Changing lives by making smiles
Infants born with orofacial clefts (OFC) have high rates of infant mortality in developing countries where access to care is limited, and feeding problems at birth can result in malnutrition, aspiration pneumonia, purposeful neglect or even infanticide.
Survivors face a lifetime of specialised multi-disciplinary care and can have serious communication problems due to both speech and hearing defects. Studies have shown that they tend to suffer psychologically and have higher rates of mortality in adulthood.
Survivors are also at major societal disadvantages in India in that they may not attend school, they are discriminated against in employment, may be shunned by society and often fail to find marriage partners because of their disability.
OFC is therefore regarded as a significant maternal and child health inequality issue that has been highlighted at a global level through the 2010 World Health Assembly, is being prioritised in the World Health Organisation (WHO) Global Burden of Disease (GBD, 2012) initiative, and forms part of India’s healthcare and social agenda in the Millennium Development Goals.
Experts in India estimate the prevalence of OFC to be higher in India than in many western countries, with between 27,000 and 35,000 infants born with OFC in India per annum, and there is an increasing research focus towards discovery of what the genetic and environmental causes are. This project aims to conduct research into the aetiology of OFC, and simultaneously raise awareness and educate communities about primary prevention.
The major focus of the proposed collaboration is to bring complementary research expertise from centres with an international reputation, in the UK, the US and India, together so that maternal metabolism, nutrition and environmental pollution can be simultaneously addressed in the context of aetiology of birth defects in general in India, and OFC in particular, can be addressed with comprehensive, validated research methodologies.
Origins of the trilateral partnership
A grant from the US National Institutes of Health (NIH) in the field of cleft lip and palate research, with myself and Professor Ronald Munger of Utah State University as two of the co-applicants, was administered by WHO between the years 2000 and 2004.
A series of consensus meetings was conducted to discuss and agree on research strategies for reducing the global health care burden of cleft lip and palate. These consensus meetings involved representation from India and parts of south-east Asia where there was a great deal of unmet need. Professor Munger was selected as one of the US representatives for his expertise in the field of cleft lip and palate and particularly the field of nutritional epidemiology and environmental factors in the aetiology of cleft lip and palate.
I was selected to provide expertise on genetics and gene environment interaction research. With the particular problem identified in India, negotiations began to target India as an area of the world in special need and dialogue on research initiatives have continued since. Documents on research strategies arising from these consensus meetings were produced by WHO and published and disseminated to all member states.
The prevalence of infant mortality in those who are born with cleft lip and palate in India is higher than infant mortality in patients born with clefts in the western world. The reasons for this require investigation and explanation, but may include feeding problems at birth resulting in malnutrition, aspiration pneumonia, purposeful neglect or even infanticide.
India has well-developed expertise in primary cleft surgery, but access to that care is limited. India’s expertise and profile in research in both genetics and environmental factors is developing rapidly, but is not matched by the efficiency of its administrative and governance systems.
The 2008 Academy Award-winning short documentary Smile Pinki illustrated the kind of problem that exists with children born with CLP in parts of rural India. Pinki Sonkar was ostracised in her local community and was not allowed to attend school because of her facial disfigurement.
Her parents were initially unaware of the possibility that her cleft could be repaired and in any case were unable to afford such surgery. The charity Smile Train, however, offered the surgery free of charge and, even though she was five-years-old when her cleft was repaired, this op has transformed her life. Accompanied by her surgeon Dr Subodh Singh, she was invited to London to toss the coin for the 2013 Wimbledon Final.
The Sri Ramachandra Hospital and Medical Research Centre in Chennai and St John’s Hospital in Bangalore are examples of centres of excellence in both treatment and research, with a high throughput of patients and, therefore, they are regarded as exemplary research collaborators.
While maternal tobacco smoking is consistently associated with OFC (Little et al, 2004), this practice is not widespread on the Indian subcontinent. The exact mechanism of the effect of smoking on the developing embryo to cause a cleft remains unknown, but one hypothesis is hypoxia (Johnstone and Bronsky, 1995), and it was suggested that the principal mechanism may be through carbon monoxide (CO) production.
