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CRITICAL REVIEW • Pesqui. Bras. Odontopediatria Clín. Integr. 21 • 2021 • https://doi.org/10.1590/pboci.2021.032   copy

Clinical and Molecular Disorders Caused by COVID-19 During Pregnancy as a Potential Risk for Enamel Defects

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

This paper discusses the potential risk that COVID-19 generates for the development of enamel defects. This hypothesis was built based on the etiopathogenesis of enamel defects and the relationship with the symptom's characteristic of COVID-19. Pregnancy is a critical period for the child's development; exposure to pathological agents can cause systemic imbalances and risks of adverse perinatal and prenatal outcomes. The main clinical symptoms of this disease and its association with that dental outcome were considered. Fever, breathing, cardiovascular disorders, and diarrhea were related as potential etiological factors of ameloblast metabolism imbalance, which can interfere qualitatively and quantitatively in the development, maturation and mineralization of the tooth enamel. Molecular disorders derived from COVID-19, as well as their clinical symptoms, can be considered potential risk factors for the development of enamel defects. Individuals with enamel defects experienced high stress levels during pregnancy or early childhood. The approach adopted may help build new research to ensure understanding of the etiology of the development of dental enamel defects and its relationship with COVID-19. However, longitudinal studies need to be conducted to confirm the association between COVID-19 and adverse events during pregnancy.

Keywords:
COVID-19; SARS-CoV-2; Dental Care; Dental Enamel; Child; Pregnancy

Introduction

Adverse events occurring prenatally, perinatally, and during birth may determine an individual's oral health [1[1] Corrêa-Faria P, Paixão-Gonçalves S, Paiva SM, Pordeus IA, Marques LS, Ramos-Jorge ML. Association between developmental defects of enamel and early childhood caries: a cross-sectional study. Int J Paediatr Dent 2015; 25(2):103-9. https://doi.org/10.1111/ipd.12105
https://doi.org/10.1111/ipd.12105... ]. Pregnancy is a critical period for the child's development. Physiological changes in pregnancy increase susceptibility to infections due to an imbalance in the immune system, increased concentrations of inflammatory proteins, activation of hypercoagulability status, deduction of oxygen deficiency tolerance and cardiovascular adaptations by hormonal action [2[2] Tan EK, Tan EL. Alterations in physiology and anatomy during pregnancy. Best Pract Res Clin Obstet Gynaecol 2013; 27(6):791-802. https://doi.org/10.1016/j.bpobgyn.2013.08.001
https://doi.org/10.1016/j.bpobgyn.2013.0... ,3[3] Omer S, Ali S, Babar ZUD. Preventive measures and management of COVID-19 in pregnancy. Drugs Ther Perspect 2020; 1-4. https://doi.org/10.1007/s40267-020-00725-x
https://doi.org/10.1007/s40267-020-00725... ].

International centers for disease control and prevention are monitoring this infectious disease outbreak; symptoms of COVID-19 infection include fever, cough, and acute respiratory disease, with severe cases leading to pneumonia, kidney failure, and even death [4[4] Guo J, Xie H, Liang M, Wu H. COVID-19: a novel coronavirus and a novel challenge for oral healthcare. Clin Oral Investig 2020; 24(6):2137-8. https://doi.org/10.1007/s00784-020-03291-8
https://doi.org/10.1007/s00784-020-03291... ]. The literature has reported the clinical symptoms of COVID-19 as a hyper inflammation or cytokine storm [5[5] Panigrahy D, Gilligan MM, Huang S, Gartung A, Cortés-Puch I, Sime PJ, et al. Inflammation resolution: a dual-pronged approach to averting cytokine storms in COVID-19? Cancer Metastasis Rev 2020; 39(2):337-40. https://doi.org/10.1007/s10555-020-09889-4
https://doi.org/10.1007/s10555-020-09889... ]. Other diseases with inflammatory characteristics, oxidative stress or endothelial dysfunction during pregnancy, such as preeclampsia, are associated with adverse perinatal outcomes [6[6] Liu H, Liu F, Li J, Zhang T, Wang D, Lan W. Clinical and CT imaging features of the COVID-19 pneumonia: Focus on pregnant women and children. J Infect 2020; 80(5):e7-e13. https://doi.org/10.1016/j.jinf.2020.03.007
https://doi.org/10.1016/j.jinf.2020.03.0... ].

