Submitted:
12 July 2025
Posted:
15 July 2025
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Abstract
Background/Objectives: There is a need to search for risk factors of CL/P, most common facial congenital deformity due to its multifactorial aetiology. The aim of this study was assessment of possible external factors influencing the occurrence of nonsyndromic CL/P. Methods: Retrospective - prospective case record analysis was performed on the sample of 224 consecutive treated patients. The data were obtained from medical records and questionnaires answered by children’s parents. Results: Factors increased the risk of CL/P were: increased fathers’ age (p=0.014), mothers’ infections in the first trimester of pregnancy (p<0.001), maternal passive smoking (p=0.001) and stress during the first trimester of pregnancy (p=0.003). Folic acid mothers’ intake in the first trimester of pregnancy reduced the risk of a CL/P in a newborns by 0.19 times. Increased fathers age was not related with the occurrence of isolated CL. Stress factor did not increased the risk of isolated CP etiology. Folic acid intake in the first trimester of pregnancy did not influenced CLP occurrence. Conclusions: CL/P in the group of Southern Eastern Poland children was related with increased father’s age and maternal external risk factors: infections, passive tobacco smoking and severe stress during the first trimester of pregnancy. Folic acid intake during first trimester reduced the risk CL and CP.
Keywords:
orofacial clefts
; cleft etiology
; risk factors
; folic acid
; tobacco
Introduction
The most common dentofacial nonsyndromic congenital malformation in craniofacial region is cleft lip and/or cleft palate (CL/P) with the incidence of 1 per 700 live births [1,2]. The classification of anomaly is based on embryological origin and structures affected. Two main types can be distinguished: cleft lip without (CL) or with cleft palate (CLP), and cleft palate (CP). [3,4,5] Due to international variety in the use of classification systems in 2023 the usage of the LAHSHAL method for orofacial clefts was recommended. [6] CL/P is often associated with additional congenital abnormalities in the different types of syndromes but more common form is nonsyndromic which occur as isolated condition [7] Etiology of CL/P is contributed to genetic and environmental factors. Among genetics complex etiology about 40 loci have been reported and several identified genetic variants associated with oral clefts has been made through genome-wide association (GWA) studies [8,9,10,11]. Lack of global network of registries impedes finding and monitoring of risk factors. Some of them like: genetic polymorphisms, gender of the affected child, ethnical origin and family history cannot be influenced. Whereas consanguinity, parental age at conception, socio-economical and educational level, maternity weight, nutritional state, diseases, stress, intake of medication, alcohol or smoking may be avoided by prospective parents. Accurate reporting cases of children born with clefts allows to identified new risks like prenatal maternal opioid exposition [12]
The aim of this retrospective - prospective case record analysis was assessment of etiological risk factors of nonsyndromic CL/P in the area of Southern Eastern Poland.
Material
The study group (SG) included 224 patients: 103 girls and 121 boys with nonsyndromic CL/P treated at the Clinic for Congenital Craniofacial Deformities, University Dental Centre in Lublin, Poland between 2017 and 2022. All participants of the survey are the residents of Southern Eastern Poland. The age of the patients ranged from 1 month to 16 years of old. The comparison group (CG) consisted of 51 children (29 girls and 22 boys) without any facial deformities requiring surgical treatment in Eastern Centre for Burns and Reconstructive Surgery.
The data used in this study were obtained from a retrospective examination of the patients medical history and from questionnaires administered to the children’s parents. All research protocols were approved by the Bioethical Committee of Medical University of Lublin (nr KB-0024/148/11/2024).
Methods
Based on the documentation, two researchers (MB and AL) noted: the type of cleft, side of cleft in case of unilateral CL and CLP, patients’ gender and age. In the questionnaires parents were asked about: mother’s and father’s age at child's birth, mother's infection in the first trimester of pregnancy, mother's folic acid intake in the 3 months before the planned pregnancy, mother's folic acid intake in the first trimester of pregnancy, maternal tobacco smoking during pregnancy (including the first trimester of pregnancy), passive maternal smoking, maternal alcohol usage during the first trimester of pregnancy, maternal stress during the first trimester of pregnancy (serious illness, death of a close relative, accident, etc.), maternal educational level (vocational, secondary, higher education), paternal educational level ((vocational, secondary, higher education).
Data were inserted in a spreadsheet (Microsoft Excel Version 16.24; 2019; Microsoft, Redmond, WA, USA). A descriptive statistics, univariate and multivariate logistic regression were used with a software Statistica 13.1 (ss p<0.05 ).
