5.1 Introduction
Congenital malformations (i.e. birth defects) are a significant public health concern; they affect approximately 1 in 33 babies born in the United States (US) (CDC, 2018a). They are costly to the healthcare system and account for a substantial portion of neonatal mortality (20%) and morbidity (CDC, 2018a). Orofacial clefts (OFCs) are one of the most common birth defects in the U.S., occurring in 8.1 to 10.63 per 10,000, or roughly 1 in in 1,000, births (Mai et al., 2014; U.S. Department of Health and Human Services, 2014). OFCs include isolated clefts of the palate (openings in the roof of the mouth) and clefts of the lip (unilateral or bilateral gaps in the upper lip which may extend to the nose). Non-syndromic or isolated forms of cleft lip, with or without cleft palate (NSCL/P), account for the majority of OFCs: 70% of all cases of isolated cleft lip with or without cleft palate, and 50% of isolated cleft palate cases are non-syndromic (IPDTOC, 2011; Mai et al., 2014). While NSCL/P is not often life-threatening to newborns in the U.S. and other developed countries, it has a significant, long-term effect on health (Lewis et al., 2017).
Recognizing the public health significance of OFCs, due to relatively high prevalence and the resulting increase in healthcare use and costs, the Centers for Disease Control (CDC) assembled a group of experts in 2006 to examine the state of public health-related research surrounding OFCs (Yazdy et al., 2007). The working group sought to identify gaps in knowledge, prioritize the most critical issues, and create a public health research agenda. Key areas the panel identified included (1) the relationship between maternal health and OFC etiology, (2) the psychosocial impact of OFCs in childhood, (3) the impact on quality of life for children with OFCs
and their families, and (4) the healthcare costs associated with OFCs (Yazdy et al., 2007). Major goals of creating this agenda surround improving the ability to prevent OFCs and improve long- term treatment outcomes and quality of life (Yazdy et al., 2007).
Another area of OFC research that appears to have gaps is recurrence risk assessment. Currently, genetic counseling and risk assessment for NSCL/P are based only on empiric risk estimates (Basha et al., 2018; Grosen, Chevrier, et al., 2010). While many predictive models exist for predicting occurrence of conditions such as breast cancer (e.g. the Gail model), and a few common, complex diseases even have polygenic risk scores (PRSs) (e.g. heart disease and diabetes), birth defects, in general, have received less attention in this regard (Agopian et al., 2012). In the past decade, a couple of research groups have noted this and explored predictive modeling methods for two congenital conditions: neural tube defects and congenital heart defects (Agopian et al., 2012; Luo et al., 2017).
Models built for open neural tube defects by Agopian et al. (2012), using known maternal risk factors in a large, population-based cohort, had poor predictive performance, leading the researchers to conclude that more research into the risk factors is needed to create a useful model. However, Luo et al. (2017) had reasonably good results predicting risk for congenital heart defects using the models they built. Their models included nine, broad risk factors: maternal age at delivery, annual per capita income, family history, maternal history of pre-conception illness, inadequate nutrition/folic acid intake, maternal illness during pregnancy, medication use during pregnancy, environmental risk factor exposures during pregnancy (e.g. radiation, pesticides), and unhealthy maternal lifestyle during pregnancy (e.g. smoking and alcohol use). The sample was large and population-based; it included 78 cases of congenital heart defects among 33,831 births between 2006 and 2008 in ShangXi, China. The true positive rate for the models was 65% and the
true negative rate was 95%, which the researchers concluded was sufficient for consideration of using them to identify women at high risk in the general population (Luo et al., 2017). OFCs have received even less attention in terms of predictive modeling using known risk factors; only one study is known, to date, and it was performed on a small sample, using risk factors that are difficult to generalize, and the statistical methodology was unsound (see section 3.4.1) (Li et al., 2016).
There have been attempts to develop PRSs for NSCL/P, with some success (Ludwig et al., 2017). However, it is expected that there are still several unknown genetic variants, gene by environment interactions, and epigenetic phenomenon that have yet to be explained in the heritability of NSCL/P (Basha et al., 2018; Ludwig et al., 2017). Regardless, it is likely that genetic and environmental risk factors have predictive value in estimating the recurrence risk of NSCL/P (Dixon et al., 2011b; Ludwig et al., 2017; S. M. Weinberg et al., 2006) and could therefore be used to create a predictive model or PRS for reproductive screening purposes. In considering the development and implementation of such a model, it is important to analyze the public health implications associated with preconception screening for NSCL/P.
The overarching goals of this essay are to (1) consider the public health implications, including public health utility, selected ethical, legal, and social issues (ELSI), and economics, of preconception population screening for NSCL/P, (2) evaluate NSCL/P, using the principles set forth by established frameworks/criteria for evaluating public health programs, and (3) conclude whether such screening warrants consideration, and, if so, in which setting it would be most appropriate to implement.
Evaluation of a population screen includes thorough assessment of test performance, which is a critical issue when a screen is used in the general population, in which prevalence of a health outcome of interest is expected to be low. Many screening tests are designed to be highly sensitive,
so they often have a significant false positive rate (Harris et al., 2011). Accomplishing the above goals within the scope of this manuscript required assuming that a method of screening with acceptable population test performance had already been developed. In order to include a brief discussion of how test performance impacts evaluation of harms and benefits, the hypothetical screen for NSCL/P will be assumed to have similar performance to other screening protocols already in use. Therefore, the starting point for discussion is a hypothetical situation, in which a reliable pre-conception screen for NSCL/P is available. This assumption allows for a thoughtful consideration of the implications of successfully developing a model, such as that described in section 3.
The following is a limited discussion of the history and current state of perinatal population screening, meant to provide background and context for evaluating preconception population screening for NSCL/P. Where there are gaps in specific literature on OFCs, other relevant examples of well-established screening programs are used to facilitate discussion of a hypothetical screening tool for NSCL/P. Various criteria, developed for evaluating public health screening programs, are also examined for their relevance and limitations in regards to screening for a congenital malformation.