Antibiotics are the most frequently prescribed medications in childhood; in Australia their use has increased by 230% in the 10 years between 2000 and 2010.1 It is suggested that antibiotics have a myriad of effects on dental health, particularly on tooth stains, defects in tooth development (enamel hypoplasia and hypomineralization) and dental diseases.2 However, the data are contradictory and both adverse and protective effects have been described.3-7
The mechanisms underlying these putative associations include direct effects on dental development and indirect influences through the oral microbiome.2,8,9
Antibiotics can directly interfere with the highly sensitive process of dental mineralization, causing dental developmental defects such as hypoplasia and enamel hypomineralization.10 These defects present clinically as dental discs. These defects present clinically in the form of discoloration and decay of the teeth, often requiring complex dental treatments.11-13
Additionally, exposure to tetracycline antibiotics in early life can lead to the formation of complexes within the tooth structure, producing the characteristic "tetracycline stain" with dark bands along the tooth.14 However, , recent studies suggest that new formulations of tetracycline antibiotics (e.g., doxycycline) may not cause dental staining.17-19 Dental caries affects 60% to 90% of children worldwide.20 -22
Dental caries is a multifactorial disease that occurs as a result of oral microbial dysbiosis caused by dietary sugar and dental plaque. Therefore, exposure to antibiotics can potentially affect the pathogenesis of dental caries, both directly (through the oral microbiome) and indirectly (by contributing to enamel defects).23 Early studies focused on the inverse relationship between antibiotic exposure and dental caries, and subsequent findings indicate a possible relationship between antibiotic exposure and enamel defects.3, 24-26
Data on new antibiotic formulations and their association with dental caries and enamel defects are inconsistent.27, 28
Therefore, a systematic review was carried out to evaluate the evidence regarding the effect of early childhood antibiotic exposure on dental caries, enamel developmental defects and dental stains.
| Methods |
This study followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines. The review was registered in the PROSPERO database (CRD42020179098).
The databases Medline (PubMed/Ovid), Embase (Ovid; 1946-current), and the Cochrane Library were searched in September 2021 using the search strategies listed in Supplementary Materials and Methods. All searches were limited to the English language. Reference lists of included articles were checked. Additionally, gray literature searches were conducted in the Pro-Quest Dissertation Abstracts and Thesis database and Google Scholar.
We included studies that reported antibiotic exposure before age 8 years (the period of dental development) and 1 or more of the relevant outcomes (dental caries, intrinsic dental staining, or enamel developmental defects) based on the visual evaluation of the dentition. Enamel developmental defects with a known etiology, such as fluorosis and amelogenesis imperfecta, were excluded as outcomes.29
For the outcomes of dental caries and enamel developmental defects, only studies using a validated index were included. Since there is no validated tool to measure tetracycline staining, studies using any clearly described method were included.
Two independent researchers assessed all studies for eligibility in Covidence (Covidence systematic review software, Veritas Health Innovation, Melbourne, Australia), in a two-stage screening process: by title and abstract, and then by full text. Initial disagreements were resolved by discussion and then by a third independent reviewer.
Data on study population, design, type of antibiotic, outcome measurement, and results were extracted from the identified studies by a single investigator using a standardized extraction form. All data extraction was audited by a second reviewer.
Odds ratios (OR), p values, and 95% confidence intervals (CI) were extracted from studies quantifying the risk of caries, enamel developmental defects, and dental stains with antibiotic exposure. If not reported and whenever possible, ORs and confidence intervals were calculated.
All analyzes were performed using Stata 16 software (StataCorp. 2019. Stata Statistical Software: Re lease 16. College Station, TX: StataCorp LLC). Due to heterogeneity and lack of data on covariates, a meta-analysis was not considered appropriate. The risk of bias of the studies was assessed by a single investigator using the Newcastle Ottawa Scale and the Risk Of Bias In Non-randomized Studies - of Exposure tool and audited by a second reviewer. 30, 31 The Newcastle Ottawa scale was modified to fit the research question.9 No studies were excluded on the basis of bias assessment.
| Results |
> Characteristics of the studies
The initial search returned 1003 articles, of which 756 were screened by title and abstract after relocating duplicates. In total, 34 were found eligible for qualitative analysis. All 34 studies were retrospective cohorts. A total of 18 studies investigated tetracyclines and/or tetracycline-derived antibiotics, 7 investigated only amoxicillin, and 9 did not specify the antibiotic class.