Results
In this study CLP was the most common anomaly with percentage of 41% followed by CP - 38%. CL was noted in 47 patients (21%). Analyzing the gender distribution there was statistically higher number of girls in CP group (p=0,002) while in the CLP group was predominantly boys (p<0.001) (Table 1). There were no statistically significant differences in gender incidence in the CL group.
CL occurred most frequently on the left side (in 31 children - 15 girls and 16 boys), less frequently on the right side (in 11 children - 6 girls and 5 boys) and the lowest frequently it was recognized bilaterally (in 5 cases - in 3 girls and 2 boys). CLP also most frequently affected the left side (in 52 children - 13 girls and 39 boys), less frequently was bilateral (in 21 children - 12 girls and 9 boys) and least frequently was right-sided (in 18 children - 3 girls and 15 boys). Statistically significant differences in cleft side and gender were identified in children with CLP (Table 2).
After a preliminary analysis of the environmental etiological factors of CL/P the following were excluded from the study: maternal alcohol consumption during pregnancy (not enough number of reported cases) and the parents education status (lack of statistical significance).
Multivariate analysis of other elements revealed the existence of 4 statistically significant risk factors of CL/P and one factor which reduced the risk. Factors increased the risk were: fathers’ age, mothers’ infections in the first trimester of pregnancy, passive smoking (smoking cigarettes by the pregnant woman's household members during the first trimester of pregnancy and stress during the first trimester of pregnancy (Table 3).
Based on the results obtained, it can be concluded that increasing the age of the father by year increased the risk of the child with CL/P by 1.2 times. Women who have undergone an infection during the first trimester of pregnancy had a 12 times greater risk of having baby with cleft lip and/or palate compared to women who had not an infection. Those who have experienced severe stress in the first trimester of pregnancy had this risk more than 8 times higher. A risk factor of increasing 10 times CL/P incidence was passive maternal tobacco smoking. Folic acid mothers’ intake in the first trimester of pregnancy reduced the risk of a CL/P in a newborn by 0.19 times.
There was no relation of acid folic intake before pregnancy and CL/P incidence and maternal tobacco smoking during pregnancy. (Table 4).
Multivariate analysis revealed four environmental factors significantly affecting the occurrence of CL in children (Table 5). Past infections during the first trimester of pregnancy increased the risk of CL by 22 times. Maternal household smoking during the first trimester of pregnancy increased the risk by 9 times, whereas stress by 13 times . In contrast, the use of folic acid during the first trimester of pregnancy reduced the risk of having a child with CL by 0.11 times (Table 5).
Statistical analysis revealed three significant environmental factors that increased the risk of having a child with CP (Table 6). Increasing the father's age by one year the risk of CP increased by 1.4 times. Women who have undergone an infection had an approximately 58 times higher risk of having a child with CP compared to women who had not undergone an infection. The risk of CP occurring in the child of a mother taking folic acid during the first trimester of pregnancy was 0.04 lower than for those who did not take folic acid at that time. Women exposed to passive smoking had about 49 times bigger risk of giving birth to a child with CP compared to women not exposed to this factor. The use of folic acid during the first trimester of pregnancy reduced the risk of having a child with CP.
Multivariate analysis detected four environmental factors that increased the risk of CLP (Table 7). A statistically significant factor was the age of the father on the day of the child's birth . Increasing the father's age by one year increased the risk of CLP by 1.2 times. Infections experienced during the first trimester of pregnancy increased the risk of CLP by approximately 11 times compared to women who did not have an infection during this time. Mothers of children who were exposed to passive tobacco smoking during the first trimester of pregnancy had an approximately 9 times bigger risk of CLP. Stress in the first trimester of pregnancy increased about 12 times more the risk of CLP. Obtained results did not revealed the preventive influence of folic acid intake in the first trimester of pregnancy.
Discussion
The multifactorial etiology of CL/P is well known and widely discussed. Although genetics finding of clefts etiology allows for better understanding of inheritance of CL/P anomaly this is the possible modified factors which are still in the biggest interest of future parents. Many risk factors was analyzed in the literature: in the Chinese population surveyed by Hong Y et al. maternal pesticide exposure and antibiotic drugs were identified as risk factors of CL/P [13]. When in contrast, in this study maternal moderate and middle physical workload, vitamin-B complex, calcium an iron supplementations were associated with reduced risk of anomaly. Ács et al. in their meta- analysis revealed that obesity, maternal underweight, maternal type 1 diabetes and the essential hypertension was associated with higher odds of developing cleft. In our study the focus was only on the few most proved external modifiable factors [14].
