The National Spina Bifida Patient Registry: A Decade's journey

1 INTRODUCTION

Neural tube defects (NTDs), frequently understood as anencephaly and spina bifida (SB), have a birth prevalence of nearly six per 10,000 live births in the United States (US) (Williams et al., 2015). Along the dorsal spine, the failure of the neural tube to close is commonly known as open SB. The most common form of open SB is myelomeningocele (MMC), which has long been associated with numerous comorbidities (Kaufman et al., 1994). The majority of cases are non-syndromic and likely are etiologically complex, arising from a combination of genetic, and environmental factors, that are poorly understood (Parker et al., 2010; Ross, Mason, & Finnell, 2016). One of the most notable epidemiologic findings related to NTDs is the protective effect of maternal supplementation of periconceptional folic acid. However, despite folic acid fortification programs globally, approximately 1,500 neonates are estimated to be born yearly in the United States with SB (Parker et al., 2010). Prevalence rates of SB are also significantly influenced by the mother's race/ethnicity (Agopian et al., 2012). For instance, a finding in the epidemiology of NTDs is that Hispanics/Latinos consistently have a higher birth prevalence of both anencephaly and SB compared with the other racial/ethnic groups (Williams et al., 2015).

The congenital anomaly of MMC has led to a range of well-recognized clinical features: impaired sensation, orthopedic issues (clubfeet, scoliosis, and hip dysplasia), limited mobility, and neurogenic bowel and bladder (Sawin et al., 2015). Additionally, affected individuals have numerous preventable condition-related comorbidities such as skin injury, infections, and renal stones, along with such sequelae as renal failure (Kinsman & Doehring, 1996). In spite of these complications, given improvements in medical interventions (e.g., intermittent clean catheterization) in recent decades, the life expectancy has improved (Dillon, Davis, Duguay, Seidel, & Shurtleff, 2000).

A “two-hit hypothesis” has been proposed to explain the damage to the spinal cord associated with MMC, and this damage may be partially preventable. Under this framework, the congenital anomaly and the prolonged exposure of the neural tissue to the proteinaceous amniotic fluid are considered to be the first and second “hits,” respectively (Heffez, Aryanpur, Hutchins, & Freeman, 1990). This finding is supported in part by prenatal surgical closure, which has demonstrated benefits in terms of outcomes for these individuals (i.e., reversal of hindbrain herniation and decreased shunting for hydrocephalus). Specifically, by eliminating (or reducing) the second “hit” (i.e., prolonged exposure of the neural tissue to the amniotic fluid), individuals often have improved outcomes (Moldenhauer & Adzick, 2017). However prenatal repair is a relative new and evolving option, and many families have not had access to, been eligible for, or have chosen not to pursue this alternative.

Given that SB is a heterogeneous disorder with significant phenotypic variations, the discussion regarding the need for evidence-based practices and a research approach has long existed and has required multidisciplinary perspectives (Fletcher & Brei, 2010; Liptak, 2004). The optimization of healthcare provided to people affected by SB was envisioned by Liptak and El Samra through a three-pronged approach: (1) utilization of a patient registry, (2) establishment of a multicenter collaborative investigational approach, and (3) use of a gene bank for research (Liptak & El Samra, 2010). In 2005, a survey of services provided by clinics was conducted by the Spina Bifida Association in collaboration with the Centers for Disease Control and Prevention (CDC), the Delmarva Foundation for Medical Care, the National Initiative for Children's Healthcare Quality, and the Agency for Healthcare Research and Quality (Thibadeau et al., 2013). Funded by Congress through collaboration with the Spina Bifida Association, the CDC developed a multisite patient registry with the trifold aims of establishing a ground work for investigation, evaluating how clinical practices modify outcomes, and improving those outcomes and the corresponding issues related to quality of life for individuals living with SB. With these aims in mind, the National Spina Bifida Patient Registry (NSBPR) was established in 2008, as a partnership between the CDC and SB clinics throughout the United States. Data collection for the NSBPR was launched in 2009, based on a systematic approach across all sites designed also to improve the quality of care provided during the concurrent clinic visit (Thibadeau, 2017). Initially comprised of 10 clinics, according to the CDC website last updated December 21, 2017, the NSBPR now encompasses nearly 8,000 participants, across 21 centers (Table 1; https://www.cdc.gov/ncbddd/spinabifida/map/sb-clinic-map.html). The purpose of this manuscript is to explore the initial work of this project through a literature review of published studies from the NSBPR and provide a description of how this body of literature has developed overtime.

