y PY Y Y N PY N N 0 0 N Y 0 Y Critically Low
Americano et al. (2016) Y PY Y PY Y N Y Y N N 0 0 Y N 0 Y Critically Low
Borges et al. (2016) Y Y Y Y Y Y PY Y Y N 0 0 Y N 0 N Moderate
Elhennawy et al. (2016) Y Y Y PY Y Y Y Y PY N O O Y N 0 N Moderate
Serna et al. (2016) Y Y Y Y Y Y N Y Y N Y Y N Y N Y Low
Silva et al. (2016) N N Y Y Y N N N Y N Y Y Y Y N Y Moderate
Alaluusua (2010) Y PY N N N N N N N N 0 0 N N 0 N Critically Low
Jalevik (2010) Y PY N N N N N PY N N 0 0 N N 0 N Critically Low
Lygidakis et al. (2010) N N N PY N N N N N N 0 0 N N 0 Y Critically Low
0: No meta-analysis conducted; N: No; Y: Yes; PY: Partial Yes.
1. Research questions and inclusion criteria?; 2. Review methods established a priori?; 3. Explanation of their selection of the study designs?; 4. Comprehensive
literature search strategy?; 5. Study selection performed in duplicate?; 6. Data selection performed in duplicate?; 7. List of excluded studies and exclusions justi-
fied?; 8. Description of the included studies in adequate detail?; 9. Satisfactory technique for assessing the risk of bias (RoB)?; 10. Report on the sources of fund-
ing for the studies included in the review?; 11. If meta-analysis was performed, did the review authors use appropriate methods for statistical combination of
results?; 12. If meta-analysis was performed, did the review authors assess the potential impact of RoB?; 13. RoB accounted when interpreting/discussing the
results of the review?; 14. Did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the results of the
review? 15. If they performed quantitative synthesis, publication bias was performed?; 16. Did the review authors report any potential sources of conflict of
interest, including funding sources?.

In the perinatal period (covering caesarean delivery, pro- diseases (asthma, pneumonia), otitis, adenoiditis, urinary tract
longed delivery, premature birth and twinning), studies were infection, chickenpox [10,14,23]. MIH was significantly more
also contradictory with reports of as well positive [23] as common among children for whom amoxicillin was the only
negative associations [10,23]. Hypoxia is common during antibiotic medicament they had received, but not among
birth (such as prematurity respiratory stress or traumatic and children who were exposed to mixed use of antibiotics,
prolonged birth) and was related to MIH due to the effect of including amoxicillin [10,14,23]. Nevertheless, it was also
oxygen insufficiency on the activity of ameloblasts [23]. mentioned in the study by Silva et al. [14] that no associ-
Another condition reported on was hypocalcaemia, given ation between amoxicillin and MIH was found, and even
that MIH is suggested to occur in cases of low calcium levels antibiotics exposure was not associated with MIH (OR ¼
that suggest possible impairment of the ameloblasts’ calcium 1.28; 95% CI 0.99-1.65) [10]. On the other hand, other types
metabolism [23]. Hypocalcaemia can occur in any of the peri- of antibiotics, like erythromycin and macrolides, were found
ods (pre-, peri- or postnatal) and is also associated with mul- to be more commonly used in children with MIH [23].
tiple conditions, like maternal diabetes, vitamin D deficiency Concerning anti-neoplastic treatment and anti-epileptic
during the prenatal and/or perinatal period and prematurity drugs, these were also reported as being associated with an
[23]. Concerning the association between MIH and preterm increased risk of developing numerous teeth with diffuse
birth (PB) and low birth weight (LBW), respectively, the opacities and even enamel hypoplasia [17]. In relation to
results were once again inconsistent. MIH was significantly asthma medication as corticosteroids and bronchodilators, an
associated with PB in both the primary and permanent denti- association with enamel defects has been reported [17]. Yet,
tions [3,6]. Considering LBW, two meta-analyses were contra- other authors found no association with anti-asthma medica-
dictory, with one showing no association (OR ¼ 1.52; 95% CI tion, although there could be an association with a subset of
cases involving post-eruptive breakdown [14].