The formation and maturation of deciduous teeth are susceptible to maternal metabolic imbalance; thus, the tooth enamel can act as a biological marker, thanks to the lack of tissue remodeling throughout the life of an individual, with alterations occurring during its formation being permanently detectable [7[7] A review of the developmental defects of enamel index (DDE Index). Commission on Oral Health, Research & Epidemiology. Report of an FDI Working Group. Int Dent J 1992; 42(6):411-26.,8[8] Takaoka LA, Goulart AL, Kopelman BI, Weiler RM. Enamel defects in the complete primary dentition of children born at term and preterm. Pediatr Dent 2011; 33(2):171-6.]. The mechanisms that link pathophysiological disorders with enamel hypoplasia are varied. Individuals with enamel defects experienced high-stress levels during pregnancy or early childhood [9[9] Corrêa-Faria P, Martins-Júnior PA, Vieira-Andrade RG, Marques LS, Ramos-Jorge ML. Perinatal factors associated with developmental defects of enamel in primary teeth: a case-control study. Braz Oral Res 2013; 27(4):363-8. https://doi.org/10.1590/S1806-83242013005000017
https://doi.org/10.1590/S1806-8324201300... ].

Amelogenesis

The amelogenesis, the process of forming dental enamel, begins in the 15th week of intrauterine life. Most of it is formed during the prenatal stage, and throughout childhood [1[1] Corrêa-Faria P, Paixão-Gonçalves S, Paiva SM, Pordeus IA, Marques LS, Ramos-Jorge ML. Association between developmental defects of enamel and early childhood caries: a cross-sectional study. Int J Paediatr Dent 2015; 25(2):103-9. https://doi.org/10.1111/ipd.12105
https://doi.org/10.1111/ipd.12105... ,10[10] Zerofsky M, Ryder M, Bhatia S, Stephensen CB, King J, Fung EB. Effects of early vitamin D deficiency rickets on bone and dental health, growth and immunity. Matern Child Nutr 2016; 12(4):898-907. https://doi.org/10.1111/mcn.12187
https://doi.org/10.1111/mcn.12187... ]. This may suggest that contamination by COVID-19 in this period can generate defects in the formation of tooth enamel. Etiology of enamel's developmental defects, there are numerous hereditary, acquired, systemic, and local etiological factors associated with enamel defects [11[11] Seow WK. Clinical diagnosis of enamel defects: pitfalls and practical guidelines. Int Dent J 1997; 47(3):173-82. https://doi.org/10.1002/j.1875-595x.1997.tb00783.x
https://doi.org/10.1002/j.1875-595x.1997... ,12[12] Salanitri S, Seow WK. Developmental enamel defects in the primary dentition: aetiology and clinical management. Aust Dent J 2015; 58(2):133-40. https://doi.org/10.1111/adj.12039
https://doi.org/10.1111/adj.12039... ]. Ameloblasts are cells sensitive to physiological or pathological variations in pregnancy. The symptoms of COVID-19 are known to disturb these cells, causing disorder in the secretion of the protein matrix or interfering with these cells' metabolism [13[13] Cruvinel VR, Gravina DB, Azevedo TD, Rezende CS, Bezerra AC, Toledo OA. Prevalence of enamel defects and associated risk factors in both dentitions in preterm and full term born children. J Appl Oral Sci 2012; 20(3):310-7. https://doi.org/10.1590/s1678-77572012000300003
https://doi.org/10.1590/s1678-7757201200... ]. These disbalance can generates defective enamel qualitatively or quantitatively in deciduous teeth [14[14] Silva MJ, Scurrah KJ, Craig JM, Manton DJ, Kilpatrick N. Etiology of molar incisor hypomineralization - a systematic review. Community Dent Oral Epidemiol 2016; 44(4):342-53. https://doi.org/10.1111/cdoe.12229
https://doi.org/10.1111/cdoe.12229... ]. In this point of view, we discuss the potential risk that COVID-19 generates for the development of enamel defects. Thus, the main symptoms of this disease and its association with such an outcome was considered.