Solid carbon fuel-burning stoves are commonly used for cooking in parts of India, but to date, no study has ever been carried out on the association between maternal exposure to environmental smoke and risk of oral clefts. This proposal aims to look for the first time at domestic environmental smoke – that is, smoky environment due to cooking and heating in the homes of Indian people.
What is unique about this particular proposal is the fact that the Chennai group has developed a reliable system for the monitoring of indoor smoke exposure that includes CO assessment, and this project is attempting to extrapolate evidence of an environmental exposure – for example, maternal smoking (which is consistently associated with clefts in the west) – to a problem in the developing world.
Aims and objectives
This application would simultaneously address three component parts that bring our complementary multi-disciplinary expertise from the three participating countries to bear. These are:
- (a) nutritional assessment using locally validated food frequency questionnaires (FFQ)
- (b) environmental exposure assessment using locally developed biomarkers and unique monitoring of the domestic environment
- (c) maternal metabolism assessment with particular interest in maternal diabetes and folic acid/vitamin B12/homocysteine metabolism.
The specific project actions would consist of the following:
- Recruitment through the Sri Ramachandra Hospital Cleft Lip and Palate Surgical Unit of mothers of children born with OFC in the past year and who have attended for primary repair of the cleft of the lip and palate.
- Recruitment of mothers of control children (without clefts) from a local community maternal hospital in Chennai, with matching criteria for children being: date of birth, sex and geographic location of birth.
- Obtaining consent for the three components of the study, i.e. nutritional, environmental exposure and metabolic markers with the knowledge that IRB approval has already been obtained.
- Eliciting the appropriate information on nutrition, environmental exposure and maternal metabolism via validated questionnaires.
- Obtaining a 5ml blood sample in EDTA tubes with an offer of screening for general health, diabetes and heart disease so that there is an immediate benefit to the participating mothers.
- Laboratory procedures to assess biomarkers of maternal nutrition, environmental exposure and maternal metabolism using unique and validated techniques.
Potential for wider collaboration
There is a significant shift in emphasis in medicine and healthcare to seek a common risk factor approach to chronic diseases, and included in this is the WHO Global Burden of Disease Initiative that includes cleft lip and palate.
The issues in reproductive health include smoking, maternal metabolic syndrome, hyperglycaemia, diabetes and obesity, cardiovascular disease, and with risk factors such as smoking, alcohol consumption and nutrition, there is an opportunity for this research to be carried out in parallel with other major chronic diseases.
The choice of cleft lip and palate is because of its aetiology and that it is regarded as a sentinel birth defect because of the high level of ascertainment and, therefore, the findings in relation to cleft lip and palate may well be transferrable to a range of other birth defects, particularly structural birth defects such as congenital heart problems, genito-urinary, digestive tract and limb reduction defects.
Research in the area of birth defects has demonstrated in the past that there are possibilities for generalisability of findings to populations around the world – and this applies to aspects of nutrition (e.g. folic acid and NTDs) and exposures (e.g. smoking and OFC).
There is also a recognition that as well as some aspects of research expertise and training being transported from the US and UK to India, the research expertise and the scientists from India bring special skills, expertise, work ethic and cultural qualities to research teams in the US and the UK.
The UK-India Education and Research Initiative (UKIERI) trilateral partnership (TRIP) grant enables such research to be conducted and the involvement of colleagues in the US and India helps fulfil not only the WHO terms of reference, but also the aspirations of the US Government in the Obama-Singh accord and pledges made by the UK Prime Minister David Cameron in his visit to India in 2011.
The role of the University of Dundee in the UKIERI TRIP project
In August 2004, Dundee was granted WHO Collaboration Centre (CC) status for research into craniofacial anomalies and technology transfer. The Terms of Reference (ToR) in the agreement with WHO means that the University of Dundee has a remit involving setting up research projects in the developing world.
The University of Dundee WHO CC has assisted with research in the developing world, most notably in Nigeria and Brazil, and this expertise can be applied to the UKIERI project in the field of craniofacial anomalies in India. The College of Medicine, Dentistry and Nursing has selected craniofacial anomalies as one of the main areas of research activity and this is also supported through the Scottish Government’s research priorities in oral health as detailed in the Transforming Research into Better Oral Health in Scotland document published in January 2011.