0.83-2.79) [10], and another reporting that LBW neonates
were about three times more likely to have MIH (OR ¼ 3.25,
95%CI: 2.28–4.62) [3]. Lastly, the association of MIH with pre- Clinical management of MIH
term (PT), LBW, caesarean delivery and birth complications Overall, MIH causes concern to children and their parents, for
was reported to be low [14]. example related to aesthetics, enamel loss, increased risk of
In the postnatal period, long duration of breastfeeding, development of caries lesions, hypersensitivity and possibility
childhood illnesses and early childhood medication were in of tooth loss, especially in severe cases [5,12]. Clinical man-
one or another way linked to MIH. Long duration of breast- agement of MIH is dependent on the disease stage (mild,
feeding had no association with MIH [10,14], as well as one moderate and/or severe) [12], and the treatment need can
review found contradictory information about the levels of be comprehensive.
pollutants in human milk [23 ]. Concerning remineralization of the affected enamel and
Concerning reports on early childhood illness, several dis- reduction of the sensitivity, fluoride varnishes may be rele-
orders were taken into consideration and found to have a vant to use. However, often such an approach is followed
positive association with MIH, for example fever, respiratory also by a need for the use of sealing or restoration [7,12]. In
8 L. BANDEIRA LOPES ET AL.

MIH cases, the effect of casein phospho-peptides and quality of the included SRs ranged from moderate to critic-
amorphous calcium phosphate (CPP-ACP) pastes has shown ally low, and therefore current evidence is far from being of
no significant differences with or without added fluoride high confidence. The main conclusion to retain relies on the
when used in MIH cases [7,12,26]. importance of prevention, since the available evidence on
Fissure sealants may be beneficial in the handling of mild prevalence, aetiology, and clinical management is still very
defects where sensitivity and enamel breakdown are not prom- heterogeneous.
inent [12]. Although some types of fissure sealants often require The present umbrella review is highly relevant given the
the need for re-treatment [12], they present higher retention relatively high number of systematic reviews published in
with fifth generation adhesives (i.e. a two-step etch-and-rinse the last few years, indicating the importance and relevance
adhesive) [11]. Some papers also reported on the use of glass of this topic. Also, this is the first umbrella review on MIH
ionomer cements were also referred to as fissure sealants as compiling evidence from multiple reviews about MIH, a
well as temporary restorations in provisional situations, in order recent clinical entity, as the term ‘Molar Incisor
to decrease sensitivity and minimize further breakdown of Hypomineralization’ was defined in 2000 established to the
enamel [8,12]. Furthermore, amalgam restorations were also European Academy Paediatric Dentistry (EAPD) definition
explored and had relatively low success rates [8,12]. Restorative [3–5,10,13,15,17,27].
approaches with, e.g. use of resin composite fillings were
assessed in several clinical trials, where the effects of deprotein-
ization and various types of adhesives also were eval- Strengths and limitations
uated [7,11,12]. Our umbrella review has several strengths. It provides a com-
Adhesion procedures are challenging in MIH lesions. In prehensive overview of the available systematic reviews pub-
the included reviews, there were no consensus regarding the lished regarding MIH using a transparent methodology.
best adhesive materials to be used and/or protocols on how It should be considered, when interpreting the results
to apply it in MIH teeth [11], although the use of several that the individual studies included in each of the present
adhesives were studied, such as ClearfilTM SE Bond, systematic review were not explored. Thus, the conclusions
OptiBondTM FL, 3 MTM Single Bond, AdperTM, ScotchbondTM lean on the interpretation of the systematic review’s authors.
Multi-Purpose and ScotchbondTM Universal) [11]. Regarding Another point worth mentioning is the existence of two
deproteinization, the results were contradictory, with some PROSPERO registers that are in an ongoing status, but not
studies showing that application of NaOCl after etching sig- published [28,29].
nificantly increased bond strength to MIH-affected enamel, It should be noted that at the meeting in Athens, Greece
and other studies reporting that NaOCl pre-treatment on the in 2003, 8 years of age was mentioned as the best age for
affected enamel did not enhance enamel bonding, but the performance of an examination of MIH. In this sense, not
caused less pre-test failures (NaOCl 23.6 MPa vs. MIH-affected all studies are based on the same clinical parameters and cri-
enamel 21.3 MPa, and sound enamel 31.2 MPa) [11]. teria using the terminology of MIH defined by
Stainless steel crowns (SSCs) were considered reliable to pre-
EAPD [3–5,10,13,15,17].