  • Fever - A common symptom of infection is fever and, therefore, its role is difficult to distinguish from that of the disease itself. Viral and bacterial infections have been reported as possible etiological agents of enamel defects, such as: zika syndrome, chickenpox, cytomegalovirus, measles, rubella, syphilis, respiratory and gastrointestinal infection [14[14] Silva MJ, Scurrah KJ, Craig JM, Manton DJ, Kilpatrick N. Etiology of molar incisor hypomineralization - a systematic review. Community Dent Oral Epidemiol 2016; 44(4):342-53. https://doi.org/10.1111/cdoe.12229
    https://doi.org/10.1111/cdoe.12229...

    [15] Jaskoll T, Abichaker G, Htet K, Bringas P Jr, Morita S, Sedghizadeh PP, et al. Cytomegalovirus induces stage-dependent enamel defects and misexpression of amelogenin, enamelin and dentin sialophosphoprotein in developing mouse molars. Cells Tissues Organs 2019; 192(4):221-39. https://doi.org/10.1159/000314909.
    https://doi.org/10.1159/000314909...     -16[16] Gusmão TPL, Faria ABS, Leão Filho JC, Carvalho AAT, Gueiros LAM, Leão JC. Dental changes in children with congenital Zika syndrome. Oral Dis 2020; 26(2):457-64. https://doi.org/10.1111/odi.13238
    https://doi.org/10.1111/odi.13238...     ]. High fever has been reported to cause enamel defects [17[17] Alaluusua S. Aetiology of Molar-Incisor Hypomineralisation: a systematic review. Eur Arch Paediatr Dent 2010; 11(2):53-8. https://doi.org/10.1007/BF03262713
    https://doi.org/10.1007/BF03262713...     ]. Altered expression of genes important in enamel formation has also been suggested as the link between fever and enamel defects [18[18] Ryynänen H, Sahlberg C, Lukinmaa PL, Alaluusua S. The effect of high temperature on the development of mouse dental enamel in vitro. Arch Oral Biol 2014; 59(4):400-6. https://doi.org/10.1016/j.archoralbio.2014.01.005
    https://doi.org/10.1016/j.archoralbio.20...     ] from this perspective, processes of gene Modulations in microRNA, DNA methylation and chromatin modifications are emerging as important regulatory mechanisms during tooth development [19[19] Fan Y, Zhou Y, Zhou X, Xu X, Pi C, Xu R, et al. Epigenetic control of gene function in enamel development. Curr Stem Cell Res Ther 2015; 10(5):405-11. https://doi.org/10.2174/1574888x10666150305104730
    https://doi.org/10.2174/1574888x10666150...     ]. Alternatively, the etiology may relate to a metabolic disturbance described in rat studies showing that acidic conditions (a result of both localized inflammation and hypoxia) can prevent crystal growth due to the build-up of hydrogen ions [20[20] Sui W, Boyd C, Wright JT. Altered pH regulation during enamel development in the cystic fibrosis mouse incisor. J Dent Res 2003; 82(5):388-92. https://doi.org/10.1177/154405910308200512
    https://doi.org/10.1177/1544059103082005...     ]. Although the literature has reported that high fever in childhood establishes a relationship with enamel defect [14[14] Silva MJ, Scurrah KJ, Craig JM, Manton DJ, Kilpatrick N. Etiology of molar incisor hypomineralization - a systematic review. Community Dent Oral Epidemiol 2016; 44(4):342-53. https://doi.org/10.1111/cdoe.12229
    https://doi.org/10.1111/cdoe.12229...     ,17[17] Alaluusua S. Aetiology of Molar-Incisor Hypomineralisation: a systematic review. Eur Arch Paediatr Dent 2010; 11(2):53-8. https://doi.org/10.1007/BF03262713
    https://doi.org/10.1007/BF03262713...     ], fever that occurs during pregnancy, especially during the formation and maturation of the enamel matrix can generate the same damage since the principle of the process itself it does not differ in relation to the moments of occurrence. It is also known that adverse events that occur in earlier stages of odontogenesis culminate in worse results [21[21] Andersson L, Andreasen JO, Day P, Heithersay G, Trope M, DiAngelis AJ, et al. Guidelines for the management of traumatic dental injuries: 2. Avulsion of permanent teeth. Pediatr Dent 2016; 38(6):369-76.].