Exposure determination was based on hospital and pharmacy records or patients’ and parents’ recollections of medication use. The median age at the time of antibiotic exposure was 6 years (range 0-8 years). Outcomes were measured between 24 months and 18 years of age. The sample size varied between 25 and 29,485 participants.3, 32
The methods used to measure and quantify the 3 outcomes (dental caries, enamel defects, and dental staining) varied considerably. A total of 3 different measurements were used for caries, 10 for dental staining, and 7 for enamel defects.33-35 In addition to the detection of tetracycline staining from visual and laboratory analyses, general intrinsic staining was used. determined by measuring tooth color using a shade guide or spectrometer and applying an arbitrary threshold.
The 7 indices used to measure enamel developmental defects were variations of 2 validated core indices (European Academy of Dentistry Pedi00E1 0078trica Molar-Incisor Hypomineralization [MIH] Criteria and Enamel Developmental Defects [DDE] Index). 36.37
> Tetracycline and tetracycline-derived antibiotics
Tetracycline and intrinsic staining
Eighteen studies investigated tetracyclines and tetracycline-derived antibiotics, the majority of which (n 16) included dental staining as an outcome. Eleven studies investigated older formulations (e.g., tetracyclines), often at relatively higher doses (10 to 38 mg/kg per day), while 5 studies investigated newer formulations (e.g., doxycycline ), often at lower doses (2.3 to 6.25 mg/kg per day). The dose was not reported in 3 studies.38-40
Three studies assessed the presence of the characteristic tetracycline staining pattern from visual inspection and 4 studies used fluorescence from exfoliated or extracted teeth. Four studies used tooth color and shade as a marker of tetracycline staining.
The remaining 5 studies used a combination of the above methods or study-specific outcome measures based on inherent tooth color (intrinsic staining). The studies investigating older formulations of tetracyclines were published between 1962 and 1980 and were at risk of bias. moderate to critical, as they often did not clearly report the method of measuring the results. Higher doses of tetracyclines were associated with a greater presence of dental staining.
In 5 studies, doses of 20 mg/kg per day for a duration of 5 to 11 days were associated with dental staining, while only 1 study of the same dose reported no association.41-46 The study that reported Strongest association (OR: 11.62, 95% CI: 5.96-24.32) assessed the highest dose for the longest consecutive time (26.7 mg/kg per day for a mean of 11 days). 41
The 5 studies that evaluated the relationship between newer formulations of tetracycline (minocycline and doxycycline) and dental stains did not show any association. The studies were published between 1998 and 2017 and the average dose ranged between 2.3 and 25 mg/kg per day with an average duration of 10.7 days.17, 19, 47-49
Of note, no cases of tetracycline staining were observed in 58 and 78 children at mean doses of 2.3 mg/kg per day and 6.25 mg/kg per day, respectively. Although the overall risk of bias varied, 3 low-bias studies provided evidence that doxycycline did not cause intrinsic staining, including tetracycline staining.17, 19, 47
Defects in enamel development
Five studies investigated the relationship between childhood use of tetracycline-derived antibiotics and enamel developmental defects.17,40,42,43,50 Four of these studies provided details on dosage.
Two studies reported conflicting results for tetracycline at a dose of 20 mg/kg per day.42, 43 One study with a critical level of bias investigated 40 premature infants with a mean treatment duration of 4 days and found increased odds of birth defects. enamel (OR 5.83; 95% CI: 0.42-314.48). However, the study did not address the role of prematurity in the relationship.43 In contrast, the other study with a moderate level of bias investigated 160 participants aged 6 to 12 years with an average of 6 days of medication and found no cases of enamel hypoplasia.42
The 2 studies of newer formulations (doxycycline at 5 mg/kg daily and minocycline at 2.3 mg/kg daily) did not report an increased odds of enamel hypoplasia (OR 0.89, 95% CI : 0.38-2.11; OR 0.92; 95% CI: 0.2-4.2). 17,50 The results of these 5 studies are contradictory and prevent clear conclusions, but they suggest that the newer formulations at lower doses are probably not related to defects in enamel development.17, 40, 42, 43, 50
Dental caries
Three of the 4 studies on dental caries used the total number of decayed, missing, filled teeth, or surfaces based on visual inspection as a measure of caries prevalence or severity; a single study used radiographic evaluation in addition to clinical judgment.