vent further enamel loss, to control the hypersensitivity, to
establish correctly interproximal and proper occlusal contacts
with a low cost and little working time required [8,12]. In severe MIH prevalence
MIH cases, extraction can be a clinical option; however, in such Referring to the prevalence and aetiology of MIH, there were
cases we should consider the child’s age, pulp involvement, two systematic reviews, from which it was possible to verify
and take orthodontic considerations into account [8,12]. the importance of using appropriate case definitions of MIH.
As anterior teeth may be affected by MIH, manifesting as The case definition of MIH was significantly associated with
white or yellow-brown defects, there may be aesthetic chal- the prevalence, thus studies using the EAPD case definition
lenges to bear in mind. Different approaches have been presented higher prevalence values compared to other stud-
mentioned [12], namely etch-bleach-seal technique, bleach- ies, where other types of definitions were used [4,13,17].
ing with 10% to 38% carbamide peroxide in permanent The MIH prevalence varies significantly. Nevertheless, it
teeth only, enamel reduction followed by the use of opaque was considered that the proportion of cases in need of care
resins and direct composite veneering, micro-abrasion using was estimated to 27.4% (95% CI: 23.5–31.7%), or nearly 5
an abrasive paste and 18% hydrochloric, or polishing with million new MIH cases every year that need dental treat-
pumice and etching with 37.5% phosphoric acid [7,12]. Very ment, and 240 million existing cases, among which some
recently, resin infiltration has been discussed as a possibility cases were not treated, particularly in poorer countries [13].
for restoration of decalcified enamel, since it masks the Another review estimated a global prevalence of 14.2% (95%
enamel whitish discolorations. However, there is no agree- CI: 12.6–15.8%) [24]. Overall, South America was the contin-
ment because of an erratic or poor penetration [7,11,25]. ent with the highest prevalence (18.0%) and Africa the low-
est (10.9%).
After all, comparing results between different studies is
Discussion
difficult, mainly because of the study material selected and
This umbrella review poignantly synthesizes the evidence different methodologies used. This differed at several points
accrued so far from studies on MIH. The methodological in the studies, such as sample size, age of observation,
 ACTA ODONTOLOGICA SCANDINAVICA 9

calibration of examiners, the way of observing and collecting prevent hypersensitivity, and for the establishment of inter-
data, among others parameters [4]. proximal and occlusal contacts [7,8]. In cases with severe
MIH, the extraction of the PFMs, eventually including also
orthodontic treatment, is well considered as part of the treat-
MIH aetiology ment regimen [7,8].
MIH is a qualitative defect of enamel with affection of the
Concerning the improvement of the aesthetic appearance
mineralization and maturation of the enamel of the PFMs
of the discolouration of MIH-affected teeth, resin infiltration
and incisors. Most of the published papers reported on are
has been reported as useful. However, there is no strong evi-
case–control studies, retrospective cohort studies, and obser-
dence to support this technique [25].
vational studies are of low quality [3,10,14,17]. Moreover, the
methodology of the studies differed in several ways, like the
type of medication focussed on, the age at which the medi- Implications for research
cation was administered, and the history of drugs used Countless recommendations can be considered in the scien-
among other events [17]. Another important problem of MIH tific literature. Perhaps, if there was a well-defined method-
aetiology is to determine, for example, if the enamel defect ology that could be applied in the assessment of clinical
is caused by the illness itself, the fever caused by the illness, outcomes, the results would be more comparable and mean-
or the medication [10,14,17,23]. Regardless of the association ingful. Forthcoming studies should include a significant num-
between systemic exposures, including other relevant factors ber of patients with long periods of follow up. Confounding
(e.g. preterm birth, low birth weight, and others) and the factors, like the patient’s age, porous enamel, MIH severity,
occurrence of MIH, the aetiology is not yet fully understood. lesion appearance/colour, number of teeth affected in sub-
In addition, it is likely that MIH is caused by many factors jects with MIH, the surfaces affected, and the presence of
acting simultaneously. For example, in a very recent study, post-eruptive breakdown should also be recorded
however not a systematic review, the results were adjusted and considered.
for potential confounding (use of antibiotics and various Therefore, designs as controlled clinical trials should be
birth outcomes), and no association was found between the recommended in order to have reliable, significant and com-
use of asthma drugs and MIH [30]. parable outcomes.
