Coast-or Inland Residence and Differences in the Occurrence of Cleft Lip and Cleft Palate

Abstract

Objetive

To analyze if differences in lifestyle and environment between coastal and inland areas are associated with differences in frequency of orofacial cleft types.

Design

Populational cross-sectional study.

Setting

All live borns with orofacial cleft registered at Brazilian Live Birth Information System between 1999 and 2020.

Participants

33,699 live borns with orofacial cleft.

Intervention

Data from borns with orofacial cleft were collected at Brazilian Live Birth Information System.

Main outcome measure

Differences in frequencies between the cleft types and covariates were determined using chi-square. Bivariate analysis was done to obtain the prevalence ratio of types of clefts by geographic origin. Multiple logistic regression analysis was used to determine adjusted odds ratios, controlling for covariates, establishing a significance level of p value <0.05.

Results

The frequency of cleft types was statistically significant different according to geographic origin (inland x coast). For syndromic clefts, the prevalence ratio for cleft lip with/without palate was 3.6 times higher inland (p value = 0.000). Regarding non-syndromics, the prevalence ratio for cleft lip with/without palate was two times higher inland (p value = 0.000). Logistic regression suggested cleft lip with/without palate was 6.33 more likely to occur in inland regions (p value = 0.000).

Conclusion

Geographic origin was associated with the type of cleft in Brazil, with a higher prevalence of cleft lip with/without palate in inland areas, compared to cleft palate, which was higher in the coast.

Keywords

cleft lip and palate cleft lip epidemiology

Introduction

Orofacial clefts (OC) are common congenital malformations caused by genetic and environmental factors that can act together or in isolation during the first trimester of intrauterine development, resulting generally in deformities of the lip and/or palate.^1,2 They constitute a serious burden worldwide due to the aesthetic, functional, and emotional alterations caused in the affected individuals.³

The most well-known classification for clefts divides them into cleft lip with or without palate (CL + P) and cleft palate only (CP) due to their embryological and epidemiological distinctions.⁴ Additionally, OC can be classified based on the presence or absence of other malformations or anomalies, respectively, as syndromic (SOC) or non-syndromic/isolated (NSOC) clefts.⁵

SOC represents a genetic defect (monogenic or chromosomal aberration), and the majority of their causal genes have been successfully identified.⁶ On the other hand, 70% of all clefts are NSOC,⁷ which have a multifactorial etiology resulting from both genetic and environmental factors identified.⁶ Socioeconomic status, family, neighborhood, and social network context are some environmental factors that can influence epigenetic regulation through DNA methylation, histone modifications, and non-coding RNAs, thereby altering gene expression and resulting in clefts.^8,9

Our hypothesis is that differences in lifestyle and the environment that exist between geographic living areas (coast vs. inland, rural vs. urban) are associated with differences in the frequency of OC.^10–12 These differences are generally related to geographic characteristics, such as air and water quality, health services and food availability, green space, and working conditions.⁸ Based on that, the objective of this study was to analyze whether differences in lifestyle and being born in coastal or inland areas are associated with differences in the frequency of OC types.

Materials and Methods

This is a population-based cross-sectional study. The study included 33,699 live births with OC registered in the Brazilian Live Birth Information System (SINASC) between 1999 and 2020. The STROBE guidelines for reporting observational studies were used. The investigators involved had no contact with human subjects, and the data used are from an open-access Brazilian information system available online,¹³ in which the data are disseminated without identifying the subjects.

Data on cleft type, geographic origin of the patient (coast or inland), presence of associated congenital anomalies or syndromes, sex of the newborn, ethnicity, Apgar score in the 1st minute, Apgar score in the 5th minute, maternal age, paternal age, maternal parity, birth weight, type of pregnancy, and the number of prenatal appointments were recorded. All variables were previously analyzed according to the incompleteness criteria proposed by Romero and Cunha 13,14: excellent (< 5%), good (5% to 9.9%), regular (10% to 19.9%), poor (20% to 49.9%), and very poor (≥ 50%). Those with a poor or very poor degree of completeness were removed from the study. Following this classification, the variable ‘geographic origin of the patient’ had 100% completeness, while the others ranged from 89.22% (parity) to 99.94% (maternal age). The only exception was information about paternal age, which was missing in 81% of the records; due to its very poor degree of completeness, this variable was not included in the study.