The use of tetracycline at 20 mg/kg per day was not associated with the presence of dental caries (OR 1.42, 95% CI: 0.34-7.06).44 A study of 100 participants found fewer tooth surfaces decayed (0.099 ± 0.088) in the exposed group compared to the comparison group (0.146 ± 0.087); However, this study had significant bias due to lack of confirmation of exposure.38
A similar association was also reported in a study of 86 patients that found a mean of 7.5 (±1.0) decayed surfaces in the exposed group compared with a mean of 13.5 (±1.3) in the exposed group. comparison.40
All 4 studies had high levels of bias, with 1 lacking a comparison group and another relying on parental recall to determine exposure, and all of them did not adjust for determinants such as socioeconomic status (an important social determinant of risk). risk of dental caries).
> Amoxicillin
Seven of the included studies evaluated the effect of amoxicillin on enamel defects and/or dental caries, while the effects on intrinsic staining were not evaluated.
Defects in enamel development
Four studies investigated the relationship between amoxicillin and enamel developmental defects.9, 51-53 One study found a positive association (OR 7.88, 95% CI: 2.43-25.12) between penicillin and enamel developmental defects in a cohort of 433 children with a median age of 7.8 years.51
This study had a low level of bias and took into account relevant confounders such as fluoride exposure, tooth wear, and age. In contrast, 2 studies at low to moderate risk of bias in populations of 120 and 367 showed a protective association between penicillin (dose not reported) and enamel developmental defects with OR of 0.44 ( 95% CI: 0.25-0.77) and 0.07 (95% CI: 0.02-0.28).9, 52
Dental caries
There were 4 studies that investigated the relationship between amoxicillin and dental caries, all of them with a moderate level of bias.3,51,54,55 Only 2 studies reported the dosage, with 1 of them having a mean of 16 mg/day. kg per day and in the other 125 mg per day.54,55 A study with an exposed group of 433 in a population of children aged 7 to 9 years found a greater number of carious surfaces in the exposed group (mean 1.46 ; SD: 0.99) than in the comparison group (0.76; SD: 1.33).51
In contrast, another study of penicillin (125 mg per day) found a lower number of decayed surfaces in the exposed group of children aged 6 to 13 years (mean 3.55, SD: 0.58) compared to the group of control (mean 4.84, SD: 0.32).54
A birth cohort study of 29,485 participants found that the number of teeth affected by cavities at 2 years of age was, on average, lower in children who had taken amoxicillin (p < 0.0001). However, the dose was not provided and ORs could not be calculated from the data provided, limiting conclusions about effect size.3
This was consistent with a cohort study of 393 participants in which amoxicillin doses of 5 to 29 mg/kg per day were found to be protective against dental caries, with a mean of 0.47 (±0.6) decayed surfaces in the exposed group, compared with 1.50 (±0.32) in the comparison group.55 Overall, a clear association could not be identified due to heterogeneity of outcome measures between studies.
> Unspecified classes of antibiotics
Nine studies evaluated the dental effects of any antibiotic exposure by combining multiple antibiotics in a single exposure group or without specifying antibiotic formulations.2, 56-63 Of the 4 studies with low to moderate bias focused on MIH, a common developmental defect, 3 found a positive association with the prevalence of MIH. In contrast, none of the 3 low-to-moderate risk of bias studies that investigated developmental enamel defects in general (as opposed to MIH specifically) reported an association.57,61,64
| Discussion |
To our knowledge, this is the first systematic review investigating antibiotics in early childhood and 3 dental outcomes (cavities, enamel defects, and dental stains). Evidence from 34 studies was included. Tetracyclines at higher doses (20 mg/kg per day) were associated with dental stains; These doses are not currently recommended.
There were conflicting results between both early childhood antibiotics and dental caries and between early childhood antibiotic use and HIM. There was no evidence that new tetracycline-related formulations (doxycycline, minocycline), or other classes of antibiotics, were associated with adverse dental outcomes.