Conclusively, more high-quality studies are needed within
this important area of research. For example, one recent clin-
Implications for practice
ical investigation of enamel defects in off-springs of mothers
An early diagnosis is fundamental in MIH, in order to prevent
randomized to a high-dose of Vitamin D supplementation in
further complications like hypersensitivity, dental caries, pulp
pregnant mothers was found to reduce the risk of having
inflammation, and pain. In this way, preventive interventions
enamel defects [31]. This study was, however, most likely
with glass ionomer cements as temporary restoration or an
due to a recent publication date or not using the termin-
early restorative treatment is advisable and indicated. When
ology of MIH, but enamel defects, not included in any of the
MIH is detected, parents and off-spring with MIH must be
systematic reviews on which this umbrella review relies.
informed about the consequences, like the risk of hypersensi-
tivity, post-eruptive breakdown, higher incidence of caries,
MIH clinical management difficulties to obtain pain control, and the possibility of
MIH is a hard tissue pathology that requires constant control numerous appointments for dental care. Recall consultations
and requires a high number of dental treatments, especially should be defined according to the severity of MIH, colour of
in severe cases, given the fact that there is a positive associ- the opacities, and even based on the presence of symptoms.
ation with the development of dental caries, possible post- Thus, the treatment modalities available are prevention and
eruptive breakdown, which may lead to pulpal inflammation, symptom control, sealant, restoration, SSCs, and extraction.
hypersensitivity or even pain. In addition, it was described The hypersensitivity requires to be addressed, because it
that hypersensitivity decreases the effect of anaesthetic does not allow effective oral hygiene, thereby an increased
agents, which makes it harder to obtain pain control [7]. risk of caries arises. Remineralization, using CPP-ACP, seems
Regarding fissure sealants which may be an effective pre- to a possibility for minimization of mild or moderate hyper-
ventive treatment, the use of an adhesive system to permit a sensitivity in teeth affected by MIH.
higher retention is still controversial, and more studies are In case of severe defects of MIH, composite restorations,
needed to confirm the best way of applying these adhesive indirect restorations (inlay, onlay or overlay) or SSCs are pos-
systems [7,8]. Taking into account atraumatic restorative sibilities for intervention/treatment. To make a composite
treatment in permanent teeth, there is still lack of informa- restoration is a reasonable treatment approach for several
tion [7,8]. Concerning resin composite restoration, several reasons, like isolation, and sealing dentine and desensitiza-
factors as the type of adhesive and deproteinization must be tion, although low adhesion to enamel and risk of marginal
taken into consideration, and despite the development of breakdown of restorations may still be challenges. However,
new techniques and materials, further long-term clinical trials despite it is advisable to end the margins in unaffected
and further laboratory research projects are needed [7,8]. enamel and to perform de-proteinization, clinical limitations
In young patients with severe MIH, the use of SSCs is a are observed, in particularly in multi-surface defects. Indirect
suitable option to avoid more enamel loss, in order to restoration is also a good treatment approach, given that it
10 L. BANDEIRA LOPES ET AL.

provides cuspid coverage, and no mechanical retention is [3] Wu X, Wang J, Y. Heng L, et al. Association of molar incisor hypo-
necessary due to the adhesion. mineralization with premature birth or low birth weight: system-
atic review and meta-analysis. J Matern Fetal Neonatal Med.