The OC types adopted by SINASC follow the Tenth Revision of the International Statistical Classification of Diseases and Related Health Problems (CID-10),¹⁴ which groups cleft types and subtypes into Q35 (cleft palate - CP), Q36 (cleft lip – CL), and Q37 (cleft lip and palate - CLP). Live births that were coded for both CL and CP simultaneously in SINASC were considered as having CLP. Later, cases were divided into CP and cleft lip with or without palate (CL + P). The geographic origin was divided into two main categories: coast and inland, based on the IBGE classification.¹⁵

The data were submitted to statistical analysis using STATA (Software for Statistics and Data Science) version 10 software, establishing a significance level of p < 0.05. CP was used as the reference dependent variable, and the inland region was considered as the exposure. Continuous variables were later categorized. Covariates included in the analysis were the sex of the infant, maternal age, and parity, as determined based on the literature.¹¹ Differences in frequencies between the cleft types and the covariates were tested using the chi-square test. Bivariate analysis was developed to obtain the crude prevalence ratio (PR) for the relationship between geographic origin and type of cleft. Multiple logistic regression analysis was performed to determine the adjusted odds ratios (ORs) for the same relationship while controlling for covariates.

Data were submitted to statistical analysis using the STATA (Software for Statistics and Data Science) version 10 software, establishing a significance level of p < 0.05. CP was used as dependent variable of reference, and inland region as exposition. Continuous variables were later categorized. Covariates included in the analysis were sex of the infant, maternal age, parity, determined based on the literature.¹¹ Differences in frequencies between the cleft types and the covariates were tested using the chi-square test. Bivariate analysis was developed in order to obtain the crude prevalence ratio (PR) for the relation between geographic origin and type of cleft. Multiple logistic regression analysis was performed to determine the adjusted ODDs for this same relation while controlling for covariates.

Results

Based on the data collected from SINASC, there were 33,699 cases of OC registered in Brazil between 1999 and 2020; 6022 (17.9%) were syndromic (SOC), and 27,677 (82.1%) were isolated (NSOC). The analysis for both types revealed that the mean maternal age was 26 (±7) years, the mean Apgar scores at 1st and 5th minutes were 7.5 (±2) and 8.8 (±2), respectively, and the mean birth weight was 2933 (±715) grams.

The frequency of cleft types was statistically significantly different according to geographic origin (inland x coast) for both syndromic and isolated cases (Figure 1). Among SOC cases, CP was more frequent at the coastline (86%), and CL + P was more equally distributed, occurring in 47% of cases inland. The bivariate analysis for these cases showed that the crude prevalence ratio for CL/P was 3.6 times higher among those born with clefts inland (p value = 0.000, OR = 3.6, 95% confidence interval 2.37 - 5.61). Regarding NSOC, CP was more common at the coastline (69%), and CL + P was more common inland (68%). NSOC showed a crude prevalence ratio for CL + P that was two times higher among those born with clefts inland (p value = 0.000, OR = 2.0, 95% confidence interval 1.99–2.34).

Figure 1.

Frequency of orofacial clefts according to type and geographic origin. *Indicates statistically significant difference.

NSOC types showed statistically significant differences in their geographic distribution (coast vs. inland) by sex, maternal age, and parity. In terms of sex, they occurred in higher proportions in males in both inland and coastal regions (65% and 62%, respectively), while CP was more equally distributed in both regions, representing approximately 47% of the cases in each area. Regarding maternal age, in both groups of clefts, the majority of the mothers were younger than 35 years (84.66%). In inland regions, the frequencies of mothers younger than 35 years were 84% (CP) and 95% (CL + P), respectively. At the coast, these frequencies were similar, 82% (CP) and 85% (CL + P), respectively. Most mothers were in their first or second pregnancy, but there was a difference in parity between cleft types according to the geographic region. While children with CL + P were more frequent in coastal areas among mothers in their first or second pregnancy (98% at the coast and 72% inland), children with CP were more frequent inland among those in their third or subsequent pregnancies (68% at the coast and 78% inland).

For NSOC, there were statistically significant differences in the distribution of sex, maternal age, and parity between the two types of clefts tested (Table 1). Due to this, they were included in the logistic regression to adjust for their influence as covariates. After applying backward selection, only maternal parity was retained in the regression model. This logistic regression model showed that CL + P was six times more likely in inland regions (p-value = 0.000; OR = 6.33, 95% confidence interval 5.43-7.37). The receiver operating characteristic (ROC) curve for the prediction model was 0.764, indicating good discrimination of the model between individuals with CP and CL + P (Figure 2).

Figure 2.

Receiver operating characteristic (ROC) curve from the logistic regression model for cleft type, geographic origin, sex, maternal age and parity.

Table 1.

Crude Associations Between the Covariates and Cleft Types.