  • Breathing disorders - After infection and wide viral replication of this disease in the epithelial cells of the respiratory system, imbalances in the immune response with leukocyte damage have been identified, especially in auxiliary and regulatory T lymphocytes that play an important role in immune homeostasis and the prevention of an exacerbated inflammatory response [22[22] Conti P, Ronconi G, Caraffa A, Gallenga CE, Ross R, Frydas I, et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies J Biol Regul Homeost Agents 2020; 34(2):327-31. https://doi.org/10.23812/CONTI-E
    https://doi.org/10.23812/CONTI-E...     ,23[23] Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Infect Dis 2020; 71(15):762-8. https://doi.org/10.1093/cid/ciaa248
    https://doi.org/10.1093/cid/ciaa248...     ]. The imbalance between the immune system and the respiratory system makes this characteristic critical for ameloblasts, sensitive to external variations and oxidative processes derived from inflammation and fever. Oxygen deficiency during childbirth or pregnancy has been reported as a possible metabolic disorder acting on odontoblasts, resulting in the formation of abnormal tissue [24[24] Arrow P. Risk factors in the occurrence of enamel defects of the first permanent molars among schoolchildren in Western Australia. Community Dent Oral Epidemiol 2009; 37(5):405-15. https://doi.org/10.1111/j.1600-0528.2009.00480.x
    https://doi.org/10.1111/j.1600-0528.2009...     ]. The reduced oxygen levels may lead to dental enamel matrix secretion disorders due to the detrimental influence on the cellular metabolism of ameloblasts [25[25] Cruvinel VR, Gravina DB, Azevedo TD, Rezende CS, Bezerra AC, Toledo OA. Prevalence of enamel defects and associated risk factors in both dentitions in preterm and full term born children. J Appl Oral Sci 2012; 20(3):310-7. https://doi.org/10.1590/s1678-77572012000300003
    https://doi.org/10.1590/s1678-7757201200...     ]. The literature has associated pneumonia and asthma at a very early age and enamel defects incidence [14[14] Silva MJ, Scurrah KJ, Craig JM, Manton DJ, Kilpatrick N. Etiology of molar incisor hypomineralization - a systematic review. Community Dent Oral Epidemiol 2016; 44(4):342-53. https://doi.org/10.1111/cdoe.12229
    https://doi.org/10.1111/cdoe.12229...     ,17[17] Alaluusua S. Aetiology of Molar-Incisor Hypomineralisation: a systematic review. Eur Arch Paediatr Dent 2010; 11(2):53-8. https://doi.org/10.1007/BF03262713
    https://doi.org/10.1007/BF03262713...     ]. Therefore, the hypothesis that this symptom of COVID-19 in pregnant women may interfere with tissue formation mechanism seems to be imminent. However, future studies need to prove this relationship.

  • Cardiovascular disorders - Clinically, the characteristic pulmonary impairment of COVID-19 has contributed to increased in cardiac and laboratory demand and has been identified as an increase in myocardial tissue injury markers [26[26] Clerkin KJ, Fried JA, Raikhelkar J, Sayer G, Griffin JM, Masoumi A, et al. COVID-19 and cardiovascular disease. Circulation 2020; 141(20):1648-55. https://doi.org/10.1161/CIRCULATIONAHA.120.046941
    https://doi.org/10.1161/CIRCULATIONAHA.1...     ]. The COVID-19 course demands exaggerated inflammation, endothelial lesions, and the potential risk of organs' involvement, directly and indirectly, related to the cardiovascular system [27[27] Henry BM, de Oliveira MHS, Benoit S, Plebani M, Lippi G. Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis. Clin Chem Lab Med 2020; 58(7):1021-8. https://doi.org/10.1515/cclm-2020-0369
    https://doi.org/10.1515/cclm-2020-0369...     ]. Such occurrences, at the cellular level, can generate disturbances in the metabolism of ameloblasts that produces damaged protein matrix and consequently enamel defects in children.