The present results are consistent with other systematic reviews of doxycycline that concluded that mean treatment durations of up to 10 days had negligible effects on dental parking.18, 27, 28, 65
The change in formulation from tetracycline to doxycycline included the removal of the hydroxyl group at C-6.66. This resulted in an inherent change in calcium binding capacity (doxycycline 19% vs. tetracycline 39.5%), making doxycycline less likely to give rise to the ionic complexes that cause intrinsic staining.27 This This change, combined with more recent studies on the safety of doxycycline, has also led the American Academy of Pediatrics’ 2021 Red Book to recommend use of doxycycline for less than 21 days, regardless of age.67
A previous systematic review reported an association between antibiotic use and developmental enamel defects (MIH), but lacked data on the dose and age of antibiotic administration, so it was not possible to determine whether the exposure was occurred during dental calcification.68 However, the findings coincide with those of the present study. No study evaluating enamel defects has determined whether the effect on the dentition is due to the antibiotic itself or the underlying disease.57,69-71
Therefore, until any risk of MIH has been quantified by prospective studies with data on any dose-response relationship, treatment of infections with antibiotics outweighs any putative risk of MIH.
No clear conclusions could be drawn regarding the effect of early childhood antibiotics on dental caries due to heterogeneity of outcome measures. Previous studies have reported an increased risk of dental caries from antibiotic use in early childhood.3 This contrasts with data from patients with cystic fibrosis, who have long cumulative exposure to antibiotics from early childhood and in the that there is a lower risk of dental caries.2, 5,6
Strengths and limitations
This study has a number of strengths, such as evaluating three different dental outcomes for the first time. Two bias tools were used to evaluate all papers, which was done in duplicate using multiple databases and at multiple time points. Most of the studies in this systematic review have methodological limitations.
All studies are based on retrospective data, and several did not adjust for potential confounders, such as socioeconomic status and age. Previous data on tetracycline antibiotics and dental stains largely come from the 1960s and 1970s, and the quality of the data is limited. The introduction of standardized information guides (such as STROBE) has improved quality and reduced bias.72
Limitations include the lack of standardized and validated outcome measures (for dental stains in particular) which made comparison between studies difficult. Although validated outcome measures were used for both enamel developmental defects and caries, several different indices were used.
A validated index for tetracycline staining is difficult to develop due to the low prevalence of staining. This systematic review applied causal inference using observational data to evaluate the effect of early childhood antibiotic use on dental outcomes. Such analyzes are powerful and increasingly common; There are inherent biases and challenges in answering causal questions from observational research.73
General associations between any antibiotic exposure and dental health without specific doses may provide a signal of association, but are limited in providing causal insights. Further studies with prospective longitudinal cohorts of patients with dose quantification would provide more complete evidence to inform clinical practice.
| Conclusions |
Five of the 18 tetracycline studies described a dose-response relationship between exposure to tetracycline doses of > 20 mg/kg per day and dental stains. Early childhood exposure to doxycycline (at any dose) was not associated with dental staining. There was no clear association between early childhood antibiotic exposure and tooth decay or enamel defects.
There is conflicting evidence on the relationship between antibiotic use and other dental outcomes (cavities and enamel defects). Further well-designed prospective longitudinal studies are needed to determine this relationship using standardized outcomes with adjustment for confounders, along with biological sampling and microbiome analysis.
| Commentary |
The use of antibiotics can cause adverse effects on dental health such as stains, developmental defects and tooth decay. The present study aims to conduct a systematic review of the effects of antibiotic exposure in early childhood on dental health.
Early childhood exposure to doxycycline was not associated with dental staining. There was no clear association between early childhood antibiotic exposure and tooth decay or enamel defects.
In the included studies, the main limitations and sources of bias were lack of comparison groups, inconsistent outcome measures, and lack of adjustment for relevant confounders.
It is concluded that there was no evidence that the new formulations of tetracycline at the currently recommended doses produced adverse effects on dental health. Findings regarding antibiotic exposure and developmental defects of enamel or dental caries were inconsistent.
More prospective studies are needed to reach better conclusions.