The older age of parents was investigated as a risk factor in many studies. Mc Donell et al. did not revealed contribution between the rising trend in the proportion of mothers aged 35 years or older in Ireland and orofacial clefts incidence associated with chromosomal syndrome [15]. This is in accordance with our report on nonsyndromic clefts. Our study results highlighted parental age which increased the risk of having the child with CL/P by 1.2 times with each year of father’s age. Analyses in the population-based study from Norway in the period from 1967 until 2010 suggested that the risk of fathering an infant with CL increases with advancing age. However it was discovered that the risk was increased only when the age of both parents was high [16]. Ahmed at al. in case-control study from Gansu Province, China on 600 CL/P cases proved the parents’ age between 25-29 reduced the incidence of anomaly [17]. The older study of Danish researchers are with agreement with our study that it is paternal age which plays more important role in the etiology of CP [18]. In this research both parents increased age was connected with the incidence of CL/P. The findings of meta-analysis of Herkrath et al. suggested that fathers forty years of age or older had a 58% higher risk of having a child with CP compared to those aged between 20 and 39 years. In the same study maternal increased age influence on CL/P incidence was also revealed [19].
Maternal smoking was identified as a modifiable environmental factor, which was considered a causal factor for CL/P in the 2014 US Surgeon General's Report [20]. Also meta-analysis performed by Fell et al. suggested that maternal smoking might have a moderate role in CL/P etiology with pooled OR of 1.42 (95% CI: 1.27, 1.59)[21]. In our study maternal tobacco smoking did not influenced the incidence of CL/P perhaps because of the failure of the parents to report it. Population-based case–control study in 10 US states confirmed smoking during the month before pregnancy or the first month of pregnancy as a risk factor: 4.0% for CL/P and 3.4% for CP which is lower than in our findings [22]. Another authors reviews also showed that maternal smoking and passive smoking increases the risk for orofacial clefts [17,23,24,25,26,27]. Ács et al. highlighted that passive smoking was even more harmful than active tobacco smoking [14]. Sabbagh et al. in meta-analysis proved that maternal passive smoking exposure resulted in a 1.5 fold increase in risk of non- syndromic orofacial clefts, similar to the magnitude of risk reported for active smoking [24]. According to our and other authors results there is a strong evidence to avoid maternal tobacco active and passive smoke before and during pregnancy.
Folic acid intake during preconception and the first trimester period plays an important preventive role in the etiology of congenital deformities [28] Our study is with agreement with other studies, that maternal folic acid intake during the first three months of pregnanacy reduces the risk of CL/P [17,29]. Darjazini et al. recommend maternal intake of folic acid supplements at a dose of 0.4 to 0.8 mg during the initial trimester of pregnancy [29].
Severe maternal stress during the first three months of pregnancy was the CL and CLP risk factor in our study. Based on 12 studies Talal et al. performed a meta-analysis also proved the effect of mothers’ stress during periconceptional period on CL/P formation [30].
Analyzing external risk factors is crucial to prevent congenital anomalies. It can help in prevention of both syndromic and nonsyndromic CL/P . Not to be overlook, the health status of children with syndromic CL/P is often more complicated with the most frequent associated congenital anomaly - congenital heart disease [31]. Also an increasing tendency of early detection of congenital deformities is encouraging [32].
Considering limitations of our study the small number of patients involved as well as limited number of factors analyzed could influence the importance of the results. Also relying on parents’ survey may introduce the risk of bias.
Conclusions
Advanced age of the father, mother’s infection during the first trimester of pregnancy mother’s severe stress in the first trimester of pregnancy and passive maternal tobacco smoking increased the risk of CL/P in children. Fathers’ age had no relation with CL incidence. Maternal severe stress did not increased the incidence of CP. For CL and CP formation maternal acid folic intake in the first trimester of pregnancy had the prevention effect. These findings can help to develop primary prevention strategies for CL/P.
Abbreviations
| CL | Cleft lip |
| CLP | Cleft lip with cleft palate |
| CP | Cleft palate |
| CL/P | Cleft lip and/or cleft palate |
| SG | study group |
| CG | comparison group |
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Table 1.