Variable	Cleft Palate		Cleft Lip with/without Palate		Total		p value
	(n)	(%)	(n)	(%)	(n)	(%)
Sex							0.000*
Female	4446	47.12	6934	38.05	11,380	41.15
Male	4989	52.88	11,287	61.95	16,276	58.85
Total	9.435	100.00	18.221	100.00	27.656	100.00
Maternal age							0.000*
< 35 years	7792	82.64	15,627	85.71	23,419	84.66
> 35 years	1637	17.36	2606	14.29	4243	15.34
Total	9429	100.00	18,233	100.00	27,662	100.00
Ethnicity							0.102
Non white	4347	48.23	8197	47.17	12,544	47.53
White	4666	51.77	9181	52.83	13,847	52.47
Total	9013	100.00	17,378	100.00	26,391	100.00
Type of pregnancy							0.633
Single	9212	97.73	17,776	97.64	26,988	97.67
Twin or more	214	2.27	430	2.36	644	2.33
Total	9426	100.00	18,206	100.00	27,632	100.00
Number of prenatal appointments							0.042
≥7 appointments	5564	59.73	10,978	61.00	16,542	60.57
<7 appointments	3751	40.27	7019	39.00	10,770	39.43
Total	9315	100.00	17,997	100.00	27,312	100.00
Parity							0.000*
First or second pregnancy	1473	22.78	13,278	72.84	14,751	59.73
Third or more	4993	77.22	4950	27.16	9943	40.27
Total	6466	100.00	18,228	100.00	24,694	100.00

*Indicates statistically significant difference.

Discussion

In the present study, geographic origin was associated with the type of OC in Brazil, with a higher prevalence ratio of CL + P occurrence in inland areas compared to CP, which had a higher prevalence ratio in coastal areas. Also, among the covariates studied here, only parity could partly explain the differences in frequency between cleft types along the coast and inland.

Few studies have focused on studying the relationship between geographic origin and OC.¹⁶ In Brazil, only one other study, which used data from a single state, attempted to investigate this relationship and also found that the frequency of CL + P was higher in inland areas, while CP prevalence was higher in coastal areas.¹¹ A few other studies have focused on classifying geographic origin based on rural vs. urban areas. A case-control study conducted to explore the association between maternal residence's region (rural x urban) and the risk of a child developing OC in Washington State, US, found that babies born to women residing in rural regions had a greater likelihood of developing NSOC compared to those born to women living in urban areas.¹² Similarly, an ecological study aimed at investigating the association of CL + P and CP with urban and rural residence in Texas, US, discovered that living in more rural areas was linked to an increased adjusted risk of CL + P.¹⁰

These results further strengthened our hypothesis that differences in lifestyle and environment, such as maternal smoking, antiepileptic drug use, stress, and nutritional deficiencies, which exist between geographic living areas (coast vs. inland; rural vs. urban), are associated with differences in the frequency of OC. This association is especially relevant in less resourced countries, where these factors tend to be more frequent, increasing the likelihood of them modifying gene function in various cleft types.

In this study, it was more likely for the child to have higher parity (third or more pregnancies) if he or she was born with CP in inland regions. This finding agrees with a previous one that found higher parity for children who were born inland.¹¹ In the literature, parity has been associated with OC,¹⁷ but it appeared to explain very little of the difference in frequencies between inland and coastal areas.¹¹

Some limitations inherent to cross-sectional studies are present in this study, such as the challenge of determining causality when exposure and outcome are measured simultaneously. However, this type of study is designed to test associations, which aligns with the purpose of this investigation.¹⁸ Other limitations to note include variability in the degree of incompleteness in the SINASC variables, which could introduce regional differences in data quality and potentially affect the analyses conducted with this data.¹⁹ Nevertheless, the variables included in this study generally exhibited an excellent degree of incompleteness (< 5%), and the results can be considered acceptable for the country. The exception was parity, which fell within the regular range of incompleteness (10.78%). It was retained in the analysis due to its relevance in previous studies.¹¹ Yet, rare cleft could not be studied separately here because this type of cleft is presented on the Spina Classification.²⁰ CID-10 includes rare cases, but classifies clefts types and its subtypes in a codification system that differ from the Spina Classification. Additionally, the years of the study were limited to 2020 as that was the last available year of data in the system at the time of consultation. However, this limitation does not diminish the significance of our findings since our analysis covers a span of 21 years, and existing evidence supports the representativeness of SINASC for the Brazilian population.¹⁹

This study aimed to test the association between geographic origins (coast vs. inland) and differences in the frequency of OC. Inequalities, such as those related to lifestyle and environmental background between geographic regions, can act as social and environmental stressors that modify the way in which genes are expressed and ultimately alter our risk for disease.²¹ CP was more common at the coastline, while CL + P was more common inland. Due to the complex etiology of OC, investigations into how environmental factors are related to OC occurrence could help researchers understand how those factors influence gene expression through epigenetic changes.²²

Conclusion

The geographic origin was associated with the type of orofacial cleft in Brazil, with a higher prevalence ratio of CL + P occurrence in inland areas compared to CP prevalence ratio, which was higher on the coast. Also, among the covariates studied here, only parity could partly explain the differences in frequency between cleft types on the coast vs. inland.

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Código de Financiamento 001, Fundação de Amparo à Pesquisa do Estado da Bahia.

Disclosure Statement

Investigators here had no contact with human subjects and the data used are from an open access Brazilian information system, available online (), in which the data are disbursed without identifying the subjects.

ORCID iDs

Adriana Mendonça da Silva

Alexandre Rezende Vieira

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