In cases of markedly severe lesions of MIH, extraction may
2020;33:1700–1708.
be considered, however, the need for orthodontic treatment [4] J€alevik B. Prevalence and diagnosis of molar-incisor-hypominerali-
may arise. Thus, when orthodontic treatment is necessary, sation (MIH): A systematic review. Eur Arch Paediatr Dent. 2010;
the extraction of teeth severely damaged by MIH is import- 11:59–64.
ant to include in the treatment plan. In cases of no dental [5] Americano GCA, Jacobsen PE, Soviero VM, et al. A systematic
review on the association between molar incisor hypomineraliza-
crowding and incisor protrusion, the upper molars should be
tion and dental caries. Int J Paediatr Dent. 2017;27:11–21.
extracted at the age of 9 to 10 years, and the lower molars [6] Bensi C, Costacurta M, Belli S, et al. Relationship between preterm
at the age of 11 to 12 years. When dental crowding is pre- birth and developmental defects of enamel: a systematic review
sent or there is incisor protrusion, tooth extraction(s) may and meta-analysis. Int J Paediatr Dent. 2020;30:676–686.
[7] da Cunha Coelho ASE, Mata PCM, Lino CA, et al. Dental hypomi-
occur later, and a suitable time for the extraction of upper
neralization treatment: a systematic review. J Esthet Restor Dent.
molars is about 12 years of age and for the lower molars it is 2019;31:26–39.
about 9 to 10 years of age. The risks due to early extraction [8] Elhennawy K, Schwendicke F. Managing molar-incisor hypominer-
are several, such as distal migration and rotation of the pre- alization: a systematic review. J Dent. 2016;55:16–24.
molar’s germs, or risk of bite deepening given the lack of [9] Elhennawy K, Manton DJ, Crombie F, et al. Structural, mechanical
and chemical evaluation of molar-incisor hypomineralization-
vertical support.
affected enamel: a systematic review. Arch Oral Biol. 2017; 83:
Regarding incisors, aesthetics is of great importance both 272–281.
for parents and for MIH-affected patients. In this case, remin- [10] Fatturi AL, Wambier LM, Chibinski AC, et al. A systematic review
eralization therapy, micro-abrasion, resin infiltration, compo- and meta-analysis of systemic exposure associated with molar
sites restoration, even veneers or crowns can be weighted. incisor hypomineralization. Community Dent Oral Epidemiol.
2019;47:407–415.
[11] Lagarde M, Vennat E, Attal JP, et al. Strategies to optimize bond-
Conclusion ing of adhesive materials to molar-incisor hypomineralization-
affected enamel: a systematic review. Int J Paediatr Dent. 2020;
In conclusion, MIH is highly prevalent seen in a global per- 30:405–420.
[12] Lygidakis NA. Treatment modalities in children with teeth
spective, the aetiology is likely to be multifactorial, and there
affected by molar-incisor enamel hypomineralisation (MIH): a sys-
are suggested different treatment approaches according to tematic review. Eur Arch Paediatr Dent. 2010;11:65–74.
the degree of severity of the MIH lesions. The results should [13] Schwendicke F, Elhennawy K, Reda S, et al. Global burden of
be interpreted cautiously due to the quality of papers molar incisor hypomineralization. J Dent. 2018;68:10–18.
included in the systematic reviews available. Furthermore, [14] Silva MJ, Scurrah KJ, Craig JM, et al. Etiology of molar incisor
hypomineralization – a systematic review. Community Dent Oral
long-term clinical trials with well-designed methodologies
Epidemiol. 2016;44:342–353.
are warranted. [15] Garot E, Denis A, Delbos Y, et al. Are hypomineralised lesions on
second primary molars (HSPM) a predictive sign of molar incisor
hypomineralisation (MIH)? A systematic review and a meta-ana-
Disclosure statement lysis. J Dent. 2018;72:8–13.
[16] Crombie FA, Manton DJ, Palamara JEA, et al. Characterisation of
No potential conflict of interest was reported by the author(s).
developmentally hypomineralised human enamel. J. Dent. 2013;
41:611–618.
[17] Serna C, Vicente A, Finke C, et al. Drugs related to the etiology of
Funding molar incisor hypomineralization: a systematic review. J Am Dent
This work was supported by FCT – Foundation Science and Technology Assoc. 2016;147:120–130.
[UIDB/0485/2020]. [18] Wogelius P, Haubek D, Poulsen S. Prevalence and distribution of
demarcated opacities in permanent 1st molars and incisors in 6
to 8-year-old Danish children. Acta Odontol Scand. 2008;66:
58–64.