Characteristics of the study group by gender and cleft type.
| CL | CP | CLP | ||
|
Gender girls boys |
24 (10,71%) 23 (10,27%) |
51 (22,77%) 35 (15,63%) |
28 (12,50%) 63 (28,13%) |
103 (45,98%) 121 (54,02%) |
| Total | 47 (20,98%) | 86 (38,39%) | 91 (40,63%) | 224 (100,00%) |
Table 2.
Cleft side and type in the study group.
| Side and type of the cleft | Gender | p** | |
| girls | boys | ||
| CL, left side | 15 (28,85%) | 16 (18,60%) | 0,162 |
| CL, right side | 6 (11,54%) | 5 (5,81%) | 0,228 |
| CL, billateral | 3 (5,77%) | 2 (2,33%) | 0,295 |
| CLP, left side | 13 (25,00%) | 39 (45,35%) | 0,017 |
| CLP, right side | 3 (5,77%) | 15 (17,44%) | 0,049 |
| CP, billateral | 12 (23,08%) | 9 (10,47%) | 0,046 |
| Total | 52 (100,00%) | 86 (100,00%) | - |
| χ^2; p* | 14,239; 0,014 |
||
*p – significance level for the χ^2. **p – significance level for the difference test between two structure indicators.
Table 3.
Results of estimation model describing cleft incidence.
| Risk factor | B | SE | χ 2 Wald | P | OR (95% CI) |
| Mother’s age | -0,054 | 0,079 | 0,463 | 0,496 | 0,948 (0,812 – 1,106) |
| Father’s age | 0,182 | 0,074 | 6,095 | 0,014 | 1,200 (1,038 – 1,387) |
| Infections | 2,494 | 0,702 | 12,623 | <0,001 | 12,107 (3,059 – 47,916) |
| Folic acid intake before pregnancy | -0,092 | 0,494 | 0,035 | 0,852 | 0,912 (0,346 – 2,401) |
| Folic acid intake during pregnancy | -1,673 | 0,623 | 7,208 | 0,007 | 0,188 (0,055 – 0,637) |
| Maternal tobacco smoking during pregnancy | 1,219 | 1,168 | 1,168 | 0,297 | 3,383 (0,343 – 33,372) |
| Passive maternal tobacco smoking during pregnancy | 2,255 | 0,703 | 10,278 | 0,001 | 9,533 (2,402 – 37,834) |
| Stress during pregnancy | 2,124 | 0,720 | 8,702 | 0,003 | 8,361 (2,039 – 34,280) |
B – evaluation of model parameters SE – standard error. χ ^2 Wald – value of the χ ^2 statistic checking the significance of the parameters p - significance level for the Wald test. OR (95% CI) – odds ratio and 95% confidence intervals.
Table 4.
Descriptive statistics and comparison of factors influencing the occurrence of of cleft lip and/or palate. p - significance level for the test of differences between two structural indicators.
Table 4.
Descriptive statistics and comparison of factors influencing the occurrence of of cleft lip and/or palate. p - significance level for the test of differences between two structural indicators.
| Risk factor | SG | CG | p | ||
| n | % | N | % | ||
| Infections | 3 | 5,88 | 53 | 28,49 | 0,001 |
| Acid folic intake before pregnancy | 15 | 29,41 | 31 | 16,49 | 0,061 |
| Acid folic intake during pregnancy | 45 | 90,00 | 132 | 70,21 | 0,008 |
| Maternal tobacco smoking during pregnancy | 1 | 1,96 | 19 | 10,16 | 0,113 |
| Maternal tobacco passive smoking during pregnancy | 3 | 5,88 | 80 | 42,78 | <0,001 |
| Maternal alcohol consumption | 0 | 0,00 | 3 | 1,60 | - |
| Stress during pregnancy | 3 | 5,88 | 39 | 22,67 | <0,001 |
Table 5.
Results of the estimation of the model describing the CL occurrence. B - estimation of model parameters SE - standard error. χ ^2 Wald - value of the χ ^2 statistic checking the significance of the parameters. p - significance level for the Wald test. OR (95% CI) - odds ratio and 95% confidence intervals.
Table 5.