2 METHODS

As a primary search, we included studies indexed in MEDLINE by means of PubMed from January 2009 through April 2018. The search strategy included search terms and synonyms for “neural tube defect,” “spina bifida,” and “National Spina Bifida Patient Registry.” Additionally, a secondary search included examining the reference lists of all included articles. We also used Google Scholar to complete our inquiry of recently published studies. Included articles were appraised by two of the authors to identify key themes relevant to SB demographics, interventions, and outcomes. Additionally, information regarding objectives, hypotheses, and results of each study was summarized. Studies that were not multicenter in nature (i.e., when only site-specific NSBPR data was reported) were excluded from the analysis. We also excluded manuscripts that mentioned the NSBPR but did not compare patient-specific data nor describe current NSBPR-specific efforts.

Numerous variables are collected by the NSBPR at baseline and/or during follow-up visits. This data collection usually is integrated into regular ongoing (e.g., annual) clinic visits. Variables collected include demographic information (age, race/ethnicity, insurance type), interventions (surgeries, nonsurgical procedures, bowel and bladder management techniques), and outcomes (bowel and bladder continence, mobility, skin integrity issues) (Sawin et al., 2015).

3 RESULTS

4 DISCUSSION

This literature review is the first to summarize published studies derived from the first decade of the NSBPR. Our review demonstrates that most of the publications from this data set were cross-sectional in nature and evaluated primarily relatively young individuals living with SB. Most studies limited their assessment to a single group of related disorders. In addition, there was an evolution of outcome definitions over studies. Data from the included studies suggest that a significant variation in rates of bowel and bladder continence occurs across registry sites. Moreover, several SB-related factors (e.g., level of lesion) and non-SB-specific factors (e.g., race/ethnicity) were associated with desired functional outcomes. Thibadeau et al. noted in an early description of the NSBPR that it was intended to be modeled after the Cystic Fibrosis Foundation Patient Registry to leverage quality improvement and provide valid data for not only descriptive reports but also hypothesis-driven analyses (Thibadeau et al., 2013). Within the first decade, five (42%) of the studies documented a hypotheses-driven approach (Table 2).

In her NSBPR study, Sawin et al. noted that the relative contribution of access to care, diet, environment, and genetics on the observable higher incidence of SB among Hispanics/Latinos is poorly understood and deserving of additional research (Sawin et al., 2015) Concurrently, Schechter et al. concluded that after controlling for SB-related intrinsic characteristics, there were still significant variations in outcomes associated with age, gender, race/ethnicity, and insurance status. For instance, they demonstrated that non-Hispanic blacks, Hispanics/Latinos, and those without private insurance had worse outcomes. Another NSBPR study documented that bladder continence was significantly greater among non-Hispanic whites and those with private insurance (Liu et al., 2018). This association perhaps could be explained by better access to care among non-Hispanic whites, as another study documented that non-Hispanic white race/ethnicity and private insurance were associated with an increased likelihood of receiving surgery to treat neurogenic bowel (Routh et al., 2017). These racial/ethnic disparities have not been previously described in a national sample. Already the findings of the NSBPR point to present disparities in care among some subpopulations within this multicenter cohort. Two publications showed that employment and bowel and bladder continence were associated (Wiener et al., 2017, 2018). Furthermore, numerous studies clearly demonstrated that outcomes were also associated with the clinical environment where individuals received care (Freeman et al., 2017; Routh et al., 2018; Thibadeau, 2017).

The roles that race/ethnicity and social determinants of health (SDH) (e.g., socioeconomics, environment, and cultural drivers) play in chronic health condition outcomes are well-recognized. (Larson, Russ, Crall, & Halfon, 2008; Marmot, 2005; Victorino & Gauthier, 2009; Walker, Strom Williams, & Egede, 2016). As with studies of other populations with complex health care needs, studies on this topic are relevant to individuals affected by SB, as they experience many changes and challenging transitions throughout their lives (Kelly et al., 2017). Studies examining health disparities suggest that for some specific racial/ethnic groups, when health status is found to be inferior, it may reflect (or act in concert with) differences in existing SDH (e.g., poverty, educational opportunity, changes in the health care system) (Flores & Lin, 2013). Although the linkages between race/ethnicity and SDH used to understand health disparities in NTDs-related research is not a foreign concept, due to ongoing changes in healthcare, such concerns are increasingly imperative (Agha, Glazier, Moineddin, Moore, & Guttmann, 2013). Additionally, as Wiener et al., 2018 documented, Hispanics/Latinos comprise a larger proportion of the younger age groups. Therefore, as the NSBPR population ages, it will become a progressively critical tool for assessing racially/ethnically salient issues and informing related services design (e.g., transition into adult-centered care programs).

