The International Family Study of Nonsyndromic Orofacial Clefts: Design and Methods.

BACKGROUND: The majority of research to understand the risk factors of nonsyndromic orofacial clefts (NSOFCs) has been conducted in high-income populations. Although patients with NSOFCs in low- and middle-income countries (LMICs) are at the highest risk of not receiving care, global health infrastructure allows innovative partnerships to explore the etiologic mechanisms of cleft and targets for prevention unique to these populations. METHODS: The International Family Study (IFS) is an ongoing case-control study with supplemental parental trio data designed to examine genetic, environmental, lifestyle, and sociodemographic risk factors for NSOFCs in 8 LMICs (through August 2020). Interview and biological samples are collected for each family. The interview includes demographics, family history of cleft, diet and water sources, maternal pregnancy history, and other lifestyle and environmental factors. RESULTS: Seven of 8 countries are currently summarized (2012-2017) for a total of 2955 case and 2774 control families with 11 946 unique biological samples from Vietnam, Philippines, Honduras, Madagascar, Morocco, Democratic Republic of the Congo, and Nicaragua. The phenotype distribution was 1641 (55.5%) cases with cleft lip and palate, 782 (26.5%) with cleft lip (CL), and 432 (14.6%) with cleft palate (CP). DISCUSSION: The International Family Study is the largest case set of NSOFCs with an associated biobank in LMICs currently assembled. The biobank, family, and case-control study now include samples from 8 LMICs where local health care infrastructure cannot address the surgical burden of cleft or investigate causal mechanisms. The International Family Study can be a source of information and may collaborate with local public health institutions regarding education and interventions to potentially prevent NSOFCs.

The role of smoke from cooking indoors over an open flame and parental smoking on the risk of cleft lip and palate: A case- control study in 7 low-resource countries.

BACKGROUND: Cleft is one of the most common birth defects globally and the lack of access to surgery means millions are living untreated. Smoke exposure from cooking occurs infrequently in developed countries but represents a high-proportion of smoke exposure in less-developed regions. We aimed to study if smoke exposure from cooking is associated with an increased risk in cleft, while accounting for other smoke sources. METHODS: We conducted a population-sampled case-control study of children with cleft lip and/or palate and healthy newborns from Vietnam, Philippines, Honduras, Nicaragua, Morocco, Congo, and Madagascar. Multivariable regression models were used to assess associations between maternal cooking during pregnancy, parental smoking, and household tobacco smoke with cleft. RESULTS: 2137 cases and 2014 controls recruited between 2012-2017 were included. While maternal smoking was uncommon (<1%), 58.3% case and 36.1% control mothers cooked over an open fire inside. Children whose mothers reported cook smoke exposure were 49% (95% confidence interval (CI) = 1.2-1.8) more likely to have a child with a cleft. This was consistent in five of seven countries. No significant associations were found for any other smoke exposure. CONCLUSIONS: Our finding of maternal cook smoke and cleft in low-resource countries, similar to maternal tobacco smoke in high-resource countries, may reflect a common etiology. This relationship was present across geographically diverse countries with variable socioeconomic statuses and access to care. Exposures specific to low-resource settings must be considered to develop public health strategies that address the populations at increased risk of living with cleft and inform the mechanisms leading to cleft development.