Results of the estimation of the model describing the CL occurrence. B - estimation of model parameters SE - standard error. χ ^2 Wald - value of the χ ^2 statistic checking the significance of the parameters. p - significance level for the Wald test. OR (95% CI) - odds ratio and 95% confidence intervals.
| Risk factor | B | SE | χ 2 Wald | P | OR (95% CI) |
| Mother’s age | -0,051 | 0,114 | 0,205 | 0,651 | 0,950 (0,760 – 1,187) |
| Father’s age | 0,166 | 0,094 | 3,123 | 0,077 | 1,181 (0,982 – 1,420) |
| Infections | 3,071 | 0,983 | 9,761 | 0,002 | 21,573 (3,141 – 148,162) |
| Folic acid intake before pregnancy | 0,194 | 0,753 | 0,066 | 0,797 | 1,214 (0,277 – 5,312) |
| Folic acid intake during pregnancy | -2,232 | 0,868 | 6,611 | 0,010 | 0,107 (0,020 – 0,588) |
| Maternal tobacco smoking during pregnancy | 1,875 | 1,588 | 1,394 | 0,238 | 6,522 (0,290 – 146,699) |
| Passive maternal tobacco smoking during pregnancy | 2,217 | 0,881 | 6,331 | 0,012 | 9,180 (1,633 – 51,626) |
| Stress during pregnancy | 2,528 | 0,962 | 6,902 | 0,009 | 12,523 (1,900 – 82,533) |
Table 6.
Results of estimation of the model describing the occurrence of CP. B - estimation of model parameters SE - standard error. χ ^2 Wald - value of the χ ^2 statistic checking the significance of the parameters p - significance level for the Wald test. OR (95% CI) - odds ratio and 95% confidence intervals.
Table 6.
Results of estimation of the model describing the occurrence of CP. B - estimation of model parameters SE - standard error. χ ^2 Wald - value of the χ ^2 statistic checking the significance of the parameters p - significance level for the Wald test. OR (95% CI) - odds ratio and 95% confidence intervals.
| Risk factor | B | SE | χ 2 Wald | P | OR (95% CI) | |
| Mother’s age | -0,094 | 0,106 | 0,794 | 0,373 | 0,910 (0,739 – 1,120) | |
| Father’s age | 0,366 | 0,124 | 8,723 | 0,003 | 1,443 (1,131 – 1,840) | |
| Infections | 4,061 | 1,106 | 13,468 | <0,001 | 58,004 (6,632 – 507,303) | |
| Folic acid intake before pregnancy | -1,238 | 0,813 | 2,320 | 0,128 | 0,290 (0,059 – 1,426) | |
| Folic acid intake during pregnancy | -3,113 | 1,030 | 9,142 | 0,002 | 0,044 (0,006 – 0,335) | |
| Maternal tobacco smoking during pregnancy | 2,066 | 1,293 | 2,551 | 0,110 | 7,891 (0,625 – 99,575) | |
| Passive maternal tobacco smoking during pregnancy | 3,882 | 1,212 | 10,269 | 0,001 | 48,539 (4,517 – 521,590) | |
| Stress during pregnancy | 3,102 | 1,087 | 8,146 | 0,004 | 22,249 (2,643 – 187,282) | |
Table 7.
Results of the estimation of the model describing the occurrence of CLP. B - estimation of model parameters SE - standard error. Wald's χ ^2 - value of the χ ^2 statistic checking the significance of the parameters. p - significance level for the Wald test. OR (95% CI) - odds ratio and 95% confidence intervals.
Table 7.
Results of the estimation of the model describing the occurrence of CLP. B - estimation of model parameters SE - standard error. Wald's χ ^2 - value of the χ ^2 statistic checking the significance of the parameters. p - significance level for the Wald test. OR (95% CI) - odds ratio and 95% confidence intervals.
| Risk factor | B | SE | χ 2 Wald | P | OR (95% CI) |
| Mother’s age | -0,057 | 0,101 | 0,316 | 0,574 | 0,945 (0,775 – 1,152) |
| Father’s age | 0,197 | 0,098 | 4,049 | 0,044 | 1,217 (1,005 – 1,474) |
| Infections | 2,357 | 0,842 | 7,832 | 0,005 | 10,556 (2,026 – 54,993) |
| Folic acid intake before pregnancy | 0,378 | 0,622 | 0,370 | 0,543 | 1,460 (0,431 – 4,938) |
| Folic acid intake during pregnancy | -1,102 | 0,739 | 2,223 | 0,136 | 0,332 (0,078 – 1,415) |
| Maternal tobacco smoking during pregnancy | -0,355 | 1,975 | 0,032 | 0,857 | 0,701 (0,015 – 33,674) |
| Passive maternal tobacco smoking during pregnancy | 2,193 | 0,759 | 8,346 | 0,004 | 8,963 (2,024 – 39,684) |
| Stress during pregnancy | 2,457 | 0,892 | 7,583 | 0,006 | 11,667 (2,030 – 67,042) |
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