As a whole, the findings from the NSBPR seem to suggest that, for a significant subpopulation, precursors to poor condition-specific outcomes may be best conceptualized through a “three-hit” model. Whereas the first two “hits” are experienced prenatally (i.e., neural tube lesion and its environmental exposure to amniotic fluid), the third “hit” may involve combinations of additional genetic and/or nongenetic exposures, such as unfavorable SDH. Perhaps over the next decade, NSBPR participants will begin to receive neuro-epigenetically minded risk assessments designed to explore environmentally adverse childhood experiences, such as toxic stress (Shonkoff, Boyce, & McEwen, 2009). Of note is that some clinics are taking steps to address these socially grounded disparities. For example, as Hispanics/Latinos are reported to have higher urinary incontinence rates and lower satisfaction with bladder management, the need for culturally appropriate interventions has been proposed as key to timely self-management and functional independence (Castillo et al., 2017; Chowanadisai et al., 2013; Smith et al., 2017).

Proposed mechanisms about not only how our environment affects our genotypic physical expression but also how our ecological surroundings influence our behavior have long been suggested (Bronfenbrenner & Ceci, 1994). As we begin to explore how SDH affect SB-related outcomes, we likely will be one step closer to understanding these mechanisms. To this end, efforts have been launched recently to leverage new surgical developments in MMC care. For example, amniotic fluid transcriptomic and pathway analysis of amniotic fluid supernatant collected from women undergoing prenatal repair has begun to demonstrate not only novel genes that are linked to neuronal regeneration and axonal growth and guidance but also the significant contribution that inflammation may play in pathogenesis (Tarui et al., 2017). As gene-environmental interactions play an important role during intrauterine life, so postuterine life is clearly modified by environmental forces. Thus, the investigation as to how the environment and its SDH modify outcomes is perhaps the next frontier in SB-related research. Future directions of the NSBPR could be to partner with other NTD investigators to explore novel, multidisciplinary research questions (Lupo et al., 2017).

Several limitations are common to the NSBPR studies and inherent to a registry of this type. First, data from the registry is not necessarily representative of all individuals with SB. As participants were all from relatively large institutions that specifically serve individuals with SB in a multidisciplinary approach, they may not represent those individuals who do not attend SB clinics; this may be particularly salient for the adult population. Also, NSBPR clinics may not be representatives of SB clinics in general (Sawin et al., 2015). Another limitation to these studies is that changes have occurred in the registry variables and definitions over time. Although this factor does not allow for direct comparison among the exact data points longitudinally, it demonstrates that the NSBPR investigators have developed a more complete understanding of specific variables and how they are best studied. A third limitation to registry studies is that errors in acquisition and entry of data cannot be eliminated in a large study encompassing a variety of sites; however, the NSBPR involves rigorous quality checks and assurance procedures to maximize the accuracy of the data (Thibadeau et al., 2013).

As the NSBPR was established a decade ago, it has pioneered the use of multicenter data to study a large cohort of individuals with SB. Previously, only comparatively smaller studies were published; therefore the NSBPR publications are novel because they are more representative of the entire SB population in the United States. This initial body of literature may be a resource for developing international evidence-based standards of care and best-practices of treatment for SB and its secondary conditions globally. It has already resulted in two targeted efforts: a urologic protocol to preserve renal function for newborns and young children and a quality improvement project to implement prevention of skin injuries (Thibadeau, 2017). The NSBPR may also be an important tool for implementing benchmarks and identifying centers of excellence to improve care across sites to promptly improve outcomes for individuals living with SB and provide interventions (including culturally appropriate initiatives) for those individuals who have already been found to be at risk for poor outcomes.

5 CONCLUSIONS

In summary, the NSBPR represents one of the largest described clinical samples of individuals living with SB. The first decade of studies on those enrolled in the NSBPR have focused primarily on descriptive analyses and on identifying predictors of clinical outcomes among individuals with SB. These initial results help to provide a delineation of the corresponding sequela, highlight the potential breadth of research topics that could be addressed in the future, and emphasize the strengths of the NSBPR's design.

CONFLICTS OF INTEREST

The authors declare that they have no conflicts of interest.