  • Diarrhea - Although it appears as a less frequent event in covid-19, diarrhea in pregnancy, when severe, can be a potential risk for the development of enamel defects in children as it causes deficiencies in macro and micronutrient absorption. The enamel tissue framework is made up of proteins, so a diet poorly made up of this macronutrient also has this harmful potential. Deficiency of micronutrients such as vitamins A, C and D and calcium are well known to be risk factors for enamel hypoplasia in preterm [28[28] Yengopal V, Harnekar SY, Patel N, Siegfried N. Dental fillings for the treatment of caries in the primary dentition. Cochrane Database Syst Rev 2016; 2016(10):CD004483. https://doi.org/10.1002/14651858.CD004483.pub3
    https://doi.org/10.1002/14651858.CD00448...     ]. Low birth weight has been linked to a risk of developing enamel defects. Apart from Ghanim et al. [29[29] Ghanim A, Manton D, Bailey D, Mariño R, Morgan M. Risk factors in the occurrence of molar-incisor hypomineralization amongst a group of Iraqi children. Int J Paediatr Dent 2013; 23(3):197-206. https://doi.org/10.1111/j.1365-263X.2012.01244.x
    https://doi.org/10.1111/j.1365-263X.2012...     ], who found higher odds of enamel defect with low birth weight after adjusting for confounding, there was little evidence of an association between enamel defect and low birthweight.

Conclusion

The mechanisms that link pathophysiological disorders with enamel hypoplasia are varied. Individuals with enamel defects experienced high stress levels during pregnancy or early childhood. Between the fourth and the fifth month of gestation, a window for the occurrence of disorders in the protein matrix and in the calcification of dental enamel in both dentitions can be checked since it is at that moment that the formation of the dental crown begins. However, the etiology of enamel defects is still unclear, but there is a strong indication that adverse events may influence this tissue's complex formation during pregnancy. The adverse events resulting from COVID-19 can be considered a risk for enamel defect as already mentioned. However, studies need to be directed to elucidate this relationship.

  • Financial Support
    None.
  • Data Availability
    The data used to support the findings of this study can be made available upon request to the corresponding author.

References

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    » https://doi.org/10.1007/s00784-020-03291-8
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    Takaoka LA, Goulart AL, Kopelman BI, Weiler RM. Enamel defects in the complete primary dentition of children born at term and preterm. Pediatr Dent 2011; 33(2):171-6.
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    Corrêa-Faria P, Martins-Júnior PA, Vieira-Andrade RG, Marques LS, Ramos-Jorge ML. Perinatal factors associated with developmental defects of enamel in primary teeth: a case-control study. Braz Oral Res 2013; 27(4):363-8. https://doi.org/10.1590/S1806-83242013005000017
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    » https://doi.org/10.1159/000314909
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    » https://doi.org/10.1111/odi.13238
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    » https://doi.org/10.1007/BF03262713
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    » https://doi.org/10.2174/1574888x10666150305104730
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    » https://doi.org/10.1177/154405910308200512
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    Conti P, Ronconi G, Caraffa A, Gallenga CE, Ross R, Frydas I, et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies J Biol Regul Homeost Agents 2020; 34(2):327-31. https://doi.org/10.23812/CONTI-E
    » https://doi.org/10.23812/CONTI-E
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    » https://doi.org/10.1093/cid/ciaa248
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    » https://doi.org/10.1111/j.1600-0528.2009.00480.x
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    » https://doi.org/10.1161/CIRCULATIONAHA.120.046941
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    » https://doi.org/10.1515/cclm-2020-0369
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    » https://doi.org/10.1002/14651858.CD004483.pub3
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    Ghanim A, Manton D, Bailey D, Mariño R, Morgan M. Risk factors in the occurrence of molar-incisor hypomineralization amongst a group of Iraqi children. Int J Paediatr Dent 2013; 23(3):197-206. https://doi.org/10.1111/j.1365-263X.2012.01244.x
    » https://doi.org/10.1111/j.1365-263X.2012.01244.x

Edited by

Academic Editor: Alessandro Leite Cavalcanti

Publication Dates

  • Publication in this collection
    01 Mar 2021
  • Date of issue
    2021

History

  • Received
    27 June 2020
  • Reviewed
    20 Aug 2020
  • Accepted
    24 Sept 2020
Creative Common - by 4.0
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