[19] Soviero V, Haubek D, Trindade C, et al. Prevalence and distribu-
ORCID
tion of demarcated opacities and their sequelae in permanent
Lu
ısa Bandeira Lopes http://orcid.org/0000-0003-4412-7102 1st molars and incisors in 7 to 13-year-old Brazilian children. Acta
Vanessa Machado http://orcid.org/0000-0003-2503-260X Odontol Scand. 2009;67:170–175.
Jo~ao Botelho http://orcid.org/0000-0002-1019-8263 [20] Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for
Dorte Haubek http://orcid.org/0000-0001-9983-8767 reporting systematic reviews and meta-analyses of studies that
evaluate health care interventions: Explanation and elaboration.
PLoS Med. 2009;6:e1000100.
References [21] Smith V, Devane D, M Begley C, et al. Methodology in conducting
a systematic review of biomedical research. Med. Reasearch
[1] Goodman AH, Allen LH, Hernandez GP, et al. Prevalence and age Methodol. 2011;1:61–73.
at development of enamel hypoplasias in Mexican children. Am J [22] Shea BJ, Reeves BC, Wells G, et al. AMSTAR 2: a critical appraisal
Phys Anthropol. 1987;72:7–19. tool for systematic reviews that include randomised or non-rand-
[2] Koch G, Hallonsten AL, Ludvigsson N, et al. Epidemiologic study omised studies of healthcare interventions, or both. Bmj. 2017;
of idiopathic enamel hypomineralization in permanent teeth of 358:1–9.
Swedish children. Community Dent Oral Epidemiol. 1987;15: [23] Alaluusua S. Aetiology of molar-incisor hypomineralisation: a sys-
279–285. tematic review. Eur Arch Paediatr Dent. 2010;11:53–58.
 ACTA ODONTOLOGICA SCANDINAVICA 11

[24] Zhao D, Dong B, Yu D, et al. The prevalence of molar incisor population Intervention(s), exposure(s). International prospective
hypomineralization: evidence from 70 studies. Int J Paediatr Dent. register of systematic reviews. PROSPERO 2020 CRD42020171765.
2018;28:170–179. 2017. Available from: https://www.crd.york.ac.uk/prospero/dis-
[25] Borges AB, Caneppele TMF, Masterson D, et al. Is resin infiltration play_record.php?ID=CRD42017078004
an effective esthetic treatment for enamel development defects [29] Ureles S, Howe M, Ureles S, et al. The association of molar incisor
and white spot lesions? A systematic review. J Dent. 2017; 56: hypomineralization (MIH) and hypomineralization of the second
11–18. primary molar (HSPM) with dental caries in the mixed dentition:
[26] Elhennawy K, Krois J, Jost-Brinkmann PG, et al. Outcome and a systematic review and meta-analysis. International prospective
comparator choice in molar incisor hypomineralisation (MIH) register of systematic reviews. PROSPERO 2017 CRD42017078004.
intervention studies: a systematic review and social network ana- 2020. Available from: https://www.crd.york.ac.uk/prospero/dis-
lysis. BMJ Open. 2019;9:e028352. play_record.php?ID=CRD42020171765
[27] Weerheijm KL, Duggal M, Mejare I, et al. Judgement criteria for [30] Wogelius P, Viuff JH, Haubek D. Use of asthma drugs and preva-
Molar Incisor Hypomineralisation (MIH) in epidemiologic studies: lence of molar incisor hypomineralization. Int J Paediatr Dent.
a summary of the European meeting on MIH held in Athens, 2020;30:734–740.
2003. Eur J Paediatr Dent. 2003;4:110–113. [31] Nørrisgaard PE, Haubek D, K€ uhnisch J, et al. Association of high-
[28] Dantas E, Cavalcanti Y, Vieira B, et al. Association between dental dose vitamin D supplementation during pregnancy with the risk
enamel development defects and low birth weight: a systematic of enamel defects in offspring: a 6-year follow-up of a random-
review and metanalysis. Citation Review question Participants/ ized clinical trial. JAMA Pediatr. 2019;173:924–930.